Roundtable

Case Presentation

This case represents a composite of many different patients and is not meant to represent an individual. Any resemblance to an actual patient is coincidental.

A 32-year-old African American woman presented with a self-palpated left breast mass (axillary tail at 9 o’clock position). The patient was a nonsmoker, was otherwise healthy, and had no family history of breast or any other cancer. She had never used oral contraceptives or hormones, was never pregnant, her menarche was at age 12 years, and she had regular menstrual periods. On physical examination she had a 1-cm left breast mass and a palpable left axillary lymph node. A complete diagnostic workup revealed a 2-cm left breast mass. An ultrasound-guided biopsy of the axillary lymph node was positive for invasive ductal carcinoma (IDC). The final diagnosis was left breast cancer, stage IIB IDC, T1N1M0, ER+, PR+, HER2 2+ by immunohistochemistry, fluorescence in situ hybridization (FISH) was 2.4, confirming a HER2+ tumor.

Anita Aggarwal, DO, PhD. What is the role of genetic counseling and testing in this young patient who does not have a family history of breast cancer?

Vickie L. Venne, MS. This patient absolutely would be a candidate for counseling and testing. From a genetic counseling perspective, one of the first points has to do with what “no family history of cancer” means. Typically, in a fast-paced clinic, a patient will be asked “Does anybody else in your family have cancer?” And it’s not uncommon to get the answer “no.” Genetic counselors collect specific information on at least the first- and second-degree relatives, so we end up with 3 generations. This includes both the maternal and the paternal histories. We find that people who initially report no family history of cancer are often just thinking of breast cancer, even if the provider’s question is broad. When we start digging, we often find other cancers because cancer is common.

The other issue is that she was diagnosed at a young age. Clearly, 32 years is much younger than we typically see in breast cancer, and we know that individuals with hereditary cancers often have an earlier age of onset. With no other information, her a priori risk of having a BRCA1/2 mutation would be < 2.5%.

Regardless, based on current National Comprehensive Cancer Network (NCCN) guidelines, she would be a testing candidate. We would also recommend testing for more than just BRCA1/2. In the last few decades, there have been many genes identified that are associated with an increased susceptibility to cancer. Many of these genes are part of syndromes, so if you had a mutation, that also would increase the risk for a cancer in another organ. If this woman’s mother and father lived into their 70s or 80s and she had a number of aunts on both sides who never developed breast cancer, it would be less likely to be BRCA1/2. However, P53 also can present in young women and as a de novo mutation. Therefore, we would offer her a panel of actionable genes. Genes that if, in fact, we identified a mutation in one of them, would mean we could do something different for this young lady.

JoAnn Manning, MD. Let’s say she does have testing, and she comes back BRCA+. Then what would be the recommendations or guidance?

Ms. Venne. Women (and men as well!) with mutations have an increased risk for a second primary breast cancer as well as cancer in other organs. Focusing first on the breast story and all the media around BRCA1/2 mutations and surgery, this is a woman who may consider a more aggressive surgery, including prophylactic contralateral mastectomy, if she is concerned. She is young, so we also would explore her fertility plans. While her next few months will be filled with breast cancer treatment choices, women with BRCA mutations also are at an increased risk to develop ovarian cancer, so that might be a decision she makes as well. Her health care team may also eventually discuss chemotherapeutic options available specifically to women with mutations.

However, we often see young women who are extremely nervous because there is a sense that if you’re younger, your cancer must be inherited. Part of the pretest counseling is to explore psychosocial issues and help these young ladies understand that, especially if she does not have a family history of cancer and the only indication is her age, then it’s highly likely that we’re not going to find an identifiable mutation. And in that circumstance, she probably could consider a more conservative surgical decision.

Dr. Aggarwal. How common is a BRCA1 or BRCA2 mutation in African American females?

Ms. Venne. I have not paid attention to the prevalence of mutations based on ethnicity, so I don’t know. While many of the initial mutations were discovered in women of European ancestry, there are large cohorts of women with African ancestry whose specimens are now available for identifying genetic markers that will improve breast cancer risk assessment in them.¹ However, because those mutations are still being characterized, it is more common to find a variant of uncertain significance (VUS) in African American women. A VUS is an alteration—a change in the gene—that we simply don’t know what it means yet. Clinicians don’t have enough information to know if that alteration is pathogenic or benign. The problem is that people try to make sense out of everything in their lives, so they also will try to make a VUS mean something. We try hard to help people understand that a VUS is really no more significant than if we had not tested in the first place, and they should not act on that information. They should use their family history, their age, their other psychosocial concerns about their experiences with cancer as they make their treatment decisions. But they also should check back periodically with their genetic counselor because VUSs can be reclassified. And if that happens, the information might be more useful for not only them, but their family members.

Dr. Manning. Would you consider this patient for any neoadjuvant chemotherapy?

Dr. Aggarwal. The patient is a young female with a small tumor that is HER2+. The indication for neoadjuvant chemotherapy is typically a big tumor or inoperable disease. Neoadjuvant chemotherapy is considered the standard of care for patients with inflammatory breast cancer and may confer a survival benefit in these patients. Of all the breast cancer subtypes, triple negative and HER2+ are considered the most chemosensitive and may benefit from neoadjuvant therapy. This patient has a small tumor, and I don’t think she’s a candidate for neoadjuvant chemotherapy unless the patient wants to see if her tumor is chemosensitive or not.

Dr. Manning, What’s the role and benefit of lumpectomy vs mastectomy?

Dr. Manning. Historically, mastectomy would have been considered the standard of care, but luckily, in the 1970s and the 1980s, we had a significant number of randomized controlled trials that demonstrated that certain women with particular characteristics would get the same overall survival if they chose mastectomy vs lumpectomy, the removal of the tumor with negative margin and whole-breast radiation. The key thing to understand is that breast-conserving surgery is now very well established with more than 20 years of data to support it. And that breast irradiation after breast-conserving surgery is essential to maximizing the local control and the overall survival (OS).

There have been a lot of major studies, but the one with the greatest follow-up now is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 protocol, which was the only trial to compare mastectomy to lumpectomy and radiation or lumpectomy alone. It required negative margins. With 20 years of follow-up, the data still support that mastectomy or lumpectomy with radiation offers equivalent OS and local control. It’s really about patient preference if they are candidates.

Who is a candidate? Clearly, there are contraindications. We tend to look primarily at the size of the tumor. However, removing an average-sized tumor (< 2 cm) with a margin may not have a good cosmetic result for a patient with very small breasts. That patient may opt to go forward with a mastectomy instead. Young patients who are candidates must have to have negative margins. If they have persistently positive resection margins after excision or reexcision, then they need to go forward with mastectomy.

A patient who has imaging evidence of multicentric disease with 2 or more primary tumors in separate quadrants would not be a candidate for breast-conserving therapy. Diffuse malignant-appearing microcalcifications on a mammogram also would suggest multicentric disease. And a patient with a prior history of radiation therapy to the breast or chest wall cannot go through breast-conserving therapy.

In the case we are discussing, we also should make sure this young lady is not pregnant. If the patient is adamant about breast-conserving surgery and pregnant, especially in the third trimester, radiation could be deferred until after delivery. Another relative contraindication is for patients who have connective tissue disorders. Sometimes if they are given whole-breast radiation, the cosmetic result is poor. So if you’re doing this procedure to save the breast, then having a good cosmetic result is an important consideration for many patients.

When you look at the size of the tumor for this patient, she seems to be a good candidate for breast-conserving surgery. I would recommend that she go forward with lumpectomy followed by whole-breast radiation.

Ms. Venne. Although the numbers aren’t nearly as large as they were in the original trials looking at the lumpectomy vs mastectomy, there are now survival data for women with BRCA1/2 mutations. With all of the caveats that Dr. Manning mentioned, even if you have an identifiable mutation, you may not necessarily need that more aggressive surgery.² Clearly, individuals with identifiable mutations would have a higher chance of a contralateral breast cancer, a second primary, so some individuals consider a prophylactic bilateral mastectomy. But from a survival perspective, there are a fair amount of data now available that say that lumpectomy vs mastectomy should really be the conversation based on all of the information that Dr. Manning outlines rather than using primarily the mutation status.

Dr. Manning. I agree.

Dr. Aggarwal. This patient had a lumpectomy and axillary lymph node dissection. Pathology reported 1.5-cm mass, grade 3 IDC; the margins were negative. There was no skin involvement, 27 lymph nodes removed were all negative. Dr. Manning, can you please discuss the role of radiation in early stage breast cancer in patients like this case?

Dr. Manning. One of the questions that is always controversial for radiation in these early stage breast cancer cases is what do you do with the nodal irradiation? Previously, radiation oncologists based treatment plans on retrospective data, but in 2015, there were 2 major studies, 1 from Canada, and 1 from the European Organisation for Research and Treatment of Cancer (EORTC).^3,4 Both studies tried to determine whether there was an advantage to doing regional nodal irradiation in early breast cancer cases. That encompassed axillary, supraclavicular, and internal mammary nodes. The studies showed that there was no survival advantage, but there was a statistically significant improvement in disease free survival and in local regional recurrence and distant mets.

Unfortunately, there are still a lot of unanswered questions, like what group potentially would benefit the most? In the MA.20 Study, some observers questioned that maybe the ER-/PR- women had the most benefit, but then, in the other study the benefit wasn’t clear.^4,5 One question is which lymph node group is having the most impact? Was the benefit from radiating the supraclavicular nodes or was it from radiating the internal mammary nodes? Determining the answer is important from a technical point of view because when you radiate the internal mammary nodes, you have the potential to expose more heart and lung to radiation. You have to put all these together and make a recommendation.

Clearly, for a patient with negative nodes there is no question: You would not treat the regional nodes. However, for a patient with positive nodes you really have to individualize the approach and consider age, anatomy, tumor location, and burden of axillary disease.

I would sit down and have a discussion with this young woman to weigh the risks and the benefits. There is a slight increased risk of lymphedema in these patients, and radiation pneumonitis increases, but not significantly. A key concern is to minimize the total dose of radiation to the heart. There have been great developments in radiation oncology technology and capabilities, so the cardiac dose is now less. But when you think about a 32-year-old patient and weigh the benefit of a 2% to 3% decrease in the incidence of distant metastases and no OS advantage, then you really need to have a conversation about how to safely treat her. At a minimum, I would treat the high axilla and the supraclavicular nodes because she had a pretty extensive lymph node dissection with more than 20 nodes, and then with her getting systemic therapy, that should be more than adequate.

Dr. Aggarwal. Is there any cutoff for age or size of the tumor where you would not do any radiation to the breast?

Dr. Manning. In this particular patient absolutely not because of the lymph node. She had breast-conserving therapy, and she’s only 32-years-old. The PRIME 2 study offered lumpectomy alone vs lumpectomy and radiation for women aged ≥ 65 years with tumors ≤ 3 cm, low grade.⁶ The study participants had to have negative lymph nodes, be ER+, and low grade. It was a very select group. The lumpectomy patients had a recurrence rate around 4%, and the other was closer to 1.3%.

You have to look at the whole picture. Is this a healthy 70-year-old woman? Is it an inconvenience for her to get treatment? Is she going to get hormone therapy and will she be adherent? There’s a very small group of women who underwent breast-conserving surgery that I would feel safe about not offering radiation.

Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.⁷

Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.

Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.

Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?

Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.

In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.

These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.

The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.

The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.

The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.

Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.

Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.⁸ Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.⁹ The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.

In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.

The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.

Mr. Crawford, How would you manage of these AEs from these treatments?

Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.

The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.

There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.

The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.

Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.

With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.

Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.

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Case Presentation

This case represents a composite of many different patients and is not meant to represent an individual. Any resemblance to an actual patient is coincidental.

A 32-year-old African American woman presented with a self-palpated left breast mass (axillary tail at 9 o’clock position). The patient was a nonsmoker, was otherwise healthy, and had no family history of breast or any other cancer. She had never used oral contraceptives or hormones, was never pregnant, her menarche was at age 12 years, and she had regular menstrual periods. On physical examination she had a 1-cm left breast mass and a palpable left axillary lymph node. A complete diagnostic workup revealed a 2-cm left breast mass. An ultrasound-guided biopsy of the axillary lymph node was positive for invasive ductal carcinoma (IDC). The final diagnosis was left breast cancer, stage IIB IDC, T1N1M0, ER+, PR+, HER2 2+ by immunohistochemistry, fluorescence in situ hybridization (FISH) was 2.4, confirming a HER2+ tumor.

Anita Aggarwal, DO, PhD. What is the role of genetic counseling and testing in this young patient who does not have a family history of breast cancer?

Vickie L. Venne, MS. This patient absolutely would be a candidate for counseling and testing. From a genetic counseling perspective, one of the first points has to do with what “no family history of cancer” means. Typically, in a fast-paced clinic, a patient will be asked “Does anybody else in your family have cancer?” And it’s not uncommon to get the answer “no.” Genetic counselors collect specific information on at least the first- and second-degree relatives, so we end up with 3 generations. This includes both the maternal and the paternal histories. We find that people who initially report no family history of cancer are often just thinking of breast cancer, even if the provider’s question is broad. When we start digging, we often find other cancers because cancer is common.

The other issue is that she was diagnosed at a young age. Clearly, 32 years is much younger than we typically see in breast cancer, and we know that individuals with hereditary cancers often have an earlier age of onset. With no other information, her a priori risk of having a BRCA1/2 mutation would be < 2.5%.

Regardless, based on current National Comprehensive Cancer Network (NCCN) guidelines, she would be a testing candidate. We would also recommend testing for more than just BRCA1/2. In the last few decades, there have been many genes identified that are associated with an increased susceptibility to cancer. Many of these genes are part of syndromes, so if you had a mutation, that also would increase the risk for a cancer in another organ. If this woman’s mother and father lived into their 70s or 80s and she had a number of aunts on both sides who never developed breast cancer, it would be less likely to be BRCA1/2. However, P53 also can present in young women and as a de novo mutation. Therefore, we would offer her a panel of actionable genes. Genes that if, in fact, we identified a mutation in one of them, would mean we could do something different for this young lady.

JoAnn Manning, MD. Let’s say she does have testing, and she comes back BRCA+. Then what would be the recommendations or guidance?

Ms. Venne. Women (and men as well!) with mutations have an increased risk for a second primary breast cancer as well as cancer in other organs. Focusing first on the breast story and all the media around BRCA1/2 mutations and surgery, this is a woman who may consider a more aggressive surgery, including prophylactic contralateral mastectomy, if she is concerned. She is young, so we also would explore her fertility plans. While her next few months will be filled with breast cancer treatment choices, women with BRCA mutations also are at an increased risk to develop ovarian cancer, so that might be a decision she makes as well. Her health care team may also eventually discuss chemotherapeutic options available specifically to women with mutations.

However, we often see young women who are extremely nervous because there is a sense that if you’re younger, your cancer must be inherited. Part of the pretest counseling is to explore psychosocial issues and help these young ladies understand that, especially if she does not have a family history of cancer and the only indication is her age, then it’s highly likely that we’re not going to find an identifiable mutation. And in that circumstance, she probably could consider a more conservative surgical decision.

Dr. Aggarwal. How common is a BRCA1 or BRCA2 mutation in African American females?

Ms. Venne. I have not paid attention to the prevalence of mutations based on ethnicity, so I don’t know. While many of the initial mutations were discovered in women of European ancestry, there are large cohorts of women with African ancestry whose specimens are now available for identifying genetic markers that will improve breast cancer risk assessment in them.¹ However, because those mutations are still being characterized, it is more common to find a variant of uncertain significance (VUS) in African American women. A VUS is an alteration—a change in the gene—that we simply don’t know what it means yet. Clinicians don’t have enough information to know if that alteration is pathogenic or benign. The problem is that people try to make sense out of everything in their lives, so they also will try to make a VUS mean something. We try hard to help people understand that a VUS is really no more significant than if we had not tested in the first place, and they should not act on that information. They should use their family history, their age, their other psychosocial concerns about their experiences with cancer as they make their treatment decisions. But they also should check back periodically with their genetic counselor because VUSs can be reclassified. And if that happens, the information might be more useful for not only them, but their family members.

Dr. Manning. Would you consider this patient for any neoadjuvant chemotherapy?

Dr. Aggarwal. The patient is a young female with a small tumor that is HER2+. The indication for neoadjuvant chemotherapy is typically a big tumor or inoperable disease. Neoadjuvant chemotherapy is considered the standard of care for patients with inflammatory breast cancer and may confer a survival benefit in these patients. Of all the breast cancer subtypes, triple negative and HER2+ are considered the most chemosensitive and may benefit from neoadjuvant therapy. This patient has a small tumor, and I don’t think she’s a candidate for neoadjuvant chemotherapy unless the patient wants to see if her tumor is chemosensitive or not.

Dr. Manning, What’s the role and benefit of lumpectomy vs mastectomy?

Dr. Manning. Historically, mastectomy would have been considered the standard of care, but luckily, in the 1970s and the 1980s, we had a significant number of randomized controlled trials that demonstrated that certain women with particular characteristics would get the same overall survival if they chose mastectomy vs lumpectomy, the removal of the tumor with negative margin and whole-breast radiation. The key thing to understand is that breast-conserving surgery is now very well established with more than 20 years of data to support it. And that breast irradiation after breast-conserving surgery is essential to maximizing the local control and the overall survival (OS).

There have been a lot of major studies, but the one with the greatest follow-up now is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 protocol, which was the only trial to compare mastectomy to lumpectomy and radiation or lumpectomy alone. It required negative margins. With 20 years of follow-up, the data still support that mastectomy or lumpectomy with radiation offers equivalent OS and local control. It’s really about patient preference if they are candidates.

Who is a candidate? Clearly, there are contraindications. We tend to look primarily at the size of the tumor. However, removing an average-sized tumor (< 2 cm) with a margin may not have a good cosmetic result for a patient with very small breasts. That patient may opt to go forward with a mastectomy instead. Young patients who are candidates must have to have negative margins. If they have persistently positive resection margins after excision or reexcision, then they need to go forward with mastectomy.

A patient who has imaging evidence of multicentric disease with 2 or more primary tumors in separate quadrants would not be a candidate for breast-conserving therapy. Diffuse malignant-appearing microcalcifications on a mammogram also would suggest multicentric disease. And a patient with a prior history of radiation therapy to the breast or chest wall cannot go through breast-conserving therapy.

In the case we are discussing, we also should make sure this young lady is not pregnant. If the patient is adamant about breast-conserving surgery and pregnant, especially in the third trimester, radiation could be deferred until after delivery. Another relative contraindication is for patients who have connective tissue disorders. Sometimes if they are given whole-breast radiation, the cosmetic result is poor. So if you’re doing this procedure to save the breast, then having a good cosmetic result is an important consideration for many patients.

When you look at the size of the tumor for this patient, she seems to be a good candidate for breast-conserving surgery. I would recommend that she go forward with lumpectomy followed by whole-breast radiation.

Ms. Venne. Although the numbers aren’t nearly as large as they were in the original trials looking at the lumpectomy vs mastectomy, there are now survival data for women with BRCA1/2 mutations. With all of the caveats that Dr. Manning mentioned, even if you have an identifiable mutation, you may not necessarily need that more aggressive surgery.² Clearly, individuals with identifiable mutations would have a higher chance of a contralateral breast cancer, a second primary, so some individuals consider a prophylactic bilateral mastectomy. But from a survival perspective, there are a fair amount of data now available that say that lumpectomy vs mastectomy should really be the conversation based on all of the information that Dr. Manning outlines rather than using primarily the mutation status.

Dr. Manning. I agree.

Dr. Aggarwal. This patient had a lumpectomy and axillary lymph node dissection. Pathology reported 1.5-cm mass, grade 3 IDC; the margins were negative. There was no skin involvement, 27 lymph nodes removed were all negative. Dr. Manning, can you please discuss the role of radiation in early stage breast cancer in patients like this case?

Dr. Manning. One of the questions that is always controversial for radiation in these early stage breast cancer cases is what do you do with the nodal irradiation? Previously, radiation oncologists based treatment plans on retrospective data, but in 2015, there were 2 major studies, 1 from Canada, and 1 from the European Organisation for Research and Treatment of Cancer (EORTC).^3,4 Both studies tried to determine whether there was an advantage to doing regional nodal irradiation in early breast cancer cases. That encompassed axillary, supraclavicular, and internal mammary nodes. The studies showed that there was no survival advantage, but there was a statistically significant improvement in disease free survival and in local regional recurrence and distant mets.

Unfortunately, there are still a lot of unanswered questions, like what group potentially would benefit the most? In the MA.20 Study, some observers questioned that maybe the ER-/PR- women had the most benefit, but then, in the other study the benefit wasn’t clear.^4,5 One question is which lymph node group is having the most impact? Was the benefit from radiating the supraclavicular nodes or was it from radiating the internal mammary nodes? Determining the answer is important from a technical point of view because when you radiate the internal mammary nodes, you have the potential to expose more heart and lung to radiation. You have to put all these together and make a recommendation.

Clearly, for a patient with negative nodes there is no question: You would not treat the regional nodes. However, for a patient with positive nodes you really have to individualize the approach and consider age, anatomy, tumor location, and burden of axillary disease.

I would sit down and have a discussion with this young woman to weigh the risks and the benefits. There is a slight increased risk of lymphedema in these patients, and radiation pneumonitis increases, but not significantly. A key concern is to minimize the total dose of radiation to the heart. There have been great developments in radiation oncology technology and capabilities, so the cardiac dose is now less. But when you think about a 32-year-old patient and weigh the benefit of a 2% to 3% decrease in the incidence of distant metastases and no OS advantage, then you really need to have a conversation about how to safely treat her. At a minimum, I would treat the high axilla and the supraclavicular nodes because she had a pretty extensive lymph node dissection with more than 20 nodes, and then with her getting systemic therapy, that should be more than adequate.

Dr. Aggarwal. Is there any cutoff for age or size of the tumor where you would not do any radiation to the breast?

Dr. Manning. In this particular patient absolutely not because of the lymph node. She had breast-conserving therapy, and she’s only 32-years-old. The PRIME 2 study offered lumpectomy alone vs lumpectomy and radiation for women aged ≥ 65 years with tumors ≤ 3 cm, low grade.⁶ The study participants had to have negative lymph nodes, be ER+, and low grade. It was a very select group. The lumpectomy patients had a recurrence rate around 4%, and the other was closer to 1.3%.

You have to look at the whole picture. Is this a healthy 70-year-old woman? Is it an inconvenience for her to get treatment? Is she going to get hormone therapy and will she be adherent? There’s a very small group of women who underwent breast-conserving surgery that I would feel safe about not offering radiation.

Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.⁷

Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.

Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.

Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?

Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.

In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.

These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.

The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.

The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.

The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.

Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.

Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.⁸ Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.⁹ The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.

In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.

The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.

Mr. Crawford, How would you manage of these AEs from these treatments?

Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.

The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.

There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.

The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.

Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.

With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.

Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.

Click here to read the digital edition.

Case Presentation

This case represents a composite of many different patients and is not meant to represent an individual. Any resemblance to an actual patient is coincidental.

A 32-year-old African American woman presented with a self-palpated left breast mass (axillary tail at 9 o’clock position). The patient was a nonsmoker, was otherwise healthy, and had no family history of breast or any other cancer. She had never used oral contraceptives or hormones, was never pregnant, her menarche was at age 12 years, and she had regular menstrual periods. On physical examination she had a 1-cm left breast mass and a palpable left axillary lymph node. A complete diagnostic workup revealed a 2-cm left breast mass. An ultrasound-guided biopsy of the axillary lymph node was positive for invasive ductal carcinoma (IDC). The final diagnosis was left breast cancer, stage IIB IDC, T1N1M0, ER+, PR+, HER2 2+ by immunohistochemistry, fluorescence in situ hybridization (FISH) was 2.4, confirming a HER2+ tumor.

Anita Aggarwal, DO, PhD. What is the role of genetic counseling and testing in this young patient who does not have a family history of breast cancer?

Vickie L. Venne, MS. This patient absolutely would be a candidate for counseling and testing. From a genetic counseling perspective, one of the first points has to do with what “no family history of cancer” means. Typically, in a fast-paced clinic, a patient will be asked “Does anybody else in your family have cancer?” And it’s not uncommon to get the answer “no.” Genetic counselors collect specific information on at least the first- and second-degree relatives, so we end up with 3 generations. This includes both the maternal and the paternal histories. We find that people who initially report no family history of cancer are often just thinking of breast cancer, even if the provider’s question is broad. When we start digging, we often find other cancers because cancer is common.

The other issue is that she was diagnosed at a young age. Clearly, 32 years is much younger than we typically see in breast cancer, and we know that individuals with hereditary cancers often have an earlier age of onset. With no other information, her a priori risk of having a BRCA1/2 mutation would be < 2.5%.

Regardless, based on current National Comprehensive Cancer Network (NCCN) guidelines, she would be a testing candidate. We would also recommend testing for more than just BRCA1/2. In the last few decades, there have been many genes identified that are associated with an increased susceptibility to cancer. Many of these genes are part of syndromes, so if you had a mutation, that also would increase the risk for a cancer in another organ. If this woman’s mother and father lived into their 70s or 80s and she had a number of aunts on both sides who never developed breast cancer, it would be less likely to be BRCA1/2. However, P53 also can present in young women and as a de novo mutation. Therefore, we would offer her a panel of actionable genes. Genes that if, in fact, we identified a mutation in one of them, would mean we could do something different for this young lady.

JoAnn Manning, MD. Let’s say she does have testing, and she comes back BRCA+. Then what would be the recommendations or guidance?

Ms. Venne. Women (and men as well!) with mutations have an increased risk for a second primary breast cancer as well as cancer in other organs. Focusing first on the breast story and all the media around BRCA1/2 mutations and surgery, this is a woman who may consider a more aggressive surgery, including prophylactic contralateral mastectomy, if she is concerned. She is young, so we also would explore her fertility plans. While her next few months will be filled with breast cancer treatment choices, women with BRCA mutations also are at an increased risk to develop ovarian cancer, so that might be a decision she makes as well. Her health care team may also eventually discuss chemotherapeutic options available specifically to women with mutations.

However, we often see young women who are extremely nervous because there is a sense that if you’re younger, your cancer must be inherited. Part of the pretest counseling is to explore psychosocial issues and help these young ladies understand that, especially if she does not have a family history of cancer and the only indication is her age, then it’s highly likely that we’re not going to find an identifiable mutation. And in that circumstance, she probably could consider a more conservative surgical decision.

Dr. Aggarwal. How common is a BRCA1 or BRCA2 mutation in African American females?

Ms. Venne. I have not paid attention to the prevalence of mutations based on ethnicity, so I don’t know. While many of the initial mutations were discovered in women of European ancestry, there are large cohorts of women with African ancestry whose specimens are now available for identifying genetic markers that will improve breast cancer risk assessment in them.¹ However, because those mutations are still being characterized, it is more common to find a variant of uncertain significance (VUS) in African American women. A VUS is an alteration—a change in the gene—that we simply don’t know what it means yet. Clinicians don’t have enough information to know if that alteration is pathogenic or benign. The problem is that people try to make sense out of everything in their lives, so they also will try to make a VUS mean something. We try hard to help people understand that a VUS is really no more significant than if we had not tested in the first place, and they should not act on that information. They should use their family history, their age, their other psychosocial concerns about their experiences with cancer as they make their treatment decisions. But they also should check back periodically with their genetic counselor because VUSs can be reclassified. And if that happens, the information might be more useful for not only them, but their family members.

Dr. Manning. Would you consider this patient for any neoadjuvant chemotherapy?

Dr. Aggarwal. The patient is a young female with a small tumor that is HER2+. The indication for neoadjuvant chemotherapy is typically a big tumor or inoperable disease. Neoadjuvant chemotherapy is considered the standard of care for patients with inflammatory breast cancer and may confer a survival benefit in these patients. Of all the breast cancer subtypes, triple negative and HER2+ are considered the most chemosensitive and may benefit from neoadjuvant therapy. This patient has a small tumor, and I don’t think she’s a candidate for neoadjuvant chemotherapy unless the patient wants to see if her tumor is chemosensitive or not.

Dr. Manning, What’s the role and benefit of lumpectomy vs mastectomy?

Dr. Manning. Historically, mastectomy would have been considered the standard of care, but luckily, in the 1970s and the 1980s, we had a significant number of randomized controlled trials that demonstrated that certain women with particular characteristics would get the same overall survival if they chose mastectomy vs lumpectomy, the removal of the tumor with negative margin and whole-breast radiation. The key thing to understand is that breast-conserving surgery is now very well established with more than 20 years of data to support it. And that breast irradiation after breast-conserving surgery is essential to maximizing the local control and the overall survival (OS).

There have been a lot of major studies, but the one with the greatest follow-up now is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 protocol, which was the only trial to compare mastectomy to lumpectomy and radiation or lumpectomy alone. It required negative margins. With 20 years of follow-up, the data still support that mastectomy or lumpectomy with radiation offers equivalent OS and local control. It’s really about patient preference if they are candidates.

Who is a candidate? Clearly, there are contraindications. We tend to look primarily at the size of the tumor. However, removing an average-sized tumor (< 2 cm) with a margin may not have a good cosmetic result for a patient with very small breasts. That patient may opt to go forward with a mastectomy instead. Young patients who are candidates must have to have negative margins. If they have persistently positive resection margins after excision or reexcision, then they need to go forward with mastectomy.

A patient who has imaging evidence of multicentric disease with 2 or more primary tumors in separate quadrants would not be a candidate for breast-conserving therapy. Diffuse malignant-appearing microcalcifications on a mammogram also would suggest multicentric disease. And a patient with a prior history of radiation therapy to the breast or chest wall cannot go through breast-conserving therapy.

In the case we are discussing, we also should make sure this young lady is not pregnant. If the patient is adamant about breast-conserving surgery and pregnant, especially in the third trimester, radiation could be deferred until after delivery. Another relative contraindication is for patients who have connective tissue disorders. Sometimes if they are given whole-breast radiation, the cosmetic result is poor. So if you’re doing this procedure to save the breast, then having a good cosmetic result is an important consideration for many patients.

When you look at the size of the tumor for this patient, she seems to be a good candidate for breast-conserving surgery. I would recommend that she go forward with lumpectomy followed by whole-breast radiation.

Ms. Venne. Although the numbers aren’t nearly as large as they were in the original trials looking at the lumpectomy vs mastectomy, there are now survival data for women with BRCA1/2 mutations. With all of the caveats that Dr. Manning mentioned, even if you have an identifiable mutation, you may not necessarily need that more aggressive surgery.² Clearly, individuals with identifiable mutations would have a higher chance of a contralateral breast cancer, a second primary, so some individuals consider a prophylactic bilateral mastectomy. But from a survival perspective, there are a fair amount of data now available that say that lumpectomy vs mastectomy should really be the conversation based on all of the information that Dr. Manning outlines rather than using primarily the mutation status.

Dr. Manning. I agree.

Dr. Aggarwal. This patient had a lumpectomy and axillary lymph node dissection. Pathology reported 1.5-cm mass, grade 3 IDC; the margins were negative. There was no skin involvement, 27 lymph nodes removed were all negative. Dr. Manning, can you please discuss the role of radiation in early stage breast cancer in patients like this case?

Dr. Manning. One of the questions that is always controversial for radiation in these early stage breast cancer cases is what do you do with the nodal irradiation? Previously, radiation oncologists based treatment plans on retrospective data, but in 2015, there were 2 major studies, 1 from Canada, and 1 from the European Organisation for Research and Treatment of Cancer (EORTC).^3,4 Both studies tried to determine whether there was an advantage to doing regional nodal irradiation in early breast cancer cases. That encompassed axillary, supraclavicular, and internal mammary nodes. The studies showed that there was no survival advantage, but there was a statistically significant improvement in disease free survival and in local regional recurrence and distant mets.

Unfortunately, there are still a lot of unanswered questions, like what group potentially would benefit the most? In the MA.20 Study, some observers questioned that maybe the ER-/PR- women had the most benefit, but then, in the other study the benefit wasn’t clear.^4,5 One question is which lymph node group is having the most impact? Was the benefit from radiating the supraclavicular nodes or was it from radiating the internal mammary nodes? Determining the answer is important from a technical point of view because when you radiate the internal mammary nodes, you have the potential to expose more heart and lung to radiation. You have to put all these together and make a recommendation.

Clearly, for a patient with negative nodes there is no question: You would not treat the regional nodes. However, for a patient with positive nodes you really have to individualize the approach and consider age, anatomy, tumor location, and burden of axillary disease.

I would sit down and have a discussion with this young woman to weigh the risks and the benefits. There is a slight increased risk of lymphedema in these patients, and radiation pneumonitis increases, but not significantly. A key concern is to minimize the total dose of radiation to the heart. There have been great developments in radiation oncology technology and capabilities, so the cardiac dose is now less. But when you think about a 32-year-old patient and weigh the benefit of a 2% to 3% decrease in the incidence of distant metastases and no OS advantage, then you really need to have a conversation about how to safely treat her. At a minimum, I would treat the high axilla and the supraclavicular nodes because she had a pretty extensive lymph node dissection with more than 20 nodes, and then with her getting systemic therapy, that should be more than adequate.

Dr. Aggarwal. Is there any cutoff for age or size of the tumor where you would not do any radiation to the breast?

Dr. Manning. In this particular patient absolutely not because of the lymph node. She had breast-conserving therapy, and she’s only 32-years-old. The PRIME 2 study offered lumpectomy alone vs lumpectomy and radiation for women aged ≥ 65 years with tumors ≤ 3 cm, low grade.⁶ The study participants had to have negative lymph nodes, be ER+, and low grade. It was a very select group. The lumpectomy patients had a recurrence rate around 4%, and the other was closer to 1.3%.

You have to look at the whole picture. Is this a healthy 70-year-old woman? Is it an inconvenience for her to get treatment? Is she going to get hormone therapy and will she be adherent? There’s a very small group of women who underwent breast-conserving surgery that I would feel safe about not offering radiation.

Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.⁷

Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.

Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.

Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?

Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.

In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.

These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.

The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.

The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.

The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.

Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.

Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.⁸ Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.⁹ The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.

In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.

The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.

Mr. Crawford, How would you manage of these AEs from these treatments?

Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.

The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.

There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.

The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.

Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.

With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.

Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.

Click here to read the digital edition.

The following is a lightly edited transcript of a teleconference discussion recorded in April 2018.

Suman Kambhampati, MD. Immuno-oncology is a paradigm-shifting treatment approach. It is an easy-to-understand term for both providers and for patients. The underlying principle is that the body’s own immune system is used or stimulated to fight cancer, and there are drugs that clearly have shown huge promise for this, not only in oncology, but also for other diseases. Time will tell whether that really pans out or not, but to begin with, the emphasis has been inoncology, and therefore, the term immunooncology is fitting.

Dr. Kaster. It was encouraging at first, especially when ipilimumab came out, to see the effects on patients with melanoma. Then the KEYNOTE-024 trial came out, and we were able to jump in anduse monoclonal antibodies directed against programmed death 1 (PD-1) in the first line, which is when things got exciting.¹ We have a smaller populationin Boise, so PD-1s in lung cancer have had the biggest impact on our patients so far.

Ellen Nason, RN, MSN. Patients are open to immunotherapies.They’re excited about it. And as the other panelists have said, you can start broadly, as the body fights the cancer on its own, to providing more specific details as a patient wants more information. Immuno-oncology is definitely accepted by patients, and they’re very excited about it, especially with all the news about new therapies.

Dr. Kambhampati. For the Department of Veteran Affairs (VA) population, lung cancer has seen significant impact, and now it’s translating into other diseases through more research, trials, and better understanding about how these drugs are used and work. 

The paradigm is shifting toward offering these drugs not only in metastatic cancers, but also in the surgically resectable tumors. The 2018 American Association for Cancer Research (AACR) meeting, just concluded. At the meeting several abstracts reported instances where immunooncology drugs are being introduced in the early phases of lung cancer and showing outstanding results. It’s very much possible that we’re going to see less use of traditional chemotherapy in the near future.

Ms. Nason. I primarily work with solid tumors,and the majority of the population I work with have lung cancer. So we’re excited about some of the results that we’ve seen and the lower toxicity involved. Recently, we’ve begun using durvalumab with patients with stage III disease. We have about 5 people now that are using it as a maintenance or consolidative treatment vs just using it for patients with stage IV disease. Hopefully, we’ll see some of the same results describedin the paper published on it.²

Dr. Kaster. Yes, we are incorporating these new changes into care as they're coming out. As Ms. Nason mentioned, we're already using immunotherapies in earlier settings, and we are seeing as much research that could be translated into care soon, like combining immunotherapies
in first-line settings, as we see in the Checkmate-227 study with nivolumab and ipilimumab.^3,4 The landscape is going to change dramatically in the next couple of years.

Accessing Testing For First-Line Treatments

Dr. Lynch. There has been an ongoing discussionin the literature on accessing appropriate testing—delays in testing can result in patients who are not able to access the best targeted drugs on a first-line basis. The drug companiesand the VA have become highly sensitized to ensuring that veterans are accessing the appropriate testing. We are expanding the capability of VA labs to do that testing.

Ms. Nason. I want to put in a plug for the VA Precision Oncology Program (POP). It’s about 2 years into its existence, and Neil Spector, MD, is the director. The POP pays for sequencing the tumor samples.

A new sequencing contract will go into effect October 2018 and will include sequencing for hematologic malignancies in addition to the current testing of solid tumors. Patients from New York who have been unable to receive testing through the current vendors used by POP, will be included in the new contract. It is important to note that POP is working closely with the National Pharmacy Benefit Management Service (PBM) to develop a policy for approving off-label use of US Food and Drug Administration-approved targeted therapies based on sequenced data collected on patients tested through POP.

In addition, the leadership of POP is working to leverage the molecular testing results conducted through POP to improve veterans' access to clinical trials, both inside and outside the VA. Within the VA people can access information at tinyurl.com/precisiononcology. There is no reason why any eligible patient with cancer in the VA health care system should not have their tumor tissue sequenced through POP, particularly once the new contract goes into effect.

Dr. Lynch. Fortunately, the cost of next-generation sequencing has come down so much that most VA contracted reference laboratories offer next-generation sequencing, including LabCorp (Burlington,NC), Quest Diagnostics (Secaucus, NJ), Fulgent (Temple City, CA), and academic partners such as Oregon Health Sciences University and University of Washington.

Ms. Nason. At the Durham VAMC, sometimes a lack of tissue has been a barrier, but we now have the ability to send blood (liquid biopsy) for next-generation sequencing. Hopefully that will open up options for veterans with inadequate tissue. Importantly, all VA facilities can request liquid biopsiesthrough POP.

Dr. Lynch. That’s an important point. There have been huge advances in liquid biopsy testing.The VA Salt Lake City Health Care System (VASLCHCS) was in talks with Genomic Health (Redwood City, CA) to do a study as part of clinical operations to look at the concordance between the liquid biopsy testing and the precision oncology data. But Genomic Health eventually abandoned its liquid biopsy testing. Currently, the VA is only reimbursing or encouraging liquid biopsy if the tissue is not available or if the veteran has too high a level of comorbidities to undergo tissue biopsy. The main point for the discussion today is that access to testing is a key component of access to all of these advanced drugs.

Dr. Kambhampati. The precision medicine piece will be a game changer—no question about that. Liquid biopsy is very timely. Many patients have difficulty getting rebiopsied, so liquid biopsy is definitely a big, big step forward.

Still, there has not been consistency across the VA as there should be. Perhaps there are a few select centers, including our site in Kansas City, where access to precision medicine is readily available and liquid biopsies are available. We use the PlasmaSELECT test from Personal Genome Diagnostics (Baltimore, MD). We have just added Foundation Medicine (Cambridge, MA) also in hematology. Access to mutational profilingis absolutely a must for precision medicine.

All that being said, the unique issue with immuno-oncology is that it pretty much transcends the mutational profile and perhaps has leveled the playing field, irrespective of the tumor mutation profile or burden. In some solid tumors these immuno-oncology drugs have been shown to work across tumor types and across different mutation types. And there is a hint now in the recent data presented at AACR and in the New England Journalof Medicine showing that the tumor mutational burden is a predictor of pathologic response to at least PD-1 blockade in the resectable stages of lung cancer.^1,3 To me, that’s a very important piece of data because that’s something that can be tested and can have a prognostic impact in immuno-oncology, particularly in the early stages of lung cancer and is further proof of the broad value of immunotherapics in targeting tumors irrespective of the precise tumor targets.

Dr. Kaster. Yes, it’s nice to see other options like tumor mutational burden and Lung Immune Prognostic Index being studied.5 It would be nice if we could rely a little more on these, and not PD-L1, which as we all know is a variable and an unreliable target.

Dr. Kambhampati. I agree.

Rural Challenges In A Veterans Population

Dr. Lynch. Providing high-quality cancer care to rural veterans care can be a challenge but it is a VA priority. The VA National Genomic Medicine Services offers better access for rural veterans to germline genetic testing than any other healthcare system in the country. In terms of access to somatic testing and next-generation sequencing, we are working toward providing the same level of cancer care as patients would receive at National Cancer Institute (NCI) cancer centers. The VA oncology leadership has done teleconsults and virtual tumor boards, but for some rural VAMCs, fellowsare leading the clinical care. As we expand use of oral agents for oncology treatment, it will be easier to ensure that rural veterans receive the same standard of care for POP that veterans being cared for at VASLCHCS, Kansas City VAMC, or Durham VAMC get.

Dr. Kambhampati. The Kansas City VAMC in its catchment area includes underserved areas, such as Topeka and Leavenworth, Kansas. What we’ve been able to do here is something that’s unique—Kansas City VAMC is the only standalone VA in the country to be recognized as a primary SWOG (Southwestern Oncology Group) institution, which provides access to many trials, such as the Lung-MAP trial and others. And that has allowed us to use the full expanse of precision medicine without financial barriers. The research has helped us improve the standard of
care for patients across VISN 15.

Dr. Lynch. In precision oncology, the chief of pathology is an important figure in access to advanced care. I’ve worked with Sharad Mathur,MD, of the Kansas City VAMC on many clinical trials. He’s on the Kansas City VAMC Institutional Review Board and the cancer committee and is tuned in to veterans’ access to precision oncology. Kansas City was ordering Foundation One for select patients that met the criteria probably sooner than any other VA and participated in NCI Cooperative Group clinical trials. It is a great example of how veterans are getting access to
the same level of care as are patients who gettreated at NCI partners.

Comorbidities

Dr. Kambhampati. I don’t treat a lot of patients with lung cancer, but I find it easier to use these immuno-oncology drugs than platinums and etoposide. I consider them absolutely nasty chemotherapy drugs now in this era of immuno-oncology and targeted therapy.

Dr. Lynch. The VA is very important in translational lung cancer research and clinical care. It used to be thought that African American patients don’t get epidermal growth factor receptor mutations. And that’s because not enough African American patients with lung cancer were included in the NCI-based clinical trial.There are7,000 veterans who get lung cancer each year, and 20% to 25% of those are African Americans. Prevalence of various mutations and the pharmacogenetics of some of these drugs differ by patient ancestry. Including veterans with lung
cancer in precision oncology clinical trials and clinical care is not just a priority for the VA but a priority for NCI and internationally. I can’t emphasize this enough—veterans with lung cancer should be included in these studies and should be getting the same level of care that our partners are getting at NCI cancer centers. In the VA we’re positioned to do this because of our nationalelectronic health record (EHR) and becauseof our ability to identify patients with specific variants and enroll them in clinical trials.

Ms. Nason. One of the barriers that I find withsome of the patients that I have treated is getting them to a trial. If the trial isn’t available locally, specifically there are socioeconomic and distance issues that are hard to overcome.

Dr. Kaster. For smaller medical centers, getting patients to clinical trials can be difficult. The Boise VAMC is putting together a proposal now to justify hiring a research pharmacist in order to get trials atour site. The goal is to offer trial participation to our patients who otherwise might not be able to participate while offsetting some of the costs of immunotherapy. We are trying to make what could be a negative into a positive.

Measuring Success

Dr. Kambhampati. Unfortunately, we do not have any calculators to incorporate the quality of lives saved to the society. I know there are clearmetrics in transplant and in hematology, but unfortunately, there are no established metrics in solid tumor treatment that allow us to predict the cost savings to the health care system or to society or the benefit to the society. I don’t use any such predictive models or metrics in my decision making. These decisions are made based on existing evidence, and the existing evidence overwhelmingly supports use of immuno-oncology in certain types of solid tumors and in a select group of hematologic malignancies.

Dr. Kaster. This is where you can get more bang for your buck with an oncology pharmacist these days. A pharmacist can make a minor dosing change that will allow the same benefit for the patient, but could equal tens of thousands of dollars in cost-benefit for the VA. They can also be the second set of eyes when adjudicating a nonformulary request to ensure that a patient will benefit.

Dr. Lynch. Inappropriate prescribing is far more expensive than appropriate treatment. And the care for veterans whose long-term health outcomes could be improved by the new immunotherapies. It’s cheaper for veterans to be healthy and live longer than it is to take care of them in
their last 6 weeks of life. Unfortunately, there are not a lot of studies that have demonstrated that empirically, but I think it’s important to do those studies.

Role of Pharmacists

Dr. Lynch. I was at a meeting recently talking about how to improve veteran access to clinical trials. Francesca Cunningham, PharmD, director of the VA Center for Medication Safety of the VA Pharmacy Benefit Management Service (PBM) described the commitment that pharmacy has in taking a leadership role in the integration of precision medicine. Linking veterans’ tumor mutation status and pharmacogenetic variants to pharmacy databases is the best way to ensure treatment is informed by genetics. We have to be realistic about what we’re asking community oncologists to do. With the onset of precision oncology, 10 cancers have become really 100 cancers. In the prior model of care, it was the oncologist, maybe in collaboration with a pathologist, but it was mostly oncologists who determined care.

And in the evolution of precision oncology, Ithink that it’s become an interdisciplinary adventure. Pharmacy is going to play an increasinglyimportant role in precision medicine around all of the molecular alterations, even immuno-oncology regardless of molecular status in which the VA has an advantage. We’re not talking about some community pharmacist. We’re talking about a national health care system where there’s a national EHR, where there’s national PBM systems. So my thoughts on this aspect is that it’s an intricate multidisciplinary team who can ensure that veteran sget the best care possible: the best most cost-effective care possible.

Dr. Kaster. As an oncology pharmacist, I have to second that.

Ms. Nason. As Dr. Kaster said earlier, having a dedicated oncology pharmacist is tremendouslybeneficial. The oncology/hematology pharmacists are following the patients closely and notice when dose adjustments need to be made, optimizing the drug benefit and providing additional safety. Not to mention the cost benefit that can be realized with appropriate adjustment and the expertise they bring to managing possible interactionsand pharmacodynamics.

Dr. Kambhampati. To brag about the Kansas City VAMC program, we have published in Federal Practitioner our best practices showing the collaboration between a pharmacist and providers^.6 And we have used several examples of cost savings, which have basically helped us build the research program, and several examples of dual monitoring oral chemotherapy monitoring. And we have created these templates within the EHR that allow everyone to get a quick snapshot of where things are, what needs to be done, and what needs to be monitored.

Now, we are taking it a step further to determine when to stop chemotherapy or when to stop treatments. For example, for chronic myeloid leukemia (CML), there are good data onstopping tyrosine kinase inhibitors.⁷ And that alone, if implemented across the VA, could bring
in huge cost savings, which perhaps could be put into investments in immuno-oncology or other efforts. We have several examples here that we have published, and we continue to increaseand strengthen our collaboration withour oncology pharmacist. We are very lucky and privileged to have a dedicated oncology pharmacistfor clinics and for research.

Dr. Lynch. The example of CML is perfect, because precision oncology has increased the complexity of care substantially. The VA is wellpositioned to be a leader in this area when care becomes this complex because of its ability to measure access to testing, to translate the results
of testing to pharmacy, to have pharmacists take the lead on prescribing, to have pathologists take the lead on molecular alterations, and to have oncologists take the lead on delivering the cancer care to the patients.

With hematologic malignancies, adherence in the early stages can result in patients getting offcare sooner, which is cost savings. But that requires access to testing, monitoring that testing, and working in partnership with pharmacy. This is a great story about how the VA is positioned to lead in this area of care.

Dr. Kaster. I would like to put a plug in for advanced practice providers and the use of nurse practitioners (NPs) and physician assistants (PAs).The VA is well positioned because it often has established interdisciplinary teams with these providers, pharmacy, nursing, and often social work, to coordinate the care and manage symptoms outside of oncologist visits.

Dr. Lynch. In the NCI cancer center model, once the patient has become stable, the ongoing careis designated to the NP or PA. Then as soon as there’s a change and it requires reevaluation, the oncologist becomes involved again. That pointabout the oncology treatment team is totally in line
with some of the previous comments.

Areas For Further Investigation

Dr. Kaster. There are so many nuances that we’re finding out all of the time about immunotherapies. A recent study brought up the role of antibiotics in the 30 or possibly 60 days prior to immunotherapy.³ How does that change treatment? Which patients are more likely to benefit from immunotherapies, and which are susceptible to “hyperprogression”? How do we integrate palliative care discussions into the carenow that patients are feeling better on treatment and may be less likely to want to discuss palliative care?

Ms. Nason. I absolutely agree with that, especially keeping palliative care integrated within our services. Our focus is now a little different, in thatwe have more optimistic outcomes in mind, butthere still are symptoms and issues where our colleaguesin palliative care are invaluable.

Dr. Lynch. I third that motion. What I would really like to see come out of this discussion is how veterans are getting access to leading oncology care. We just published an analysis of Medicare data and access to EGFR testing. The result of that analysis showed that testing in the VA was consistent with testing in Medicare.

For palliative care, I think the VA does a better job. And it’s just so discouraging as VA employees and as clinicians treating veterans to see publicationsthat suggest that veterans are getting a lower quality of care and that they would be better if care was privatized or outsourced. It’s just fundamentally not the case.

In CML, we see it. We’ve analyzed the data, in that there’s a far lower number of patients with CML who are included in the registry because patients who are diagnosed outside the VA are incorporated in other cancer registries^.8 But as soon as their copays increase for access to targeted drugs, they immediately activate their VA benefits so that theycan get their drugs at the VA. For hematologic malignancies that are diagnosed outside the VA and are captured in other cancer registries, as soon as the drugs become expensive, they start getting their care in the VA. I don’t think there’s beena lot of empirical research that’s shown this, but we have the data to illustrate this trend. I hope thatthere are more publications that show that veterans with cancer are getting really good care inside the VA in the existing VA health care system.

Ms. Nason. It is disheartening to see negativepublicity, knowing that I work with colleagues who are strongly committed to providing up-to-date and relevant oncology care.

Dr. Lynch. As we record this conversation, I am in Rotterdam, Netherlands, in a meeting about genomewide testing. In hematologic malignancies, prostate cancer, and breast cancer, it’s a huge issue. And that is the other area that MVP (Million Veteran Program) is leading the way with the MVP biorepository data. Frankly, there’s no other biorepository that has this many patients, that has so many African Americans, and that has such rich EHR data. So inthat other area, the VA is doing really well.

The following is a lightly edited transcript of a teleconference discussion recorded in April 2018.

Suman Kambhampati, MD. Immuno-oncology is a paradigm-shifting treatment approach. It is an easy-to-understand term for both providers and for patients. The underlying principle is that the body’s own immune system is used or stimulated to fight cancer, and there are drugs that clearly have shown huge promise for this, not only in oncology, but also for other diseases. Time will tell whether that really pans out or not, but to begin with, the emphasis has been inoncology, and therefore, the term immunooncology is fitting.

Dr. Kaster. It was encouraging at first, especially when ipilimumab came out, to see the effects on patients with melanoma. Then the KEYNOTE-024 trial came out, and we were able to jump in anduse monoclonal antibodies directed against programmed death 1 (PD-1) in the first line, which is when things got exciting.¹ We have a smaller populationin Boise, so PD-1s in lung cancer have had the biggest impact on our patients so far.

Ellen Nason, RN, MSN. Patients are open to immunotherapies.They’re excited about it. And as the other panelists have said, you can start broadly, as the body fights the cancer on its own, to providing more specific details as a patient wants more information. Immuno-oncology is definitely accepted by patients, and they’re very excited about it, especially with all the news about new therapies.

Dr. Kambhampati. For the Department of Veteran Affairs (VA) population, lung cancer has seen significant impact, and now it’s translating into other diseases through more research, trials, and better understanding about how these drugs are used and work. 

The paradigm is shifting toward offering these drugs not only in metastatic cancers, but also in the surgically resectable tumors. The 2018 American Association for Cancer Research (AACR) meeting, just concluded. At the meeting several abstracts reported instances where immunooncology drugs are being introduced in the early phases of lung cancer and showing outstanding results. It’s very much possible that we’re going to see less use of traditional chemotherapy in the near future.

Ms. Nason. I primarily work with solid tumors,and the majority of the population I work with have lung cancer. So we’re excited about some of the results that we’ve seen and the lower toxicity involved. Recently, we’ve begun using durvalumab with patients with stage III disease. We have about 5 people now that are using it as a maintenance or consolidative treatment vs just using it for patients with stage IV disease. Hopefully, we’ll see some of the same results describedin the paper published on it.²

Dr. Kaster. Yes, we are incorporating these new changes into care as they're coming out. As Ms. Nason mentioned, we're already using immunotherapies in earlier settings, and we are seeing as much research that could be translated into care soon, like combining immunotherapies
in first-line settings, as we see in the Checkmate-227 study with nivolumab and ipilimumab.^3,4 The landscape is going to change dramatically in the next couple of years.

Accessing Testing For First-Line Treatments

Dr. Lynch. There has been an ongoing discussionin the literature on accessing appropriate testing—delays in testing can result in patients who are not able to access the best targeted drugs on a first-line basis. The drug companiesand the VA have become highly sensitized to ensuring that veterans are accessing the appropriate testing. We are expanding the capability of VA labs to do that testing.

Ms. Nason. I want to put in a plug for the VA Precision Oncology Program (POP). It’s about 2 years into its existence, and Neil Spector, MD, is the director. The POP pays for sequencing the tumor samples.

A new sequencing contract will go into effect October 2018 and will include sequencing for hematologic malignancies in addition to the current testing of solid tumors. Patients from New York who have been unable to receive testing through the current vendors used by POP, will be included in the new contract. It is important to note that POP is working closely with the National Pharmacy Benefit Management Service (PBM) to develop a policy for approving off-label use of US Food and Drug Administration-approved targeted therapies based on sequenced data collected on patients tested through POP.

In addition, the leadership of POP is working to leverage the molecular testing results conducted through POP to improve veterans' access to clinical trials, both inside and outside the VA. Within the VA people can access information at tinyurl.com/precisiononcology. There is no reason why any eligible patient with cancer in the VA health care system should not have their tumor tissue sequenced through POP, particularly once the new contract goes into effect.

Dr. Lynch. Fortunately, the cost of next-generation sequencing has come down so much that most VA contracted reference laboratories offer next-generation sequencing, including LabCorp (Burlington,NC), Quest Diagnostics (Secaucus, NJ), Fulgent (Temple City, CA), and academic partners such as Oregon Health Sciences University and University of Washington.

Ms. Nason. At the Durham VAMC, sometimes a lack of tissue has been a barrier, but we now have the ability to send blood (liquid biopsy) for next-generation sequencing. Hopefully that will open up options for veterans with inadequate tissue. Importantly, all VA facilities can request liquid biopsiesthrough POP.

Dr. Lynch. That’s an important point. There have been huge advances in liquid biopsy testing.The VA Salt Lake City Health Care System (VASLCHCS) was in talks with Genomic Health (Redwood City, CA) to do a study as part of clinical operations to look at the concordance between the liquid biopsy testing and the precision oncology data. But Genomic Health eventually abandoned its liquid biopsy testing. Currently, the VA is only reimbursing or encouraging liquid biopsy if the tissue is not available or if the veteran has too high a level of comorbidities to undergo tissue biopsy. The main point for the discussion today is that access to testing is a key component of access to all of these advanced drugs.

Dr. Kambhampati. The precision medicine piece will be a game changer—no question about that. Liquid biopsy is very timely. Many patients have difficulty getting rebiopsied, so liquid biopsy is definitely a big, big step forward.

Still, there has not been consistency across the VA as there should be. Perhaps there are a few select centers, including our site in Kansas City, where access to precision medicine is readily available and liquid biopsies are available. We use the PlasmaSELECT test from Personal Genome Diagnostics (Baltimore, MD). We have just added Foundation Medicine (Cambridge, MA) also in hematology. Access to mutational profilingis absolutely a must for precision medicine.

All that being said, the unique issue with immuno-oncology is that it pretty much transcends the mutational profile and perhaps has leveled the playing field, irrespective of the tumor mutation profile or burden. In some solid tumors these immuno-oncology drugs have been shown to work across tumor types and across different mutation types. And there is a hint now in the recent data presented at AACR and in the New England Journalof Medicine showing that the tumor mutational burden is a predictor of pathologic response to at least PD-1 blockade in the resectable stages of lung cancer.^1,3 To me, that’s a very important piece of data because that’s something that can be tested and can have a prognostic impact in immuno-oncology, particularly in the early stages of lung cancer and is further proof of the broad value of immunotherapics in targeting tumors irrespective of the precise tumor targets.

Dr. Kaster. Yes, it’s nice to see other options like tumor mutational burden and Lung Immune Prognostic Index being studied.5 It would be nice if we could rely a little more on these, and not PD-L1, which as we all know is a variable and an unreliable target.

Dr. Kambhampati. I agree.

Rural Challenges In A Veterans Population

Dr. Lynch. Providing high-quality cancer care to rural veterans care can be a challenge but it is a VA priority. The VA National Genomic Medicine Services offers better access for rural veterans to germline genetic testing than any other healthcare system in the country. In terms of access to somatic testing and next-generation sequencing, we are working toward providing the same level of cancer care as patients would receive at National Cancer Institute (NCI) cancer centers. The VA oncology leadership has done teleconsults and virtual tumor boards, but for some rural VAMCs, fellowsare leading the clinical care. As we expand use of oral agents for oncology treatment, it will be easier to ensure that rural veterans receive the same standard of care for POP that veterans being cared for at VASLCHCS, Kansas City VAMC, or Durham VAMC get.

Dr. Kambhampati. The Kansas City VAMC in its catchment area includes underserved areas, such as Topeka and Leavenworth, Kansas. What we’ve been able to do here is something that’s unique—Kansas City VAMC is the only standalone VA in the country to be recognized as a primary SWOG (Southwestern Oncology Group) institution, which provides access to many trials, such as the Lung-MAP trial and others. And that has allowed us to use the full expanse of precision medicine without financial barriers. The research has helped us improve the standard of
care for patients across VISN 15.

Dr. Lynch. In precision oncology, the chief of pathology is an important figure in access to advanced care. I’ve worked with Sharad Mathur,MD, of the Kansas City VAMC on many clinical trials. He’s on the Kansas City VAMC Institutional Review Board and the cancer committee and is tuned in to veterans’ access to precision oncology. Kansas City was ordering Foundation One for select patients that met the criteria probably sooner than any other VA and participated in NCI Cooperative Group clinical trials. It is a great example of how veterans are getting access to
the same level of care as are patients who gettreated at NCI partners.

Comorbidities

Dr. Kambhampati. I don’t treat a lot of patients with lung cancer, but I find it easier to use these immuno-oncology drugs than platinums and etoposide. I consider them absolutely nasty chemotherapy drugs now in this era of immuno-oncology and targeted therapy.

Dr. Lynch. The VA is very important in translational lung cancer research and clinical care. It used to be thought that African American patients don’t get epidermal growth factor receptor mutations. And that’s because not enough African American patients with lung cancer were included in the NCI-based clinical trial.There are7,000 veterans who get lung cancer each year, and 20% to 25% of those are African Americans. Prevalence of various mutations and the pharmacogenetics of some of these drugs differ by patient ancestry. Including veterans with lung
cancer in precision oncology clinical trials and clinical care is not just a priority for the VA but a priority for NCI and internationally. I can’t emphasize this enough—veterans with lung cancer should be included in these studies and should be getting the same level of care that our partners are getting at NCI cancer centers. In the VA we’re positioned to do this because of our nationalelectronic health record (EHR) and becauseof our ability to identify patients with specific variants and enroll them in clinical trials.

Ms. Nason. One of the barriers that I find withsome of the patients that I have treated is getting them to a trial. If the trial isn’t available locally, specifically there are socioeconomic and distance issues that are hard to overcome.

Dr. Kaster. For smaller medical centers, getting patients to clinical trials can be difficult. The Boise VAMC is putting together a proposal now to justify hiring a research pharmacist in order to get trials atour site. The goal is to offer trial participation to our patients who otherwise might not be able to participate while offsetting some of the costs of immunotherapy. We are trying to make what could be a negative into a positive.

Measuring Success

Dr. Kambhampati. Unfortunately, we do not have any calculators to incorporate the quality of lives saved to the society. I know there are clearmetrics in transplant and in hematology, but unfortunately, there are no established metrics in solid tumor treatment that allow us to predict the cost savings to the health care system or to society or the benefit to the society. I don’t use any such predictive models or metrics in my decision making. These decisions are made based on existing evidence, and the existing evidence overwhelmingly supports use of immuno-oncology in certain types of solid tumors and in a select group of hematologic malignancies.

Dr. Kaster. This is where you can get more bang for your buck with an oncology pharmacist these days. A pharmacist can make a minor dosing change that will allow the same benefit for the patient, but could equal tens of thousands of dollars in cost-benefit for the VA. They can also be the second set of eyes when adjudicating a nonformulary request to ensure that a patient will benefit.

Dr. Lynch. Inappropriate prescribing is far more expensive than appropriate treatment. And the care for veterans whose long-term health outcomes could be improved by the new immunotherapies. It’s cheaper for veterans to be healthy and live longer than it is to take care of them in
their last 6 weeks of life. Unfortunately, there are not a lot of studies that have demonstrated that empirically, but I think it’s important to do those studies.

Role of Pharmacists

Dr. Lynch. I was at a meeting recently talking about how to improve veteran access to clinical trials. Francesca Cunningham, PharmD, director of the VA Center for Medication Safety of the VA Pharmacy Benefit Management Service (PBM) described the commitment that pharmacy has in taking a leadership role in the integration of precision medicine. Linking veterans’ tumor mutation status and pharmacogenetic variants to pharmacy databases is the best way to ensure treatment is informed by genetics. We have to be realistic about what we’re asking community oncologists to do. With the onset of precision oncology, 10 cancers have become really 100 cancers. In the prior model of care, it was the oncologist, maybe in collaboration with a pathologist, but it was mostly oncologists who determined care.

And in the evolution of precision oncology, Ithink that it’s become an interdisciplinary adventure. Pharmacy is going to play an increasinglyimportant role in precision medicine around all of the molecular alterations, even immuno-oncology regardless of molecular status in which the VA has an advantage. We’re not talking about some community pharmacist. We’re talking about a national health care system where there’s a national EHR, where there’s national PBM systems. So my thoughts on this aspect is that it’s an intricate multidisciplinary team who can ensure that veteran sget the best care possible: the best most cost-effective care possible.

Dr. Kaster. As an oncology pharmacist, I have to second that.

Ms. Nason. As Dr. Kaster said earlier, having a dedicated oncology pharmacist is tremendouslybeneficial. The oncology/hematology pharmacists are following the patients closely and notice when dose adjustments need to be made, optimizing the drug benefit and providing additional safety. Not to mention the cost benefit that can be realized with appropriate adjustment and the expertise they bring to managing possible interactionsand pharmacodynamics.

Dr. Kambhampati. To brag about the Kansas City VAMC program, we have published in Federal Practitioner our best practices showing the collaboration between a pharmacist and providers^.6 And we have used several examples of cost savings, which have basically helped us build the research program, and several examples of dual monitoring oral chemotherapy monitoring. And we have created these templates within the EHR that allow everyone to get a quick snapshot of where things are, what needs to be done, and what needs to be monitored.

Now, we are taking it a step further to determine when to stop chemotherapy or when to stop treatments. For example, for chronic myeloid leukemia (CML), there are good data onstopping tyrosine kinase inhibitors.⁷ And that alone, if implemented across the VA, could bring
in huge cost savings, which perhaps could be put into investments in immuno-oncology or other efforts. We have several examples here that we have published, and we continue to increaseand strengthen our collaboration withour oncology pharmacist. We are very lucky and privileged to have a dedicated oncology pharmacistfor clinics and for research.

Dr. Lynch. The example of CML is perfect, because precision oncology has increased the complexity of care substantially. The VA is wellpositioned to be a leader in this area when care becomes this complex because of its ability to measure access to testing, to translate the results
of testing to pharmacy, to have pharmacists take the lead on prescribing, to have pathologists take the lead on molecular alterations, and to have oncologists take the lead on delivering the cancer care to the patients.

With hematologic malignancies, adherence in the early stages can result in patients getting offcare sooner, which is cost savings. But that requires access to testing, monitoring that testing, and working in partnership with pharmacy. This is a great story about how the VA is positioned to lead in this area of care.

Dr. Kaster. I would like to put a plug in for advanced practice providers and the use of nurse practitioners (NPs) and physician assistants (PAs).The VA is well positioned because it often has established interdisciplinary teams with these providers, pharmacy, nursing, and often social work, to coordinate the care and manage symptoms outside of oncologist visits.

Dr. Lynch. In the NCI cancer center model, once the patient has become stable, the ongoing careis designated to the NP or PA. Then as soon as there’s a change and it requires reevaluation, the oncologist becomes involved again. That pointabout the oncology treatment team is totally in line
with some of the previous comments.

Areas For Further Investigation

Dr. Kaster. There are so many nuances that we’re finding out all of the time about immunotherapies. A recent study brought up the role of antibiotics in the 30 or possibly 60 days prior to immunotherapy.³ How does that change treatment? Which patients are more likely to benefit from immunotherapies, and which are susceptible to “hyperprogression”? How do we integrate palliative care discussions into the carenow that patients are feeling better on treatment and may be less likely to want to discuss palliative care?

Ms. Nason. I absolutely agree with that, especially keeping palliative care integrated within our services. Our focus is now a little different, in thatwe have more optimistic outcomes in mind, butthere still are symptoms and issues where our colleaguesin palliative care are invaluable.

Dr. Lynch. I third that motion. What I would really like to see come out of this discussion is how veterans are getting access to leading oncology care. We just published an analysis of Medicare data and access to EGFR testing. The result of that analysis showed that testing in the VA was consistent with testing in Medicare.

For palliative care, I think the VA does a better job. And it’s just so discouraging as VA employees and as clinicians treating veterans to see publicationsthat suggest that veterans are getting a lower quality of care and that they would be better if care was privatized or outsourced. It’s just fundamentally not the case.

In CML, we see it. We’ve analyzed the data, in that there’s a far lower number of patients with CML who are included in the registry because patients who are diagnosed outside the VA are incorporated in other cancer registries^.8 But as soon as their copays increase for access to targeted drugs, they immediately activate their VA benefits so that theycan get their drugs at the VA. For hematologic malignancies that are diagnosed outside the VA and are captured in other cancer registries, as soon as the drugs become expensive, they start getting their care in the VA. I don’t think there’s beena lot of empirical research that’s shown this, but we have the data to illustrate this trend. I hope thatthere are more publications that show that veterans with cancer are getting really good care inside the VA in the existing VA health care system.

Ms. Nason. It is disheartening to see negativepublicity, knowing that I work with colleagues who are strongly committed to providing up-to-date and relevant oncology care.

Dr. Lynch. As we record this conversation, I am in Rotterdam, Netherlands, in a meeting about genomewide testing. In hematologic malignancies, prostate cancer, and breast cancer, it’s a huge issue. And that is the other area that MVP (Million Veteran Program) is leading the way with the MVP biorepository data. Frankly, there’s no other biorepository that has this many patients, that has so many African Americans, and that has such rich EHR data. So inthat other area, the VA is doing really well.

The following is a lightly edited transcript of a teleconference discussion recorded in April 2018.

Suman Kambhampati, MD. Immuno-oncology is a paradigm-shifting treatment approach. It is an easy-to-understand term for both providers and for patients. The underlying principle is that the body’s own immune system is used or stimulated to fight cancer, and there are drugs that clearly have shown huge promise for this, not only in oncology, but also for other diseases. Time will tell whether that really pans out or not, but to begin with, the emphasis has been inoncology, and therefore, the term immunooncology is fitting.

Dr. Kaster. It was encouraging at first, especially when ipilimumab came out, to see the effects on patients with melanoma. Then the KEYNOTE-024 trial came out, and we were able to jump in anduse monoclonal antibodies directed against programmed death 1 (PD-1) in the first line, which is when things got exciting.¹ We have a smaller populationin Boise, so PD-1s in lung cancer have had the biggest impact on our patients so far.

Ellen Nason, RN, MSN. Patients are open to immunotherapies.They’re excited about it. And as the other panelists have said, you can start broadly, as the body fights the cancer on its own, to providing more specific details as a patient wants more information. Immuno-oncology is definitely accepted by patients, and they’re very excited about it, especially with all the news about new therapies.

Dr. Kambhampati. For the Department of Veteran Affairs (VA) population, lung cancer has seen significant impact, and now it’s translating into other diseases through more research, trials, and better understanding about how these drugs are used and work. 

The paradigm is shifting toward offering these drugs not only in metastatic cancers, but also in the surgically resectable tumors. The 2018 American Association for Cancer Research (AACR) meeting, just concluded. At the meeting several abstracts reported instances where immunooncology drugs are being introduced in the early phases of lung cancer and showing outstanding results. It’s very much possible that we’re going to see less use of traditional chemotherapy in the near future.

Ms. Nason. I primarily work with solid tumors,and the majority of the population I work with have lung cancer. So we’re excited about some of the results that we’ve seen and the lower toxicity involved. Recently, we’ve begun using durvalumab with patients with stage III disease. We have about 5 people now that are using it as a maintenance or consolidative treatment vs just using it for patients with stage IV disease. Hopefully, we’ll see some of the same results describedin the paper published on it.²

Dr. Kaster. Yes, we are incorporating these new changes into care as they're coming out. As Ms. Nason mentioned, we're already using immunotherapies in earlier settings, and we are seeing as much research that could be translated into care soon, like combining immunotherapies
in first-line settings, as we see in the Checkmate-227 study with nivolumab and ipilimumab.^3,4 The landscape is going to change dramatically in the next couple of years.

Accessing Testing For First-Line Treatments

Dr. Lynch. There has been an ongoing discussionin the literature on accessing appropriate testing—delays in testing can result in patients who are not able to access the best targeted drugs on a first-line basis. The drug companiesand the VA have become highly sensitized to ensuring that veterans are accessing the appropriate testing. We are expanding the capability of VA labs to do that testing.

Ms. Nason. I want to put in a plug for the VA Precision Oncology Program (POP). It’s about 2 years into its existence, and Neil Spector, MD, is the director. The POP pays for sequencing the tumor samples.

A new sequencing contract will go into effect October 2018 and will include sequencing for hematologic malignancies in addition to the current testing of solid tumors. Patients from New York who have been unable to receive testing through the current vendors used by POP, will be included in the new contract. It is important to note that POP is working closely with the National Pharmacy Benefit Management Service (PBM) to develop a policy for approving off-label use of US Food and Drug Administration-approved targeted therapies based on sequenced data collected on patients tested through POP.

In addition, the leadership of POP is working to leverage the molecular testing results conducted through POP to improve veterans' access to clinical trials, both inside and outside the VA. Within the VA people can access information at tinyurl.com/precisiononcology. There is no reason why any eligible patient with cancer in the VA health care system should not have their tumor tissue sequenced through POP, particularly once the new contract goes into effect.

Dr. Lynch. Fortunately, the cost of next-generation sequencing has come down so much that most VA contracted reference laboratories offer next-generation sequencing, including LabCorp (Burlington,NC), Quest Diagnostics (Secaucus, NJ), Fulgent (Temple City, CA), and academic partners such as Oregon Health Sciences University and University of Washington.

Ms. Nason. At the Durham VAMC, sometimes a lack of tissue has been a barrier, but we now have the ability to send blood (liquid biopsy) for next-generation sequencing. Hopefully that will open up options for veterans with inadequate tissue. Importantly, all VA facilities can request liquid biopsiesthrough POP.

Dr. Lynch. That’s an important point. There have been huge advances in liquid biopsy testing.The VA Salt Lake City Health Care System (VASLCHCS) was in talks with Genomic Health (Redwood City, CA) to do a study as part of clinical operations to look at the concordance between the liquid biopsy testing and the precision oncology data. But Genomic Health eventually abandoned its liquid biopsy testing. Currently, the VA is only reimbursing or encouraging liquid biopsy if the tissue is not available or if the veteran has too high a level of comorbidities to undergo tissue biopsy. The main point for the discussion today is that access to testing is a key component of access to all of these advanced drugs.

Dr. Kambhampati. The precision medicine piece will be a game changer—no question about that. Liquid biopsy is very timely. Many patients have difficulty getting rebiopsied, so liquid biopsy is definitely a big, big step forward.

Still, there has not been consistency across the VA as there should be. Perhaps there are a few select centers, including our site in Kansas City, where access to precision medicine is readily available and liquid biopsies are available. We use the PlasmaSELECT test from Personal Genome Diagnostics (Baltimore, MD). We have just added Foundation Medicine (Cambridge, MA) also in hematology. Access to mutational profilingis absolutely a must for precision medicine.

All that being said, the unique issue with immuno-oncology is that it pretty much transcends the mutational profile and perhaps has leveled the playing field, irrespective of the tumor mutation profile or burden. In some solid tumors these immuno-oncology drugs have been shown to work across tumor types and across different mutation types. And there is a hint now in the recent data presented at AACR and in the New England Journalof Medicine showing that the tumor mutational burden is a predictor of pathologic response to at least PD-1 blockade in the resectable stages of lung cancer.^1,3 To me, that’s a very important piece of data because that’s something that can be tested and can have a prognostic impact in immuno-oncology, particularly in the early stages of lung cancer and is further proof of the broad value of immunotherapics in targeting tumors irrespective of the precise tumor targets.

Dr. Kaster. Yes, it’s nice to see other options like tumor mutational burden and Lung Immune Prognostic Index being studied.5 It would be nice if we could rely a little more on these, and not PD-L1, which as we all know is a variable and an unreliable target.

Dr. Kambhampati. I agree.

Rural Challenges In A Veterans Population

Dr. Lynch. Providing high-quality cancer care to rural veterans care can be a challenge but it is a VA priority. The VA National Genomic Medicine Services offers better access for rural veterans to germline genetic testing than any other healthcare system in the country. In terms of access to somatic testing and next-generation sequencing, we are working toward providing the same level of cancer care as patients would receive at National Cancer Institute (NCI) cancer centers. The VA oncology leadership has done teleconsults and virtual tumor boards, but for some rural VAMCs, fellowsare leading the clinical care. As we expand use of oral agents for oncology treatment, it will be easier to ensure that rural veterans receive the same standard of care for POP that veterans being cared for at VASLCHCS, Kansas City VAMC, or Durham VAMC get.

Dr. Kambhampati. The Kansas City VAMC in its catchment area includes underserved areas, such as Topeka and Leavenworth, Kansas. What we’ve been able to do here is something that’s unique—Kansas City VAMC is the only standalone VA in the country to be recognized as a primary SWOG (Southwestern Oncology Group) institution, which provides access to many trials, such as the Lung-MAP trial and others. And that has allowed us to use the full expanse of precision medicine without financial barriers. The research has helped us improve the standard of
care for patients across VISN 15.

Dr. Lynch. In precision oncology, the chief of pathology is an important figure in access to advanced care. I’ve worked with Sharad Mathur,MD, of the Kansas City VAMC on many clinical trials. He’s on the Kansas City VAMC Institutional Review Board and the cancer committee and is tuned in to veterans’ access to precision oncology. Kansas City was ordering Foundation One for select patients that met the criteria probably sooner than any other VA and participated in NCI Cooperative Group clinical trials. It is a great example of how veterans are getting access to
the same level of care as are patients who gettreated at NCI partners.

Comorbidities

Dr. Kambhampati. I don’t treat a lot of patients with lung cancer, but I find it easier to use these immuno-oncology drugs than platinums and etoposide. I consider them absolutely nasty chemotherapy drugs now in this era of immuno-oncology and targeted therapy.

Dr. Lynch. The VA is very important in translational lung cancer research and clinical care. It used to be thought that African American patients don’t get epidermal growth factor receptor mutations. And that’s because not enough African American patients with lung cancer were included in the NCI-based clinical trial.There are7,000 veterans who get lung cancer each year, and 20% to 25% of those are African Americans. Prevalence of various mutations and the pharmacogenetics of some of these drugs differ by patient ancestry. Including veterans with lung
cancer in precision oncology clinical trials and clinical care is not just a priority for the VA but a priority for NCI and internationally. I can’t emphasize this enough—veterans with lung cancer should be included in these studies and should be getting the same level of care that our partners are getting at NCI cancer centers. In the VA we’re positioned to do this because of our nationalelectronic health record (EHR) and becauseof our ability to identify patients with specific variants and enroll them in clinical trials.

Ms. Nason. One of the barriers that I find withsome of the patients that I have treated is getting them to a trial. If the trial isn’t available locally, specifically there are socioeconomic and distance issues that are hard to overcome.

Dr. Kaster. For smaller medical centers, getting patients to clinical trials can be difficult. The Boise VAMC is putting together a proposal now to justify hiring a research pharmacist in order to get trials atour site. The goal is to offer trial participation to our patients who otherwise might not be able to participate while offsetting some of the costs of immunotherapy. We are trying to make what could be a negative into a positive.

Measuring Success

Dr. Kambhampati. Unfortunately, we do not have any calculators to incorporate the quality of lives saved to the society. I know there are clearmetrics in transplant and in hematology, but unfortunately, there are no established metrics in solid tumor treatment that allow us to predict the cost savings to the health care system or to society or the benefit to the society. I don’t use any such predictive models or metrics in my decision making. These decisions are made based on existing evidence, and the existing evidence overwhelmingly supports use of immuno-oncology in certain types of solid tumors and in a select group of hematologic malignancies.

Dr. Kaster. This is where you can get more bang for your buck with an oncology pharmacist these days. A pharmacist can make a minor dosing change that will allow the same benefit for the patient, but could equal tens of thousands of dollars in cost-benefit for the VA. They can also be the second set of eyes when adjudicating a nonformulary request to ensure that a patient will benefit.

Dr. Lynch. Inappropriate prescribing is far more expensive than appropriate treatment. And the care for veterans whose long-term health outcomes could be improved by the new immunotherapies. It’s cheaper for veterans to be healthy and live longer than it is to take care of them in
their last 6 weeks of life. Unfortunately, there are not a lot of studies that have demonstrated that empirically, but I think it’s important to do those studies.

Role of Pharmacists

Dr. Lynch. I was at a meeting recently talking about how to improve veteran access to clinical trials. Francesca Cunningham, PharmD, director of the VA Center for Medication Safety of the VA Pharmacy Benefit Management Service (PBM) described the commitment that pharmacy has in taking a leadership role in the integration of precision medicine. Linking veterans’ tumor mutation status and pharmacogenetic variants to pharmacy databases is the best way to ensure treatment is informed by genetics. We have to be realistic about what we’re asking community oncologists to do. With the onset of precision oncology, 10 cancers have become really 100 cancers. In the prior model of care, it was the oncologist, maybe in collaboration with a pathologist, but it was mostly oncologists who determined care.

And in the evolution of precision oncology, Ithink that it’s become an interdisciplinary adventure. Pharmacy is going to play an increasinglyimportant role in precision medicine around all of the molecular alterations, even immuno-oncology regardless of molecular status in which the VA has an advantage. We’re not talking about some community pharmacist. We’re talking about a national health care system where there’s a national EHR, where there’s national PBM systems. So my thoughts on this aspect is that it’s an intricate multidisciplinary team who can ensure that veteran sget the best care possible: the best most cost-effective care possible.

Dr. Kaster. As an oncology pharmacist, I have to second that.

Ms. Nason. As Dr. Kaster said earlier, having a dedicated oncology pharmacist is tremendouslybeneficial. The oncology/hematology pharmacists are following the patients closely and notice when dose adjustments need to be made, optimizing the drug benefit and providing additional safety. Not to mention the cost benefit that can be realized with appropriate adjustment and the expertise they bring to managing possible interactionsand pharmacodynamics.

Dr. Kambhampati. To brag about the Kansas City VAMC program, we have published in Federal Practitioner our best practices showing the collaboration between a pharmacist and providers^.6 And we have used several examples of cost savings, which have basically helped us build the research program, and several examples of dual monitoring oral chemotherapy monitoring. And we have created these templates within the EHR that allow everyone to get a quick snapshot of where things are, what needs to be done, and what needs to be monitored.

Now, we are taking it a step further to determine when to stop chemotherapy or when to stop treatments. For example, for chronic myeloid leukemia (CML), there are good data onstopping tyrosine kinase inhibitors.⁷ And that alone, if implemented across the VA, could bring
in huge cost savings, which perhaps could be put into investments in immuno-oncology or other efforts. We have several examples here that we have published, and we continue to increaseand strengthen our collaboration withour oncology pharmacist. We are very lucky and privileged to have a dedicated oncology pharmacistfor clinics and for research.

Dr. Lynch. The example of CML is perfect, because precision oncology has increased the complexity of care substantially. The VA is wellpositioned to be a leader in this area when care becomes this complex because of its ability to measure access to testing, to translate the results
of testing to pharmacy, to have pharmacists take the lead on prescribing, to have pathologists take the lead on molecular alterations, and to have oncologists take the lead on delivering the cancer care to the patients.

With hematologic malignancies, adherence in the early stages can result in patients getting offcare sooner, which is cost savings. But that requires access to testing, monitoring that testing, and working in partnership with pharmacy. This is a great story about how the VA is positioned to lead in this area of care.

Dr. Kaster. I would like to put a plug in for advanced practice providers and the use of nurse practitioners (NPs) and physician assistants (PAs).The VA is well positioned because it often has established interdisciplinary teams with these providers, pharmacy, nursing, and often social work, to coordinate the care and manage symptoms outside of oncologist visits.

Dr. Lynch. In the NCI cancer center model, once the patient has become stable, the ongoing careis designated to the NP or PA. Then as soon as there’s a change and it requires reevaluation, the oncologist becomes involved again. That pointabout the oncology treatment team is totally in line
with some of the previous comments.

Areas For Further Investigation

Dr. Kaster. There are so many nuances that we’re finding out all of the time about immunotherapies. A recent study brought up the role of antibiotics in the 30 or possibly 60 days prior to immunotherapy.³ How does that change treatment? Which patients are more likely to benefit from immunotherapies, and which are susceptible to “hyperprogression”? How do we integrate palliative care discussions into the carenow that patients are feeling better on treatment and may be less likely to want to discuss palliative care?

Ms. Nason. I absolutely agree with that, especially keeping palliative care integrated within our services. Our focus is now a little different, in thatwe have more optimistic outcomes in mind, butthere still are symptoms and issues where our colleaguesin palliative care are invaluable.

Dr. Lynch. I third that motion. What I would really like to see come out of this discussion is how veterans are getting access to leading oncology care. We just published an analysis of Medicare data and access to EGFR testing. The result of that analysis showed that testing in the VA was consistent with testing in Medicare.

For palliative care, I think the VA does a better job. And it’s just so discouraging as VA employees and as clinicians treating veterans to see publicationsthat suggest that veterans are getting a lower quality of care and that they would be better if care was privatized or outsourced. It’s just fundamentally not the case.

In CML, we see it. We’ve analyzed the data, in that there’s a far lower number of patients with CML who are included in the registry because patients who are diagnosed outside the VA are incorporated in other cancer registries^.8 But as soon as their copays increase for access to targeted drugs, they immediately activate their VA benefits so that theycan get their drugs at the VA. For hematologic malignancies that are diagnosed outside the VA and are captured in other cancer registries, as soon as the drugs become expensive, they start getting their care in the VA. I don’t think there’s beena lot of empirical research that’s shown this, but we have the data to illustrate this trend. I hope thatthere are more publications that show that veterans with cancer are getting really good care inside the VA in the existing VA health care system.

Ms. Nason. It is disheartening to see negativepublicity, knowing that I work with colleagues who are strongly committed to providing up-to-date and relevant oncology care.

Dr. Lynch. As we record this conversation, I am in Rotterdam, Netherlands, in a meeting about genomewide testing. In hematologic malignancies, prostate cancer, and breast cancer, it’s a huge issue. And that is the other area that MVP (Million Veteran Program) is leading the way with the MVP biorepository data. Frankly, there’s no other biorepository that has this many patients, that has so many African Americans, and that has such rich EHR data. So inthat other area, the VA is doing really well.

Case 1

Tracy Minichiello, MD. The first case we’ll discuss is a 75-year-old man with mild chronic kidney disease (CKD). His calculated creatinine clearance (CrCl) is about 52 mL/min, and he has a remote history of a gastrointestinal (GI) bleeding 3 years previously from a peptic ulcer. He presents with new onset nonvalvular atrial fibrillation (AF), and he’s already on aspirin for his stable coronary artery disease (CAD).

How do we think about anticoagulant selection in this patient? We have a number of new oral anticoagulants and we have warfarin. How do we decide between warfarin vs one of the direct-acting oral anticoagulants (DOACs)? If we choose a DOAC, which one would we select?

David Parra, PharmD. The first step for anticoagulation is to assess a patient’s thromboembolic risk utilizing the CHA₂DS₂-VASc and bleeding risk using a HAS-BLED score, or something similar. The next question is which oral anticoagulant to use. We have widespread experience with warfarin and can measure the anticoagulant effect easily. Warfarin has a long duration of action, so perhaps it’s more forgiving if you miss a dose. It also has an antidote. Lastly, organ dysfunction doesn’t preclude use of warfarin as you can still monitor the anticoagulant effect. So there still may be patients that may benefit significantly from warfarin vs a DOAC.

On the flip side, DOACs are easier to use and perform quite acceptably in comparison with warfarin in nonvalvular AF. There are some scenarios where a specific DOAC may be preferred over another, such as recent GI bleeding.

Dr. Minichiello. Do you consider renal function, bleeding history, or concomitant antiplatelet therapy?

Geoffrey Barnes, MD, MSc. A couple of factors are relevant. I think we should consider renal function for this gentleman. However, I look at some of the other features as Dr. Parra suggested. What’s the likelihood that this patient is going to take the medicine as prescribed? Is a twice-a-day regimen going to be something that’s particularly challenging? I also look at the real-world vs randomized trial experience.

This patient has a remote GI bleeding history. Some of the real-world data suggest there might be some more GI bleeding with rivaroxaban, but across the board, apixaban (in both the randomized trials and much of the real-world data) seem to have a favorable bleeding risk profile. For a patient who is open and reliable for taking medicine twice a day, apixaban might be a good option as long as we make sure that the dose is appropriate.

Arthur L. Allen, PharmD, CACP. In pivotal trial experience, dabigatran and rivaroxaban demonstrated an increased incidence of GI bleeding compared with warfarin. In some of the real-world studies, rivaroxaban mirrors warfarin with regard to bleeding, whereas dabigatran and apixaban have a lower incidence. In the pivotal trials, apixaban did not have a trigger of increased GI bleeding, but I would let the details of this patient’s GI bleeding history help me determine how important an issue this is at this point.

The other thing that is important to understand when considering choice of agents: As Dr. Parra mentioned, we do have quite a bit of experience with warfarin. But comparing the quality of evidence, the DOACs have been investigated in a far more rigorous fashion and in far more patients than warfarin ever was in its more than 60 years on the market. For example, the RE-LY trial alone enrolled more than 18,000 patients. Each of the DOACs have been studied in tens of thousands of patients for their approved indications. Further, we shouldn’t forget that the risk of intracranial hemorrhage is reduced by roughly 50% by choosing a DOAC over warfarin, which should be a consideration in this elderly gentleman.

Dr. Minichiello. In the veteran population, there is a sense of comfort with warfarin, and some concerns have been raised over a lack of reversibility for the newer agents. We have patients who have trepidation about starting one of the new anticoagulants. However, there is a marked reduction in the risk of the most devastating bleeding complication, namely intracranial hemorrhage, making the use of these agents most compelling. And when they did have bleeding complications, at least in the trials, their outcomes were no worse than they were with warfarin, where there is a reversal agent. In most cases the outcomes were actually better.

Dr. Barnes. You often have to remind patients that there was no reversal agent in these huge trials where the DOACs showed similar or safer bleeding risk profiles, especially for the most serious bleeding, such as intracranial hemorrhage. I find patients often are reassured by knowing that.

Dr. Allen. I agree that there is concern about the lack of reversibility, but I think it has been completely overplayed. In the pivotal trials, patients who bled on DOAC therapy actually had better outcomes than those that bled on warfarin. This includes intracranial hemorrhage. There was a paper published in Stroke in 2012 that evaluated the subgroup of patients in the RE-LY trial that suffered intracranial hemorrhage. Patients on dabigatran actually fared better despite a lack of a specific reversal agent. When evaluating the available data about reversal of the DOACs, I’m not 100% convinced that we’re significantly impacting outcomes by reversing these agents. We’re certainly running up the bill, but are we treating the patient or treating the providers? As long as the renal function remains intact, the DOACs clear quickly, perhaps more quickly than warfarin can typically be reversed with standard reversal agents.

Dr. Minichiello. Remember that this patient has a history of a GI bleed. We are going to start him on full-dose anticoagulation for stroke prevention for his nonvalvular AF. He’s also on aspirin, and he has stable coronary disease. He does not have any stents in place but he did have a remote non-ST elevation myocardial infarction (MI) a number of years ago. Do we feel that the risk of dual therapy—anticoagulation combined with antiplatelet therapy—outweighs the risks? And how do we approach that risk?

Dr. Barnes. This is an important point to discuss. There has been a lot of discussion in the literature recently. When I start this type of patient on an oral anticoagulant, I try to discontinue the antiplatelet agent because I know how much bleeding risk that brings. The European guidelines (for example, Eur Heart J. 2014;35[45]:3155-3179) have been forward thinking with this for the last couple of years and have highlighted that if there’s an indication for anticoagulation for patients with stable coronary disease, meaning no MI and no stent within the past year, then we should stop the antiplatelet agents after a year in order to reduce the risk of MI. This is based on a lot of older literature where warfarin was compared with aspirin and shown to be protective in coronary patients, but at the risk of bleeding.

It’s important because there have been recent studies that have raised questions, including a recent Swedish article in (Circulation. 2017;136:1183-1192) that suggested discontinuing aspirin led to increased mortality. But it’s important to look at the details. While that was true for most patients, it was not true for the group of patients who were on an oral anticoagulant. Many colleagues ask me questions about that particular paper and its media coverage. I tell them that for our patients on chronic oral anticoagulants, the paper supports the notion that there is not increased mortality when aspirin use is stopped. We know that aspirin plus an anticoagulant leads to increased bleeding, so I try to stop it for patients who have stable CAD but are on long-term anticoagulation.

Dr. Allen. This isn’t a new thought. Back in early 2012, the 9th edition of the American College of Chest Physicians (CHEST) Antithrombotic Guidelines probably gave us the best guidance that we had ever seen to help us address this issue. Since that time the cardiology guidelines have caught up to recommend that we do not need additional antiplatelet therapy for stable CAD, and, in fact, it should be limited even in the setting of acute coronary syndromes and percutaneous coronary intervention (PCI).

Dr. Minichiello. That’s a good point because people are not necessarily clear about when there would be an indication to continue dual therapy and when it is safe to go to monotherapy. Scenarios where benefit of dual therapy may outweigh risk suggested in the CHEST 2012 guidelines include acute coronary syndrome or a recent stent, high-risk mechanical valves, and history of coronary artery bypass surgery.

I think the important thing is to consider each case individually and not to reflexively continue aspirin therapy. Often what we see is once on aspirin—always on aspirin. Being thoughtful about it, we should acknowledge that it likely results in a 2-fold increased risk of bleeding and make sure that we believe that the benefit outweighs the risk.

Dr. Allen. I agree. We probably have better evidence in the CAD population, but what do we do for patients with significant peripheral vascular disease, or those patients with symptomatic carotid stenosis or history of strokes? Some of the European guidance suggests taking a similar approach to CAD, but these are the patients for whom stopping aspirin makes me more nervous.

Dr. Parra. This is a perfect example of where less is more. All too often the reflex is to continue aspirin treatment indefinitely because the patient has a history of acute coronary syndrome or even peripheral arterial disease, when the best thing to do would be to drop the aspirin. It involves an individualized risk assessment and underscores the need to periodically do a risk/benefit assessment in all patients on anticoagulants, whether it’s warfarin or a DOAC.

I’d like to take a moment and step back to the case in the context of the GI bleeding. When we look at patients with a history of GI bleeding, it is important to understand the circumstances that surround it. This individual had a GI bleed 3 years previously and peptic ulcer disease. In these situations I ask whether the patient was taking over-the-counter nonsteroidal anti-inflamitory drugs at the time, had excessive alcohol use, or was successfully treated for Helicobacter pylori. All of these may influence whether or not I think the GI bleed is significant to influence the DOAC choice.

The other thing I consider is that the overall risk of major GI bleeding in those pivotal DOAC trials was quite small, < 1.5% per year with dabigatran 150 mg twice daily and < 1% per year with apixaban. The numbers needed to harm were quite high, over 200 patients per year with dabigatran 150 mg twice daily vs warfarin and over 350 patients per year with edoxaban 60 mg daily vs warfarin. There are no head-to-head comparisons with DOACs, but this small increased risk vs warfarin may still be an important consideration in some patients. In addition, it is important to remember that intracranial hemorrhage and fatal bleeding was less in all the pivotal NVAF trials with the DOACs when compared with warfarin. So that is something we need to reinforce with patients when we discuss treatment regardless of the DOAC selected.

Case 2

Dr. Minichiello. The next case is a 63-year-old man with hypertension, diabetes mellitus, nonvalvular AF, and he is taking dabigatran for stroke prevention. He presents in the emergency department with chest pain, and he is found to have a non-ST elevation MI. He goes to the cath lab and he is found to have a lesion in his left circumflex. The patient receives a newer generation drug-eluting stent. What are we going to do with his anticoagulation? We know he’s going to get some antiplatelet therapy, but what are our thoughts on this?

Dr. Parra. This is something that we run into all too often. I think the estimates are about 20% to 30% of patients who have indications for anticoagulation also end up having ischemic heart disease that requires PCI. The second thing is that we know combining an anticoagulant with antiplatelet therapy is associated with a 4% to 16% risk of fatal and nonfatal bleeding, and we have found out in patients with ischemic heart disease that when they bleed, they also have a higher mortality rate.

We’re trying to find the optimal balance between ischemic and thrombotic risk and bleeding risk. This is where some of the risk assessment tools that we have come into play. First, we need to establish the thrombotic risk by considering the CHA₂DS₂-VASc score, and the factors associated with increasing bleeding risk and stent thrombosis. You have time to work this out because, initially, all patients that are at sufficiently high thrombotic risk will receive dual antiplatelet therapy and anticoagulation therapy for a given period. This gives providers time to use some of those resources and figure out a long-term plan for the patient.

Dr. Allen. The fear and loathing that this brings up comes back to some historic things that should be considered. What we did for drug-eluting stents or bare-metal stents comes from older data where different stent technology was used. The stents used today are safer with a lower risk of in-stent thrombosis. Historically, we knew what to do for ACS and PCI and we knew what to do for AF, but we didn’t know what to do when the 2 crossed paths. We would put patients on warfarin and say, “Well, for now, target the INR between 2 and 2.5 and good luck with that.” That was all we had. The good news is now we have some evidence to move away from the use of dual antiplatelet plus anticoagulant therapies.

There were 2 DOAC studies recently published: The PIONEER-AF trial used rivaroxaban and more recently the RE-DUAL PCI trial used dabigatran. Each of the studies had some issues, but they were both studied in AF populations and aimed to address this issue of triple therapy. The PIONEER-AF trial looked at a number of different scenarios on different doses of rivaroxaban with either single or dual antiplatelet therapy compared to triple therapy with warfarin. The RE-DUAL PCI trial with dabigatran was less complex. Both studies were powered to look at safety, and they did show that with single antiplatelet plus oral anticoagulation regimens, the incidence of major bleeding complications was reduced.

However, that brings up some issues about how the studies were conducted. Both studied AF populations and in some cases did not study doses approved for AF. Yet at the same time, the studies were not powered to look at stroke outcomes, which raises the question: Are we running the risk of giving up stroke efficacy for reduced bleeding? I don’t think that we’ve fully answered that, certainly not with the PIONEER AF trial.

Dr. Parra. I agree. When we look at those trials, 2 things come to mind. First, the doses of dabigatran used in the RE-DUAL PCI trial were doses that have been shown to be beneficial in the nonvalvular AF population. Second, a take-home point from those trials is the P2Y12 inhibitor that was utilized—close to 90% or more used clopidogrel in the PIONEER-AF trial. Clopidogrel remains the P2Y12 inhibitor of choice. One of the other findings is that the aspirin dosing should be low, < 100 mg daily, and that we need to consider routine use of proton pump inhibitors to protect against the bleeding that can be found with the antiplatelet agents.

Also of interest, the European Society of Cardiology (ESC) recently released a focused update with some excellent recommendations on dual antiplatelet therapy in coronary artery disease in which they incorporated the results from the PIONEER-AF-PCI trial. The RE-DUAL PCI trial had not been published when these came out. If you’re concerned about ischemic risk prevailing, ESC recommendations based upon risk stratification are triple therapy with aspirin, clopidogrel, and an oral anticoagulant for longer than 1 month and up to 6 months and then dual therapy with 1 antiplatelet agent and an oral anticoagulant to complete the 12 months; afterward just oral anticoagulation alone. If the concerns about bleeding prevail, then we have 2 different pathways: one limiting triple therapy to 1 month and then dual therapy with 1 antiplatelet agent and an oral anticoagulant to complete the 12 months. But the ESC also has a second recommendation for patients at high risk of bleeding, which is dual therapy with clopidogrel and an oral anticoagulant at the offset for up to 12 months. I found these guidelines to be particularly helpful in terms of how to put this into practice.

Dr. Allen. There’s still so much concern about in-stent thrombosis. Although a smaller trial, we knew from the WOEST trial that single antiplatelet therapy with warfarin was reasonable. We know from the PIONEER-AF and RE-DUAL PCI trials that we didn’t get significantly more in-stent thrombosis by giving up the second antiplatelet. Whether or not we answered the stroke question is another issue, but the cardiology societies are still hanging on to dual antiplatelet therapy. I question if that’s based on the older data and the older stent technologies.

Dr. Minichiello. This highlights again that often we have to consider these patients’ case-by-case analysis, and that these decisions require multidisciplinary input. It involves coming together and figuring out in this particular patient, which of those 3 options would be best. We have a lot more options than we did just a short year or year and a half ago with at least some data providing comfort that DOACs at effective doses for stroke prevention in nonvalvular AF look like they can be combined with single antiplatelet therapy for post-PCI patients.

Dr. Barnes. Speaking as a cardiologist, this is a question I encounter all the time. I think everything said here is really well taken. I’ll just summarize to say for patients who have acute coronary syndromes and AF. First, I’m okay with using warfarin and now I’m okay using the DOACs, but the anticoagulant needs to continue for stroke prevention. Second, the patient has to be on clopidogrel as a P2Y12 inhibitor because it has the lowest bleeding risk profile. Third, the patient doesn’t always need 1 year of dual antiplatelet therapy the way we used to think of it. With newer generation stents and ongoing anticoagulation, you can get away with shorter courses of your antiplatelets, albeit 3 or 6 months. Providers should have a conversation with patients and think hard about how to balance clotting vs that bleeding profile.

Case 3

Dr. Minichiello. This case involves a 66-year-old man who has nonvalvular AF and is on warfarin. He has CKD, and his CrCl is about 30. He has hypertension, diabetes mellitus, and he is going to go for a colonoscopy. The proceduralist lets you know about the date and wants to know whether he needs to be bridged. He also has a remote history of a transient ischemic attack.

Dr. Allen. Historically, we’ve had detailed guidance on how to risk assess patients with AF, venous thromboembolism (VT), and mechanical heart valves in the periprocedural period. From that risk assessment the guidance helped us determine whether or not we should offer periprocedural bridging with heparin or low-molecularweight heparin.

The issue is that the detailed guidance was always based on expert opinion not hard science and there was no great evidence that we were preventing thrombotic events or that there was a net clinical benefit to bridging. Some retrospective cohort studies started coming out around 2012 that demonstrated an increased incidence of major bleeding events associated with bridging with no reduction in thrombotic complications. Some might argue that this is because thrombotic complications are so rare that you would have to have tens of thousands of patients for adequate power. Nonetheless, these studies were adequately powered to show a significant increase in major bleeding.

The best prospective trial data we have for this population comes from the BRIDGE trial, which randomized AF patients to receive dalteparin bridge therapy vs placebo during periprocedural interruptions in warfarin therapy. It too demonstrated a significant increase in the risk of bleeding complications associated with bridging with no significant reduction in the risk of thromboembolic events. Critics point out that some of the higher risk patients were underrepresented, and the same could be said about some of the other retrospective studies in the VT and mechanical valve populations.

We have waited for quite a while for guidances to catch up with these data. The most recent guidance published would apply to this patient. It was guidance for the AF population published by the American College of Cardiology (ACC) in early 2017. This guidance still encourages bridging in some of the moderate-to-high-risk AF patients.

To make a decision to bridge, you not only have to make an assumption that your patient is at such extraordinary thrombotic risk that you would find some reduction in thrombotic events associated with bridging, but also that the benefit is going to be so great that it would overcome this very clear increased risk of bleeding, resulting in a net clinical benefit. Only then would it make sense to bridge. Based on the available data, it is quite possible that no such patient population exists.

Dr. Parra. I agree. We found from the BRIDGE trial, with the caveat that you pointed out, that high or moderately high thrombotic risk individuals weren’t as well represented, that there is at least a 2.5-fold increase in major bleeding. We also know that higher thrombotic-risk patients tend to also have higher bleeding risk. So in high thrombotic-risk patients, while there is uncertainty about whether or not there’s going to be a thrombotic benefit from bridging, we can be confident there will be an increased risk of major bleeding perhaps even more than that seen in the BRIDGE trial.

One thing that really illustrates this is the 2017 American Heart Association/ACC-focused update on the 2014 guideline for the management of patients with valvular heart disease. The guideline has a section on bridging therapy for prosthetic valves. And that was recently downgraded from a Class I recommendation to Class IIA, recognizing that the data are limited in terms of even when to bridge prosthetic valves.

Dr. Allen. Bridging is an area where we continue to do something that we know causes harm because we hope it has some benefit. Despite what some societal guidance still says, I very rarely bridge patients. If I do, it’s because the patient and/or caregivers have heard the facts and have opted to do it.

Dr. Minichiello. Practically speaking, the data—the retrospective data, the observational data, the BRIDGE trial, etc—definitely make us step back and think about bridging and realize that it’s a HIGH RISK of intervention. We really need to be informing patients about that risk. We know that bridging increases the risk of bleeding. We do not have data showing a reduction in the risk of thromboembolic disease with bridge therapy. That’s all based on what we think would happen, what we hope would be the result of bridge therapy, but in truth we do not know if this is the case. The risks of bridge therapy must be weighed heavily each time we consider using it.

In my practice I reserve bridge therapy, which we know is associated with increased harm for patients in whom we think there is the very highest risk of thromboembolism, ie, those with very recent arterial or venous thrombosis, and by recently, I mean within the past 1 to 3 months; patients who have very severe thrombophilia like antitphospholipid antibody syndrome, some cancer patients, and those with mechanical valves in the mitral position or those with high-risk mechanical aortic valves.

I don’t bridge most AF patients. In fact, I can’t remember the last time I bridged an AF patient. I do know that this is somewhat discordant with the ACC recommendations, but absent the data to support bridge therapy, I’m really concerned that the risk outweighs the benefit. This is particularly true in our VA population where the bleeding risk is high because of CKD or a history of bleeding or thrombocytopenia or concomitant aspirin or something else.

Dr. Barnes. We know from some studies that have been published that the biggest driver of a clinician deciding whether or not a patient should bridge is actually whether or not they’ve had a stroke. The truth is that the BRIDGE trial enrolled a sizeable population; it was about 15% of patients with a prior TIA or stroke. So it gave us some insight. Despite that, our event rates for thromboembolism, arterial thromboembolism, including stroke, were quite low.

I tend to look far more at the collection of risk factors and not just at a history of stroke. Now as you mentioned, Dr. Minichiello, a stroke within the past 1 to 3 months, I ask, “does this procedure even need to happen?” But outside of that, it’s not a history of stroke that’s going to make the decision for me: It’s all the risk factors together.

There’s an ongoing study, the PERIOP 2 study, that is enrolling patients at higher risk for stroke and patients with mechanical valves. This study may give us more insight into exactly what kind of risks these patients are at and whether they get benefit from bridging. But in the meantime, I’m really reserving bridging for my highest risk patients, those with multiple risk factors, CHADS₂ scores of 5 and 6 or CHA₂DS₂-VASc of 7, 8, 9, and those with a recent VT or mechanical mitral valves.

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Case 1

Tracy Minichiello, MD. The first case we’ll discuss is a 75-year-old man with mild chronic kidney disease (CKD). His calculated creatinine clearance (CrCl) is about 52 mL/min, and he has a remote history of a gastrointestinal (GI) bleeding 3 years previously from a peptic ulcer. He presents with new onset nonvalvular atrial fibrillation (AF), and he’s already on aspirin for his stable coronary artery disease (CAD).

How do we think about anticoagulant selection in this patient? We have a number of new oral anticoagulants and we have warfarin. How do we decide between warfarin vs one of the direct-acting oral anticoagulants (DOACs)? If we choose a DOAC, which one would we select?

David Parra, PharmD. The first step for anticoagulation is to assess a patient’s thromboembolic risk utilizing the CHA₂DS₂-VASc and bleeding risk using a HAS-BLED score, or something similar. The next question is which oral anticoagulant to use. We have widespread experience with warfarin and can measure the anticoagulant effect easily. Warfarin has a long duration of action, so perhaps it’s more forgiving if you miss a dose. It also has an antidote. Lastly, organ dysfunction doesn’t preclude use of warfarin as you can still monitor the anticoagulant effect. So there still may be patients that may benefit significantly from warfarin vs a DOAC.

On the flip side, DOACs are easier to use and perform quite acceptably in comparison with warfarin in nonvalvular AF. There are some scenarios where a specific DOAC may be preferred over another, such as recent GI bleeding.

Dr. Minichiello. Do you consider renal function, bleeding history, or concomitant antiplatelet therapy?

Geoffrey Barnes, MD, MSc. A couple of factors are relevant. I think we should consider renal function for this gentleman. However, I look at some of the other features as Dr. Parra suggested. What’s the likelihood that this patient is going to take the medicine as prescribed? Is a twice-a-day regimen going to be something that’s particularly challenging? I also look at the real-world vs randomized trial experience.

This patient has a remote GI bleeding history. Some of the real-world data suggest there might be some more GI bleeding with rivaroxaban, but across the board, apixaban (in both the randomized trials and much of the real-world data) seem to have a favorable bleeding risk profile. For a patient who is open and reliable for taking medicine twice a day, apixaban might be a good option as long as we make sure that the dose is appropriate.

Arthur L. Allen, PharmD, CACP. In pivotal trial experience, dabigatran and rivaroxaban demonstrated an increased incidence of GI bleeding compared with warfarin. In some of the real-world studies, rivaroxaban mirrors warfarin with regard to bleeding, whereas dabigatran and apixaban have a lower incidence. In the pivotal trials, apixaban did not have a trigger of increased GI bleeding, but I would let the details of this patient’s GI bleeding history help me determine how important an issue this is at this point.

The other thing that is important to understand when considering choice of agents: As Dr. Parra mentioned, we do have quite a bit of experience with warfarin. But comparing the quality of evidence, the DOACs have been investigated in a far more rigorous fashion and in far more patients than warfarin ever was in its more than 60 years on the market. For example, the RE-LY trial alone enrolled more than 18,000 patients. Each of the DOACs have been studied in tens of thousands of patients for their approved indications. Further, we shouldn’t forget that the risk of intracranial hemorrhage is reduced by roughly 50% by choosing a DOAC over warfarin, which should be a consideration in this elderly gentleman.

Dr. Minichiello. In the veteran population, there is a sense of comfort with warfarin, and some concerns have been raised over a lack of reversibility for the newer agents. We have patients who have trepidation about starting one of the new anticoagulants. However, there is a marked reduction in the risk of the most devastating bleeding complication, namely intracranial hemorrhage, making the use of these agents most compelling. And when they did have bleeding complications, at least in the trials, their outcomes were no worse than they were with warfarin, where there is a reversal agent. In most cases the outcomes were actually better.

Dr. Barnes. You often have to remind patients that there was no reversal agent in these huge trials where the DOACs showed similar or safer bleeding risk profiles, especially for the most serious bleeding, such as intracranial hemorrhage. I find patients often are reassured by knowing that.

Dr. Allen. I agree that there is concern about the lack of reversibility, but I think it has been completely overplayed. In the pivotal trials, patients who bled on DOAC therapy actually had better outcomes than those that bled on warfarin. This includes intracranial hemorrhage. There was a paper published in Stroke in 2012 that evaluated the subgroup of patients in the RE-LY trial that suffered intracranial hemorrhage. Patients on dabigatran actually fared better despite a lack of a specific reversal agent. When evaluating the available data about reversal of the DOACs, I’m not 100% convinced that we’re significantly impacting outcomes by reversing these agents. We’re certainly running up the bill, but are we treating the patient or treating the providers? As long as the renal function remains intact, the DOACs clear quickly, perhaps more quickly than warfarin can typically be reversed with standard reversal agents.

Dr. Minichiello. Remember that this patient has a history of a GI bleed. We are going to start him on full-dose anticoagulation for stroke prevention for his nonvalvular AF. He’s also on aspirin, and he has stable coronary disease. He does not have any stents in place but he did have a remote non-ST elevation myocardial infarction (MI) a number of years ago. Do we feel that the risk of dual therapy—anticoagulation combined with antiplatelet therapy—outweighs the risks? And how do we approach that risk?

Dr. Barnes. This is an important point to discuss. There has been a lot of discussion in the literature recently. When I start this type of patient on an oral anticoagulant, I try to discontinue the antiplatelet agent because I know how much bleeding risk that brings. The European guidelines (for example, Eur Heart J. 2014;35[45]:3155-3179) have been forward thinking with this for the last couple of years and have highlighted that if there’s an indication for anticoagulation for patients with stable coronary disease, meaning no MI and no stent within the past year, then we should stop the antiplatelet agents after a year in order to reduce the risk of MI. This is based on a lot of older literature where warfarin was compared with aspirin and shown to be protective in coronary patients, but at the risk of bleeding.

It’s important because there have been recent studies that have raised questions, including a recent Swedish article in (Circulation. 2017;136:1183-1192) that suggested discontinuing aspirin led to increased mortality. But it’s important to look at the details. While that was true for most patients, it was not true for the group of patients who were on an oral anticoagulant. Many colleagues ask me questions about that particular paper and its media coverage. I tell them that for our patients on chronic oral anticoagulants, the paper supports the notion that there is not increased mortality when aspirin use is stopped. We know that aspirin plus an anticoagulant leads to increased bleeding, so I try to stop it for patients who have stable CAD but are on long-term anticoagulation.

Dr. Allen. This isn’t a new thought. Back in early 2012, the 9th edition of the American College of Chest Physicians (CHEST) Antithrombotic Guidelines probably gave us the best guidance that we had ever seen to help us address this issue. Since that time the cardiology guidelines have caught up to recommend that we do not need additional antiplatelet therapy for stable CAD, and, in fact, it should be limited even in the setting of acute coronary syndromes and percutaneous coronary intervention (PCI).

Dr. Minichiello. That’s a good point because people are not necessarily clear about when there would be an indication to continue dual therapy and when it is safe to go to monotherapy. Scenarios where benefit of dual therapy may outweigh risk suggested in the CHEST 2012 guidelines include acute coronary syndrome or a recent stent, high-risk mechanical valves, and history of coronary artery bypass surgery.

I think the important thing is to consider each case individually and not to reflexively continue aspirin therapy. Often what we see is once on aspirin—always on aspirin. Being thoughtful about it, we should acknowledge that it likely results in a 2-fold increased risk of bleeding and make sure that we believe that the benefit outweighs the risk.

Dr. Allen. I agree. We probably have better evidence in the CAD population, but what do we do for patients with significant peripheral vascular disease, or those patients with symptomatic carotid stenosis or history of strokes? Some of the European guidance suggests taking a similar approach to CAD, but these are the patients for whom stopping aspirin makes me more nervous.

Dr. Parra. This is a perfect example of where less is more. All too often the reflex is to continue aspirin treatment indefinitely because the patient has a history of acute coronary syndrome or even peripheral arterial disease, when the best thing to do would be to drop the aspirin. It involves an individualized risk assessment and underscores the need to periodically do a risk/benefit assessment in all patients on anticoagulants, whether it’s warfarin or a DOAC.

I’d like to take a moment and step back to the case in the context of the GI bleeding. When we look at patients with a history of GI bleeding, it is important to understand the circumstances that surround it. This individual had a GI bleed 3 years previously and peptic ulcer disease. In these situations I ask whether the patient was taking over-the-counter nonsteroidal anti-inflamitory drugs at the time, had excessive alcohol use, or was successfully treated for Helicobacter pylori. All of these may influence whether or not I think the GI bleed is significant to influence the DOAC choice.

The other thing I consider is that the overall risk of major GI bleeding in those pivotal DOAC trials was quite small, < 1.5% per year with dabigatran 150 mg twice daily and < 1% per year with apixaban. The numbers needed to harm were quite high, over 200 patients per year with dabigatran 150 mg twice daily vs warfarin and over 350 patients per year with edoxaban 60 mg daily vs warfarin. There are no head-to-head comparisons with DOACs, but this small increased risk vs warfarin may still be an important consideration in some patients. In addition, it is important to remember that intracranial hemorrhage and fatal bleeding was less in all the pivotal NVAF trials with the DOACs when compared with warfarin. So that is something we need to reinforce with patients when we discuss treatment regardless of the DOAC selected.

Case 2

Dr. Minichiello. The next case is a 63-year-old man with hypertension, diabetes mellitus, nonvalvular AF, and he is taking dabigatran for stroke prevention. He presents in the emergency department with chest pain, and he is found to have a non-ST elevation MI. He goes to the cath lab and he is found to have a lesion in his left circumflex. The patient receives a newer generation drug-eluting stent. What are we going to do with his anticoagulation? We know he’s going to get some antiplatelet therapy, but what are our thoughts on this?

Dr. Parra. This is something that we run into all too often. I think the estimates are about 20% to 30% of patients who have indications for anticoagulation also end up having ischemic heart disease that requires PCI. The second thing is that we know combining an anticoagulant with antiplatelet therapy is associated with a 4% to 16% risk of fatal and nonfatal bleeding, and we have found out in patients with ischemic heart disease that when they bleed, they also have a higher mortality rate.

We’re trying to find the optimal balance between ischemic and thrombotic risk and bleeding risk. This is where some of the risk assessment tools that we have come into play. First, we need to establish the thrombotic risk by considering the CHA₂DS₂-VASc score, and the factors associated with increasing bleeding risk and stent thrombosis. You have time to work this out because, initially, all patients that are at sufficiently high thrombotic risk will receive dual antiplatelet therapy and anticoagulation therapy for a given period. This gives providers time to use some of those resources and figure out a long-term plan for the patient.

Dr. Allen. The fear and loathing that this brings up comes back to some historic things that should be considered. What we did for drug-eluting stents or bare-metal stents comes from older data where different stent technology was used. The stents used today are safer with a lower risk of in-stent thrombosis. Historically, we knew what to do for ACS and PCI and we knew what to do for AF, but we didn’t know what to do when the 2 crossed paths. We would put patients on warfarin and say, “Well, for now, target the INR between 2 and 2.5 and good luck with that.” That was all we had. The good news is now we have some evidence to move away from the use of dual antiplatelet plus anticoagulant therapies.

There were 2 DOAC studies recently published: The PIONEER-AF trial used rivaroxaban and more recently the RE-DUAL PCI trial used dabigatran. Each of the studies had some issues, but they were both studied in AF populations and aimed to address this issue of triple therapy. The PIONEER-AF trial looked at a number of different scenarios on different doses of rivaroxaban with either single or dual antiplatelet therapy compared to triple therapy with warfarin. The RE-DUAL PCI trial with dabigatran was less complex. Both studies were powered to look at safety, and they did show that with single antiplatelet plus oral anticoagulation regimens, the incidence of major bleeding complications was reduced.

However, that brings up some issues about how the studies were conducted. Both studied AF populations and in some cases did not study doses approved for AF. Yet at the same time, the studies were not powered to look at stroke outcomes, which raises the question: Are we running the risk of giving up stroke efficacy for reduced bleeding? I don’t think that we’ve fully answered that, certainly not with the PIONEER AF trial.

Dr. Parra. I agree. When we look at those trials, 2 things come to mind. First, the doses of dabigatran used in the RE-DUAL PCI trial were doses that have been shown to be beneficial in the nonvalvular AF population. Second, a take-home point from those trials is the P2Y12 inhibitor that was utilized—close to 90% or more used clopidogrel in the PIONEER-AF trial. Clopidogrel remains the P2Y12 inhibitor of choice. One of the other findings is that the aspirin dosing should be low, < 100 mg daily, and that we need to consider routine use of proton pump inhibitors to protect against the bleeding that can be found with the antiplatelet agents.

Also of interest, the European Society of Cardiology (ESC) recently released a focused update with some excellent recommendations on dual antiplatelet therapy in coronary artery disease in which they incorporated the results from the PIONEER-AF-PCI trial. The RE-DUAL PCI trial had not been published when these came out. If you’re concerned about ischemic risk prevailing, ESC recommendations based upon risk stratification are triple therapy with aspirin, clopidogrel, and an oral anticoagulant for longer than 1 month and up to 6 months and then dual therapy with 1 antiplatelet agent and an oral anticoagulant to complete the 12 months; afterward just oral anticoagulation alone. If the concerns about bleeding prevail, then we have 2 different pathways: one limiting triple therapy to 1 month and then dual therapy with 1 antiplatelet agent and an oral anticoagulant to complete the 12 months. But the ESC also has a second recommendation for patients at high risk of bleeding, which is dual therapy with clopidogrel and an oral anticoagulant at the offset for up to 12 months. I found these guidelines to be particularly helpful in terms of how to put this into practice.

Dr. Allen. There’s still so much concern about in-stent thrombosis. Although a smaller trial, we knew from the WOEST trial that single antiplatelet therapy with warfarin was reasonable. We know from the PIONEER-AF and RE-DUAL PCI trials that we didn’t get significantly more in-stent thrombosis by giving up the second antiplatelet. Whether or not we answered the stroke question is another issue, but the cardiology societies are still hanging on to dual antiplatelet therapy. I question if that’s based on the older data and the older stent technologies.

Dr. Minichiello. This highlights again that often we have to consider these patients’ case-by-case analysis, and that these decisions require multidisciplinary input. It involves coming together and figuring out in this particular patient, which of those 3 options would be best. We have a lot more options than we did just a short year or year and a half ago with at least some data providing comfort that DOACs at effective doses for stroke prevention in nonvalvular AF look like they can be combined with single antiplatelet therapy for post-PCI patients.

Dr. Barnes. Speaking as a cardiologist, this is a question I encounter all the time. I think everything said here is really well taken. I’ll just summarize to say for patients who have acute coronary syndromes and AF. First, I’m okay with using warfarin and now I’m okay using the DOACs, but the anticoagulant needs to continue for stroke prevention. Second, the patient has to be on clopidogrel as a P2Y12 inhibitor because it has the lowest bleeding risk profile. Third, the patient doesn’t always need 1 year of dual antiplatelet therapy the way we used to think of it. With newer generation stents and ongoing anticoagulation, you can get away with shorter courses of your antiplatelets, albeit 3 or 6 months. Providers should have a conversation with patients and think hard about how to balance clotting vs that bleeding profile.

Case 3

Dr. Minichiello. This case involves a 66-year-old man who has nonvalvular AF and is on warfarin. He has CKD, and his CrCl is about 30. He has hypertension, diabetes mellitus, and he is going to go for a colonoscopy. The proceduralist lets you know about the date and wants to know whether he needs to be bridged. He also has a remote history of a transient ischemic attack.

Dr. Allen. Historically, we’ve had detailed guidance on how to risk assess patients with AF, venous thromboembolism (VT), and mechanical heart valves in the periprocedural period. From that risk assessment the guidance helped us determine whether or not we should offer periprocedural bridging with heparin or low-molecularweight heparin.

The issue is that the detailed guidance was always based on expert opinion not hard science and there was no great evidence that we were preventing thrombotic events or that there was a net clinical benefit to bridging. Some retrospective cohort studies started coming out around 2012 that demonstrated an increased incidence of major bleeding events associated with bridging with no reduction in thrombotic complications. Some might argue that this is because thrombotic complications are so rare that you would have to have tens of thousands of patients for adequate power. Nonetheless, these studies were adequately powered to show a significant increase in major bleeding.

The best prospective trial data we have for this population comes from the BRIDGE trial, which randomized AF patients to receive dalteparin bridge therapy vs placebo during periprocedural interruptions in warfarin therapy. It too demonstrated a significant increase in the risk of bleeding complications associated with bridging with no significant reduction in the risk of thromboembolic events. Critics point out that some of the higher risk patients were underrepresented, and the same could be said about some of the other retrospective studies in the VT and mechanical valve populations.

We have waited for quite a while for guidances to catch up with these data. The most recent guidance published would apply to this patient. It was guidance for the AF population published by the American College of Cardiology (ACC) in early 2017. This guidance still encourages bridging in some of the moderate-to-high-risk AF patients.

To make a decision to bridge, you not only have to make an assumption that your patient is at such extraordinary thrombotic risk that you would find some reduction in thrombotic events associated with bridging, but also that the benefit is going to be so great that it would overcome this very clear increased risk of bleeding, resulting in a net clinical benefit. Only then would it make sense to bridge. Based on the available data, it is quite possible that no such patient population exists.

Dr. Parra. I agree. We found from the BRIDGE trial, with the caveat that you pointed out, that high or moderately high thrombotic risk individuals weren’t as well represented, that there is at least a 2.5-fold increase in major bleeding. We also know that higher thrombotic-risk patients tend to also have higher bleeding risk. So in high thrombotic-risk patients, while there is uncertainty about whether or not there’s going to be a thrombotic benefit from bridging, we can be confident there will be an increased risk of major bleeding perhaps even more than that seen in the BRIDGE trial.

One thing that really illustrates this is the 2017 American Heart Association/ACC-focused update on the 2014 guideline for the management of patients with valvular heart disease. The guideline has a section on bridging therapy for prosthetic valves. And that was recently downgraded from a Class I recommendation to Class IIA, recognizing that the data are limited in terms of even when to bridge prosthetic valves.

Dr. Allen. Bridging is an area where we continue to do something that we know causes harm because we hope it has some benefit. Despite what some societal guidance still says, I very rarely bridge patients. If I do, it’s because the patient and/or caregivers have heard the facts and have opted to do it.

Dr. Minichiello. Practically speaking, the data—the retrospective data, the observational data, the BRIDGE trial, etc—definitely make us step back and think about bridging and realize that it’s a HIGH RISK of intervention. We really need to be informing patients about that risk. We know that bridging increases the risk of bleeding. We do not have data showing a reduction in the risk of thromboembolic disease with bridge therapy. That’s all based on what we think would happen, what we hope would be the result of bridge therapy, but in truth we do not know if this is the case. The risks of bridge therapy must be weighed heavily each time we consider using it.

In my practice I reserve bridge therapy, which we know is associated with increased harm for patients in whom we think there is the very highest risk of thromboembolism, ie, those with very recent arterial or venous thrombosis, and by recently, I mean within the past 1 to 3 months; patients who have very severe thrombophilia like antitphospholipid antibody syndrome, some cancer patients, and those with mechanical valves in the mitral position or those with high-risk mechanical aortic valves.

I don’t bridge most AF patients. In fact, I can’t remember the last time I bridged an AF patient. I do know that this is somewhat discordant with the ACC recommendations, but absent the data to support bridge therapy, I’m really concerned that the risk outweighs the benefit. This is particularly true in our VA population where the bleeding risk is high because of CKD or a history of bleeding or thrombocytopenia or concomitant aspirin or something else.

Dr. Barnes. We know from some studies that have been published that the biggest driver of a clinician deciding whether or not a patient should bridge is actually whether or not they’ve had a stroke. The truth is that the BRIDGE trial enrolled a sizeable population; it was about 15% of patients with a prior TIA or stroke. So it gave us some insight. Despite that, our event rates for thromboembolism, arterial thromboembolism, including stroke, were quite low.

I tend to look far more at the collection of risk factors and not just at a history of stroke. Now as you mentioned, Dr. Minichiello, a stroke within the past 1 to 3 months, I ask, “does this procedure even need to happen?” But outside of that, it’s not a history of stroke that’s going to make the decision for me: It’s all the risk factors together.

There’s an ongoing study, the PERIOP 2 study, that is enrolling patients at higher risk for stroke and patients with mechanical valves. This study may give us more insight into exactly what kind of risks these patients are at and whether they get benefit from bridging. But in the meantime, I’m really reserving bridging for my highest risk patients, those with multiple risk factors, CHADS₂ scores of 5 and 6 or CHA₂DS₂-VASc of 7, 8, 9, and those with a recent VT or mechanical mitral valves.

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Case 1

Tracy Minichiello, MD. The first case we’ll discuss is a 75-year-old man with mild chronic kidney disease (CKD). His calculated creatinine clearance (CrCl) is about 52 mL/min, and he has a remote history of a gastrointestinal (GI) bleeding 3 years previously from a peptic ulcer. He presents with new onset nonvalvular atrial fibrillation (AF), and he’s already on aspirin for his stable coronary artery disease (CAD).

How do we think about anticoagulant selection in this patient? We have a number of new oral anticoagulants and we have warfarin. How do we decide between warfarin vs one of the direct-acting oral anticoagulants (DOACs)? If we choose a DOAC, which one would we select?

David Parra, PharmD. The first step for anticoagulation is to assess a patient’s thromboembolic risk utilizing the CHA₂DS₂-VASc and bleeding risk using a HAS-BLED score, or something similar. The next question is which oral anticoagulant to use. We have widespread experience with warfarin and can measure the anticoagulant effect easily. Warfarin has a long duration of action, so perhaps it’s more forgiving if you miss a dose. It also has an antidote. Lastly, organ dysfunction doesn’t preclude use of warfarin as you can still monitor the anticoagulant effect. So there still may be patients that may benefit significantly from warfarin vs a DOAC.

On the flip side, DOACs are easier to use and perform quite acceptably in comparison with warfarin in nonvalvular AF. There are some scenarios where a specific DOAC may be preferred over another, such as recent GI bleeding.

Dr. Minichiello. Do you consider renal function, bleeding history, or concomitant antiplatelet therapy?

Geoffrey Barnes, MD, MSc. A couple of factors are relevant. I think we should consider renal function for this gentleman. However, I look at some of the other features as Dr. Parra suggested. What’s the likelihood that this patient is going to take the medicine as prescribed? Is a twice-a-day regimen going to be something that’s particularly challenging? I also look at the real-world vs randomized trial experience.

This patient has a remote GI bleeding history. Some of the real-world data suggest there might be some more GI bleeding with rivaroxaban, but across the board, apixaban (in both the randomized trials and much of the real-world data) seem to have a favorable bleeding risk profile. For a patient who is open and reliable for taking medicine twice a day, apixaban might be a good option as long as we make sure that the dose is appropriate.

Arthur L. Allen, PharmD, CACP. In pivotal trial experience, dabigatran and rivaroxaban demonstrated an increased incidence of GI bleeding compared with warfarin. In some of the real-world studies, rivaroxaban mirrors warfarin with regard to bleeding, whereas dabigatran and apixaban have a lower incidence. In the pivotal trials, apixaban did not have a trigger of increased GI bleeding, but I would let the details of this patient’s GI bleeding history help me determine how important an issue this is at this point.

The other thing that is important to understand when considering choice of agents: As Dr. Parra mentioned, we do have quite a bit of experience with warfarin. But comparing the quality of evidence, the DOACs have been investigated in a far more rigorous fashion and in far more patients than warfarin ever was in its more than 60 years on the market. For example, the RE-LY trial alone enrolled more than 18,000 patients. Each of the DOACs have been studied in tens of thousands of patients for their approved indications. Further, we shouldn’t forget that the risk of intracranial hemorrhage is reduced by roughly 50% by choosing a DOAC over warfarin, which should be a consideration in this elderly gentleman.

Dr. Minichiello. In the veteran population, there is a sense of comfort with warfarin, and some concerns have been raised over a lack of reversibility for the newer agents. We have patients who have trepidation about starting one of the new anticoagulants. However, there is a marked reduction in the risk of the most devastating bleeding complication, namely intracranial hemorrhage, making the use of these agents most compelling. And when they did have bleeding complications, at least in the trials, their outcomes were no worse than they were with warfarin, where there is a reversal agent. In most cases the outcomes were actually better.

Dr. Barnes. You often have to remind patients that there was no reversal agent in these huge trials where the DOACs showed similar or safer bleeding risk profiles, especially for the most serious bleeding, such as intracranial hemorrhage. I find patients often are reassured by knowing that.

Dr. Allen. I agree that there is concern about the lack of reversibility, but I think it has been completely overplayed. In the pivotal trials, patients who bled on DOAC therapy actually had better outcomes than those that bled on warfarin. This includes intracranial hemorrhage. There was a paper published in Stroke in 2012 that evaluated the subgroup of patients in the RE-LY trial that suffered intracranial hemorrhage. Patients on dabigatran actually fared better despite a lack of a specific reversal agent. When evaluating the available data about reversal of the DOACs, I’m not 100% convinced that we’re significantly impacting outcomes by reversing these agents. We’re certainly running up the bill, but are we treating the patient or treating the providers? As long as the renal function remains intact, the DOACs clear quickly, perhaps more quickly than warfarin can typically be reversed with standard reversal agents.

Dr. Minichiello. Remember that this patient has a history of a GI bleed. We are going to start him on full-dose anticoagulation for stroke prevention for his nonvalvular AF. He’s also on aspirin, and he has stable coronary disease. He does not have any stents in place but he did have a remote non-ST elevation myocardial infarction (MI) a number of years ago. Do we feel that the risk of dual therapy—anticoagulation combined with antiplatelet therapy—outweighs the risks? And how do we approach that risk?

Dr. Barnes. This is an important point to discuss. There has been a lot of discussion in the literature recently. When I start this type of patient on an oral anticoagulant, I try to discontinue the antiplatelet agent because I know how much bleeding risk that brings. The European guidelines (for example, Eur Heart J. 2014;35[45]:3155-3179) have been forward thinking with this for the last couple of years and have highlighted that if there’s an indication for anticoagulation for patients with stable coronary disease, meaning no MI and no stent within the past year, then we should stop the antiplatelet agents after a year in order to reduce the risk of MI. This is based on a lot of older literature where warfarin was compared with aspirin and shown to be protective in coronary patients, but at the risk of bleeding.

It’s important because there have been recent studies that have raised questions, including a recent Swedish article in (Circulation. 2017;136:1183-1192) that suggested discontinuing aspirin led to increased mortality. But it’s important to look at the details. While that was true for most patients, it was not true for the group of patients who were on an oral anticoagulant. Many colleagues ask me questions about that particular paper and its media coverage. I tell them that for our patients on chronic oral anticoagulants, the paper supports the notion that there is not increased mortality when aspirin use is stopped. We know that aspirin plus an anticoagulant leads to increased bleeding, so I try to stop it for patients who have stable CAD but are on long-term anticoagulation.

Dr. Allen. This isn’t a new thought. Back in early 2012, the 9th edition of the American College of Chest Physicians (CHEST) Antithrombotic Guidelines probably gave us the best guidance that we had ever seen to help us address this issue. Since that time the cardiology guidelines have caught up to recommend that we do not need additional antiplatelet therapy for stable CAD, and, in fact, it should be limited even in the setting of acute coronary syndromes and percutaneous coronary intervention (PCI).

Dr. Minichiello. That’s a good point because people are not necessarily clear about when there would be an indication to continue dual therapy and when it is safe to go to monotherapy. Scenarios where benefit of dual therapy may outweigh risk suggested in the CHEST 2012 guidelines include acute coronary syndrome or a recent stent, high-risk mechanical valves, and history of coronary artery bypass surgery.

I think the important thing is to consider each case individually and not to reflexively continue aspirin therapy. Often what we see is once on aspirin—always on aspirin. Being thoughtful about it, we should acknowledge that it likely results in a 2-fold increased risk of bleeding and make sure that we believe that the benefit outweighs the risk.

Dr. Allen. I agree. We probably have better evidence in the CAD population, but what do we do for patients with significant peripheral vascular disease, or those patients with symptomatic carotid stenosis or history of strokes? Some of the European guidance suggests taking a similar approach to CAD, but these are the patients for whom stopping aspirin makes me more nervous.

Dr. Parra. This is a perfect example of where less is more. All too often the reflex is to continue aspirin treatment indefinitely because the patient has a history of acute coronary syndrome or even peripheral arterial disease, when the best thing to do would be to drop the aspirin. It involves an individualized risk assessment and underscores the need to periodically do a risk/benefit assessment in all patients on anticoagulants, whether it’s warfarin or a DOAC.

I’d like to take a moment and step back to the case in the context of the GI bleeding. When we look at patients with a history of GI bleeding, it is important to understand the circumstances that surround it. This individual had a GI bleed 3 years previously and peptic ulcer disease. In these situations I ask whether the patient was taking over-the-counter nonsteroidal anti-inflamitory drugs at the time, had excessive alcohol use, or was successfully treated for Helicobacter pylori. All of these may influence whether or not I think the GI bleed is significant to influence the DOAC choice.

The other thing I consider is that the overall risk of major GI bleeding in those pivotal DOAC trials was quite small, < 1.5% per year with dabigatran 150 mg twice daily and < 1% per year with apixaban. The numbers needed to harm were quite high, over 200 patients per year with dabigatran 150 mg twice daily vs warfarin and over 350 patients per year with edoxaban 60 mg daily vs warfarin. There are no head-to-head comparisons with DOACs, but this small increased risk vs warfarin may still be an important consideration in some patients. In addition, it is important to remember that intracranial hemorrhage and fatal bleeding was less in all the pivotal NVAF trials with the DOACs when compared with warfarin. So that is something we need to reinforce with patients when we discuss treatment regardless of the DOAC selected.

Case 2

Dr. Minichiello. The next case is a 63-year-old man with hypertension, diabetes mellitus, nonvalvular AF, and he is taking dabigatran for stroke prevention. He presents in the emergency department with chest pain, and he is found to have a non-ST elevation MI. He goes to the cath lab and he is found to have a lesion in his left circumflex. The patient receives a newer generation drug-eluting stent. What are we going to do with his anticoagulation? We know he’s going to get some antiplatelet therapy, but what are our thoughts on this?

Dr. Parra. This is something that we run into all too often. I think the estimates are about 20% to 30% of patients who have indications for anticoagulation also end up having ischemic heart disease that requires PCI. The second thing is that we know combining an anticoagulant with antiplatelet therapy is associated with a 4% to 16% risk of fatal and nonfatal bleeding, and we have found out in patients with ischemic heart disease that when they bleed, they also have a higher mortality rate.

We’re trying to find the optimal balance between ischemic and thrombotic risk and bleeding risk. This is where some of the risk assessment tools that we have come into play. First, we need to establish the thrombotic risk by considering the CHA₂DS₂-VASc score, and the factors associated with increasing bleeding risk and stent thrombosis. You have time to work this out because, initially, all patients that are at sufficiently high thrombotic risk will receive dual antiplatelet therapy and anticoagulation therapy for a given period. This gives providers time to use some of those resources and figure out a long-term plan for the patient.

Dr. Allen. The fear and loathing that this brings up comes back to some historic things that should be considered. What we did for drug-eluting stents or bare-metal stents comes from older data where different stent technology was used. The stents used today are safer with a lower risk of in-stent thrombosis. Historically, we knew what to do for ACS and PCI and we knew what to do for AF, but we didn’t know what to do when the 2 crossed paths. We would put patients on warfarin and say, “Well, for now, target the INR between 2 and 2.5 and good luck with that.” That was all we had. The good news is now we have some evidence to move away from the use of dual antiplatelet plus anticoagulant therapies.

There were 2 DOAC studies recently published: The PIONEER-AF trial used rivaroxaban and more recently the RE-DUAL PCI trial used dabigatran. Each of the studies had some issues, but they were both studied in AF populations and aimed to address this issue of triple therapy. The PIONEER-AF trial looked at a number of different scenarios on different doses of rivaroxaban with either single or dual antiplatelet therapy compared to triple therapy with warfarin. The RE-DUAL PCI trial with dabigatran was less complex. Both studies were powered to look at safety, and they did show that with single antiplatelet plus oral anticoagulation regimens, the incidence of major bleeding complications was reduced.

However, that brings up some issues about how the studies were conducted. Both studied AF populations and in some cases did not study doses approved for AF. Yet at the same time, the studies were not powered to look at stroke outcomes, which raises the question: Are we running the risk of giving up stroke efficacy for reduced bleeding? I don’t think that we’ve fully answered that, certainly not with the PIONEER AF trial.

Dr. Parra. I agree. When we look at those trials, 2 things come to mind. First, the doses of dabigatran used in the RE-DUAL PCI trial were doses that have been shown to be beneficial in the nonvalvular AF population. Second, a take-home point from those trials is the P2Y12 inhibitor that was utilized—close to 90% or more used clopidogrel in the PIONEER-AF trial. Clopidogrel remains the P2Y12 inhibitor of choice. One of the other findings is that the aspirin dosing should be low, < 100 mg daily, and that we need to consider routine use of proton pump inhibitors to protect against the bleeding that can be found with the antiplatelet agents.

Also of interest, the European Society of Cardiology (ESC) recently released a focused update with some excellent recommendations on dual antiplatelet therapy in coronary artery disease in which they incorporated the results from the PIONEER-AF-PCI trial. The RE-DUAL PCI trial had not been published when these came out. If you’re concerned about ischemic risk prevailing, ESC recommendations based upon risk stratification are triple therapy with aspirin, clopidogrel, and an oral anticoagulant for longer than 1 month and up to 6 months and then dual therapy with 1 antiplatelet agent and an oral anticoagulant to complete the 12 months; afterward just oral anticoagulation alone. If the concerns about bleeding prevail, then we have 2 different pathways: one limiting triple therapy to 1 month and then dual therapy with 1 antiplatelet agent and an oral anticoagulant to complete the 12 months. But the ESC also has a second recommendation for patients at high risk of bleeding, which is dual therapy with clopidogrel and an oral anticoagulant at the offset for up to 12 months. I found these guidelines to be particularly helpful in terms of how to put this into practice.

Dr. Allen. There’s still so much concern about in-stent thrombosis. Although a smaller trial, we knew from the WOEST trial that single antiplatelet therapy with warfarin was reasonable. We know from the PIONEER-AF and RE-DUAL PCI trials that we didn’t get significantly more in-stent thrombosis by giving up the second antiplatelet. Whether or not we answered the stroke question is another issue, but the cardiology societies are still hanging on to dual antiplatelet therapy. I question if that’s based on the older data and the older stent technologies.

Dr. Minichiello. This highlights again that often we have to consider these patients’ case-by-case analysis, and that these decisions require multidisciplinary input. It involves coming together and figuring out in this particular patient, which of those 3 options would be best. We have a lot more options than we did just a short year or year and a half ago with at least some data providing comfort that DOACs at effective doses for stroke prevention in nonvalvular AF look like they can be combined with single antiplatelet therapy for post-PCI patients.

Dr. Barnes. Speaking as a cardiologist, this is a question I encounter all the time. I think everything said here is really well taken. I’ll just summarize to say for patients who have acute coronary syndromes and AF. First, I’m okay with using warfarin and now I’m okay using the DOACs, but the anticoagulant needs to continue for stroke prevention. Second, the patient has to be on clopidogrel as a P2Y12 inhibitor because it has the lowest bleeding risk profile. Third, the patient doesn’t always need 1 year of dual antiplatelet therapy the way we used to think of it. With newer generation stents and ongoing anticoagulation, you can get away with shorter courses of your antiplatelets, albeit 3 or 6 months. Providers should have a conversation with patients and think hard about how to balance clotting vs that bleeding profile.

Case 3

Dr. Minichiello. This case involves a 66-year-old man who has nonvalvular AF and is on warfarin. He has CKD, and his CrCl is about 30. He has hypertension, diabetes mellitus, and he is going to go for a colonoscopy. The proceduralist lets you know about the date and wants to know whether he needs to be bridged. He also has a remote history of a transient ischemic attack.

Dr. Allen. Historically, we’ve had detailed guidance on how to risk assess patients with AF, venous thromboembolism (VT), and mechanical heart valves in the periprocedural period. From that risk assessment the guidance helped us determine whether or not we should offer periprocedural bridging with heparin or low-molecularweight heparin.

The issue is that the detailed guidance was always based on expert opinion not hard science and there was no great evidence that we were preventing thrombotic events or that there was a net clinical benefit to bridging. Some retrospective cohort studies started coming out around 2012 that demonstrated an increased incidence of major bleeding events associated with bridging with no reduction in thrombotic complications. Some might argue that this is because thrombotic complications are so rare that you would have to have tens of thousands of patients for adequate power. Nonetheless, these studies were adequately powered to show a significant increase in major bleeding.

The best prospective trial data we have for this population comes from the BRIDGE trial, which randomized AF patients to receive dalteparin bridge therapy vs placebo during periprocedural interruptions in warfarin therapy. It too demonstrated a significant increase in the risk of bleeding complications associated with bridging with no significant reduction in the risk of thromboembolic events. Critics point out that some of the higher risk patients were underrepresented, and the same could be said about some of the other retrospective studies in the VT and mechanical valve populations.

We have waited for quite a while for guidances to catch up with these data. The most recent guidance published would apply to this patient. It was guidance for the AF population published by the American College of Cardiology (ACC) in early 2017. This guidance still encourages bridging in some of the moderate-to-high-risk AF patients.

To make a decision to bridge, you not only have to make an assumption that your patient is at such extraordinary thrombotic risk that you would find some reduction in thrombotic events associated with bridging, but also that the benefit is going to be so great that it would overcome this very clear increased risk of bleeding, resulting in a net clinical benefit. Only then would it make sense to bridge. Based on the available data, it is quite possible that no such patient population exists.

Dr. Parra. I agree. We found from the BRIDGE trial, with the caveat that you pointed out, that high or moderately high thrombotic risk individuals weren’t as well represented, that there is at least a 2.5-fold increase in major bleeding. We also know that higher thrombotic-risk patients tend to also have higher bleeding risk. So in high thrombotic-risk patients, while there is uncertainty about whether or not there’s going to be a thrombotic benefit from bridging, we can be confident there will be an increased risk of major bleeding perhaps even more than that seen in the BRIDGE trial.

One thing that really illustrates this is the 2017 American Heart Association/ACC-focused update on the 2014 guideline for the management of patients with valvular heart disease. The guideline has a section on bridging therapy for prosthetic valves. And that was recently downgraded from a Class I recommendation to Class IIA, recognizing that the data are limited in terms of even when to bridge prosthetic valves.

Dr. Allen. Bridging is an area where we continue to do something that we know causes harm because we hope it has some benefit. Despite what some societal guidance still says, I very rarely bridge patients. If I do, it’s because the patient and/or caregivers have heard the facts and have opted to do it.

Dr. Minichiello. Practically speaking, the data—the retrospective data, the observational data, the BRIDGE trial, etc—definitely make us step back and think about bridging and realize that it’s a HIGH RISK of intervention. We really need to be informing patients about that risk. We know that bridging increases the risk of bleeding. We do not have data showing a reduction in the risk of thromboembolic disease with bridge therapy. That’s all based on what we think would happen, what we hope would be the result of bridge therapy, but in truth we do not know if this is the case. The risks of bridge therapy must be weighed heavily each time we consider using it.

In my practice I reserve bridge therapy, which we know is associated with increased harm for patients in whom we think there is the very highest risk of thromboembolism, ie, those with very recent arterial or venous thrombosis, and by recently, I mean within the past 1 to 3 months; patients who have very severe thrombophilia like antitphospholipid antibody syndrome, some cancer patients, and those with mechanical valves in the mitral position or those with high-risk mechanical aortic valves.

I don’t bridge most AF patients. In fact, I can’t remember the last time I bridged an AF patient. I do know that this is somewhat discordant with the ACC recommendations, but absent the data to support bridge therapy, I’m really concerned that the risk outweighs the benefit. This is particularly true in our VA population where the bleeding risk is high because of CKD or a history of bleeding or thrombocytopenia or concomitant aspirin or something else.

Dr. Barnes. We know from some studies that have been published that the biggest driver of a clinician deciding whether or not a patient should bridge is actually whether or not they’ve had a stroke. The truth is that the BRIDGE trial enrolled a sizeable population; it was about 15% of patients with a prior TIA or stroke. So it gave us some insight. Despite that, our event rates for thromboembolism, arterial thromboembolism, including stroke, were quite low.

I tend to look far more at the collection of risk factors and not just at a history of stroke. Now as you mentioned, Dr. Minichiello, a stroke within the past 1 to 3 months, I ask, “does this procedure even need to happen?” But outside of that, it’s not a history of stroke that’s going to make the decision for me: It’s all the risk factors together.

There’s an ongoing study, the PERIOP 2 study, that is enrolling patients at higher risk for stroke and patients with mechanical valves. This study may give us more insight into exactly what kind of risks these patients are at and whether they get benefit from bridging. But in the meantime, I’m really reserving bridging for my highest risk patients, those with multiple risk factors, CHADS₂ scores of 5 and 6 or CHA₂DS₂-VASc of 7, 8, 9, and those with a recent VT or mechanical mitral valves.

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Paul Conlin, MD. Thank you all for joining us to talk about the recently released VA/DoD Clinical Practice Guideline for the Management of Type 2 Diabetes Mellitus in Primary Care (CPG). We’ve gathered together a group of experts who were part of the CPG development committee. We’re going to talk about some topics that were highlighted in the CPG that might provide additional detail to those in primary-care practices and help them in their management of patients with diabetes.

A unique feature of the VA/DoD CPG is that it emphasizes shared decision making as an important tool that clinicians should employ in their patient encounters. Dr. Watts, health care providers may wonder how they can make time for an intervention involving shared decision making using the SHARE approach, (ie, seek, help, assess, reach, and evaluate). Can you give us some advice on this?

Sharon Watts, DNP. Shared decision making is really crucial to success in diabetes. It’s been around for a while. We are trying to make an emphasis on this. The SHARE approach is from the Agency for Healthcare Research and Quality (AHRQ). The AHRQ has a wealth of information on its website. What AHRQ emphasizes is making it brief but conversational when you’re using the SHARE approach with your patient. Most importantly, the patient needs to be in the center of this dialogue, expressing his or her values and preferences of what’s most important to the whole team. This is a team effort. It’s not just with a provider. That’s where providers get overwhelmed. You can ask your nurse to advise the patient to write down 1 or 2 questions that are really important about diabetes before they come to see you, before the encounter. We can refer patients to diabetes classes where a lot of this information is given. The patient can talk to the dietitian or the pharmacist. There’s a whole team out there that will help in SHARE decision making. It’s crucial in the end for the provider to help the patient reach the decision and determine how best to treat the diabetes with them.

Dr. Conlin. Can you give a brief description of the key components of the SHARE approach?

Dr. Watts. Breaking it down simply, providers can start off by asking permission to go over the condition or treatment options because this immediately sets the stage as a signal to the patient that they are important in controlling the dialogue. It’s not the provider giving a discourse. You’re asking for permission. The next step would be to explore the benefits and risks of any course taken. Use decision aids if you have them. Keep in mind your patient’s current health literacy, numeracy, and other limitations.

Next ask about values, preferences, or barriers to whatever treatment you’re talking about. For instance, will this work with your work schedule?

Then the last thing would be ask what the patient wants to do next. Reach a decision on treatment, whatever it is, and make sure that you revisit that decision. Follow up later to see if it’s really working.

Dr. Conlin. If I’m a busy clinician and I have a limited amount of time with a patient, when are the appropriate times to employ the SHARE approach? Can I break it into components, where I address some elements during one visit and other elements in another visit?

Dr. Watts. Absolutely. It can be spread out. Your team is probably already providing information that will help in the SHARE approach. Just chart that you’ve done it. We know the SHARE approach is important because people
tend to be adherent if they came up with part of the plan.

Dr. Conlin. Where does diabetes self-management education and diabetes self-management support fall into this framework?

Dr. Watts. Diabetes is a complex disease for providers and for the team and even more so for our patients. Invite them to diabetes classes. There’s so much to understand. The classes go over medications and blood sugar ranges, though you still may have to review it with the patient in your office. It saves the provider time if you have an informed and activated patient. It’s the same with sending a patient to a dietitian. I do all of the above.

Dr. Conlin. Many providers may not be familiar with this type of approach. How can I tell whether or not I’m doing it correctly?

Dr. Watts. The AHRQ website has conversation starters (www.ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/tools/index.html). Then make sure when you are with the patient to use Teach-Back. Have that conversation and say, “I want to make sure I understood correctly what we decided would work best for you.” Ask patients to say in their own words what they understand. Then I think you’re off to a great start.

Dr. Conlin. Many patients tend to be deferential to their health care providers. They were brought up in an era where they needed to listen to and respect clinicians rather than participate in discussions about their ongoing care. How do you engage with these patients?

Dr. Watts. That is a tough one. Before the patient leaves the office, I ask them: Are there any barriers? Does this work for your schedule? Is this a preference and value that you have? Is there anything that might get in the way of this working when you go home? I try to pull out a little bit more, making sure to give them some decision aids and revisit it at the next visit to make sure it’s working.

Dr. Conlin. We’ll now turn to a discussion of using hemoglobin A1c (HbA_1c) measurements in clinical practice. Dr. Aron, what factors can impact the relationship between HbA_1c and blood glucose? How should we use HbA_1c in the treatment of patients who come from varied ethnic and racial backgrounds, where the relationship to average blood glucose may be different?

David C. Aron, MD, MS. The identification of HbA_1c has been a tremendous advance in our ability to manage patients with diabetes. It represents an average blood glucose over the preceding 3 months but like everything in this world, it has issues. One is the fact that there is a certain degree of inaccuracy in measurement, and that’s true of any measurement that you make of anything. Just as you allow a little bit of wiggle room when you’re driving down the New Jersey Turnpike and watching your speedometer, which is not 100% accurate. It says you are going 65 but it could, for example be 68 or 62. You don’t want to go too fast or you’ll get a speeding ticket. You don’t want to go too slowly or the person behind you will start honking at you. You want to be at the speed limit plus or minus. The first thing to think about in using HbA_1c is the issue of accuracy. Rather than choose a specific target number, health care providers should choose a range between this and that. There’ll be more detail on that later.

The second thing is that part of the degree to which HbA_1c represents the average blood glucose depends on a lot of factors, and some of these factors are things that we can do absolutely nothing about because we are born with them. African Americans tend to have higher HbA_1c levels than do whites for the same glucose. That difference is as much as 0.4. An HbA^_1c of 6.2 in African Americans gets you a 5.8 in whites for the same average blood glucose. Similarly, Native Americans have somewhat higher HbA_1c, although not quite as high as African Americans. Hispanics and Asians do as well, so you have to take your patient’s ethnicity into account.

The second has to do with the way that HbA_1c is measured and the fact that there are many things that can affect the measurement. An HbA_1c is dependent upon the lifespan of the red blood cell, so if there are alterations in red cell lifespan or if someone has anemia, that can affect HbA_1c. Certain hemoglobin variants, for example, hemoglobin F, which is typically elevated in someone with thalassemia, migrates with some assays in the same place as thalassemia, so the assay can’t tell the difference between thalassemia and hemoglobin F. There are drugs and other conditions that can also affect HbA_1c. You should think about HbA_1c as a guide, but no number should be considered to be written in stone.

Dr. Conlin. I can imagine that this would be particularly important if you were using HbA_1c as a criterion for diagnosing diabetes.

Dr. Aron. Quite right. The effects of race and ethnicity on HbA_1c account for one of the differences between the VA/DoD guidelines and those of the American Diabetes Association (ADA).

Dr. Conlin. Isn’t < 8% HbA_1c a national performance measure that people are asked to adhere to?

Dr. Aron. Not in the VA. In fact, the only performance measure that the VA has with a target is percent of patients with HbA_1c > 9%, and we don’t want any of those or very few of them anyway. We have specifically avoided targets like < 8% HbA_1c or < 7% HbA_1c, which was prevalent some years ago, because the choice of HbA_1c is very dependent upon the needs and desires of the individual patient. The VA has had stratified targets based on life expectancy and complications going back more than 15 years.

Dr. Conlin. Another issue that can confuse clinicians is when the HbA_1c is in the target range but actually reflects an average of glucose levels that are at times very high and very low. How do we address this problem clinically?

Dr. Aron. In managing patients, you use whatever data you can get. The HbA_1c gives you a general indication of average blood glucose, but particularly for those patients who are on insulin, it’s not a complete substitute for measuring blood glucose at appropriate times and taking the degree of glucose variability into account. We don’t want patients getting hypoglycemic, and particularly if they’re elderly, falling, or getting into a car accident. Similarly, we don’t want people to have very high blood sugars, even for limited periods of time, because they can lead to dehydration and other symptoms as well. We use a combination of both HbA_1c and individual measures of blood glucose, like finger-stick blood sugar testing, typically.

Dr. Conlin. The VA/DoD CPG differs from other published guidelines in that we proposed patients are treated to HbA_1c target ranges, whereas most other guidelines propose upper limits or threshold values, such as the HbA_1c should be < 7% or < 8% but without lower bounds. Dr. Colburn, what are the target ranges that are recommended in the CPG? How were they determined?

Maj. Jeffrey A. Colburn, MD. It may be helpful to pull up the Determination of Average Target HbA_1c Level Over Time table (page S17), which lays out risk for patients of treatment as well as the benefits of treatment. We first look at the patient’s state of health and whether they have a major comorbidity, a physiologic age that could be high risk, or advanced physiologic age with a diminished life expectancy. In controlling the levels of glucose, we’re often trying to benefit the microvascular health of the patient, realizing also that eventually poor management over time will lead to macrovascular disease as well. The main things that we see in child data is that the benefits of tight glucose control for younger patients with shorter duration of type 2 diabetes mellitus (T2DM) is the prevention of retinopathy, nephropathy, and peripheral neuropathy. Those patients that already have advanced microvascular disease are less likely to benefit from tight control. Trying to push glucose very low can harm the patient. It’s a delicate balance between the possible benefit vs the real harm.

The major trials are the ADVANCE, ACCORD, and the VADT trial, which was done in a VA population. To generalize the results, you are looking at an intensive control, which was trying to keep the HbA_1c in general down below the 7% threshold. The patients enrolled in those trials all had microvascular and macrovascular disease and typically longer durations of diabetes at the time of the study. The studies revealed that we were not preventing macrovascular disease, heart attacks, strokes, the types of things that kill patients with diabetes. Individuals at higher HbA_1c levels that went down to better HbA_1c levels saw some improvement in the microvascular risk. Individuals already at the lower end didn’t see as much improvement. What we saw though that was surprising and concerning was that hypoglycemia, particularly severe hypoglycemia in the VADT trial was a lot more frequent when you try and target the HbA_1c on the lower end. Because of these findings, we proposed the table with a set of ranges. As Dr. Aron noted, HbA_1c is not a perfect test. It does have some variance in the number it presents. The CPG proposed to give individuals target ranges. They should be individualized based upon physiologic age, comorbidities, and life expectancy.

A criticism of the table that I commonly hear is what’s the magic crystal ball for determining somebody’s life expectancy? We don’t have one. This is a clinician’s judgment. The findings might actually change over time with the patient. A target HbA_1c range is something that should be adapted and evolve along with the clinician and patient experience of the diabetes.

There are other important studies. For example, the UKPDS trials that included patients with shorter durations of diabetes and lesser disease to try and get their HbA_1c levels on the lower end. We included that in the chart. Another concept we put forward is the idea of relative risk (RR) vs absolute risk. The RR reduction doesn’t speak to what the actual beginning risk is lowered to for a patient. The UKPDS is often cited for RR reduction of microvascular disease as 37% when an HbA_1c of 7.9% is targeted down to 7.0%. The absolute risk reduction is actually 5 with the number needed to treat to do so is 20 patients. When we present the data, we give it a fair shake. We want individuals to guide therapy that is going to be both beneficial to preventing outcomes but also not harmful to the patient. I would highly recommend clinicians and patients look at this table together when making their decisions.

Dr. Conlin. In the VA/DoD CPG, the HbA_1c target range for individuals with limited life expectancy extends to 9%. That may seem high for some, since most other guidelines propose lower HbA_1c levels. How strong are the data that a person with limited life expectancy, say with end-stage renal disease or advanced complications, could be treated to a range of 8% to 9%? Shouldn’t lower levels actually improve life expectancy in such people?

Dr. Colburn. There’s much less data to support this level, which is why it’s cited in CPG as having weaker evidence. The reason it’s proposed is the experience of the workgroup and the evidence that is available of a high risk for patients with low life expectancy when they reduce their HbA_1c greatly. One of the concerns about being at that level might be the real issue of renal glycosuria for individuals when their blood glucose is reaching above 180 mg/dL, which correlates to the 8% to 9% HbA_1c range. You may have renal loss and risk of dehydration. It is an area where the clinician should be cautious in monitoring a patient in the 8% to 9% HbA_1c range. With that being said, a patient who is having a lot of challenges in their health and extremely advanced conditions could be in that range. We would not expect a reversing of a micro- or macrovascular disease with glycemia control. We’re not going to go back from that level of disease they have. The idea about keeping them there is to prevent the risks of overtreatment and harm to the patient.

Dr. Conlin. Since patients with diabetes can progress over their lifetime from no complications to mild-to-moderate complications to advanced complications, how does the HbA_1c target range evolve as a patient’s condition changes?

Dr. Colburn. As we check for evidence of microvascular disease or neuropathy signs, that evidence often is good for discussion between the clinician and patient to advise them that better control early on may help stem off or reverse some of that change. As those changes solidify, the patient is challenged by microvascular conditions. I would entertain allowing more relaxed HbA_1c ranges to prevent harm to the patient given that we’re not going back. But you have to be careful. We have to consider benefits to the patient and the challenges for controlling glucose.

I hope that this table doesn’t make providers throw up their hands and give up. It’s meant to start a conversation on safety and benefits. With newer agents coming out that can help us control glucose quite well, without as much hypoglycemia risk, clinicians and patients potentially can try and get that HbA_1c into a well-managed range.

Dr. Conlin. The CPG discusses various treatment options that might be available for patients who require pharmacologic therapy. The number of agents available is growing quite markedly. Dr. Colburn, can you describe how the CPG put together the pharmacologic therapy preferences.

Dr. Colburn. The CPG expressively stayed away from trying to promote specific regimens of medications. For example, other guidelines promote starting with certain agents followed by a second-line agent by a third-line agents. The concern that we had about that approach is that the medication landscape is rapidly evolving. The options available to clinicians and patients are really diverse at this moment, and the data are not concrete regarding what works best for a single patient.

Rather than trying to go from one agent to the next, we thought it best to discuss with patients using the SHARE decision-making model, the adverse effects (AEs) and relative benefits that are involved with each medication class to determine what might be best for the person. We have many new agents with evidence for possible reductions in cardiovascular outcomes outside of their glycemic control properties. As those evidences promote a potentially better option for a patient, we wanted to allow the room in management tomake a decision together. I will say the CPG as well as all of the other applicable diabetes guidelines for T2DM promote metformin as the first therapy to consider for somebody with newly diagnosed T2DM because of safety and availability and the benefit that’s seen with that medication class. We ask clinicians to access the AHRQ website for updates as the medicines evolve.

In a rapidly changing landscape with new drugs coming into the market, each agency has on their individual website information about individual agents and their formulary status, criteria for use, and prior authorization requirements. We refer clinicians to the appropriate website for more information.

Dr. Conlin. There are a series of new medications that have recently come to market that seem to mitigate risk for hypoglycemia. Dr. Lugo, which treatment options carry greater risk? Which treatment options seem to have lesser risk for hypoglycemia?

Amy M. Lugo, PharmD. Insulin and the sulfonylureas have the highest risk of hypoglycemia. The sulfonylureas have fallen out of favor somewhat. One reason is that there are many newer agents that do not cause weight gain or increase the risk of hypoglycemia. Some of the newer insulins may have a lower risk of hypoglycemia and nocturnal hypoglycemia, in particular; however, it is difficult to conclude emphatically that one basal insulin analog is less likely to cause clinically relevant severe or nocturnal hypoglycemia events. This is due to the differences in the definitions of hypoglycemia used in the individual clinical trials, the open label study designs, and the different primary endpoints.

Dr. Conlin. How much affect on HbA_1c might I expect to see using SGLT2 inhibitors or GLP-1 agonists? What would be some of the potential AEs I have to be aware of and therefore could counsel patients about?

Dr. Lugo. Let’s start with SGLT2 inhibitors. It depends on whether they are used as monotherapy or in combination. We prefer that patients start on metformin unless they have a contraindication. When used as monotherapy, the SGLT2s may decrease HbA_1c from 0.4% to 1% from baseline. When combined with additional agents, they can have > 1% improvement in HbA_1c from baseline. There are no head-to-head trials between any of the SGLT2 inhibitors. We cannot say that one is more efficacious than another in lowering HbA_1c. The most common AEs include genital mycotic infections and urinary tract infections. The SGLT2 inhibitors also should be avoided in renal impairment. There was a recent FDA safety alert for the class for risk of ketoacidosis. Additionally, the FDA warned that patients
with a history of bladder cancer should avoid dapagliflozin, and canagliflozin has a warning for increased risk of bone fractures, amputation, and decreased bone density.

Other actions of the SGLT2 inhibitors include a reduction in triglycerides and a modest increase in both low-density lipoprotein cholesterol and highdensity lipoprotein cholesterol. The SGLT2 inhibitors also slightly decrease systolic blood pressure (by 4 mm Hg to 6 mm Hg) and body weight (reduction of 1.8 kg)

The GLP-1s are likely to be more efficacious in reducing HbA_1c. Typically we see 1% or greater lowering in HbA_1c from baseline. As a class, the GLP-1 agonists have a lower risk of hypoglycemia; however, the risk increases when combined with sulfonylureas or insulin. The dose of insulin or sulfonylurea will likely need to be decreased when used concomitantly.

Patients are likely to experience weight loss when on a GLP-1 agonist, which is a great benefit. Gastrointestinal AEs such as nausea are common. Adverse effects may differ somewhat between the agents.

Dr. Conlin. Patients’ experience of care is integral to their engagement with treatment as well as their adherence. Ms. Decesare, what are patients looking for from their health care team?

Elaine M. Decesare. Patients are looking for a knowledgeable and compassionate health care team that has a consistent approach and a consistent message and that the team is updated on the knowledge of appropriate treatments and appropriate lifestyle modifications and targets for the care of diabetes.

Also, I think that the team needs to have some empathy for the challenges of living with diabetes. It’s a 24-hour-a-day disorder, 7 days a week. They can’t take vacation from it. They just can’t take a pill and forget about it. It’s a fairly demanding disorder, and sometimes just acknowledging that with the patient can help you with the dialog.

The second thing I think patients want is an effective treatment plan that’s tailored to their needs and lifestyles. That goes in with the shared decision-making approach, but the plan itself really has to be likely to achieve the targets and the goals that you’ve set up. Sometimes I see patients who are doing all they can with their lifestyle changes, but they can’t get to goal, because there isn’t enough medication in the plan. The plan has to be adequate so that the patient can manage their diabetes. In the shared approach, the patient has to buy in to the plan. With the shared decision making they’re more likely to take the plan on as their plan.

Dr. Conlin. How do you respond to patients who feel treatment burnout from having a new dietary plan, an exercise program, regular monitoring of glucose through finger sticks, and in many cases multiple medications and or injections, while potentially not achieving the goals that you and the patient have arrived at?

Ms. Decesare. First, I want to assess their mood. Sometimes patients are depressed, and they actually need help with that. If they have trouble with just the management, we do have behavioral health psychologists on our team that work with patients to get through some of the barriers and discuss some of the feelings that they have about diabetes and diabetes management.

Sometimes we look at the plan again and see if there’s something we can do to make the plan easier. Occasionally, something has happened in their life. Maybe they’re taking care of an elderly parent or they’ve had other health problems that have come about that we need to reassess the plan and make sure that it’s actually doable for them at this point in time.

Certainly diabetes self-management education can be helpful. Some of those approaches can be helpful for finding something that’s going to work for patients in the long run, because it can be a very difficult disorder to manage as time goes on.

Dr. Colburn. Type 2 DM disproportionately affects individuals who are ≥ 65 years compared with younger individuals. Such older patients also are more likely to have cognitive impairment or visual issues. How do we best manage such patients?

Ms. Decesare. When I’m looking at the care plan, social support is very important. If someone has social support and they have a spouse or a son or daughter or someone else that can help them with their diabetes, we oftentimes will get them involved with the plan, as long as it’s fine with the patient, to offer some help, especially with the patients with cognitive problems, because sometimes the patients just cognitively cannot manage diabetes on their own. Prandial insulin could be a really dangerous product for someone who has cognitive disease.

I think you have to look at all the resources that are available. Sometimes you have to change your HbA_1c target range to something that’s going to be manageable for that patient at that time. It might not be perfect, but it would be better to have no hypoglycemia rather than a real aggressive HbA_1c target or a target range, if that’s what’s going to keep the patient safe.

Dr. Conlin. We thank our discussants for sharing very practical advice on how to implement the CPG. We hope this information supports clinicians as they develop treatment plans based on each patient's unique characteristics and goals of care.

Click here to read the digital edition.

Paul Conlin, MD. Thank you all for joining us to talk about the recently released VA/DoD Clinical Practice Guideline for the Management of Type 2 Diabetes Mellitus in Primary Care (CPG). We’ve gathered together a group of experts who were part of the CPG development committee. We’re going to talk about some topics that were highlighted in the CPG that might provide additional detail to those in primary-care practices and help them in their management of patients with diabetes.

A unique feature of the VA/DoD CPG is that it emphasizes shared decision making as an important tool that clinicians should employ in their patient encounters. Dr. Watts, health care providers may wonder how they can make time for an intervention involving shared decision making using the SHARE approach, (ie, seek, help, assess, reach, and evaluate). Can you give us some advice on this?

Sharon Watts, DNP. Shared decision making is really crucial to success in diabetes. It’s been around for a while. We are trying to make an emphasis on this. The SHARE approach is from the Agency for Healthcare Research and Quality (AHRQ). The AHRQ has a wealth of information on its website. What AHRQ emphasizes is making it brief but conversational when you’re using the SHARE approach with your patient. Most importantly, the patient needs to be in the center of this dialogue, expressing his or her values and preferences of what’s most important to the whole team. This is a team effort. It’s not just with a provider. That’s where providers get overwhelmed. You can ask your nurse to advise the patient to write down 1 or 2 questions that are really important about diabetes before they come to see you, before the encounter. We can refer patients to diabetes classes where a lot of this information is given. The patient can talk to the dietitian or the pharmacist. There’s a whole team out there that will help in SHARE decision making. It’s crucial in the end for the provider to help the patient reach the decision and determine how best to treat the diabetes with them.

Dr. Conlin. Can you give a brief description of the key components of the SHARE approach?

Dr. Watts. Breaking it down simply, providers can start off by asking permission to go over the condition or treatment options because this immediately sets the stage as a signal to the patient that they are important in controlling the dialogue. It’s not the provider giving a discourse. You’re asking for permission. The next step would be to explore the benefits and risks of any course taken. Use decision aids if you have them. Keep in mind your patient’s current health literacy, numeracy, and other limitations.

Next ask about values, preferences, or barriers to whatever treatment you’re talking about. For instance, will this work with your work schedule?

Then the last thing would be ask what the patient wants to do next. Reach a decision on treatment, whatever it is, and make sure that you revisit that decision. Follow up later to see if it’s really working.

Dr. Conlin. If I’m a busy clinician and I have a limited amount of time with a patient, when are the appropriate times to employ the SHARE approach? Can I break it into components, where I address some elements during one visit and other elements in another visit?

Dr. Watts. Absolutely. It can be spread out. Your team is probably already providing information that will help in the SHARE approach. Just chart that you’ve done it. We know the SHARE approach is important because people
tend to be adherent if they came up with part of the plan.

Dr. Conlin. Where does diabetes self-management education and diabetes self-management support fall into this framework?

Dr. Watts. Diabetes is a complex disease for providers and for the team and even more so for our patients. Invite them to diabetes classes. There’s so much to understand. The classes go over medications and blood sugar ranges, though you still may have to review it with the patient in your office. It saves the provider time if you have an informed and activated patient. It’s the same with sending a patient to a dietitian. I do all of the above.

Dr. Conlin. Many providers may not be familiar with this type of approach. How can I tell whether or not I’m doing it correctly?

Dr. Watts. The AHRQ website has conversation starters (www.ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/tools/index.html). Then make sure when you are with the patient to use Teach-Back. Have that conversation and say, “I want to make sure I understood correctly what we decided would work best for you.” Ask patients to say in their own words what they understand. Then I think you’re off to a great start.

Dr. Conlin. Many patients tend to be deferential to their health care providers. They were brought up in an era where they needed to listen to and respect clinicians rather than participate in discussions about their ongoing care. How do you engage with these patients?

Dr. Watts. That is a tough one. Before the patient leaves the office, I ask them: Are there any barriers? Does this work for your schedule? Is this a preference and value that you have? Is there anything that might get in the way of this working when you go home? I try to pull out a little bit more, making sure to give them some decision aids and revisit it at the next visit to make sure it’s working.

Dr. Conlin. We’ll now turn to a discussion of using hemoglobin A1c (HbA_1c) measurements in clinical practice. Dr. Aron, what factors can impact the relationship between HbA_1c and blood glucose? How should we use HbA_1c in the treatment of patients who come from varied ethnic and racial backgrounds, where the relationship to average blood glucose may be different?

David C. Aron, MD, MS. The identification of HbA_1c has been a tremendous advance in our ability to manage patients with diabetes. It represents an average blood glucose over the preceding 3 months but like everything in this world, it has issues. One is the fact that there is a certain degree of inaccuracy in measurement, and that’s true of any measurement that you make of anything. Just as you allow a little bit of wiggle room when you’re driving down the New Jersey Turnpike and watching your speedometer, which is not 100% accurate. It says you are going 65 but it could, for example be 68 or 62. You don’t want to go too fast or you’ll get a speeding ticket. You don’t want to go too slowly or the person behind you will start honking at you. You want to be at the speed limit plus or minus. The first thing to think about in using HbA_1c is the issue of accuracy. Rather than choose a specific target number, health care providers should choose a range between this and that. There’ll be more detail on that later.

The second thing is that part of the degree to which HbA_1c represents the average blood glucose depends on a lot of factors, and some of these factors are things that we can do absolutely nothing about because we are born with them. African Americans tend to have higher HbA_1c levels than do whites for the same glucose. That difference is as much as 0.4. An HbA^_1c of 6.2 in African Americans gets you a 5.8 in whites for the same average blood glucose. Similarly, Native Americans have somewhat higher HbA_1c, although not quite as high as African Americans. Hispanics and Asians do as well, so you have to take your patient’s ethnicity into account.

The second has to do with the way that HbA_1c is measured and the fact that there are many things that can affect the measurement. An HbA_1c is dependent upon the lifespan of the red blood cell, so if there are alterations in red cell lifespan or if someone has anemia, that can affect HbA_1c. Certain hemoglobin variants, for example, hemoglobin F, which is typically elevated in someone with thalassemia, migrates with some assays in the same place as thalassemia, so the assay can’t tell the difference between thalassemia and hemoglobin F. There are drugs and other conditions that can also affect HbA_1c. You should think about HbA_1c as a guide, but no number should be considered to be written in stone.

Dr. Conlin. I can imagine that this would be particularly important if you were using HbA_1c as a criterion for diagnosing diabetes.

Dr. Aron. Quite right. The effects of race and ethnicity on HbA_1c account for one of the differences between the VA/DoD guidelines and those of the American Diabetes Association (ADA).

Dr. Conlin. Isn’t < 8% HbA_1c a national performance measure that people are asked to adhere to?

Dr. Aron. Not in the VA. In fact, the only performance measure that the VA has with a target is percent of patients with HbA_1c > 9%, and we don’t want any of those or very few of them anyway. We have specifically avoided targets like < 8% HbA_1c or < 7% HbA_1c, which was prevalent some years ago, because the choice of HbA_1c is very dependent upon the needs and desires of the individual patient. The VA has had stratified targets based on life expectancy and complications going back more than 15 years.

Dr. Conlin. Another issue that can confuse clinicians is when the HbA_1c is in the target range but actually reflects an average of glucose levels that are at times very high and very low. How do we address this problem clinically?

Dr. Aron. In managing patients, you use whatever data you can get. The HbA_1c gives you a general indication of average blood glucose, but particularly for those patients who are on insulin, it’s not a complete substitute for measuring blood glucose at appropriate times and taking the degree of glucose variability into account. We don’t want patients getting hypoglycemic, and particularly if they’re elderly, falling, or getting into a car accident. Similarly, we don’t want people to have very high blood sugars, even for limited periods of time, because they can lead to dehydration and other symptoms as well. We use a combination of both HbA_1c and individual measures of blood glucose, like finger-stick blood sugar testing, typically.

Dr. Conlin. The VA/DoD CPG differs from other published guidelines in that we proposed patients are treated to HbA_1c target ranges, whereas most other guidelines propose upper limits or threshold values, such as the HbA_1c should be < 7% or < 8% but without lower bounds. Dr. Colburn, what are the target ranges that are recommended in the CPG? How were they determined?

Maj. Jeffrey A. Colburn, MD. It may be helpful to pull up the Determination of Average Target HbA_1c Level Over Time table (page S17), which lays out risk for patients of treatment as well as the benefits of treatment. We first look at the patient’s state of health and whether they have a major comorbidity, a physiologic age that could be high risk, or advanced physiologic age with a diminished life expectancy. In controlling the levels of glucose, we’re often trying to benefit the microvascular health of the patient, realizing also that eventually poor management over time will lead to macrovascular disease as well. The main things that we see in child data is that the benefits of tight glucose control for younger patients with shorter duration of type 2 diabetes mellitus (T2DM) is the prevention of retinopathy, nephropathy, and peripheral neuropathy. Those patients that already have advanced microvascular disease are less likely to benefit from tight control. Trying to push glucose very low can harm the patient. It’s a delicate balance between the possible benefit vs the real harm.

The major trials are the ADVANCE, ACCORD, and the VADT trial, which was done in a VA population. To generalize the results, you are looking at an intensive control, which was trying to keep the HbA_1c in general down below the 7% threshold. The patients enrolled in those trials all had microvascular and macrovascular disease and typically longer durations of diabetes at the time of the study. The studies revealed that we were not preventing macrovascular disease, heart attacks, strokes, the types of things that kill patients with diabetes. Individuals at higher HbA_1c levels that went down to better HbA_1c levels saw some improvement in the microvascular risk. Individuals already at the lower end didn’t see as much improvement. What we saw though that was surprising and concerning was that hypoglycemia, particularly severe hypoglycemia in the VADT trial was a lot more frequent when you try and target the HbA_1c on the lower end. Because of these findings, we proposed the table with a set of ranges. As Dr. Aron noted, HbA_1c is not a perfect test. It does have some variance in the number it presents. The CPG proposed to give individuals target ranges. They should be individualized based upon physiologic age, comorbidities, and life expectancy.

A criticism of the table that I commonly hear is what’s the magic crystal ball for determining somebody’s life expectancy? We don’t have one. This is a clinician’s judgment. The findings might actually change over time with the patient. A target HbA_1c range is something that should be adapted and evolve along with the clinician and patient experience of the diabetes.

There are other important studies. For example, the UKPDS trials that included patients with shorter durations of diabetes and lesser disease to try and get their HbA_1c levels on the lower end. We included that in the chart. Another concept we put forward is the idea of relative risk (RR) vs absolute risk. The RR reduction doesn’t speak to what the actual beginning risk is lowered to for a patient. The UKPDS is often cited for RR reduction of microvascular disease as 37% when an HbA_1c of 7.9% is targeted down to 7.0%. The absolute risk reduction is actually 5 with the number needed to treat to do so is 20 patients. When we present the data, we give it a fair shake. We want individuals to guide therapy that is going to be both beneficial to preventing outcomes but also not harmful to the patient. I would highly recommend clinicians and patients look at this table together when making their decisions.

Dr. Conlin. In the VA/DoD CPG, the HbA_1c target range for individuals with limited life expectancy extends to 9%. That may seem high for some, since most other guidelines propose lower HbA_1c levels. How strong are the data that a person with limited life expectancy, say with end-stage renal disease or advanced complications, could be treated to a range of 8% to 9%? Shouldn’t lower levels actually improve life expectancy in such people?

Dr. Colburn. There’s much less data to support this level, which is why it’s cited in CPG as having weaker evidence. The reason it’s proposed is the experience of the workgroup and the evidence that is available of a high risk for patients with low life expectancy when they reduce their HbA_1c greatly. One of the concerns about being at that level might be the real issue of renal glycosuria for individuals when their blood glucose is reaching above 180 mg/dL, which correlates to the 8% to 9% HbA_1c range. You may have renal loss and risk of dehydration. It is an area where the clinician should be cautious in monitoring a patient in the 8% to 9% HbA_1c range. With that being said, a patient who is having a lot of challenges in their health and extremely advanced conditions could be in that range. We would not expect a reversing of a micro- or macrovascular disease with glycemia control. We’re not going to go back from that level of disease they have. The idea about keeping them there is to prevent the risks of overtreatment and harm to the patient.

Dr. Conlin. Since patients with diabetes can progress over their lifetime from no complications to mild-to-moderate complications to advanced complications, how does the HbA_1c target range evolve as a patient’s condition changes?

Dr. Colburn. As we check for evidence of microvascular disease or neuropathy signs, that evidence often is good for discussion between the clinician and patient to advise them that better control early on may help stem off or reverse some of that change. As those changes solidify, the patient is challenged by microvascular conditions. I would entertain allowing more relaxed HbA_1c ranges to prevent harm to the patient given that we’re not going back. But you have to be careful. We have to consider benefits to the patient and the challenges for controlling glucose.

I hope that this table doesn’t make providers throw up their hands and give up. It’s meant to start a conversation on safety and benefits. With newer agents coming out that can help us control glucose quite well, without as much hypoglycemia risk, clinicians and patients potentially can try and get that HbA_1c into a well-managed range.

Dr. Conlin. The CPG discusses various treatment options that might be available for patients who require pharmacologic therapy. The number of agents available is growing quite markedly. Dr. Colburn, can you describe how the CPG put together the pharmacologic therapy preferences.

Dr. Colburn. The CPG expressively stayed away from trying to promote specific regimens of medications. For example, other guidelines promote starting with certain agents followed by a second-line agent by a third-line agents. The concern that we had about that approach is that the medication landscape is rapidly evolving. The options available to clinicians and patients are really diverse at this moment, and the data are not concrete regarding what works best for a single patient.

Rather than trying to go from one agent to the next, we thought it best to discuss with patients using the SHARE decision-making model, the adverse effects (AEs) and relative benefits that are involved with each medication class to determine what might be best for the person. We have many new agents with evidence for possible reductions in cardiovascular outcomes outside of their glycemic control properties. As those evidences promote a potentially better option for a patient, we wanted to allow the room in management tomake a decision together. I will say the CPG as well as all of the other applicable diabetes guidelines for T2DM promote metformin as the first therapy to consider for somebody with newly diagnosed T2DM because of safety and availability and the benefit that’s seen with that medication class. We ask clinicians to access the AHRQ website for updates as the medicines evolve.

In a rapidly changing landscape with new drugs coming into the market, each agency has on their individual website information about individual agents and their formulary status, criteria for use, and prior authorization requirements. We refer clinicians to the appropriate website for more information.

Dr. Conlin. There are a series of new medications that have recently come to market that seem to mitigate risk for hypoglycemia. Dr. Lugo, which treatment options carry greater risk? Which treatment options seem to have lesser risk for hypoglycemia?

Amy M. Lugo, PharmD. Insulin and the sulfonylureas have the highest risk of hypoglycemia. The sulfonylureas have fallen out of favor somewhat. One reason is that there are many newer agents that do not cause weight gain or increase the risk of hypoglycemia. Some of the newer insulins may have a lower risk of hypoglycemia and nocturnal hypoglycemia, in particular; however, it is difficult to conclude emphatically that one basal insulin analog is less likely to cause clinically relevant severe or nocturnal hypoglycemia events. This is due to the differences in the definitions of hypoglycemia used in the individual clinical trials, the open label study designs, and the different primary endpoints.

Dr. Conlin. How much affect on HbA_1c might I expect to see using SGLT2 inhibitors or GLP-1 agonists? What would be some of the potential AEs I have to be aware of and therefore could counsel patients about?

Dr. Lugo. Let’s start with SGLT2 inhibitors. It depends on whether they are used as monotherapy or in combination. We prefer that patients start on metformin unless they have a contraindication. When used as monotherapy, the SGLT2s may decrease HbA_1c from 0.4% to 1% from baseline. When combined with additional agents, they can have > 1% improvement in HbA_1c from baseline. There are no head-to-head trials between any of the SGLT2 inhibitors. We cannot say that one is more efficacious than another in lowering HbA_1c. The most common AEs include genital mycotic infections and urinary tract infections. The SGLT2 inhibitors also should be avoided in renal impairment. There was a recent FDA safety alert for the class for risk of ketoacidosis. Additionally, the FDA warned that patients
with a history of bladder cancer should avoid dapagliflozin, and canagliflozin has a warning for increased risk of bone fractures, amputation, and decreased bone density.

Other actions of the SGLT2 inhibitors include a reduction in triglycerides and a modest increase in both low-density lipoprotein cholesterol and highdensity lipoprotein cholesterol. The SGLT2 inhibitors also slightly decrease systolic blood pressure (by 4 mm Hg to 6 mm Hg) and body weight (reduction of 1.8 kg)

The GLP-1s are likely to be more efficacious in reducing HbA_1c. Typically we see 1% or greater lowering in HbA_1c from baseline. As a class, the GLP-1 agonists have a lower risk of hypoglycemia; however, the risk increases when combined with sulfonylureas or insulin. The dose of insulin or sulfonylurea will likely need to be decreased when used concomitantly.

Patients are likely to experience weight loss when on a GLP-1 agonist, which is a great benefit. Gastrointestinal AEs such as nausea are common. Adverse effects may differ somewhat between the agents.

Dr. Conlin. Patients’ experience of care is integral to their engagement with treatment as well as their adherence. Ms. Decesare, what are patients looking for from their health care team?

Elaine M. Decesare. Patients are looking for a knowledgeable and compassionate health care team that has a consistent approach and a consistent message and that the team is updated on the knowledge of appropriate treatments and appropriate lifestyle modifications and targets for the care of diabetes.

Also, I think that the team needs to have some empathy for the challenges of living with diabetes. It’s a 24-hour-a-day disorder, 7 days a week. They can’t take vacation from it. They just can’t take a pill and forget about it. It’s a fairly demanding disorder, and sometimes just acknowledging that with the patient can help you with the dialog.

The second thing I think patients want is an effective treatment plan that’s tailored to their needs and lifestyles. That goes in with the shared decision-making approach, but the plan itself really has to be likely to achieve the targets and the goals that you’ve set up. Sometimes I see patients who are doing all they can with their lifestyle changes, but they can’t get to goal, because there isn’t enough medication in the plan. The plan has to be adequate so that the patient can manage their diabetes. In the shared approach, the patient has to buy in to the plan. With the shared decision making they’re more likely to take the plan on as their plan.

Dr. Conlin. How do you respond to patients who feel treatment burnout from having a new dietary plan, an exercise program, regular monitoring of glucose through finger sticks, and in many cases multiple medications and or injections, while potentially not achieving the goals that you and the patient have arrived at?

Ms. Decesare. First, I want to assess their mood. Sometimes patients are depressed, and they actually need help with that. If they have trouble with just the management, we do have behavioral health psychologists on our team that work with patients to get through some of the barriers and discuss some of the feelings that they have about diabetes and diabetes management.

Sometimes we look at the plan again and see if there’s something we can do to make the plan easier. Occasionally, something has happened in their life. Maybe they’re taking care of an elderly parent or they’ve had other health problems that have come about that we need to reassess the plan and make sure that it’s actually doable for them at this point in time.

Certainly diabetes self-management education can be helpful. Some of those approaches can be helpful for finding something that’s going to work for patients in the long run, because it can be a very difficult disorder to manage as time goes on.

Dr. Colburn. Type 2 DM disproportionately affects individuals who are ≥ 65 years compared with younger individuals. Such older patients also are more likely to have cognitive impairment or visual issues. How do we best manage such patients?

Ms. Decesare. When I’m looking at the care plan, social support is very important. If someone has social support and they have a spouse or a son or daughter or someone else that can help them with their diabetes, we oftentimes will get them involved with the plan, as long as it’s fine with the patient, to offer some help, especially with the patients with cognitive problems, because sometimes the patients just cognitively cannot manage diabetes on their own. Prandial insulin could be a really dangerous product for someone who has cognitive disease.

I think you have to look at all the resources that are available. Sometimes you have to change your HbA_1c target range to something that’s going to be manageable for that patient at that time. It might not be perfect, but it would be better to have no hypoglycemia rather than a real aggressive HbA_1c target or a target range, if that’s what’s going to keep the patient safe.

Dr. Conlin. We thank our discussants for sharing very practical advice on how to implement the CPG. We hope this information supports clinicians as they develop treatment plans based on each patient's unique characteristics and goals of care.

Click here to read the digital edition.

Paul Conlin, MD. Thank you all for joining us to talk about the recently released VA/DoD Clinical Practice Guideline for the Management of Type 2 Diabetes Mellitus in Primary Care (CPG). We’ve gathered together a group of experts who were part of the CPG development committee. We’re going to talk about some topics that were highlighted in the CPG that might provide additional detail to those in primary-care practices and help them in their management of patients with diabetes.

A unique feature of the VA/DoD CPG is that it emphasizes shared decision making as an important tool that clinicians should employ in their patient encounters. Dr. Watts, health care providers may wonder how they can make time for an intervention involving shared decision making using the SHARE approach, (ie, seek, help, assess, reach, and evaluate). Can you give us some advice on this?

Sharon Watts, DNP. Shared decision making is really crucial to success in diabetes. It’s been around for a while. We are trying to make an emphasis on this. The SHARE approach is from the Agency for Healthcare Research and Quality (AHRQ). The AHRQ has a wealth of information on its website. What AHRQ emphasizes is making it brief but conversational when you’re using the SHARE approach with your patient. Most importantly, the patient needs to be in the center of this dialogue, expressing his or her values and preferences of what’s most important to the whole team. This is a team effort. It’s not just with a provider. That’s where providers get overwhelmed. You can ask your nurse to advise the patient to write down 1 or 2 questions that are really important about diabetes before they come to see you, before the encounter. We can refer patients to diabetes classes where a lot of this information is given. The patient can talk to the dietitian or the pharmacist. There’s a whole team out there that will help in SHARE decision making. It’s crucial in the end for the provider to help the patient reach the decision and determine how best to treat the diabetes with them.

Dr. Conlin. Can you give a brief description of the key components of the SHARE approach?

Dr. Watts. Breaking it down simply, providers can start off by asking permission to go over the condition or treatment options because this immediately sets the stage as a signal to the patient that they are important in controlling the dialogue. It’s not the provider giving a discourse. You’re asking for permission. The next step would be to explore the benefits and risks of any course taken. Use decision aids if you have them. Keep in mind your patient’s current health literacy, numeracy, and other limitations.

Next ask about values, preferences, or barriers to whatever treatment you’re talking about. For instance, will this work with your work schedule?

Then the last thing would be ask what the patient wants to do next. Reach a decision on treatment, whatever it is, and make sure that you revisit that decision. Follow up later to see if it’s really working.

Dr. Conlin. If I’m a busy clinician and I have a limited amount of time with a patient, when are the appropriate times to employ the SHARE approach? Can I break it into components, where I address some elements during one visit and other elements in another visit?

Dr. Watts. Absolutely. It can be spread out. Your team is probably already providing information that will help in the SHARE approach. Just chart that you’ve done it. We know the SHARE approach is important because people
tend to be adherent if they came up with part of the plan.

Dr. Conlin. Where does diabetes self-management education and diabetes self-management support fall into this framework?

Dr. Watts. Diabetes is a complex disease for providers and for the team and even more so for our patients. Invite them to diabetes classes. There’s so much to understand. The classes go over medications and blood sugar ranges, though you still may have to review it with the patient in your office. It saves the provider time if you have an informed and activated patient. It’s the same with sending a patient to a dietitian. I do all of the above.

Dr. Conlin. Many providers may not be familiar with this type of approach. How can I tell whether or not I’m doing it correctly?

Dr. Watts. The AHRQ website has conversation starters (www.ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/tools/index.html). Then make sure when you are with the patient to use Teach-Back. Have that conversation and say, “I want to make sure I understood correctly what we decided would work best for you.” Ask patients to say in their own words what they understand. Then I think you’re off to a great start.

Dr. Conlin. Many patients tend to be deferential to their health care providers. They were brought up in an era where they needed to listen to and respect clinicians rather than participate in discussions about their ongoing care. How do you engage with these patients?

Dr. Watts. That is a tough one. Before the patient leaves the office, I ask them: Are there any barriers? Does this work for your schedule? Is this a preference and value that you have? Is there anything that might get in the way of this working when you go home? I try to pull out a little bit more, making sure to give them some decision aids and revisit it at the next visit to make sure it’s working.

Dr. Conlin. We’ll now turn to a discussion of using hemoglobin A1c (HbA_1c) measurements in clinical practice. Dr. Aron, what factors can impact the relationship between HbA_1c and blood glucose? How should we use HbA_1c in the treatment of patients who come from varied ethnic and racial backgrounds, where the relationship to average blood glucose may be different?

David C. Aron, MD, MS. The identification of HbA_1c has been a tremendous advance in our ability to manage patients with diabetes. It represents an average blood glucose over the preceding 3 months but like everything in this world, it has issues. One is the fact that there is a certain degree of inaccuracy in measurement, and that’s true of any measurement that you make of anything. Just as you allow a little bit of wiggle room when you’re driving down the New Jersey Turnpike and watching your speedometer, which is not 100% accurate. It says you are going 65 but it could, for example be 68 or 62. You don’t want to go too fast or you’ll get a speeding ticket. You don’t want to go too slowly or the person behind you will start honking at you. You want to be at the speed limit plus or minus. The first thing to think about in using HbA_1c is the issue of accuracy. Rather than choose a specific target number, health care providers should choose a range between this and that. There’ll be more detail on that later.

The second thing is that part of the degree to which HbA_1c represents the average blood glucose depends on a lot of factors, and some of these factors are things that we can do absolutely nothing about because we are born with them. African Americans tend to have higher HbA_1c levels than do whites for the same glucose. That difference is as much as 0.4. An HbA^_1c of 6.2 in African Americans gets you a 5.8 in whites for the same average blood glucose. Similarly, Native Americans have somewhat higher HbA_1c, although not quite as high as African Americans. Hispanics and Asians do as well, so you have to take your patient’s ethnicity into account.

The second has to do with the way that HbA_1c is measured and the fact that there are many things that can affect the measurement. An HbA_1c is dependent upon the lifespan of the red blood cell, so if there are alterations in red cell lifespan or if someone has anemia, that can affect HbA_1c. Certain hemoglobin variants, for example, hemoglobin F, which is typically elevated in someone with thalassemia, migrates with some assays in the same place as thalassemia, so the assay can’t tell the difference between thalassemia and hemoglobin F. There are drugs and other conditions that can also affect HbA_1c. You should think about HbA_1c as a guide, but no number should be considered to be written in stone.

Dr. Conlin. I can imagine that this would be particularly important if you were using HbA_1c as a criterion for diagnosing diabetes.

Dr. Aron. Quite right. The effects of race and ethnicity on HbA_1c account for one of the differences between the VA/DoD guidelines and those of the American Diabetes Association (ADA).

Dr. Conlin. Isn’t < 8% HbA_1c a national performance measure that people are asked to adhere to?

Dr. Aron. Not in the VA. In fact, the only performance measure that the VA has with a target is percent of patients with HbA_1c > 9%, and we don’t want any of those or very few of them anyway. We have specifically avoided targets like < 8% HbA_1c or < 7% HbA_1c, which was prevalent some years ago, because the choice of HbA_1c is very dependent upon the needs and desires of the individual patient. The VA has had stratified targets based on life expectancy and complications going back more than 15 years.

Dr. Conlin. Another issue that can confuse clinicians is when the HbA_1c is in the target range but actually reflects an average of glucose levels that are at times very high and very low. How do we address this problem clinically?

Dr. Aron. In managing patients, you use whatever data you can get. The HbA_1c gives you a general indication of average blood glucose, but particularly for those patients who are on insulin, it’s not a complete substitute for measuring blood glucose at appropriate times and taking the degree of glucose variability into account. We don’t want patients getting hypoglycemic, and particularly if they’re elderly, falling, or getting into a car accident. Similarly, we don’t want people to have very high blood sugars, even for limited periods of time, because they can lead to dehydration and other symptoms as well. We use a combination of both HbA_1c and individual measures of blood glucose, like finger-stick blood sugar testing, typically.

Dr. Conlin. The VA/DoD CPG differs from other published guidelines in that we proposed patients are treated to HbA_1c target ranges, whereas most other guidelines propose upper limits or threshold values, such as the HbA_1c should be < 7% or < 8% but without lower bounds. Dr. Colburn, what are the target ranges that are recommended in the CPG? How were they determined?

Maj. Jeffrey A. Colburn, MD. It may be helpful to pull up the Determination of Average Target HbA_1c Level Over Time table (page S17), which lays out risk for patients of treatment as well as the benefits of treatment. We first look at the patient’s state of health and whether they have a major comorbidity, a physiologic age that could be high risk, or advanced physiologic age with a diminished life expectancy. In controlling the levels of glucose, we’re often trying to benefit the microvascular health of the patient, realizing also that eventually poor management over time will lead to macrovascular disease as well. The main things that we see in child data is that the benefits of tight glucose control for younger patients with shorter duration of type 2 diabetes mellitus (T2DM) is the prevention of retinopathy, nephropathy, and peripheral neuropathy. Those patients that already have advanced microvascular disease are less likely to benefit from tight control. Trying to push glucose very low can harm the patient. It’s a delicate balance between the possible benefit vs the real harm.

The major trials are the ADVANCE, ACCORD, and the VADT trial, which was done in a VA population. To generalize the results, you are looking at an intensive control, which was trying to keep the HbA_1c in general down below the 7% threshold. The patients enrolled in those trials all had microvascular and macrovascular disease and typically longer durations of diabetes at the time of the study. The studies revealed that we were not preventing macrovascular disease, heart attacks, strokes, the types of things that kill patients with diabetes. Individuals at higher HbA_1c levels that went down to better HbA_1c levels saw some improvement in the microvascular risk. Individuals already at the lower end didn’t see as much improvement. What we saw though that was surprising and concerning was that hypoglycemia, particularly severe hypoglycemia in the VADT trial was a lot more frequent when you try and target the HbA_1c on the lower end. Because of these findings, we proposed the table with a set of ranges. As Dr. Aron noted, HbA_1c is not a perfect test. It does have some variance in the number it presents. The CPG proposed to give individuals target ranges. They should be individualized based upon physiologic age, comorbidities, and life expectancy.

A criticism of the table that I commonly hear is what’s the magic crystal ball for determining somebody’s life expectancy? We don’t have one. This is a clinician’s judgment. The findings might actually change over time with the patient. A target HbA_1c range is something that should be adapted and evolve along with the clinician and patient experience of the diabetes.

There are other important studies. For example, the UKPDS trials that included patients with shorter durations of diabetes and lesser disease to try and get their HbA_1c levels on the lower end. We included that in the chart. Another concept we put forward is the idea of relative risk (RR) vs absolute risk. The RR reduction doesn’t speak to what the actual beginning risk is lowered to for a patient. The UKPDS is often cited for RR reduction of microvascular disease as 37% when an HbA_1c of 7.9% is targeted down to 7.0%. The absolute risk reduction is actually 5 with the number needed to treat to do so is 20 patients. When we present the data, we give it a fair shake. We want individuals to guide therapy that is going to be both beneficial to preventing outcomes but also not harmful to the patient. I would highly recommend clinicians and patients look at this table together when making their decisions.

Dr. Conlin. In the VA/DoD CPG, the HbA_1c target range for individuals with limited life expectancy extends to 9%. That may seem high for some, since most other guidelines propose lower HbA_1c levels. How strong are the data that a person with limited life expectancy, say with end-stage renal disease or advanced complications, could be treated to a range of 8% to 9%? Shouldn’t lower levels actually improve life expectancy in such people?

Dr. Colburn. There’s much less data to support this level, which is why it’s cited in CPG as having weaker evidence. The reason it’s proposed is the experience of the workgroup and the evidence that is available of a high risk for patients with low life expectancy when they reduce their HbA_1c greatly. One of the concerns about being at that level might be the real issue of renal glycosuria for individuals when their blood glucose is reaching above 180 mg/dL, which correlates to the 8% to 9% HbA_1c range. You may have renal loss and risk of dehydration. It is an area where the clinician should be cautious in monitoring a patient in the 8% to 9% HbA_1c range. With that being said, a patient who is having a lot of challenges in their health and extremely advanced conditions could be in that range. We would not expect a reversing of a micro- or macrovascular disease with glycemia control. We’re not going to go back from that level of disease they have. The idea about keeping them there is to prevent the risks of overtreatment and harm to the patient.

Dr. Conlin. Since patients with diabetes can progress over their lifetime from no complications to mild-to-moderate complications to advanced complications, how does the HbA_1c target range evolve as a patient’s condition changes?

Dr. Colburn. As we check for evidence of microvascular disease or neuropathy signs, that evidence often is good for discussion between the clinician and patient to advise them that better control early on may help stem off or reverse some of that change. As those changes solidify, the patient is challenged by microvascular conditions. I would entertain allowing more relaxed HbA_1c ranges to prevent harm to the patient given that we’re not going back. But you have to be careful. We have to consider benefits to the patient and the challenges for controlling glucose.

I hope that this table doesn’t make providers throw up their hands and give up. It’s meant to start a conversation on safety and benefits. With newer agents coming out that can help us control glucose quite well, without as much hypoglycemia risk, clinicians and patients potentially can try and get that HbA_1c into a well-managed range.

Dr. Conlin. The CPG discusses various treatment options that might be available for patients who require pharmacologic therapy. The number of agents available is growing quite markedly. Dr. Colburn, can you describe how the CPG put together the pharmacologic therapy preferences.

Dr. Colburn. The CPG expressively stayed away from trying to promote specific regimens of medications. For example, other guidelines promote starting with certain agents followed by a second-line agent by a third-line agents. The concern that we had about that approach is that the medication landscape is rapidly evolving. The options available to clinicians and patients are really diverse at this moment, and the data are not concrete regarding what works best for a single patient.

Rather than trying to go from one agent to the next, we thought it best to discuss with patients using the SHARE decision-making model, the adverse effects (AEs) and relative benefits that are involved with each medication class to determine what might be best for the person. We have many new agents with evidence for possible reductions in cardiovascular outcomes outside of their glycemic control properties. As those evidences promote a potentially better option for a patient, we wanted to allow the room in management tomake a decision together. I will say the CPG as well as all of the other applicable diabetes guidelines for T2DM promote metformin as the first therapy to consider for somebody with newly diagnosed T2DM because of safety and availability and the benefit that’s seen with that medication class. We ask clinicians to access the AHRQ website for updates as the medicines evolve.

In a rapidly changing landscape with new drugs coming into the market, each agency has on their individual website information about individual agents and their formulary status, criteria for use, and prior authorization requirements. We refer clinicians to the appropriate website for more information.

Dr. Conlin. There are a series of new medications that have recently come to market that seem to mitigate risk for hypoglycemia. Dr. Lugo, which treatment options carry greater risk? Which treatment options seem to have lesser risk for hypoglycemia?

Amy M. Lugo, PharmD. Insulin and the sulfonylureas have the highest risk of hypoglycemia. The sulfonylureas have fallen out of favor somewhat. One reason is that there are many newer agents that do not cause weight gain or increase the risk of hypoglycemia. Some of the newer insulins may have a lower risk of hypoglycemia and nocturnal hypoglycemia, in particular; however, it is difficult to conclude emphatically that one basal insulin analog is less likely to cause clinically relevant severe or nocturnal hypoglycemia events. This is due to the differences in the definitions of hypoglycemia used in the individual clinical trials, the open label study designs, and the different primary endpoints.

Dr. Conlin. How much affect on HbA_1c might I expect to see using SGLT2 inhibitors or GLP-1 agonists? What would be some of the potential AEs I have to be aware of and therefore could counsel patients about?

Dr. Lugo. Let’s start with SGLT2 inhibitors. It depends on whether they are used as monotherapy or in combination. We prefer that patients start on metformin unless they have a contraindication. When used as monotherapy, the SGLT2s may decrease HbA_1c from 0.4% to 1% from baseline. When combined with additional agents, they can have > 1% improvement in HbA_1c from baseline. There are no head-to-head trials between any of the SGLT2 inhibitors. We cannot say that one is more efficacious than another in lowering HbA_1c. The most common AEs include genital mycotic infections and urinary tract infections. The SGLT2 inhibitors also should be avoided in renal impairment. There was a recent FDA safety alert for the class for risk of ketoacidosis. Additionally, the FDA warned that patients
with a history of bladder cancer should avoid dapagliflozin, and canagliflozin has a warning for increased risk of bone fractures, amputation, and decreased bone density.

Other actions of the SGLT2 inhibitors include a reduction in triglycerides and a modest increase in both low-density lipoprotein cholesterol and highdensity lipoprotein cholesterol. The SGLT2 inhibitors also slightly decrease systolic blood pressure (by 4 mm Hg to 6 mm Hg) and body weight (reduction of 1.8 kg)

The GLP-1s are likely to be more efficacious in reducing HbA_1c. Typically we see 1% or greater lowering in HbA_1c from baseline. As a class, the GLP-1 agonists have a lower risk of hypoglycemia; however, the risk increases when combined with sulfonylureas or insulin. The dose of insulin or sulfonylurea will likely need to be decreased when used concomitantly.

Patients are likely to experience weight loss when on a GLP-1 agonist, which is a great benefit. Gastrointestinal AEs such as nausea are common. Adverse effects may differ somewhat between the agents.

Dr. Conlin. Patients’ experience of care is integral to their engagement with treatment as well as their adherence. Ms. Decesare, what are patients looking for from their health care team?

Elaine M. Decesare. Patients are looking for a knowledgeable and compassionate health care team that has a consistent approach and a consistent message and that the team is updated on the knowledge of appropriate treatments and appropriate lifestyle modifications and targets for the care of diabetes.

Also, I think that the team needs to have some empathy for the challenges of living with diabetes. It’s a 24-hour-a-day disorder, 7 days a week. They can’t take vacation from it. They just can’t take a pill and forget about it. It’s a fairly demanding disorder, and sometimes just acknowledging that with the patient can help you with the dialog.

The second thing I think patients want is an effective treatment plan that’s tailored to their needs and lifestyles. That goes in with the shared decision-making approach, but the plan itself really has to be likely to achieve the targets and the goals that you’ve set up. Sometimes I see patients who are doing all they can with their lifestyle changes, but they can’t get to goal, because there isn’t enough medication in the plan. The plan has to be adequate so that the patient can manage their diabetes. In the shared approach, the patient has to buy in to the plan. With the shared decision making they’re more likely to take the plan on as their plan.

Dr. Conlin. How do you respond to patients who feel treatment burnout from having a new dietary plan, an exercise program, regular monitoring of glucose through finger sticks, and in many cases multiple medications and or injections, while potentially not achieving the goals that you and the patient have arrived at?

Ms. Decesare. First, I want to assess their mood. Sometimes patients are depressed, and they actually need help with that. If they have trouble with just the management, we do have behavioral health psychologists on our team that work with patients to get through some of the barriers and discuss some of the feelings that they have about diabetes and diabetes management.

Sometimes we look at the plan again and see if there’s something we can do to make the plan easier. Occasionally, something has happened in their life. Maybe they’re taking care of an elderly parent or they’ve had other health problems that have come about that we need to reassess the plan and make sure that it’s actually doable for them at this point in time.

Certainly diabetes self-management education can be helpful. Some of those approaches can be helpful for finding something that’s going to work for patients in the long run, because it can be a very difficult disorder to manage as time goes on.

Dr. Colburn. Type 2 DM disproportionately affects individuals who are ≥ 65 years compared with younger individuals. Such older patients also are more likely to have cognitive impairment or visual issues. How do we best manage such patients?

Ms. Decesare. When I’m looking at the care plan, social support is very important. If someone has social support and they have a spouse or a son or daughter or someone else that can help them with their diabetes, we oftentimes will get them involved with the plan, as long as it’s fine with the patient, to offer some help, especially with the patients with cognitive problems, because sometimes the patients just cognitively cannot manage diabetes on their own. Prandial insulin could be a really dangerous product for someone who has cognitive disease.

I think you have to look at all the resources that are available. Sometimes you have to change your HbA_1c target range to something that’s going to be manageable for that patient at that time. It might not be perfect, but it would be better to have no hypoglycemia rather than a real aggressive HbA_1c target or a target range, if that’s what’s going to keep the patient safe.

Dr. Conlin. We thank our discussants for sharing very practical advice on how to implement the CPG. We hope this information supports clinicians as they develop treatment plans based on each patient's unique characteristics and goals of care.

Click here to read the digital edition.

Comorbidities

Joshua M. Bauml, MD, Corporal Michael J. Crescenz VAMC, Philadelphia, PA. One of the comorbidities that most commonly affects my patients is hearing loss—this is one of the most common causes of service-connected disability for veterans. Patients who have clinically significant hearing loss cannot receive cisplatin, which I frequently use in the adjuvant treatment of non-small cell lung cancer (NSCLC).

In addition, kidney dysfunction is quite common as a result of comorbid cardiovascular and hypertensive diseases. Kidney dysfunction can negatively impact our ability to administer both cisplatin and other systemic therapies.

Millie Das, MD, Palo Alto Health Care System, CA. Another major comorbidity for a lot of our veterans is COPD (chronic obstructive pulmonary disease). It doesn’t complicate the chemotherapy choice, but it affects surgical candidacy for those patients who present with early stage disease. Many times if you obtain pulmonary function tests in patients with COPD, the tests are abnormal and can prohibit safe surgical resection. These are patients that I see in the clinic and refer for definitive radiation, usually SABR (stereotactic ablative radiotherapy)/SBRT (stereotactic body radiation therapy), at a local radiation facility that can offer specialized radiation treatment.

Dr. Bauml. The fact that the VA has so many patients who require stereotactic radiosurgery for their early stage lung cancer represents an opportunity. There is a newly opened study that is evaluating SBRT vs surgery for these early stage lung cancer patients within the VA system. That study model has previously failed in multiple health care settings, but the VA is uniquely suited to answer this question.

Kelly A. Tammaro, PharmD, BCOP, Boston VA Healthcare System, MA. I would add heart failure patients or patients who have cardiac comorbidities and fluid restrictions. These restrictions can affect hydration that is needed for cisplatin, for example, as well as final volumes used to mix other chemotherapeutic agents with narrow concentration maximums, such as etoposide.

Julie Beck, RN, MSN, MPH, APRN-BC, VA Connecticut Healthcare System West Haven Campus. As a lung cancer navigator, I find that psychosocial comorbidities are an impediment to getting patients to diagnosis and treatment. Patients will miss appointments because they don’t have rides or will be reluctant to get imaging or other diagnostic testing because of anxiety or because it triggers PTSD (posttraumatic stress disorder) or because they are concerned about cost.

Dr. Das. I couldn’t agree more.

Dr. Bauml. It’s a great point.

Ms. Beck. You have to think outside the box with this patient population. We treat patients from as far away as Western Massachusetts. We have a dedicated oncology social worker who helps to arrange transportation. We have  our CLC ( community living center), which is a rehabilitation and hospice unit but is also a resource for patients who live alone or far away and are getting an aggressive daily treatment regimen such as combined chemotherapy and radiation. We admit some patients to the CLC during their treatment to ensure that they get their treatment on time, maintain their nutritional status, and to provide emotional support. This is not an acute medical bed. Patients will sometimes go home on the weekend, but the support of the CLC increases the chance that they will get through their treatment safely.

Cancer care requires a lot of handholding. We often have to make multiple telephone calls to persuade our patients to get imaging or biopsies. Some of our patients require admission following biopsy because they live alone and have no one to drive them home following the procedure.

Dr. Tammaro. Boston has a similar model. We have a social worker who is highly dedicated and is able address our patients needs immediately. We also have many patients with PTSD and other psychological comorbidities, and depending on the severity, may require admission for their treatment to avoid the overwhelming nature of the ambulatory setting. For those who have to travel long distances for treatment we the Huntington House, which is housing located next door to our ambulatory campus. This accommodation can be used by our patients and their caregivers. We also have long term care facilities and a hospice unit located at our Brockton facility.

Ms. Beck. In West Haven, we have both palliative care and health psychology providers embedded in our clinic. They assist with symptom management and issues related to coping with diagnosis, anxiety, sleep, pain, smoking cessation, and lifestyle changes. We have also been offering pet therapy through our social work team, which has been very helpful for many of our patients.

Dr. Bauml. Mental health issues also can affect the choice of the type of treatment. Patients who have severe claustrophobia associated with their PTSD may have difficulty undergoing radiation. This can impact their ability to comply with therapy, and we have to adjust the treatment accordingly. For instance, I have a patient who has a known brain metastasis that was treated with definitive intent, but this gentleman gets highly agitated doing a brain magnetic resonance image (MRI). Instead we have had to follow him with serial computed tomography (CAT) scans, which is suboptimal. We have discussed that, but the distress that it causes him is simply not worth it.

Dr. Das. In some instances, we have had to use IV sedation for some of our patients with severe claustrophobia just to be able to get them through a positron emission tomography (PET) scan as part of their staging workup. We discuss these types of challenging cases in a multidisciplinary setting in our thoracic tumor board in order to brainstorm and figure out a realistic plan with our radiology and anesthesia colleagues, with the goal of getting the patient through the necessary tests in order to establish a treatment recommendation.

Due to underlying mental health or other health issues, some of our patients may also have difficulty with breath holding or with following other necessary instructions during their radiation treatments. We sometimes have to get creative on an individual basis in order to help a patient get through the needed treatment.

We have a dedicated psychologist and social worker who are embedded in our clinics and work closely with the oncology providers to offer strategies that can help our patients comply and complete the recommended treatment plan.

Rural Care

Dr. Bauml. One of the questions that comes up frequently when you have a patient who is remote is the type of treatment that you can administer. It’s difficult to administer a weekly therapy if somebody’s traveling 3 hours to see you every time. That can play into your decision making as you’re choosing a chemotherapy. If there are equivalent treatment regimens and one involves visits every 3 weeks and one involves weekly visits, well, that will help sway your decision making after discussion with the patient.

We often have to balance things. For instance, when I give someone carboplatin and paclitaxel, my preference is to administer it weekly with 3 weeks on and 1 week off. However, if a patient tells me, “You know, I do not want to come in once a week,” then I will discuss with them my concern for the increased adverse effects (AEs) with the every-3-week dosing. We will do it and then watch them closely. Of course, this gets even more complicated when you consider the fact that many of these patients have multiple medical comorbidities, so you’d like to administer the treatments in the least toxic way possible.

Ms. Beck. We have overcome some of those challenges by partnering with the primary care doctors. We are very close to our primary care colleagues in Massachusetts. They will order labs for the patient the day before the patient's appointment, so if the patient has a long drive, we already have their lab work; and they are ready to go when they get here for their treatment. The nursing staff is very aware of who needs to get on a shuttle back to Massachusetts. For some patients, we will have them stay overnight before their treatment.

Precision Oncology

Dr. Tammaro. In Boston, we have integrated Precision Oncology to be part of clinical practice, which we started with metastatic lung cancer patients. The VA Precision Oncology Program (POP) began at our healthcare center. We had to evaluate the genetic testing platforms, the accuracy of the results, and amount of tissue necessary for the laboratories. We have since succeeded in sending high-quality samples to the laboratories that generate accurate results. However, for your standard mutation panel for identifying therapy for first line treatment in lung cancer, we still use our local send out laboratory.

The POP has rolled out nationwide, and it is another clinical tool, especially for patients who have already failed multiple lines of therapy. When we send for a precision oncology consult, the “N of 1” report provides annotation. The report will generate a review of relevant literature and provide available abstracts or phase 1 or 2 trials that support a targeted therapy against potential point mutation for your patient.

The POP also has a research component, known as Re-POP. The goal is to open bucket trials that assess targeted therapy off label. Re-POP allows us to recontact these patients in the future to say, “You had your tissue sent through precision oncology, and you were diagnosed with a certain point mutation. Now we have a clinical trial that’s available. Would you be interested?” The plan is to have those clinical trials open and available to our patients when we receive the results from precision oncology.

I have used POP for 2 metastatic prostate cancer patient who exhausted all lines of therapy in hopes to identify a potential BCRA 1/2 mutation in order for us to use a PARP inhibitor. Unfortunately, neither harbored this mutation. Precision oncology does not perform immunohistochemistry, therefore identifying HER-2 or PD-L1 status for example, would need to be done through your local laboratory. I have found POP to be helpful in identifying a patients potential therapeutic option after progression on first/second line therapy, by sending tissue to POP initially or at the time of relapse.

Dr. Das. In our clinical practice at the Palo Alto VA, we follow the National Comprehensive Cancer Network (NCCN) guidelines, and we routinely evaluate for the presence of an EGFR mutation and also for ALK and ROS1 translocations in all lung cancer patients with nonsquamous histology. We send our molecular testing through Quest Diagnostics (Madison, NJ), and we usually get results back within a week or so.

For those patients who do not have any of those targetable gene alterations, we will go ahead and send for next-generation sequencing through POP, which allows testing of a much broader gene panel. Those results can take about a month or so to come back. I usually don’t wait for these results in order to get someone started on treatment. For patients without EGFR, ALK, or ROS1 found on initial testing, I will go ahead and start them on IV systemic chemotherapy. It is often very useful when you do get the next-generation sequencing results back, since in almost all cases, a gene alteration can be detected and is provided in the accompanying report. In a large subset of lung cancer cases, a gene alteration is seen in KRAS, for which we still do not have an effective targeted therapy. Despite this, I still find it useful to obtain the results because we generally feel that the driving genetic alterations occur mutually exclusive of one another. When we do see KRAS reported from a patient’s tumor specimen, we’re not generally looking for other types of mutations, so I find it helpful to know what is the alteration that is driving the growth of a patient’s tumor. The trend moving forward is to perform next-generation sequencing on all tumor specimens regardless of tumor type or histology, which can hopefully enable us to get to the bottom of what the driving genetic alteration is and to see if there are any targeted treatment approaches that can be offered to the patient.

In a few lung cancer cases, I have seen alterations in HER2 and BRAF that have been detected and reported using a next-generation sequencing platform. Just recently the FDA approved the BRAF-directed therapies of dabrafenib and trametinib for patients with lung cancer who are found to have a BRAF V600E mutation. It is hoped that as the FDA continues to provide approvals for targeted drugs in patients with lung cancer, the VA formulary will be able to offer these therapies to our veteran patients with the ultimate goal of providing treatment that has increased efficacy and less toxicity compared to conventional IV chemotherapy.

One of my frustrations earlier on was when we did find these more rare targetable mutations, I would run into problems with the VA formulary in allowing me to prescribe certain targeted therapies. In many cases, if the drug was not FDA-approved for lung cancer, I was told that I couldn’t use it and would have to go through the appeal process, which was quite onerous. Moving forward, we are seeing more and more data and trials with newer targeted agents in lung cancer, leading to new FDA approvals. With these approvals, I think it will be easier to be able to offer these targeted therapies to our patients.

Dr. Bauml. One of the issues that arises when we’re discussing even the FDA-approved therapies, is that many of these targeted therapies are relatively rare, and they’re especially rare amongst veterans. Now others have mentioned BRAF and HER2, and these do have some overexpression and mutations that occur among smokers. But the more common targetable genetic aberrations, EGFR, ALK, and ROS1 are more common amongst never-smokers. Given the high prevalence of tobacco use among veterans, these changes are rare. The incidence of ALK translocation is 3% to 7%. The incidence amongst veterans is likely much lower than that, given the tobacco abuse—to the point that I actually had a patient who had an ALK translocation; and of course, I prescribed the patient crizotinib. This was prior to the ALEX Trial and alectinib data. I prescribed crizotinib and was told it wasn’t on the formulary. Initially I was surprised, but when I said, “Well, look, when was the last time someone within our VA has prescribed crizotinib?” The answer was never.

This is the difficulty: As we enter this era of molecularly targetable therapy, the way we structure our formularies and the way that we review these data is going to have to change. This year at the American Society of Clinical Oncology (ASCO) meeting there were some very exciting lung cancer abstracts that evaluated ado-trastuzumab emtansine, which is an antibody drug conjugate currently approved for the treatment of HER2 overexpressing breast cancer. The abstracts showed response rates of up to 40% in lung cancer with the administration of this drug in HER2-mutated lung cancer. The HER2-amplified still had a response rate of 20%, which given the toxicity profile of this agent, is quite appealing. Being able to explore these early phase studies, as was described through the personalized medicine pathway, is, a great step forward for VA care.

Dr. Tammaro. The PBM in collaboration with the POP Advisory Board, are developing different levels of evidence to support the use of targeted medications identified to be potential therapy in those diagnosed with a point mutation. Even if a medication does not have an FDA approval, it has to have some evidence to support its use in a particular cancer. If you identify a point mutation or biomarker in a patient and provide evidence to supports its use within that particular disease state, the VA pharmacy could approve its use based off of that evidence. VA pharmacy would not require an actual FDA approval for that indication.

What the VISNs, PBM, and precision oncology are trying to do is determine the level of evidence that we have to support or approve use of a targeted therapy. We are definitely moving forward and changing the horizon on how we actually treat our patients after they’ve gone through first-line therapy. We are trying to figure out where these point mutations come in, the line of the therapy, and how we actually treat these cancers. Pharmacy is making a step forward in conjunction with Michael Kelley, MD, the National Program Director for Oncology, Specialty Care Services, whose group is establishing those guidelines.

Dr. Bauml. I don’t mean to downplay the difficulty of that process. This is a huge, difficult process. One only needs to look at the long line of failed trials looking at PI3 kinase inhibitors to show that just knowing that a mutation exists does not necessarily mean that a targeted therapy works in that space.

Drawing that line is really complicated, both within the VA and, indeed, outside of the VA. It’s a really complicated process, and understanding the implications of different mutations is only going to get more complicated. Of course, now we have things like NTRK and even rarer genetic aberrations that are going to affect not only lung cancer, but also a wide range of malignancies.

Promising Research

Dr. Bauml. The pathways that are emerging as clear driver mutations for which we have available therapies, at least within lung cancer, are MET exon 14, RET, and NTRK. I am also intrigued by the emerging data in the HER2 space.

Dr. Das. The other therapy that has been getting a lot of press is immunotherapy, of course. And I’ve been seeing many really good responders to immunotherapy within the veteran population that I treat. It is felt that degree of PD-L1 expression correlates with responsiveness to the immune check point inhibitors that are being used in lung cancer, and we are tending to see higher rates of PD-L1 expression in patients who are prior or current smokers who have a higher overall tumor mutation burden.

I see patients both at Stanford and at the Palo Alto VA, and I have noticed that the patients that I have been treating at the VA tend to have higher levels of PD-L1 expression with better responses to the immunotherapy drugs, probably because most of the VA patients are former or current smokers. And, another interesting observation is that these veteran patients are, for whatever reason, having a lower incidence of some of the autoimmune AEs seen with these immune checkpoint inhibitors. I have been keeping an eye out for more data and information to support these observations I have had in my clinical practice and I specifically attended ASCO this year to learn more about what others have seen and studied with immune check point inhibition in lung cancer. We are learning now that PD-L1 is not a perfect marker for predicting response to the checkpoint inhibitors and the other immunotherapeutic agents, and there is a great deal of research going on to try to figure out what other biomarkers could be useful and which patients are most likely to benefit from these drugs.

I was excited to hear about the combination of nivolumab and ipilimumab that is being tested in both mesothelioma and in small-cell lung cancer where we really don’t have as many treatment options as we have in non-small cell lung cancer. That data was quite exciting, and interestingly, there does not seem to be a correlation with PD-L1 expression and responsiveness to treatment with the immunotherapeutic agents in those histologic subtypes. The story is still unfolding, and we await additional data to help guide us in our treatment decisions.

Dr. Tammaro. Immunotherapy is the new fad in oncology. We have just scheduled our first patient for first-line therapy due to PD-L1 tumor proportion score is > 50%. Recently, at ASCO KEYNOTE-021 researchers looked at using pembrolizumab in combination with carboplatin plus pemetrexed chemotherapy for first-line metastatic non-squamous NSCLC. The research suggested that patients treated with pembrolizumab + chemotherapy continued to derive a higher overall response rate and progression free survival when compare with those on chemotherapy alone despite a low or no PD-L1 tumor expression.

It’s very interesting that many clinical trials that we’re evaluating are now using some type of checkpoint inhibitor up front with cytotoxic chemotherapy. If they are positive trials, this could change how patients are treated up front.

Dr. Bauml. There was some really interesting data that were presented at ASCO this year by Matthew Hellmann, MD, which evaluated the predictive nature of PD-L1 vs tumor mutation burden and other biomarkers, including gene expression profiling. In this particular abstract, the PD-L1 and tumor mutation burden really do function as orthogonal biomarkers such that a patient who has high PD-L1 and high tumor mutation burden is the most likely to respond. Patients who are really low for both are unlikely to respond. We really need better biomarkers for immunotherapy, though. PD-L1 has a lot of limitations, namely, it is dynamic, so over time it changes. So I can do a biopsy at one point, then treat the patient and the PD-L1 may change.

More importantly, it’s heterogeneous. There was this great paper by McLaughlin and colleagues in JAMA Oncology (2016) who described a patient who had a small tumor biopsy. They took a micrograph of the tumor and showed that one part of the micrograph was completely floridly PD-L1 positive. At another site of the same biopsy it was completely stone-cold negative, which is humbling when you think about the fact that we stick small needles into tumors and make clinical decisions on the basis of that.

The KEYNOTE-024 study evaluated pembrolizumab vs chemotherapy in high PD-L1 expressers. It’s a very exciting study, but at the end of the day even in this highly select patient population, the response rate to immunotherapy was only about 50%, which is not the sort of biomarker-driven response that we’re used to seeing with our EGFR inhibitors. That’s really what we want to get to. More important even than that is being able to say the negative predictive value. One of the reasons that we’re probably seeing more responses among veterans is that we know that patients who are veterans who have high tobacco exposure have a higher tumor mutation burden. I’m surprised to hear about the immune-related AEs, actually, because one of the things that was reported this year at ASCO was some data that showed that patients who have immune-related AEs are more likely to have a better outcome, which is an interesting biomarker of response.

Dr. Das. I heard that as well, and I found that to be really interesting. The patients that I’ve had on nivolumab for over a year are doing very well. These are stage IV patients who have essentially had complete responses to treatment and have not had any or have had very minor immune-related AEs to date.

Overall, these are a small numbers of patients, but I have been curious to see why that might be the case. Anecdotally, my colleagues and I who treat patients at Stanford have seen significantly higher rates of grades 3 and 4 pneumonitis and other autoimmune toxicities, such as myocarditis and enterocolitis, in those lung cancer patients who are light or never-smokers treated with immune checkpoint inhibitors.

Dr. Bauml. I really feel that PD-L1 as a biomarker has significant limitations. I certainly hope that in at least 2 or 3 years we’re not going to be talking about PD-L1 anymore. I’m hopeful that we’ll be able to use better predictive biomarkers, such as mutational burden and gene expression profiling. In the data in head and neck that was presented this year at ASCO, patients who were low for both gene expression profiling and mutational burden had a very low response (Haddad et al, ASCO 2017).

That’s really what you want to be. You want to be able to say, “Here’s a person who will not benefit from this therapy.” From there you can identify, based upon these biomarkers, the combination that is going to be best for this person. Is it chemoimmunotherapy or combination immunotherapy with CTLA4, or another checkpoint blockade? That is really the way that we’re going to be able to fine-tune this, because the toxicity is substantial for some treatments, like the nivolumab/ipilimumab combination. Using them in a biomarker-blind fashion is just scary to me, honestly.

Managing Adverse Reactions

Dr. Tammaro. The increasing amount of oral chemotherapy has posed a significant challenge. As a clinical oncology pharmacist, it was difficult to grasp the most effective way to follow all these patients and ensure adherence, adverse drug event reporting/significance and adequate follow up. When patients are receiving IV chemotherapy, we know we will see them, we are assured compliance and are able to assess side effects in a timely manner. When we give oral chemotherapy, the tables are turned, where the responsibility is now on the patient. We are now depending on the patient to ensure they are taking the medication correctly and we may not see AEs if the patient misses an appointment or feels as though they are bothering the provider by calling.

In 2012, we started an oral oncology clinic here at the VA in Boston that I found to be extremely effective. When you’re sending a patient home with an oral chemotherapy, you have to make sure that you are counseling them correctly and encourage them to call at any time if they are experiencing any type of AE. One of the newest issues we have been seeing is bleeding with ibrutinib, especially in those patients on anticoagulation therapies.

A general strategy we employee for oral chemotherapy is to start at half dose and titrate slowly. This method has been effective in identifying AEs and preventing delays in therapy. We do this for the majority of oral chemotherapy. Patients are given a 2 week supply to start and then are reassessed on follow up for escalation to the target dose. We do not place refills on oral oncology prescriptions. They are instructed to call 10 days prior to running out if they are not scheduled to come in for an appointment. Having consistent dialogue with our patients allows us to assess for adherence, AEs, and tolerability. The other advantage to this clinic is ensuring our patients have someone to speak to at all times and answer all their questions. Direct lines of communication is what most of our patients are appreciative of when paying gratitude to the clinic.

Ms. Beck. We have an oral chemotherapy clinic staffed by dedicated oncology pharmacists. Patients meet with the pharmacist and have education prior to starting a new oral chemotherapy. They will then be followed by both the oncology provider and the pharmacist.

Dr. Das. One of the challenges we also face is with so many of our patients living so far away. When our patients do have AEs that require hospitalization, it can be very tricky to really get a sense for how they are being managed at the outside community (non-VA) facility. Sharing of electronic medical records can be a challenge in these cases, and I worry that the care teams at the more remote hospitals may not be as familiar with the newer cancer treatments and the toxicities associated with them, such as the autoimmune AEs associated with many of the immune checkpoint inhibitors.

I provide patients with pocket cards to keep in their wallets with my contact information and the name of the drug that they are getting because not all patients can remember or even pronounce the names of the drugs and may not be able to tell their local treating physician and care team what they are getting. I have been getting more frequent phone calls from emergency department physicians and hospitalists from the local communities where many of our veterans live, because they want guidance on how best to approach treatment for our patients when they show up with an AE related to their cancer treatment.

At times, the presenting symptoms may be vague or nonspecific, but for our patients being treated with immunotherapy, we always have to keep in mind the possibility of immune-related AEs because we know that prompt initiation of steroids is critical in these cases and can really help the patients feel better quickly.

Dr. Tammaro. You bring up a valid point. Our pharmacists meet with all the patients on checkpoint inhibitors. Specifically, when we started using ipilimumab it was uncharted territory for our team. We put together take home medication bag that included hydrocortisone cream, methylprednisolone dose pak, dipheydramine, and loperamide. This was utilized for all patients and specific attention was given to patients who lived far away from an emergency room. This bag system was accompanied by “what to do if I have this symptom” handout that outlined which medication to take depending on the severity of the AE. A direct line phone line to the oncology pharmacy also was supplied.

With the evolution to the PD-L1s and the anti-PD inhibitors, we haven’t seen the same level of AEs. Patients go home with wallet cards that includes our staff contact numbers/pagers. The wallet card also serves as information to a treating provider if the patient presents outside the VA, to ensure they understand the severity of a potential autoimmune AE, such as diarrhea.

Another challenge is shared-care patients. We have patients coming from outside hospitals, and at times they want to use this pharmacy like a CVS, and it just doesn’t operate that way. We want to collaborate with others. Most shared care patients present to our service for oral chemotherapy because the veteran just can’t afford the copays. So, we will see the patient concurrently. They can still see their outside hospital physician as well, but they have to fax us the laboratory results and progress notes on a monthly basis (or longer depending on where they are in there therapy). Before we fill their medications, we talk to the patients, the same way we would treat a veteran who was getting their oral chemotherapy here. In addition, they need to be seen by the VA physician at least every 3 months. We want our veterans to feel comfortable with the cancer care and help them out as best as we can.

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Comorbidities

Joshua M. Bauml, MD, Corporal Michael J. Crescenz VAMC, Philadelphia, PA. One of the comorbidities that most commonly affects my patients is hearing loss—this is one of the most common causes of service-connected disability for veterans. Patients who have clinically significant hearing loss cannot receive cisplatin, which I frequently use in the adjuvant treatment of non-small cell lung cancer (NSCLC).

In addition, kidney dysfunction is quite common as a result of comorbid cardiovascular and hypertensive diseases. Kidney dysfunction can negatively impact our ability to administer both cisplatin and other systemic therapies.

Millie Das, MD, Palo Alto Health Care System, CA. Another major comorbidity for a lot of our veterans is COPD (chronic obstructive pulmonary disease). It doesn’t complicate the chemotherapy choice, but it affects surgical candidacy for those patients who present with early stage disease. Many times if you obtain pulmonary function tests in patients with COPD, the tests are abnormal and can prohibit safe surgical resection. These are patients that I see in the clinic and refer for definitive radiation, usually SABR (stereotactic ablative radiotherapy)/SBRT (stereotactic body radiation therapy), at a local radiation facility that can offer specialized radiation treatment.

Dr. Bauml. The fact that the VA has so many patients who require stereotactic radiosurgery for their early stage lung cancer represents an opportunity. There is a newly opened study that is evaluating SBRT vs surgery for these early stage lung cancer patients within the VA system. That study model has previously failed in multiple health care settings, but the VA is uniquely suited to answer this question.

Kelly A. Tammaro, PharmD, BCOP, Boston VA Healthcare System, MA. I would add heart failure patients or patients who have cardiac comorbidities and fluid restrictions. These restrictions can affect hydration that is needed for cisplatin, for example, as well as final volumes used to mix other chemotherapeutic agents with narrow concentration maximums, such as etoposide.

Julie Beck, RN, MSN, MPH, APRN-BC, VA Connecticut Healthcare System West Haven Campus. As a lung cancer navigator, I find that psychosocial comorbidities are an impediment to getting patients to diagnosis and treatment. Patients will miss appointments because they don’t have rides or will be reluctant to get imaging or other diagnostic testing because of anxiety or because it triggers PTSD (posttraumatic stress disorder) or because they are concerned about cost.

Dr. Das. I couldn’t agree more.

Dr. Bauml. It’s a great point.

Ms. Beck. You have to think outside the box with this patient population. We treat patients from as far away as Western Massachusetts. We have a dedicated oncology social worker who helps to arrange transportation. We have  our CLC ( community living center), which is a rehabilitation and hospice unit but is also a resource for patients who live alone or far away and are getting an aggressive daily treatment regimen such as combined chemotherapy and radiation. We admit some patients to the CLC during their treatment to ensure that they get their treatment on time, maintain their nutritional status, and to provide emotional support. This is not an acute medical bed. Patients will sometimes go home on the weekend, but the support of the CLC increases the chance that they will get through their treatment safely.

Cancer care requires a lot of handholding. We often have to make multiple telephone calls to persuade our patients to get imaging or biopsies. Some of our patients require admission following biopsy because they live alone and have no one to drive them home following the procedure.

Dr. Tammaro. Boston has a similar model. We have a social worker who is highly dedicated and is able address our patients needs immediately. We also have many patients with PTSD and other psychological comorbidities, and depending on the severity, may require admission for their treatment to avoid the overwhelming nature of the ambulatory setting. For those who have to travel long distances for treatment we the Huntington House, which is housing located next door to our ambulatory campus. This accommodation can be used by our patients and their caregivers. We also have long term care facilities and a hospice unit located at our Brockton facility.

Ms. Beck. In West Haven, we have both palliative care and health psychology providers embedded in our clinic. They assist with symptom management and issues related to coping with diagnosis, anxiety, sleep, pain, smoking cessation, and lifestyle changes. We have also been offering pet therapy through our social work team, which has been very helpful for many of our patients.

Dr. Bauml. Mental health issues also can affect the choice of the type of treatment. Patients who have severe claustrophobia associated with their PTSD may have difficulty undergoing radiation. This can impact their ability to comply with therapy, and we have to adjust the treatment accordingly. For instance, I have a patient who has a known brain metastasis that was treated with definitive intent, but this gentleman gets highly agitated doing a brain magnetic resonance image (MRI). Instead we have had to follow him with serial computed tomography (CAT) scans, which is suboptimal. We have discussed that, but the distress that it causes him is simply not worth it.

Dr. Das. In some instances, we have had to use IV sedation for some of our patients with severe claustrophobia just to be able to get them through a positron emission tomography (PET) scan as part of their staging workup. We discuss these types of challenging cases in a multidisciplinary setting in our thoracic tumor board in order to brainstorm and figure out a realistic plan with our radiology and anesthesia colleagues, with the goal of getting the patient through the necessary tests in order to establish a treatment recommendation.

Due to underlying mental health or other health issues, some of our patients may also have difficulty with breath holding or with following other necessary instructions during their radiation treatments. We sometimes have to get creative on an individual basis in order to help a patient get through the needed treatment.

We have a dedicated psychologist and social worker who are embedded in our clinics and work closely with the oncology providers to offer strategies that can help our patients comply and complete the recommended treatment plan.

Rural Care

Dr. Bauml. One of the questions that comes up frequently when you have a patient who is remote is the type of treatment that you can administer. It’s difficult to administer a weekly therapy if somebody’s traveling 3 hours to see you every time. That can play into your decision making as you’re choosing a chemotherapy. If there are equivalent treatment regimens and one involves visits every 3 weeks and one involves weekly visits, well, that will help sway your decision making after discussion with the patient.

We often have to balance things. For instance, when I give someone carboplatin and paclitaxel, my preference is to administer it weekly with 3 weeks on and 1 week off. However, if a patient tells me, “You know, I do not want to come in once a week,” then I will discuss with them my concern for the increased adverse effects (AEs) with the every-3-week dosing. We will do it and then watch them closely. Of course, this gets even more complicated when you consider the fact that many of these patients have multiple medical comorbidities, so you’d like to administer the treatments in the least toxic way possible.

Ms. Beck. We have overcome some of those challenges by partnering with the primary care doctors. We are very close to our primary care colleagues in Massachusetts. They will order labs for the patient the day before the patient's appointment, so if the patient has a long drive, we already have their lab work; and they are ready to go when they get here for their treatment. The nursing staff is very aware of who needs to get on a shuttle back to Massachusetts. For some patients, we will have them stay overnight before their treatment.

Precision Oncology

Dr. Tammaro. In Boston, we have integrated Precision Oncology to be part of clinical practice, which we started with metastatic lung cancer patients. The VA Precision Oncology Program (POP) began at our healthcare center. We had to evaluate the genetic testing platforms, the accuracy of the results, and amount of tissue necessary for the laboratories. We have since succeeded in sending high-quality samples to the laboratories that generate accurate results. However, for your standard mutation panel for identifying therapy for first line treatment in lung cancer, we still use our local send out laboratory.

The POP has rolled out nationwide, and it is another clinical tool, especially for patients who have already failed multiple lines of therapy. When we send for a precision oncology consult, the “N of 1” report provides annotation. The report will generate a review of relevant literature and provide available abstracts or phase 1 or 2 trials that support a targeted therapy against potential point mutation for your patient.

The POP also has a research component, known as Re-POP. The goal is to open bucket trials that assess targeted therapy off label. Re-POP allows us to recontact these patients in the future to say, “You had your tissue sent through precision oncology, and you were diagnosed with a certain point mutation. Now we have a clinical trial that’s available. Would you be interested?” The plan is to have those clinical trials open and available to our patients when we receive the results from precision oncology.

I have used POP for 2 metastatic prostate cancer patient who exhausted all lines of therapy in hopes to identify a potential BCRA 1/2 mutation in order for us to use a PARP inhibitor. Unfortunately, neither harbored this mutation. Precision oncology does not perform immunohistochemistry, therefore identifying HER-2 or PD-L1 status for example, would need to be done through your local laboratory. I have found POP to be helpful in identifying a patients potential therapeutic option after progression on first/second line therapy, by sending tissue to POP initially or at the time of relapse.

Dr. Das. In our clinical practice at the Palo Alto VA, we follow the National Comprehensive Cancer Network (NCCN) guidelines, and we routinely evaluate for the presence of an EGFR mutation and also for ALK and ROS1 translocations in all lung cancer patients with nonsquamous histology. We send our molecular testing through Quest Diagnostics (Madison, NJ), and we usually get results back within a week or so.

For those patients who do not have any of those targetable gene alterations, we will go ahead and send for next-generation sequencing through POP, which allows testing of a much broader gene panel. Those results can take about a month or so to come back. I usually don’t wait for these results in order to get someone started on treatment. For patients without EGFR, ALK, or ROS1 found on initial testing, I will go ahead and start them on IV systemic chemotherapy. It is often very useful when you do get the next-generation sequencing results back, since in almost all cases, a gene alteration can be detected and is provided in the accompanying report. In a large subset of lung cancer cases, a gene alteration is seen in KRAS, for which we still do not have an effective targeted therapy. Despite this, I still find it useful to obtain the results because we generally feel that the driving genetic alterations occur mutually exclusive of one another. When we do see KRAS reported from a patient’s tumor specimen, we’re not generally looking for other types of mutations, so I find it helpful to know what is the alteration that is driving the growth of a patient’s tumor. The trend moving forward is to perform next-generation sequencing on all tumor specimens regardless of tumor type or histology, which can hopefully enable us to get to the bottom of what the driving genetic alteration is and to see if there are any targeted treatment approaches that can be offered to the patient.

In a few lung cancer cases, I have seen alterations in HER2 and BRAF that have been detected and reported using a next-generation sequencing platform. Just recently the FDA approved the BRAF-directed therapies of dabrafenib and trametinib for patients with lung cancer who are found to have a BRAF V600E mutation. It is hoped that as the FDA continues to provide approvals for targeted drugs in patients with lung cancer, the VA formulary will be able to offer these therapies to our veteran patients with the ultimate goal of providing treatment that has increased efficacy and less toxicity compared to conventional IV chemotherapy.

One of my frustrations earlier on was when we did find these more rare targetable mutations, I would run into problems with the VA formulary in allowing me to prescribe certain targeted therapies. In many cases, if the drug was not FDA-approved for lung cancer, I was told that I couldn’t use it and would have to go through the appeal process, which was quite onerous. Moving forward, we are seeing more and more data and trials with newer targeted agents in lung cancer, leading to new FDA approvals. With these approvals, I think it will be easier to be able to offer these targeted therapies to our patients.

Dr. Bauml. One of the issues that arises when we’re discussing even the FDA-approved therapies, is that many of these targeted therapies are relatively rare, and they’re especially rare amongst veterans. Now others have mentioned BRAF and HER2, and these do have some overexpression and mutations that occur among smokers. But the more common targetable genetic aberrations, EGFR, ALK, and ROS1 are more common amongst never-smokers. Given the high prevalence of tobacco use among veterans, these changes are rare. The incidence of ALK translocation is 3% to 7%. The incidence amongst veterans is likely much lower than that, given the tobacco abuse—to the point that I actually had a patient who had an ALK translocation; and of course, I prescribed the patient crizotinib. This was prior to the ALEX Trial and alectinib data. I prescribed crizotinib and was told it wasn’t on the formulary. Initially I was surprised, but when I said, “Well, look, when was the last time someone within our VA has prescribed crizotinib?” The answer was never.

This is the difficulty: As we enter this era of molecularly targetable therapy, the way we structure our formularies and the way that we review these data is going to have to change. This year at the American Society of Clinical Oncology (ASCO) meeting there were some very exciting lung cancer abstracts that evaluated ado-trastuzumab emtansine, which is an antibody drug conjugate currently approved for the treatment of HER2 overexpressing breast cancer. The abstracts showed response rates of up to 40% in lung cancer with the administration of this drug in HER2-mutated lung cancer. The HER2-amplified still had a response rate of 20%, which given the toxicity profile of this agent, is quite appealing. Being able to explore these early phase studies, as was described through the personalized medicine pathway, is, a great step forward for VA care.

Dr. Tammaro. The PBM in collaboration with the POP Advisory Board, are developing different levels of evidence to support the use of targeted medications identified to be potential therapy in those diagnosed with a point mutation. Even if a medication does not have an FDA approval, it has to have some evidence to support its use in a particular cancer. If you identify a point mutation or biomarker in a patient and provide evidence to supports its use within that particular disease state, the VA pharmacy could approve its use based off of that evidence. VA pharmacy would not require an actual FDA approval for that indication.

What the VISNs, PBM, and precision oncology are trying to do is determine the level of evidence that we have to support or approve use of a targeted therapy. We are definitely moving forward and changing the horizon on how we actually treat our patients after they’ve gone through first-line therapy. We are trying to figure out where these point mutations come in, the line of the therapy, and how we actually treat these cancers. Pharmacy is making a step forward in conjunction with Michael Kelley, MD, the National Program Director for Oncology, Specialty Care Services, whose group is establishing those guidelines.

Dr. Bauml. I don’t mean to downplay the difficulty of that process. This is a huge, difficult process. One only needs to look at the long line of failed trials looking at PI3 kinase inhibitors to show that just knowing that a mutation exists does not necessarily mean that a targeted therapy works in that space.

Drawing that line is really complicated, both within the VA and, indeed, outside of the VA. It’s a really complicated process, and understanding the implications of different mutations is only going to get more complicated. Of course, now we have things like NTRK and even rarer genetic aberrations that are going to affect not only lung cancer, but also a wide range of malignancies.

Promising Research

Dr. Bauml. The pathways that are emerging as clear driver mutations for which we have available therapies, at least within lung cancer, are MET exon 14, RET, and NTRK. I am also intrigued by the emerging data in the HER2 space.

Dr. Das. The other therapy that has been getting a lot of press is immunotherapy, of course. And I’ve been seeing many really good responders to immunotherapy within the veteran population that I treat. It is felt that degree of PD-L1 expression correlates with responsiveness to the immune check point inhibitors that are being used in lung cancer, and we are tending to see higher rates of PD-L1 expression in patients who are prior or current smokers who have a higher overall tumor mutation burden.

I see patients both at Stanford and at the Palo Alto VA, and I have noticed that the patients that I have been treating at the VA tend to have higher levels of PD-L1 expression with better responses to the immunotherapy drugs, probably because most of the VA patients are former or current smokers. And, another interesting observation is that these veteran patients are, for whatever reason, having a lower incidence of some of the autoimmune AEs seen with these immune checkpoint inhibitors. I have been keeping an eye out for more data and information to support these observations I have had in my clinical practice and I specifically attended ASCO this year to learn more about what others have seen and studied with immune check point inhibition in lung cancer. We are learning now that PD-L1 is not a perfect marker for predicting response to the checkpoint inhibitors and the other immunotherapeutic agents, and there is a great deal of research going on to try to figure out what other biomarkers could be useful and which patients are most likely to benefit from these drugs.

I was excited to hear about the combination of nivolumab and ipilimumab that is being tested in both mesothelioma and in small-cell lung cancer where we really don’t have as many treatment options as we have in non-small cell lung cancer. That data was quite exciting, and interestingly, there does not seem to be a correlation with PD-L1 expression and responsiveness to treatment with the immunotherapeutic agents in those histologic subtypes. The story is still unfolding, and we await additional data to help guide us in our treatment decisions.

Dr. Tammaro. Immunotherapy is the new fad in oncology. We have just scheduled our first patient for first-line therapy due to PD-L1 tumor proportion score is > 50%. Recently, at ASCO KEYNOTE-021 researchers looked at using pembrolizumab in combination with carboplatin plus pemetrexed chemotherapy for first-line metastatic non-squamous NSCLC. The research suggested that patients treated with pembrolizumab + chemotherapy continued to derive a higher overall response rate and progression free survival when compare with those on chemotherapy alone despite a low or no PD-L1 tumor expression.

It’s very interesting that many clinical trials that we’re evaluating are now using some type of checkpoint inhibitor up front with cytotoxic chemotherapy. If they are positive trials, this could change how patients are treated up front.

Dr. Bauml. There was some really interesting data that were presented at ASCO this year by Matthew Hellmann, MD, which evaluated the predictive nature of PD-L1 vs tumor mutation burden and other biomarkers, including gene expression profiling. In this particular abstract, the PD-L1 and tumor mutation burden really do function as orthogonal biomarkers such that a patient who has high PD-L1 and high tumor mutation burden is the most likely to respond. Patients who are really low for both are unlikely to respond. We really need better biomarkers for immunotherapy, though. PD-L1 has a lot of limitations, namely, it is dynamic, so over time it changes. So I can do a biopsy at one point, then treat the patient and the PD-L1 may change.

More importantly, it’s heterogeneous. There was this great paper by McLaughlin and colleagues in JAMA Oncology (2016) who described a patient who had a small tumor biopsy. They took a micrograph of the tumor and showed that one part of the micrograph was completely floridly PD-L1 positive. At another site of the same biopsy it was completely stone-cold negative, which is humbling when you think about the fact that we stick small needles into tumors and make clinical decisions on the basis of that.

The KEYNOTE-024 study evaluated pembrolizumab vs chemotherapy in high PD-L1 expressers. It’s a very exciting study, but at the end of the day even in this highly select patient population, the response rate to immunotherapy was only about 50%, which is not the sort of biomarker-driven response that we’re used to seeing with our EGFR inhibitors. That’s really what we want to get to. More important even than that is being able to say the negative predictive value. One of the reasons that we’re probably seeing more responses among veterans is that we know that patients who are veterans who have high tobacco exposure have a higher tumor mutation burden. I’m surprised to hear about the immune-related AEs, actually, because one of the things that was reported this year at ASCO was some data that showed that patients who have immune-related AEs are more likely to have a better outcome, which is an interesting biomarker of response.

Dr. Das. I heard that as well, and I found that to be really interesting. The patients that I’ve had on nivolumab for over a year are doing very well. These are stage IV patients who have essentially had complete responses to treatment and have not had any or have had very minor immune-related AEs to date.

Overall, these are a small numbers of patients, but I have been curious to see why that might be the case. Anecdotally, my colleagues and I who treat patients at Stanford have seen significantly higher rates of grades 3 and 4 pneumonitis and other autoimmune toxicities, such as myocarditis and enterocolitis, in those lung cancer patients who are light or never-smokers treated with immune checkpoint inhibitors.

Dr. Bauml. I really feel that PD-L1 as a biomarker has significant limitations. I certainly hope that in at least 2 or 3 years we’re not going to be talking about PD-L1 anymore. I’m hopeful that we’ll be able to use better predictive biomarkers, such as mutational burden and gene expression profiling. In the data in head and neck that was presented this year at ASCO, patients who were low for both gene expression profiling and mutational burden had a very low response (Haddad et al, ASCO 2017).

That’s really what you want to be. You want to be able to say, “Here’s a person who will not benefit from this therapy.” From there you can identify, based upon these biomarkers, the combination that is going to be best for this person. Is it chemoimmunotherapy or combination immunotherapy with CTLA4, or another checkpoint blockade? That is really the way that we’re going to be able to fine-tune this, because the toxicity is substantial for some treatments, like the nivolumab/ipilimumab combination. Using them in a biomarker-blind fashion is just scary to me, honestly.

Managing Adverse Reactions

Dr. Tammaro. The increasing amount of oral chemotherapy has posed a significant challenge. As a clinical oncology pharmacist, it was difficult to grasp the most effective way to follow all these patients and ensure adherence, adverse drug event reporting/significance and adequate follow up. When patients are receiving IV chemotherapy, we know we will see them, we are assured compliance and are able to assess side effects in a timely manner. When we give oral chemotherapy, the tables are turned, where the responsibility is now on the patient. We are now depending on the patient to ensure they are taking the medication correctly and we may not see AEs if the patient misses an appointment or feels as though they are bothering the provider by calling.

In 2012, we started an oral oncology clinic here at the VA in Boston that I found to be extremely effective. When you’re sending a patient home with an oral chemotherapy, you have to make sure that you are counseling them correctly and encourage them to call at any time if they are experiencing any type of AE. One of the newest issues we have been seeing is bleeding with ibrutinib, especially in those patients on anticoagulation therapies.

A general strategy we employee for oral chemotherapy is to start at half dose and titrate slowly. This method has been effective in identifying AEs and preventing delays in therapy. We do this for the majority of oral chemotherapy. Patients are given a 2 week supply to start and then are reassessed on follow up for escalation to the target dose. We do not place refills on oral oncology prescriptions. They are instructed to call 10 days prior to running out if they are not scheduled to come in for an appointment. Having consistent dialogue with our patients allows us to assess for adherence, AEs, and tolerability. The other advantage to this clinic is ensuring our patients have someone to speak to at all times and answer all their questions. Direct lines of communication is what most of our patients are appreciative of when paying gratitude to the clinic.

Ms. Beck. We have an oral chemotherapy clinic staffed by dedicated oncology pharmacists. Patients meet with the pharmacist and have education prior to starting a new oral chemotherapy. They will then be followed by both the oncology provider and the pharmacist.

Dr. Das. One of the challenges we also face is with so many of our patients living so far away. When our patients do have AEs that require hospitalization, it can be very tricky to really get a sense for how they are being managed at the outside community (non-VA) facility. Sharing of electronic medical records can be a challenge in these cases, and I worry that the care teams at the more remote hospitals may not be as familiar with the newer cancer treatments and the toxicities associated with them, such as the autoimmune AEs associated with many of the immune checkpoint inhibitors.

I provide patients with pocket cards to keep in their wallets with my contact information and the name of the drug that they are getting because not all patients can remember or even pronounce the names of the drugs and may not be able to tell their local treating physician and care team what they are getting. I have been getting more frequent phone calls from emergency department physicians and hospitalists from the local communities where many of our veterans live, because they want guidance on how best to approach treatment for our patients when they show up with an AE related to their cancer treatment.

At times, the presenting symptoms may be vague or nonspecific, but for our patients being treated with immunotherapy, we always have to keep in mind the possibility of immune-related AEs because we know that prompt initiation of steroids is critical in these cases and can really help the patients feel better quickly.

Dr. Tammaro. You bring up a valid point. Our pharmacists meet with all the patients on checkpoint inhibitors. Specifically, when we started using ipilimumab it was uncharted territory for our team. We put together take home medication bag that included hydrocortisone cream, methylprednisolone dose pak, dipheydramine, and loperamide. This was utilized for all patients and specific attention was given to patients who lived far away from an emergency room. This bag system was accompanied by “what to do if I have this symptom” handout that outlined which medication to take depending on the severity of the AE. A direct line phone line to the oncology pharmacy also was supplied.

With the evolution to the PD-L1s and the anti-PD inhibitors, we haven’t seen the same level of AEs. Patients go home with wallet cards that includes our staff contact numbers/pagers. The wallet card also serves as information to a treating provider if the patient presents outside the VA, to ensure they understand the severity of a potential autoimmune AE, such as diarrhea.

Another challenge is shared-care patients. We have patients coming from outside hospitals, and at times they want to use this pharmacy like a CVS, and it just doesn’t operate that way. We want to collaborate with others. Most shared care patients present to our service for oral chemotherapy because the veteran just can’t afford the copays. So, we will see the patient concurrently. They can still see their outside hospital physician as well, but they have to fax us the laboratory results and progress notes on a monthly basis (or longer depending on where they are in there therapy). Before we fill their medications, we talk to the patients, the same way we would treat a veteran who was getting their oral chemotherapy here. In addition, they need to be seen by the VA physician at least every 3 months. We want our veterans to feel comfortable with the cancer care and help them out as best as we can.

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Comorbidities

Joshua M. Bauml, MD, Corporal Michael J. Crescenz VAMC, Philadelphia, PA. One of the comorbidities that most commonly affects my patients is hearing loss—this is one of the most common causes of service-connected disability for veterans. Patients who have clinically significant hearing loss cannot receive cisplatin, which I frequently use in the adjuvant treatment of non-small cell lung cancer (NSCLC).

In addition, kidney dysfunction is quite common as a result of comorbid cardiovascular and hypertensive diseases. Kidney dysfunction can negatively impact our ability to administer both cisplatin and other systemic therapies.

Millie Das, MD, Palo Alto Health Care System, CA. Another major comorbidity for a lot of our veterans is COPD (chronic obstructive pulmonary disease). It doesn’t complicate the chemotherapy choice, but it affects surgical candidacy for those patients who present with early stage disease. Many times if you obtain pulmonary function tests in patients with COPD, the tests are abnormal and can prohibit safe surgical resection. These are patients that I see in the clinic and refer for definitive radiation, usually SABR (stereotactic ablative radiotherapy)/SBRT (stereotactic body radiation therapy), at a local radiation facility that can offer specialized radiation treatment.

Dr. Bauml. The fact that the VA has so many patients who require stereotactic radiosurgery for their early stage lung cancer represents an opportunity. There is a newly opened study that is evaluating SBRT vs surgery for these early stage lung cancer patients within the VA system. That study model has previously failed in multiple health care settings, but the VA is uniquely suited to answer this question.

Kelly A. Tammaro, PharmD, BCOP, Boston VA Healthcare System, MA. I would add heart failure patients or patients who have cardiac comorbidities and fluid restrictions. These restrictions can affect hydration that is needed for cisplatin, for example, as well as final volumes used to mix other chemotherapeutic agents with narrow concentration maximums, such as etoposide.

Julie Beck, RN, MSN, MPH, APRN-BC, VA Connecticut Healthcare System West Haven Campus. As a lung cancer navigator, I find that psychosocial comorbidities are an impediment to getting patients to diagnosis and treatment. Patients will miss appointments because they don’t have rides or will be reluctant to get imaging or other diagnostic testing because of anxiety or because it triggers PTSD (posttraumatic stress disorder) or because they are concerned about cost.

Dr. Das. I couldn’t agree more.

Dr. Bauml. It’s a great point.

Ms. Beck. You have to think outside the box with this patient population. We treat patients from as far away as Western Massachusetts. We have a dedicated oncology social worker who helps to arrange transportation. We have  our CLC ( community living center), which is a rehabilitation and hospice unit but is also a resource for patients who live alone or far away and are getting an aggressive daily treatment regimen such as combined chemotherapy and radiation. We admit some patients to the CLC during their treatment to ensure that they get their treatment on time, maintain their nutritional status, and to provide emotional support. This is not an acute medical bed. Patients will sometimes go home on the weekend, but the support of the CLC increases the chance that they will get through their treatment safely.

Cancer care requires a lot of handholding. We often have to make multiple telephone calls to persuade our patients to get imaging or biopsies. Some of our patients require admission following biopsy because they live alone and have no one to drive them home following the procedure.

Dr. Tammaro. Boston has a similar model. We have a social worker who is highly dedicated and is able address our patients needs immediately. We also have many patients with PTSD and other psychological comorbidities, and depending on the severity, may require admission for their treatment to avoid the overwhelming nature of the ambulatory setting. For those who have to travel long distances for treatment we the Huntington House, which is housing located next door to our ambulatory campus. This accommodation can be used by our patients and their caregivers. We also have long term care facilities and a hospice unit located at our Brockton facility.

Ms. Beck. In West Haven, we have both palliative care and health psychology providers embedded in our clinic. They assist with symptom management and issues related to coping with diagnosis, anxiety, sleep, pain, smoking cessation, and lifestyle changes. We have also been offering pet therapy through our social work team, which has been very helpful for many of our patients.

Dr. Bauml. Mental health issues also can affect the choice of the type of treatment. Patients who have severe claustrophobia associated with their PTSD may have difficulty undergoing radiation. This can impact their ability to comply with therapy, and we have to adjust the treatment accordingly. For instance, I have a patient who has a known brain metastasis that was treated with definitive intent, but this gentleman gets highly agitated doing a brain magnetic resonance image (MRI). Instead we have had to follow him with serial computed tomography (CAT) scans, which is suboptimal. We have discussed that, but the distress that it causes him is simply not worth it.

Dr. Das. In some instances, we have had to use IV sedation for some of our patients with severe claustrophobia just to be able to get them through a positron emission tomography (PET) scan as part of their staging workup. We discuss these types of challenging cases in a multidisciplinary setting in our thoracic tumor board in order to brainstorm and figure out a realistic plan with our radiology and anesthesia colleagues, with the goal of getting the patient through the necessary tests in order to establish a treatment recommendation.

Due to underlying mental health or other health issues, some of our patients may also have difficulty with breath holding or with following other necessary instructions during their radiation treatments. We sometimes have to get creative on an individual basis in order to help a patient get through the needed treatment.

We have a dedicated psychologist and social worker who are embedded in our clinics and work closely with the oncology providers to offer strategies that can help our patients comply and complete the recommended treatment plan.

Rural Care

Dr. Bauml. One of the questions that comes up frequently when you have a patient who is remote is the type of treatment that you can administer. It’s difficult to administer a weekly therapy if somebody’s traveling 3 hours to see you every time. That can play into your decision making as you’re choosing a chemotherapy. If there are equivalent treatment regimens and one involves visits every 3 weeks and one involves weekly visits, well, that will help sway your decision making after discussion with the patient.

We often have to balance things. For instance, when I give someone carboplatin and paclitaxel, my preference is to administer it weekly with 3 weeks on and 1 week off. However, if a patient tells me, “You know, I do not want to come in once a week,” then I will discuss with them my concern for the increased adverse effects (AEs) with the every-3-week dosing. We will do it and then watch them closely. Of course, this gets even more complicated when you consider the fact that many of these patients have multiple medical comorbidities, so you’d like to administer the treatments in the least toxic way possible.

Ms. Beck. We have overcome some of those challenges by partnering with the primary care doctors. We are very close to our primary care colleagues in Massachusetts. They will order labs for the patient the day before the patient's appointment, so if the patient has a long drive, we already have their lab work; and they are ready to go when they get here for their treatment. The nursing staff is very aware of who needs to get on a shuttle back to Massachusetts. For some patients, we will have them stay overnight before their treatment.

Precision Oncology

Dr. Tammaro. In Boston, we have integrated Precision Oncology to be part of clinical practice, which we started with metastatic lung cancer patients. The VA Precision Oncology Program (POP) began at our healthcare center. We had to evaluate the genetic testing platforms, the accuracy of the results, and amount of tissue necessary for the laboratories. We have since succeeded in sending high-quality samples to the laboratories that generate accurate results. However, for your standard mutation panel for identifying therapy for first line treatment in lung cancer, we still use our local send out laboratory.

The POP has rolled out nationwide, and it is another clinical tool, especially for patients who have already failed multiple lines of therapy. When we send for a precision oncology consult, the “N of 1” report provides annotation. The report will generate a review of relevant literature and provide available abstracts or phase 1 or 2 trials that support a targeted therapy against potential point mutation for your patient.

The POP also has a research component, known as Re-POP. The goal is to open bucket trials that assess targeted therapy off label. Re-POP allows us to recontact these patients in the future to say, “You had your tissue sent through precision oncology, and you were diagnosed with a certain point mutation. Now we have a clinical trial that’s available. Would you be interested?” The plan is to have those clinical trials open and available to our patients when we receive the results from precision oncology.

I have used POP for 2 metastatic prostate cancer patient who exhausted all lines of therapy in hopes to identify a potential BCRA 1/2 mutation in order for us to use a PARP inhibitor. Unfortunately, neither harbored this mutation. Precision oncology does not perform immunohistochemistry, therefore identifying HER-2 or PD-L1 status for example, would need to be done through your local laboratory. I have found POP to be helpful in identifying a patients potential therapeutic option after progression on first/second line therapy, by sending tissue to POP initially or at the time of relapse.

Dr. Das. In our clinical practice at the Palo Alto VA, we follow the National Comprehensive Cancer Network (NCCN) guidelines, and we routinely evaluate for the presence of an EGFR mutation and also for ALK and ROS1 translocations in all lung cancer patients with nonsquamous histology. We send our molecular testing through Quest Diagnostics (Madison, NJ), and we usually get results back within a week or so.

For those patients who do not have any of those targetable gene alterations, we will go ahead and send for next-generation sequencing through POP, which allows testing of a much broader gene panel. Those results can take about a month or so to come back. I usually don’t wait for these results in order to get someone started on treatment. For patients without EGFR, ALK, or ROS1 found on initial testing, I will go ahead and start them on IV systemic chemotherapy. It is often very useful when you do get the next-generation sequencing results back, since in almost all cases, a gene alteration can be detected and is provided in the accompanying report. In a large subset of lung cancer cases, a gene alteration is seen in KRAS, for which we still do not have an effective targeted therapy. Despite this, I still find it useful to obtain the results because we generally feel that the driving genetic alterations occur mutually exclusive of one another. When we do see KRAS reported from a patient’s tumor specimen, we’re not generally looking for other types of mutations, so I find it helpful to know what is the alteration that is driving the growth of a patient’s tumor. The trend moving forward is to perform next-generation sequencing on all tumor specimens regardless of tumor type or histology, which can hopefully enable us to get to the bottom of what the driving genetic alteration is and to see if there are any targeted treatment approaches that can be offered to the patient.

In a few lung cancer cases, I have seen alterations in HER2 and BRAF that have been detected and reported using a next-generation sequencing platform. Just recently the FDA approved the BRAF-directed therapies of dabrafenib and trametinib for patients with lung cancer who are found to have a BRAF V600E mutation. It is hoped that as the FDA continues to provide approvals for targeted drugs in patients with lung cancer, the VA formulary will be able to offer these therapies to our veteran patients with the ultimate goal of providing treatment that has increased efficacy and less toxicity compared to conventional IV chemotherapy.

One of my frustrations earlier on was when we did find these more rare targetable mutations, I would run into problems with the VA formulary in allowing me to prescribe certain targeted therapies. In many cases, if the drug was not FDA-approved for lung cancer, I was told that I couldn’t use it and would have to go through the appeal process, which was quite onerous. Moving forward, we are seeing more and more data and trials with newer targeted agents in lung cancer, leading to new FDA approvals. With these approvals, I think it will be easier to be able to offer these targeted therapies to our patients.

Dr. Bauml. One of the issues that arises when we’re discussing even the FDA-approved therapies, is that many of these targeted therapies are relatively rare, and they’re especially rare amongst veterans. Now others have mentioned BRAF and HER2, and these do have some overexpression and mutations that occur among smokers. But the more common targetable genetic aberrations, EGFR, ALK, and ROS1 are more common amongst never-smokers. Given the high prevalence of tobacco use among veterans, these changes are rare. The incidence of ALK translocation is 3% to 7%. The incidence amongst veterans is likely much lower than that, given the tobacco abuse—to the point that I actually had a patient who had an ALK translocation; and of course, I prescribed the patient crizotinib. This was prior to the ALEX Trial and alectinib data. I prescribed crizotinib and was told it wasn’t on the formulary. Initially I was surprised, but when I said, “Well, look, when was the last time someone within our VA has prescribed crizotinib?” The answer was never.

This is the difficulty: As we enter this era of molecularly targetable therapy, the way we structure our formularies and the way that we review these data is going to have to change. This year at the American Society of Clinical Oncology (ASCO) meeting there were some very exciting lung cancer abstracts that evaluated ado-trastuzumab emtansine, which is an antibody drug conjugate currently approved for the treatment of HER2 overexpressing breast cancer. The abstracts showed response rates of up to 40% in lung cancer with the administration of this drug in HER2-mutated lung cancer. The HER2-amplified still had a response rate of 20%, which given the toxicity profile of this agent, is quite appealing. Being able to explore these early phase studies, as was described through the personalized medicine pathway, is, a great step forward for VA care.

Dr. Tammaro. The PBM in collaboration with the POP Advisory Board, are developing different levels of evidence to support the use of targeted medications identified to be potential therapy in those diagnosed with a point mutation. Even if a medication does not have an FDA approval, it has to have some evidence to support its use in a particular cancer. If you identify a point mutation or biomarker in a patient and provide evidence to supports its use within that particular disease state, the VA pharmacy could approve its use based off of that evidence. VA pharmacy would not require an actual FDA approval for that indication.

What the VISNs, PBM, and precision oncology are trying to do is determine the level of evidence that we have to support or approve use of a targeted therapy. We are definitely moving forward and changing the horizon on how we actually treat our patients after they’ve gone through first-line therapy. We are trying to figure out where these point mutations come in, the line of the therapy, and how we actually treat these cancers. Pharmacy is making a step forward in conjunction with Michael Kelley, MD, the National Program Director for Oncology, Specialty Care Services, whose group is establishing those guidelines.

Dr. Bauml. I don’t mean to downplay the difficulty of that process. This is a huge, difficult process. One only needs to look at the long line of failed trials looking at PI3 kinase inhibitors to show that just knowing that a mutation exists does not necessarily mean that a targeted therapy works in that space.

Drawing that line is really complicated, both within the VA and, indeed, outside of the VA. It’s a really complicated process, and understanding the implications of different mutations is only going to get more complicated. Of course, now we have things like NTRK and even rarer genetic aberrations that are going to affect not only lung cancer, but also a wide range of malignancies.

Promising Research

Dr. Bauml. The pathways that are emerging as clear driver mutations for which we have available therapies, at least within lung cancer, are MET exon 14, RET, and NTRK. I am also intrigued by the emerging data in the HER2 space.

Dr. Das. The other therapy that has been getting a lot of press is immunotherapy, of course. And I’ve been seeing many really good responders to immunotherapy within the veteran population that I treat. It is felt that degree of PD-L1 expression correlates with responsiveness to the immune check point inhibitors that are being used in lung cancer, and we are tending to see higher rates of PD-L1 expression in patients who are prior or current smokers who have a higher overall tumor mutation burden.

I see patients both at Stanford and at the Palo Alto VA, and I have noticed that the patients that I have been treating at the VA tend to have higher levels of PD-L1 expression with better responses to the immunotherapy drugs, probably because most of the VA patients are former or current smokers. And, another interesting observation is that these veteran patients are, for whatever reason, having a lower incidence of some of the autoimmune AEs seen with these immune checkpoint inhibitors. I have been keeping an eye out for more data and information to support these observations I have had in my clinical practice and I specifically attended ASCO this year to learn more about what others have seen and studied with immune check point inhibition in lung cancer. We are learning now that PD-L1 is not a perfect marker for predicting response to the checkpoint inhibitors and the other immunotherapeutic agents, and there is a great deal of research going on to try to figure out what other biomarkers could be useful and which patients are most likely to benefit from these drugs.

I was excited to hear about the combination of nivolumab and ipilimumab that is being tested in both mesothelioma and in small-cell lung cancer where we really don’t have as many treatment options as we have in non-small cell lung cancer. That data was quite exciting, and interestingly, there does not seem to be a correlation with PD-L1 expression and responsiveness to treatment with the immunotherapeutic agents in those histologic subtypes. The story is still unfolding, and we await additional data to help guide us in our treatment decisions.

Dr. Tammaro. Immunotherapy is the new fad in oncology. We have just scheduled our first patient for first-line therapy due to PD-L1 tumor proportion score is > 50%. Recently, at ASCO KEYNOTE-021 researchers looked at using pembrolizumab in combination with carboplatin plus pemetrexed chemotherapy for first-line metastatic non-squamous NSCLC. The research suggested that patients treated with pembrolizumab + chemotherapy continued to derive a higher overall response rate and progression free survival when compare with those on chemotherapy alone despite a low or no PD-L1 tumor expression.

It’s very interesting that many clinical trials that we’re evaluating are now using some type of checkpoint inhibitor up front with cytotoxic chemotherapy. If they are positive trials, this could change how patients are treated up front.

Dr. Bauml. There was some really interesting data that were presented at ASCO this year by Matthew Hellmann, MD, which evaluated the predictive nature of PD-L1 vs tumor mutation burden and other biomarkers, including gene expression profiling. In this particular abstract, the PD-L1 and tumor mutation burden really do function as orthogonal biomarkers such that a patient who has high PD-L1 and high tumor mutation burden is the most likely to respond. Patients who are really low for both are unlikely to respond. We really need better biomarkers for immunotherapy, though. PD-L1 has a lot of limitations, namely, it is dynamic, so over time it changes. So I can do a biopsy at one point, then treat the patient and the PD-L1 may change.

More importantly, it’s heterogeneous. There was this great paper by McLaughlin and colleagues in JAMA Oncology (2016) who described a patient who had a small tumor biopsy. They took a micrograph of the tumor and showed that one part of the micrograph was completely floridly PD-L1 positive. At another site of the same biopsy it was completely stone-cold negative, which is humbling when you think about the fact that we stick small needles into tumors and make clinical decisions on the basis of that.

The KEYNOTE-024 study evaluated pembrolizumab vs chemotherapy in high PD-L1 expressers. It’s a very exciting study, but at the end of the day even in this highly select patient population, the response rate to immunotherapy was only about 50%, which is not the sort of biomarker-driven response that we’re used to seeing with our EGFR inhibitors. That’s really what we want to get to. More important even than that is being able to say the negative predictive value. One of the reasons that we’re probably seeing more responses among veterans is that we know that patients who are veterans who have high tobacco exposure have a higher tumor mutation burden. I’m surprised to hear about the immune-related AEs, actually, because one of the things that was reported this year at ASCO was some data that showed that patients who have immune-related AEs are more likely to have a better outcome, which is an interesting biomarker of response.

Dr. Das. I heard that as well, and I found that to be really interesting. The patients that I’ve had on nivolumab for over a year are doing very well. These are stage IV patients who have essentially had complete responses to treatment and have not had any or have had very minor immune-related AEs to date.

Overall, these are a small numbers of patients, but I have been curious to see why that might be the case. Anecdotally, my colleagues and I who treat patients at Stanford have seen significantly higher rates of grades 3 and 4 pneumonitis and other autoimmune toxicities, such as myocarditis and enterocolitis, in those lung cancer patients who are light or never-smokers treated with immune checkpoint inhibitors.

Dr. Bauml. I really feel that PD-L1 as a biomarker has significant limitations. I certainly hope that in at least 2 or 3 years we’re not going to be talking about PD-L1 anymore. I’m hopeful that we’ll be able to use better predictive biomarkers, such as mutational burden and gene expression profiling. In the data in head and neck that was presented this year at ASCO, patients who were low for both gene expression profiling and mutational burden had a very low response (Haddad et al, ASCO 2017).

That’s really what you want to be. You want to be able to say, “Here’s a person who will not benefit from this therapy.” From there you can identify, based upon these biomarkers, the combination that is going to be best for this person. Is it chemoimmunotherapy or combination immunotherapy with CTLA4, or another checkpoint blockade? That is really the way that we’re going to be able to fine-tune this, because the toxicity is substantial for some treatments, like the nivolumab/ipilimumab combination. Using them in a biomarker-blind fashion is just scary to me, honestly.

Managing Adverse Reactions

Dr. Tammaro. The increasing amount of oral chemotherapy has posed a significant challenge. As a clinical oncology pharmacist, it was difficult to grasp the most effective way to follow all these patients and ensure adherence, adverse drug event reporting/significance and adequate follow up. When patients are receiving IV chemotherapy, we know we will see them, we are assured compliance and are able to assess side effects in a timely manner. When we give oral chemotherapy, the tables are turned, where the responsibility is now on the patient. We are now depending on the patient to ensure they are taking the medication correctly and we may not see AEs if the patient misses an appointment or feels as though they are bothering the provider by calling.

In 2012, we started an oral oncology clinic here at the VA in Boston that I found to be extremely effective. When you’re sending a patient home with an oral chemotherapy, you have to make sure that you are counseling them correctly and encourage them to call at any time if they are experiencing any type of AE. One of the newest issues we have been seeing is bleeding with ibrutinib, especially in those patients on anticoagulation therapies.

A general strategy we employee for oral chemotherapy is to start at half dose and titrate slowly. This method has been effective in identifying AEs and preventing delays in therapy. We do this for the majority of oral chemotherapy. Patients are given a 2 week supply to start and then are reassessed on follow up for escalation to the target dose. We do not place refills on oral oncology prescriptions. They are instructed to call 10 days prior to running out if they are not scheduled to come in for an appointment. Having consistent dialogue with our patients allows us to assess for adherence, AEs, and tolerability. The other advantage to this clinic is ensuring our patients have someone to speak to at all times and answer all their questions. Direct lines of communication is what most of our patients are appreciative of when paying gratitude to the clinic.

Ms. Beck. We have an oral chemotherapy clinic staffed by dedicated oncology pharmacists. Patients meet with the pharmacist and have education prior to starting a new oral chemotherapy. They will then be followed by both the oncology provider and the pharmacist.

Dr. Das. One of the challenges we also face is with so many of our patients living so far away. When our patients do have AEs that require hospitalization, it can be very tricky to really get a sense for how they are being managed at the outside community (non-VA) facility. Sharing of electronic medical records can be a challenge in these cases, and I worry that the care teams at the more remote hospitals may not be as familiar with the newer cancer treatments and the toxicities associated with them, such as the autoimmune AEs associated with many of the immune checkpoint inhibitors.

I provide patients with pocket cards to keep in their wallets with my contact information and the name of the drug that they are getting because not all patients can remember or even pronounce the names of the drugs and may not be able to tell their local treating physician and care team what they are getting. I have been getting more frequent phone calls from emergency department physicians and hospitalists from the local communities where many of our veterans live, because they want guidance on how best to approach treatment for our patients when they show up with an AE related to their cancer treatment.

At times, the presenting symptoms may be vague or nonspecific, but for our patients being treated with immunotherapy, we always have to keep in mind the possibility of immune-related AEs because we know that prompt initiation of steroids is critical in these cases and can really help the patients feel better quickly.

Dr. Tammaro. You bring up a valid point. Our pharmacists meet with all the patients on checkpoint inhibitors. Specifically, when we started using ipilimumab it was uncharted territory for our team. We put together take home medication bag that included hydrocortisone cream, methylprednisolone dose pak, dipheydramine, and loperamide. This was utilized for all patients and specific attention was given to patients who lived far away from an emergency room. This bag system was accompanied by “what to do if I have this symptom” handout that outlined which medication to take depending on the severity of the AE. A direct line phone line to the oncology pharmacy also was supplied.

With the evolution to the PD-L1s and the anti-PD inhibitors, we haven’t seen the same level of AEs. Patients go home with wallet cards that includes our staff contact numbers/pagers. The wallet card also serves as information to a treating provider if the patient presents outside the VA, to ensure they understand the severity of a potential autoimmune AE, such as diarrhea.

Another challenge is shared-care patients. We have patients coming from outside hospitals, and at times they want to use this pharmacy like a CVS, and it just doesn’t operate that way. We want to collaborate with others. Most shared care patients present to our service for oral chemotherapy because the veteran just can’t afford the copays. So, we will see the patient concurrently. They can still see their outside hospital physician as well, but they have to fax us the laboratory results and progress notes on a monthly basis (or longer depending on where they are in there therapy). Before we fill their medications, we talk to the patients, the same way we would treat a veteran who was getting their oral chemotherapy here. In addition, they need to be seen by the VA physician at least every 3 months. We want our veterans to feel comfortable with the cancer care and help them out as best as we can.

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PSA Screening

William J. Aronson, MD. I’m very encouraged that the U.S. Preventive Services Task Force (USPSTF) has recently drafted revised guidelines for screening men for prostate cancer in which they now are proposing a C grade for prostate specific antigen (PSA) screening in men aged < 70 years. In this age group they now propose an informed discussion with the patient regarding the pros and cons of screening (shared decision making). The USPSTF recommended against PSA screening in men aged ≥ 75 years in 2008 (D grade), and they recommended against PSA screening in all men in 2012 (D grade). Previously the USPSTF put a great deal of emphasis on the PLCO (Prostate, Lung, Colorectal, and Ovarian Screening Trial). In that trial, there was no difference in prostate cancer mortality between the study groups, but, it appears that up to 90% of men in the control group received PSA screening, therefore, invalidating the studies findings.

I still have serious concerns about giving a D grade for men aged > 70 years. Dr. Jim Hu from Cornell University recently published a study in JAMA Oncology and reported that men aged > 74 years now have twice the rate (12%) of presenting with metastatic disease at the time of diagnosis compared with men aged > 74 years prior to the 2008 USPSTF recommendations. In my view, otherwise healthy men with a good life expectancy, even if they’re aged > 70 years, should still have an informed discussion with their physician about getting PSA screening.

Julie N. Graff, MD. I completely agree with Dr. Aronson, and I would add that our veterans are a special group of patients who have risk factors that aren’t seen in the general population. For example, Agent Orange exposure, and I think the VA has not necessarily embraced those recommendations. I’d also add that people are living longer, and most of the men who die of prostate cancer are over the age of 80 years. We need to consider each patient individually and his life expectancy. It’s okay to diagnose someone with prostate cancer, and it’s important to have a conversation about how likely that cancer is to shorten his life and not just turn a blind eye to it.

Nicholas G. Nickols, MD, PhD. I don’t think there’s really anything clinically meaningful about PSA screening that can be gleaned from the PLCO trial. However, there was another trial that looked at PSA screening, the ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, and had less contamination in the nonscreened arm and actually did ultimately show a 27% reduction in prostate cancer mortality in the screened men. We also know that local treatment in men with high-risk prostate cancer actually improves survival. By not screening, men with high-risk disease are going to miss out on potentially curative therapy.

Dr. Aronson. I think other endpoints are crucial to consider beyond just survival. Once patients have metastatic disease that can markedly impact their quality of life. Also, patients who are starting androgen deprivation therapy (ADT) have very significant issues with quality of life as well. I believe these other endpoints should also be considered by the USPSTF.

Jenna M. Houranieh, PharmD, BCOP. The American Cancer Society, ASCO (American Society of Clinical Oncology), NCCN (National Comprehensive Cancer Network), and the American Urological Association all had a different view on screening compared with the USPSTF that I think go more in line with some of the ways that we practice, because they take into consideration life expectancy, patients’ risks, and the age of screening as well.

Active Surveillance

Dr. Aronson. Active surveillance is now a wellestablished, reasonable approach to managing patients with low-risk prostate cancer. When we talk about the various treatment options, we always include a discussion of active surveillance and watchful waiting. Certainly, patients who have a Gleason score of 3+3, a low PSA (< 10) and low volume disease are ideal candidates for active surveillance. There is no established protocol for active surveillance, though there are a number of large series that report specific ways to go about doing it. The key issue for patients is to deemphasize the importance of the PSA, which is a very poor tool for monitoring progression of prostate cancer in men on active surveillance, and to focus on periodically obtaining prostate biopsies.

For patients with prostate cancer who have multiple medical problems and limited life expectancy, there is no reason to do biopsies on a regular basis. Watchful waiting would be more appropriate for these patients. One key issue, which is challenging right now, is that probably the best way to do active surveillance is with the more sophisticated biopsy technology that is now available. That includes both fusing magnetic resonance imaging (MRI) of the prostate into the ultrasound unit we are using to perform transrectal prostate biopsies. The more advanced biopsy units also provide the ability to perform same-site biopsies. There are specific coordinates at each site where a biopsy is performed so that we can go back to that same site on subsequent biopsies. Due to cost issues, these advanced biopsy units are not yet being used at a high frequency.

Dr. Nickols. The large ProtecT trial in the UK randomized men diagnosed with prostate cancer out of a PSA screening cohort to an active surveillance arm, a radical prostatectomy arm, and a radical radiation arm, and has a median of 10 years’ followup. Importantly, the endpoints of overall survival and prostate cancer specific survival were actually the same for all 3 arms, and were quite high. A little more than half of the patients who were on surveillance ended up getting delayed radical therapy of some kind within 10 years.

There was, however, a difference in metastasis-free survival and clinical progression, which were both higher in the active surveillance arm as compared to the treatment arms. Progression to metastatic disease was more than twice as high in the active surveillance arm than the other 2. Most of the patients who had progressed on the active surveillance arm were Gleason 7, and probably were not ideal candidates for active surveillance by today’s standards and would not normally be recommended active surveillance.

Androgen Deprivation Therapies

Dr. Houranieh. Androgen deprivation therapy plays a large role in prostate cancer management and is used in several areas of prostate cancer care. Androgen deprivation therapy can given be before, during or after radiation or alone in the metastatic setting. It's also continued along with chemotherapy in the more advanced stages. It's use is generally guided by our urologists and the duration of therapy is determined by the risk and stage of the cancer. It can be used for as little as a few months for lower risk, early stage disease or for a few years for higher risk disease. It can also be continued indefinitely for metastatic disease. Androgen deprivation therapy is a combination of 2 types of therapies, injectable LHRH (luteinizing hormone-releasing hormone) agonists and oral antiandrogens.

A number of products are available. The most commonly used LHRH agonist, at least at the Lexington VAMC in Kentucky, is leuprolide, which comes either in an intramuscular or subcutaneous formulation and can be given at different frequencies either monthly, every 3 months, or every 6 months.

There are also a number of antiandrogens available on the market. The most commonly used one is bicalutamide. It is generally the best tolerated and given once daily, as opposed to the other 2, which are either given twice or 3 times daily.

Dr. Nickols. We typically add ADT to radiation for patients with high-risk prostate cancer, defined as any of the following: A PSA ≥ 20, clinical T3 or higher disease, or Gleason score of ≥ 8. The addition of ADT to radiation in high-risk patients improves overall survival, prostate cancer survival, and biochemical recurrence-free survival. The backbone of this hormone therapy is usually a GnRH analogue like leuprolide.

The data are extensive, including many large phase 3 randomized trials of patients with highrisk prostate cancer treated with radiation plus or minus androgen suppression. Many of these trials were led by the big cooperative trial groups: the Radiation Therapy Oncology Group (RTOG), the European Organisation for Research and Treatment of Cancer (EORTC), and others. Looking
at all of the data, the answer to the general question of whether hormone therapy is beneficial is yes. The unknown question is what is the optimal duration for this concurrent and adjuvant hormone therapy. The optimal duration is probably somewhere between 1 and 3 years. That’s a large range, and clearly preferences of the patient and the comorbidities play a role in the decision of duration. The radiation doses were considerably lower than what is considered standard of care at this time in the trials that have established the use of concurrent and adjuvant hormone therapy with radiation, which needs to be taken in context.

For patients with localized intermediate-risk prostate cancer, a shorter course of hormone therapy is reasonable. The RTOG 9408 and DFCI 95096 trials showed that a 4- to 6-month course of ADT with RT in mostly intermediate-risk patients was better than RT alone. However, studies looking at the different comorbidities present in these patients showed that patients with less comorbidity actually benefit more from the addition of hormone therapy, which needs to be taken into account.

The benefit to the intermediate-risk patients is probably driven by the patients with unfavorable intermediate-risk disease, for example, with the primary Gleason 4 patterns, such as Gleason 4+3 patients rather than Gleason 3+4, patients with higher volume of prostate cancer, patients with multiple intermediate-risk features, etc. For the truly favorable intermediate-risk patients, low-volume disease, low PSA, and Gleason 3+4 pattern, the added value of concurrent ADT may be small.

The mechanism of why ADT may contribute to radiation efficacy may be explained by direct radio-sensitization: the transcription factor androgen receptor activates expression of many genes involved in DNA repair. Interfere with that, and you sensitize to radiation.

Dr. Graff. Of note, we don’t use ADT as the primary treatment for localized prostate cancer. This is for use in combination with radiation, in people with positive lymph nodes after surgery and in people with incurable prostate cancer.

Dr. Nickols. The question of whether or not to treat patients with localized high-risk prostate cancer with hormone therapy alone has been answered: The SPCG-7 and NCIC CTG PR3/MRC PR07 trials proved that adding radiation to long-term ADT improved survival in these patients.

The DFCI 95096 trial also showed that patients with a high level of comorbidities benefitted the least from concurrent hormone therapy; cardiovascular risks from the hormone therapy can offset the anticancer effect in these patients.

Analyses of the large randomized trials of radiation with or without hormones looking at the question of whether or not there was increased cardiovascular mortality in the patients that had hormone therapy did not show more cardiovascular mortality. Importantly, those trials were not enriched for patients with comorbidities that would set them up for this risk. One needs to weigh the benefits of adding hormones to radiation against the risks on a patient-to-patient basis.

Dr. Aronson. Another scenario where we used ADT is for patients whose cancer progressed after primary therapy; for example, when radical prostatectomy and RT are not successful for a patient. We see patients on a regular basis with a rising PSA after primary therapy. Our main goal is to avoid giving ADT to these patients as long as possible and only use it when it is clearly indicated.

The best measure that we typically use is the PSA doubling time. If the PSA doubling time, for example, is > 1 year, than we feel more confident in holding off on starting ADT and instead just monitoring the PSA. Adverse effects (AEs) of ADT are dramatic. We know that patients can get significant fatigue, gain weight, lose muscle mass, have an increased risk of diabetes mellitus, get hot flashes, and develop impotence and loss of libido. And now there are emerging data on an increased risk of Alzheimer disease. We use ADT but only when clearly indicated.

When I start patients on ADT, in addition to explaining the AEs, I also strongly suggest that, if their health allows, they walk at a brisk rate for at least 30 minutes daily and get on a regular weight training or a resistance training program to try to maintain muscle mass. They need to watch their diet more carefully because they are at increased risk for weight gain. And if they also can do balancing exercises, that would also be ideal. Typically, we also start patients on calcium and vitamin D as there is a risk for bone loss and osteoporosis, and we monitor their bone density.

Dr. Nickols. There’s another role for ADT. In patients who have a PSA recurrence after surgery, RT directed to the prostate bed and/or pelvic nodes is a potential curative therapy. There’s now some emerging evidence that analogous to the definitive radiation setting, the addition of hormone therapy to salvage radiation may be of value.

There were 2 recent trials published. The RTOG-9601 trial showed a benefit to the addition of bicalutamide for patients who had rising PSA after a surgery and were randomized to radiation that was directed to the prostate bed plus or minus 2 years of bicalutamide. The second trial, GETUG-AFU 16, was similar except that in this case the hormone therapy used was 6 months of the GnRH analogue leuprolide. The RTOG-9601 trial had positive outcomes in multiple endpoints, including survival. The GETUG trial is not as mature but had a biochemical improvement.

I don’t think the interpretation of this should be to use hormones with salvage radiation all the time. Importantly, in the RTOG 9601 trial, the patients that had the greatest benefit to the addition of concurrent hormone therapy were those that had a PSA of higher than 0.5 or 0.7. Most patients who get salvage radiation now get it at a much lower PSA, so we probably don’t want to overinterpret that data. And, of course, we have to wait for the GETUG-AFU data to mature more to see if there’s any hard clinical endpoints met
there. Notably, the incidence of gynecomastia in the bicalutamide arm of RTOG 9601 was near 70%. I discuss the addition of hormones with my patients who are getting salvage radiation and usually recommend it to the ones who have the high-risk features, those who would have gotten the concurrent hormones in the definitive setting, those with a PSA greater than 0.5 at the time of salvage, and those with a rapid PSA doubling time.

Dr. Houranieh. Androgen deprivation therapy includes use of LHRH agonists, like leuprolide and antiandrogens like bicalutamide. Some of the short-term AEs from androgen deprivation that we counsel patients on are things like tumor flare, hot flashes, erectile dysfunction, and injection site reactions. Some of the more long-term complications that we touch upon are osteoporosis, obesity, insulin resistance, increased risk of diabetes mellitus and cardiovascular events. We counsel patients on these adverse reactions and do our best with monitoring and prevention.

Dr. Nickols. The ProtecT trial also had some valuable patient-reported outcomes that were very carefully tracked. It confirmed what we already believe. The patients that had primary RT had the greatest negative impact on bowel function and on urinary irritative and obstructive symptoms. The patients who had surgery had the greatest negative impact on sexual function and on urinary incontinence. Obviously, active surveillance had the benefit of avoiding or postponing AEs of local therapy.

You can break up RT for localized disease, into 2 general approaches. The first is external beam radiation. This can be delivered as intensity-modulated radiotherapy (IMRT), which is the most common approach right now, typically stretched over more than 2 months of daily treatments. In addition, there is a newer technique called stereotactic body radiation therapy (SBRT), which has been applied to localized prostate cancer now for more than a decade. It’s efficacy was demonstrated first in low-risk patients as normally is the case. It has the advantage of convenience; it is just 5 treatment days total, which can be accomplished in a couple of weeks. And its convenient for patients who are commuting some distance. That’s really important for veterans, as radiotherapy is not available at all VAs.

At the West LA VAMC, we offer SBRT as a standard treatment for men with low and favorable intermediate risk prostate cancer. In addition, we offer it in the context of a clinical trial for patients with unfavorable intermediate- and high-risk prostate cancer.

The other type of radiation therapy is brachytherapy in which the radiation is temporarily or permanently inserted into the target, the prostate. It is a good stand-alone option for men with low- or intermediate-risk prostate cancer. It has the advantage of being relatively fast in that it is done in a day, although it is more invasive than IMRT or SBRT, and certain anatomic features of the prostate and the patient’s baseline urinary function can limit its appropriateness in some patients.

There are some recent data of interest for the combination of brachytherapy and externalbeam radiation therapy (EBRT). The recently reported ASCENDE-RT trial randomized mostly high-risk patients to either EBRT with 1 year of androgen suppression or EBRT with a boost of brachytherapy to the prostate and 1 year of ADT.

The arm that got the brachytherapy boost actually had half the biochemical recurrence of the EBRT alone but had double the rate of grade 2 acute genitourinary toxicity and triple the rate of grade 3. Metastasis-free survival and other hard clinical endpoints will need longer follow-up, but the biochemical control was quite high: It was about 80% at 10 years out.

Dr. Aronson. For surgical approaches, many VAs now have the da Vinci robot system (Sunnyvale, CA). When we look at the key results, which examine cancer care and AEs, such as incontinence and impotence, there actually is no clear advantage over the open procedure that we previously used. That being said, with the robotic surgery, because we do it laparoscopically, there’s significantly less blood loss. The magnification is such that it is much easier to do the surgery. It’s also much easier on the surgeon’s body, given that you’re in an anatomically, ergonomically good position, and patients go home much sooner, typically on postoperative day 1 or postoperative day 2 with less morbidity following the procedure and a much quicker recovery.

Precision Medicine

Dr. Graff. Prostate cancer may not be cured, even after the best attempts at surgery or radiation. The medical oncologist is probably most utilized with people with incurable prostate cancer. Once it’s incurable, it develops tumors in the bones and lymph nodes most commonly, and we call it metastatic prostate cancer.

Right now we use mostly a once-size-fits-all approach. Everyone initially gets some form of castration therapy, usually medical castration with LHRH agonists. However, prostate cancer invariably becomes resistant to those maneuvers. We call that castration-resistant prostate cancer. That opens the door to 6 other treatments that can prolong survival in prostate cancer. Two of the treatments are hormonal (enzalutamide and abiraterone), 2 are chemotherapy (docetaxel and cabazitaxel), 1 is IV radiation with radium-223, and 1 is an immunotherapy (sipuleucel-T).

At this point, there’s not a lot of guidance about what to use when except that each of these therapies has unique AEs, so we may not use one of the therapies because it causes a lot of fatigue or it could cause seizures, for example, in a patient at risk for those. Sometimes the therapies are inappropriate. For example, with radium, you wouldn’t give it to a patient with a tumor in the liver.

We don’t have readily available companion diagnostics to help us narrow the selection. In 2015, there was an article in Cell that looked at men with metastatic castration-resistant prostate cancer. The tumors were biopsied and analyzed, and we found some surprising things, including certain mutations called DNA repair defects that could make them susceptible to a drug already approved in ovarian cancer, such as olaparib and rucaparib.

A subsequent study in the New England Journal of Medicine looked at patients with advanced prostate cancer whose cancers have these DNA repair defects. Those cancers were susceptible to the PARP (poly ADP ribose polymerase) inhibitor olaparib. That’s an example of where looking and sequencing a tumor could lead to a treatment selection. The PARP inhibitors are not yet approved in prostate cancer, but the Prostate Cancer Foundation is interested in supporting research that could help deliver appropriate therapies to veterans in particular whose cancers have certain markers.

So, we are biopsying patients’ tumors, looking at the mutations in their germline DNA, and matching patients to treatments and vice versa. The DNA repair defects is the one that’s probably under most active evaluation right now. Another example of a biomarker is the AR-V7, which is a mutation in the androgen receptor that renders the cancer resistant to enzalutamide and abiraterone.

Also, I have a study of pembrolizumab which is a PD-1 inhibitor, and I’ve seen some very good responses to that therapy. And we’re not yet sure how to identify prospectively those patients who are likely to respond.

Use of Imaging

Dr. Nickols. The sensitivity of technetium-99m bone scans and CT (computed tomography) scans is not good enough. Many patients that we classify as M0, but with clear evidence of disease with a rising PSA, will be more accurately classified as M1 when the imaging allows this to be the case.

I think prostate-specific membrane antigen positron emission tomography (PET), which is not approved at this time, is going to be of value. A lot of data are coming out of Europe and in the recurrence setting show that PET imaging can detect metastatic sites at PSA values as low as 0.2 with the per lesion sensitivity around 80% and a specificity upward of 97%. This is clearly far and away much better than anything we have now.

There’s going to be a whole cohort of patients that we literally can’t see now, patients with essentially minimally metastatic disease, and they will be revealed when the imaging gets there. And the question is what to do for these patients. Treating patients with a heavy metastatic disease burden is much different from treating patients who may have just one or a few areas of disease outside of their prostate. And we need new strategies for these patients. We are now looking at new treatment regimens for patients with limited metastatic disease burden. I think this is going to be important going forward.

It’s also worth asking: What is the role of local therapy in patients with advanced prostate cancer, patients with metastatic disease? If you look at the patients who were in a lot of the old trials, for example, the NCIC trial, that was adding radiation to hormone therapy for high-risk patients, about 25% of patients in that trial had a PSA > 50. That’s a lot. Many of those patients probably had occult metastases. And there are trials now looking at the role of local therapy in metastatic patients.

Another area of interest is precision oncology, which Dr. Graff touched on, is starting to play a big role in the metastatic setting, but what about the local setting? There are now genomic classifiers available to help with risk assessments, but we don’t yet have much in the way of predictive tools that help guide specific therapies in the localized setting. We know that patients, for example, who have germline BRCA1 or 2 mutations have a worse outcome, period, after local therapy; and right now it may play some into treatment decisions, but we don’t have tailored therapy yet in the localized setting at the molecular level. And I think this is something that we need to start looking at.

Dr. Aronson. The VA is a very rich environment for performing clinical research as well as translational research (bench to bedside). And for example, at the West Los Angeles VAMC, I think one of the key steps that we have taken, moving forward is now our urology, radiation oncology, and hematology-oncology research groups have now merged together. This allows us to not only combine our administrative resources but to really improve the ability for us to perform highquality research in our veterans. And so that’s a model which I think other VAs might consider pursuing, depending upon their circumstances.

Author Disclosures
Dr. Graff has received research support from Sanofi, Astellas, Merck, Janssen, and Bristol Myers Squibb; an honorarium from Astellas; travel support from Clovis and Sanofi; and has consulted for Bayer and Dendreon. No other authors report actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

PSA Screening

William J. Aronson, MD. I’m very encouraged that the U.S. Preventive Services Task Force (USPSTF) has recently drafted revised guidelines for screening men for prostate cancer in which they now are proposing a C grade for prostate specific antigen (PSA) screening in men aged < 70 years. In this age group they now propose an informed discussion with the patient regarding the pros and cons of screening (shared decision making). The USPSTF recommended against PSA screening in men aged ≥ 75 years in 2008 (D grade), and they recommended against PSA screening in all men in 2012 (D grade). Previously the USPSTF put a great deal of emphasis on the PLCO (Prostate, Lung, Colorectal, and Ovarian Screening Trial). In that trial, there was no difference in prostate cancer mortality between the study groups, but, it appears that up to 90% of men in the control group received PSA screening, therefore, invalidating the studies findings.

I still have serious concerns about giving a D grade for men aged > 70 years. Dr. Jim Hu from Cornell University recently published a study in JAMA Oncology and reported that men aged > 74 years now have twice the rate (12%) of presenting with metastatic disease at the time of diagnosis compared with men aged > 74 years prior to the 2008 USPSTF recommendations. In my view, otherwise healthy men with a good life expectancy, even if they’re aged > 70 years, should still have an informed discussion with their physician about getting PSA screening.

Julie N. Graff, MD. I completely agree with Dr. Aronson, and I would add that our veterans are a special group of patients who have risk factors that aren’t seen in the general population. For example, Agent Orange exposure, and I think the VA has not necessarily embraced those recommendations. I’d also add that people are living longer, and most of the men who die of prostate cancer are over the age of 80 years. We need to consider each patient individually and his life expectancy. It’s okay to diagnose someone with prostate cancer, and it’s important to have a conversation about how likely that cancer is to shorten his life and not just turn a blind eye to it.

Nicholas G. Nickols, MD, PhD. I don’t think there’s really anything clinically meaningful about PSA screening that can be gleaned from the PLCO trial. However, there was another trial that looked at PSA screening, the ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, and had less contamination in the nonscreened arm and actually did ultimately show a 27% reduction in prostate cancer mortality in the screened men. We also know that local treatment in men with high-risk prostate cancer actually improves survival. By not screening, men with high-risk disease are going to miss out on potentially curative therapy.

Dr. Aronson. I think other endpoints are crucial to consider beyond just survival. Once patients have metastatic disease that can markedly impact their quality of life. Also, patients who are starting androgen deprivation therapy (ADT) have very significant issues with quality of life as well. I believe these other endpoints should also be considered by the USPSTF.

Jenna M. Houranieh, PharmD, BCOP. The American Cancer Society, ASCO (American Society of Clinical Oncology), NCCN (National Comprehensive Cancer Network), and the American Urological Association all had a different view on screening compared with the USPSTF that I think go more in line with some of the ways that we practice, because they take into consideration life expectancy, patients’ risks, and the age of screening as well.

Active Surveillance

Dr. Aronson. Active surveillance is now a wellestablished, reasonable approach to managing patients with low-risk prostate cancer. When we talk about the various treatment options, we always include a discussion of active surveillance and watchful waiting. Certainly, patients who have a Gleason score of 3+3, a low PSA (< 10) and low volume disease are ideal candidates for active surveillance. There is no established protocol for active surveillance, though there are a number of large series that report specific ways to go about doing it. The key issue for patients is to deemphasize the importance of the PSA, which is a very poor tool for monitoring progression of prostate cancer in men on active surveillance, and to focus on periodically obtaining prostate biopsies.

For patients with prostate cancer who have multiple medical problems and limited life expectancy, there is no reason to do biopsies on a regular basis. Watchful waiting would be more appropriate for these patients. One key issue, which is challenging right now, is that probably the best way to do active surveillance is with the more sophisticated biopsy technology that is now available. That includes both fusing magnetic resonance imaging (MRI) of the prostate into the ultrasound unit we are using to perform transrectal prostate biopsies. The more advanced biopsy units also provide the ability to perform same-site biopsies. There are specific coordinates at each site where a biopsy is performed so that we can go back to that same site on subsequent biopsies. Due to cost issues, these advanced biopsy units are not yet being used at a high frequency.

Dr. Nickols. The large ProtecT trial in the UK randomized men diagnosed with prostate cancer out of a PSA screening cohort to an active surveillance arm, a radical prostatectomy arm, and a radical radiation arm, and has a median of 10 years’ followup. Importantly, the endpoints of overall survival and prostate cancer specific survival were actually the same for all 3 arms, and were quite high. A little more than half of the patients who were on surveillance ended up getting delayed radical therapy of some kind within 10 years.

There was, however, a difference in metastasis-free survival and clinical progression, which were both higher in the active surveillance arm as compared to the treatment arms. Progression to metastatic disease was more than twice as high in the active surveillance arm than the other 2. Most of the patients who had progressed on the active surveillance arm were Gleason 7, and probably were not ideal candidates for active surveillance by today’s standards and would not normally be recommended active surveillance.

Androgen Deprivation Therapies

Dr. Houranieh. Androgen deprivation therapy plays a large role in prostate cancer management and is used in several areas of prostate cancer care. Androgen deprivation therapy can given be before, during or after radiation or alone in the metastatic setting. It's also continued along with chemotherapy in the more advanced stages. It's use is generally guided by our urologists and the duration of therapy is determined by the risk and stage of the cancer. It can be used for as little as a few months for lower risk, early stage disease or for a few years for higher risk disease. It can also be continued indefinitely for metastatic disease. Androgen deprivation therapy is a combination of 2 types of therapies, injectable LHRH (luteinizing hormone-releasing hormone) agonists and oral antiandrogens.

A number of products are available. The most commonly used LHRH agonist, at least at the Lexington VAMC in Kentucky, is leuprolide, which comes either in an intramuscular or subcutaneous formulation and can be given at different frequencies either monthly, every 3 months, or every 6 months.

There are also a number of antiandrogens available on the market. The most commonly used one is bicalutamide. It is generally the best tolerated and given once daily, as opposed to the other 2, which are either given twice or 3 times daily.

Dr. Nickols. We typically add ADT to radiation for patients with high-risk prostate cancer, defined as any of the following: A PSA ≥ 20, clinical T3 or higher disease, or Gleason score of ≥ 8. The addition of ADT to radiation in high-risk patients improves overall survival, prostate cancer survival, and biochemical recurrence-free survival. The backbone of this hormone therapy is usually a GnRH analogue like leuprolide.

The data are extensive, including many large phase 3 randomized trials of patients with highrisk prostate cancer treated with radiation plus or minus androgen suppression. Many of these trials were led by the big cooperative trial groups: the Radiation Therapy Oncology Group (RTOG), the European Organisation for Research and Treatment of Cancer (EORTC), and others. Looking
at all of the data, the answer to the general question of whether hormone therapy is beneficial is yes. The unknown question is what is the optimal duration for this concurrent and adjuvant hormone therapy. The optimal duration is probably somewhere between 1 and 3 years. That’s a large range, and clearly preferences of the patient and the comorbidities play a role in the decision of duration. The radiation doses were considerably lower than what is considered standard of care at this time in the trials that have established the use of concurrent and adjuvant hormone therapy with radiation, which needs to be taken in context.

For patients with localized intermediate-risk prostate cancer, a shorter course of hormone therapy is reasonable. The RTOG 9408 and DFCI 95096 trials showed that a 4- to 6-month course of ADT with RT in mostly intermediate-risk patients was better than RT alone. However, studies looking at the different comorbidities present in these patients showed that patients with less comorbidity actually benefit more from the addition of hormone therapy, which needs to be taken into account.

The benefit to the intermediate-risk patients is probably driven by the patients with unfavorable intermediate-risk disease, for example, with the primary Gleason 4 patterns, such as Gleason 4+3 patients rather than Gleason 3+4, patients with higher volume of prostate cancer, patients with multiple intermediate-risk features, etc. For the truly favorable intermediate-risk patients, low-volume disease, low PSA, and Gleason 3+4 pattern, the added value of concurrent ADT may be small.

The mechanism of why ADT may contribute to radiation efficacy may be explained by direct radio-sensitization: the transcription factor androgen receptor activates expression of many genes involved in DNA repair. Interfere with that, and you sensitize to radiation.

Dr. Graff. Of note, we don’t use ADT as the primary treatment for localized prostate cancer. This is for use in combination with radiation, in people with positive lymph nodes after surgery and in people with incurable prostate cancer.

Dr. Nickols. The question of whether or not to treat patients with localized high-risk prostate cancer with hormone therapy alone has been answered: The SPCG-7 and NCIC CTG PR3/MRC PR07 trials proved that adding radiation to long-term ADT improved survival in these patients.

The DFCI 95096 trial also showed that patients with a high level of comorbidities benefitted the least from concurrent hormone therapy; cardiovascular risks from the hormone therapy can offset the anticancer effect in these patients.

Analyses of the large randomized trials of radiation with or without hormones looking at the question of whether or not there was increased cardiovascular mortality in the patients that had hormone therapy did not show more cardiovascular mortality. Importantly, those trials were not enriched for patients with comorbidities that would set them up for this risk. One needs to weigh the benefits of adding hormones to radiation against the risks on a patient-to-patient basis.

Dr. Aronson. Another scenario where we used ADT is for patients whose cancer progressed after primary therapy; for example, when radical prostatectomy and RT are not successful for a patient. We see patients on a regular basis with a rising PSA after primary therapy. Our main goal is to avoid giving ADT to these patients as long as possible and only use it when it is clearly indicated.

The best measure that we typically use is the PSA doubling time. If the PSA doubling time, for example, is > 1 year, than we feel more confident in holding off on starting ADT and instead just monitoring the PSA. Adverse effects (AEs) of ADT are dramatic. We know that patients can get significant fatigue, gain weight, lose muscle mass, have an increased risk of diabetes mellitus, get hot flashes, and develop impotence and loss of libido. And now there are emerging data on an increased risk of Alzheimer disease. We use ADT but only when clearly indicated.

When I start patients on ADT, in addition to explaining the AEs, I also strongly suggest that, if their health allows, they walk at a brisk rate for at least 30 minutes daily and get on a regular weight training or a resistance training program to try to maintain muscle mass. They need to watch their diet more carefully because they are at increased risk for weight gain. And if they also can do balancing exercises, that would also be ideal. Typically, we also start patients on calcium and vitamin D as there is a risk for bone loss and osteoporosis, and we monitor their bone density.

Dr. Nickols. There’s another role for ADT. In patients who have a PSA recurrence after surgery, RT directed to the prostate bed and/or pelvic nodes is a potential curative therapy. There’s now some emerging evidence that analogous to the definitive radiation setting, the addition of hormone therapy to salvage radiation may be of value.

There were 2 recent trials published. The RTOG-9601 trial showed a benefit to the addition of bicalutamide for patients who had rising PSA after a surgery and were randomized to radiation that was directed to the prostate bed plus or minus 2 years of bicalutamide. The second trial, GETUG-AFU 16, was similar except that in this case the hormone therapy used was 6 months of the GnRH analogue leuprolide. The RTOG-9601 trial had positive outcomes in multiple endpoints, including survival. The GETUG trial is not as mature but had a biochemical improvement.

I don’t think the interpretation of this should be to use hormones with salvage radiation all the time. Importantly, in the RTOG 9601 trial, the patients that had the greatest benefit to the addition of concurrent hormone therapy were those that had a PSA of higher than 0.5 or 0.7. Most patients who get salvage radiation now get it at a much lower PSA, so we probably don’t want to overinterpret that data. And, of course, we have to wait for the GETUG-AFU data to mature more to see if there’s any hard clinical endpoints met
there. Notably, the incidence of gynecomastia in the bicalutamide arm of RTOG 9601 was near 70%. I discuss the addition of hormones with my patients who are getting salvage radiation and usually recommend it to the ones who have the high-risk features, those who would have gotten the concurrent hormones in the definitive setting, those with a PSA greater than 0.5 at the time of salvage, and those with a rapid PSA doubling time.

Dr. Houranieh. Androgen deprivation therapy includes use of LHRH agonists, like leuprolide and antiandrogens like bicalutamide. Some of the short-term AEs from androgen deprivation that we counsel patients on are things like tumor flare, hot flashes, erectile dysfunction, and injection site reactions. Some of the more long-term complications that we touch upon are osteoporosis, obesity, insulin resistance, increased risk of diabetes mellitus and cardiovascular events. We counsel patients on these adverse reactions and do our best with monitoring and prevention.

Dr. Nickols. The ProtecT trial also had some valuable patient-reported outcomes that were very carefully tracked. It confirmed what we already believe. The patients that had primary RT had the greatest negative impact on bowel function and on urinary irritative and obstructive symptoms. The patients who had surgery had the greatest negative impact on sexual function and on urinary incontinence. Obviously, active surveillance had the benefit of avoiding or postponing AEs of local therapy.

You can break up RT for localized disease, into 2 general approaches. The first is external beam radiation. This can be delivered as intensity-modulated radiotherapy (IMRT), which is the most common approach right now, typically stretched over more than 2 months of daily treatments. In addition, there is a newer technique called stereotactic body radiation therapy (SBRT), which has been applied to localized prostate cancer now for more than a decade. It’s efficacy was demonstrated first in low-risk patients as normally is the case. It has the advantage of convenience; it is just 5 treatment days total, which can be accomplished in a couple of weeks. And its convenient for patients who are commuting some distance. That’s really important for veterans, as radiotherapy is not available at all VAs.

At the West LA VAMC, we offer SBRT as a standard treatment for men with low and favorable intermediate risk prostate cancer. In addition, we offer it in the context of a clinical trial for patients with unfavorable intermediate- and high-risk prostate cancer.

The other type of radiation therapy is brachytherapy in which the radiation is temporarily or permanently inserted into the target, the prostate. It is a good stand-alone option for men with low- or intermediate-risk prostate cancer. It has the advantage of being relatively fast in that it is done in a day, although it is more invasive than IMRT or SBRT, and certain anatomic features of the prostate and the patient’s baseline urinary function can limit its appropriateness in some patients.

There are some recent data of interest for the combination of brachytherapy and externalbeam radiation therapy (EBRT). The recently reported ASCENDE-RT trial randomized mostly high-risk patients to either EBRT with 1 year of androgen suppression or EBRT with a boost of brachytherapy to the prostate and 1 year of ADT.

The arm that got the brachytherapy boost actually had half the biochemical recurrence of the EBRT alone but had double the rate of grade 2 acute genitourinary toxicity and triple the rate of grade 3. Metastasis-free survival and other hard clinical endpoints will need longer follow-up, but the biochemical control was quite high: It was about 80% at 10 years out.

Dr. Aronson. For surgical approaches, many VAs now have the da Vinci robot system (Sunnyvale, CA). When we look at the key results, which examine cancer care and AEs, such as incontinence and impotence, there actually is no clear advantage over the open procedure that we previously used. That being said, with the robotic surgery, because we do it laparoscopically, there’s significantly less blood loss. The magnification is such that it is much easier to do the surgery. It’s also much easier on the surgeon’s body, given that you’re in an anatomically, ergonomically good position, and patients go home much sooner, typically on postoperative day 1 or postoperative day 2 with less morbidity following the procedure and a much quicker recovery.

Precision Medicine

Dr. Graff. Prostate cancer may not be cured, even after the best attempts at surgery or radiation. The medical oncologist is probably most utilized with people with incurable prostate cancer. Once it’s incurable, it develops tumors in the bones and lymph nodes most commonly, and we call it metastatic prostate cancer.

Right now we use mostly a once-size-fits-all approach. Everyone initially gets some form of castration therapy, usually medical castration with LHRH agonists. However, prostate cancer invariably becomes resistant to those maneuvers. We call that castration-resistant prostate cancer. That opens the door to 6 other treatments that can prolong survival in prostate cancer. Two of the treatments are hormonal (enzalutamide and abiraterone), 2 are chemotherapy (docetaxel and cabazitaxel), 1 is IV radiation with radium-223, and 1 is an immunotherapy (sipuleucel-T).

At this point, there’s not a lot of guidance about what to use when except that each of these therapies has unique AEs, so we may not use one of the therapies because it causes a lot of fatigue or it could cause seizures, for example, in a patient at risk for those. Sometimes the therapies are inappropriate. For example, with radium, you wouldn’t give it to a patient with a tumor in the liver.

We don’t have readily available companion diagnostics to help us narrow the selection. In 2015, there was an article in Cell that looked at men with metastatic castration-resistant prostate cancer. The tumors were biopsied and analyzed, and we found some surprising things, including certain mutations called DNA repair defects that could make them susceptible to a drug already approved in ovarian cancer, such as olaparib and rucaparib.

A subsequent study in the New England Journal of Medicine looked at patients with advanced prostate cancer whose cancers have these DNA repair defects. Those cancers were susceptible to the PARP (poly ADP ribose polymerase) inhibitor olaparib. That’s an example of where looking and sequencing a tumor could lead to a treatment selection. The PARP inhibitors are not yet approved in prostate cancer, but the Prostate Cancer Foundation is interested in supporting research that could help deliver appropriate therapies to veterans in particular whose cancers have certain markers.

So, we are biopsying patients’ tumors, looking at the mutations in their germline DNA, and matching patients to treatments and vice versa. The DNA repair defects is the one that’s probably under most active evaluation right now. Another example of a biomarker is the AR-V7, which is a mutation in the androgen receptor that renders the cancer resistant to enzalutamide and abiraterone.

Also, I have a study of pembrolizumab which is a PD-1 inhibitor, and I’ve seen some very good responses to that therapy. And we’re not yet sure how to identify prospectively those patients who are likely to respond.

Use of Imaging

Dr. Nickols. The sensitivity of technetium-99m bone scans and CT (computed tomography) scans is not good enough. Many patients that we classify as M0, but with clear evidence of disease with a rising PSA, will be more accurately classified as M1 when the imaging allows this to be the case.

I think prostate-specific membrane antigen positron emission tomography (PET), which is not approved at this time, is going to be of value. A lot of data are coming out of Europe and in the recurrence setting show that PET imaging can detect metastatic sites at PSA values as low as 0.2 with the per lesion sensitivity around 80% and a specificity upward of 97%. This is clearly far and away much better than anything we have now.

There’s going to be a whole cohort of patients that we literally can’t see now, patients with essentially minimally metastatic disease, and they will be revealed when the imaging gets there. And the question is what to do for these patients. Treating patients with a heavy metastatic disease burden is much different from treating patients who may have just one or a few areas of disease outside of their prostate. And we need new strategies for these patients. We are now looking at new treatment regimens for patients with limited metastatic disease burden. I think this is going to be important going forward.

It’s also worth asking: What is the role of local therapy in patients with advanced prostate cancer, patients with metastatic disease? If you look at the patients who were in a lot of the old trials, for example, the NCIC trial, that was adding radiation to hormone therapy for high-risk patients, about 25% of patients in that trial had a PSA > 50. That’s a lot. Many of those patients probably had occult metastases. And there are trials now looking at the role of local therapy in metastatic patients.

Another area of interest is precision oncology, which Dr. Graff touched on, is starting to play a big role in the metastatic setting, but what about the local setting? There are now genomic classifiers available to help with risk assessments, but we don’t yet have much in the way of predictive tools that help guide specific therapies in the localized setting. We know that patients, for example, who have germline BRCA1 or 2 mutations have a worse outcome, period, after local therapy; and right now it may play some into treatment decisions, but we don’t have tailored therapy yet in the localized setting at the molecular level. And I think this is something that we need to start looking at.

Dr. Aronson. The VA is a very rich environment for performing clinical research as well as translational research (bench to bedside). And for example, at the West Los Angeles VAMC, I think one of the key steps that we have taken, moving forward is now our urology, radiation oncology, and hematology-oncology research groups have now merged together. This allows us to not only combine our administrative resources but to really improve the ability for us to perform highquality research in our veterans. And so that’s a model which I think other VAs might consider pursuing, depending upon their circumstances.

Author Disclosures
Dr. Graff has received research support from Sanofi, Astellas, Merck, Janssen, and Bristol Myers Squibb; an honorarium from Astellas; travel support from Clovis and Sanofi; and has consulted for Bayer and Dendreon. No other authors report actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

PSA Screening

William J. Aronson, MD. I’m very encouraged that the U.S. Preventive Services Task Force (USPSTF) has recently drafted revised guidelines for screening men for prostate cancer in which they now are proposing a C grade for prostate specific antigen (PSA) screening in men aged < 70 years. In this age group they now propose an informed discussion with the patient regarding the pros and cons of screening (shared decision making). The USPSTF recommended against PSA screening in men aged ≥ 75 years in 2008 (D grade), and they recommended against PSA screening in all men in 2012 (D grade). Previously the USPSTF put a great deal of emphasis on the PLCO (Prostate, Lung, Colorectal, and Ovarian Screening Trial). In that trial, there was no difference in prostate cancer mortality between the study groups, but, it appears that up to 90% of men in the control group received PSA screening, therefore, invalidating the studies findings.

I still have serious concerns about giving a D grade for men aged > 70 years. Dr. Jim Hu from Cornell University recently published a study in JAMA Oncology and reported that men aged > 74 years now have twice the rate (12%) of presenting with metastatic disease at the time of diagnosis compared with men aged > 74 years prior to the 2008 USPSTF recommendations. In my view, otherwise healthy men with a good life expectancy, even if they’re aged > 70 years, should still have an informed discussion with their physician about getting PSA screening.

Julie N. Graff, MD. I completely agree with Dr. Aronson, and I would add that our veterans are a special group of patients who have risk factors that aren’t seen in the general population. For example, Agent Orange exposure, and I think the VA has not necessarily embraced those recommendations. I’d also add that people are living longer, and most of the men who die of prostate cancer are over the age of 80 years. We need to consider each patient individually and his life expectancy. It’s okay to diagnose someone with prostate cancer, and it’s important to have a conversation about how likely that cancer is to shorten his life and not just turn a blind eye to it.

Nicholas G. Nickols, MD, PhD. I don’t think there’s really anything clinically meaningful about PSA screening that can be gleaned from the PLCO trial. However, there was another trial that looked at PSA screening, the ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, and had less contamination in the nonscreened arm and actually did ultimately show a 27% reduction in prostate cancer mortality in the screened men. We also know that local treatment in men with high-risk prostate cancer actually improves survival. By not screening, men with high-risk disease are going to miss out on potentially curative therapy.

Dr. Aronson. I think other endpoints are crucial to consider beyond just survival. Once patients have metastatic disease that can markedly impact their quality of life. Also, patients who are starting androgen deprivation therapy (ADT) have very significant issues with quality of life as well. I believe these other endpoints should also be considered by the USPSTF.

Jenna M. Houranieh, PharmD, BCOP. The American Cancer Society, ASCO (American Society of Clinical Oncology), NCCN (National Comprehensive Cancer Network), and the American Urological Association all had a different view on screening compared with the USPSTF that I think go more in line with some of the ways that we practice, because they take into consideration life expectancy, patients’ risks, and the age of screening as well.

Active Surveillance

Dr. Aronson. Active surveillance is now a wellestablished, reasonable approach to managing patients with low-risk prostate cancer. When we talk about the various treatment options, we always include a discussion of active surveillance and watchful waiting. Certainly, patients who have a Gleason score of 3+3, a low PSA (< 10) and low volume disease are ideal candidates for active surveillance. There is no established protocol for active surveillance, though there are a number of large series that report specific ways to go about doing it. The key issue for patients is to deemphasize the importance of the PSA, which is a very poor tool for monitoring progression of prostate cancer in men on active surveillance, and to focus on periodically obtaining prostate biopsies.

For patients with prostate cancer who have multiple medical problems and limited life expectancy, there is no reason to do biopsies on a regular basis. Watchful waiting would be more appropriate for these patients. One key issue, which is challenging right now, is that probably the best way to do active surveillance is with the more sophisticated biopsy technology that is now available. That includes both fusing magnetic resonance imaging (MRI) of the prostate into the ultrasound unit we are using to perform transrectal prostate biopsies. The more advanced biopsy units also provide the ability to perform same-site biopsies. There are specific coordinates at each site where a biopsy is performed so that we can go back to that same site on subsequent biopsies. Due to cost issues, these advanced biopsy units are not yet being used at a high frequency.

Dr. Nickols. The large ProtecT trial in the UK randomized men diagnosed with prostate cancer out of a PSA screening cohort to an active surveillance arm, a radical prostatectomy arm, and a radical radiation arm, and has a median of 10 years’ followup. Importantly, the endpoints of overall survival and prostate cancer specific survival were actually the same for all 3 arms, and were quite high. A little more than half of the patients who were on surveillance ended up getting delayed radical therapy of some kind within 10 years.

There was, however, a difference in metastasis-free survival and clinical progression, which were both higher in the active surveillance arm as compared to the treatment arms. Progression to metastatic disease was more than twice as high in the active surveillance arm than the other 2. Most of the patients who had progressed on the active surveillance arm were Gleason 7, and probably were not ideal candidates for active surveillance by today’s standards and would not normally be recommended active surveillance.

Androgen Deprivation Therapies

Dr. Houranieh. Androgen deprivation therapy plays a large role in prostate cancer management and is used in several areas of prostate cancer care. Androgen deprivation therapy can given be before, during or after radiation or alone in the metastatic setting. It's also continued along with chemotherapy in the more advanced stages. It's use is generally guided by our urologists and the duration of therapy is determined by the risk and stage of the cancer. It can be used for as little as a few months for lower risk, early stage disease or for a few years for higher risk disease. It can also be continued indefinitely for metastatic disease. Androgen deprivation therapy is a combination of 2 types of therapies, injectable LHRH (luteinizing hormone-releasing hormone) agonists and oral antiandrogens.

A number of products are available. The most commonly used LHRH agonist, at least at the Lexington VAMC in Kentucky, is leuprolide, which comes either in an intramuscular or subcutaneous formulation and can be given at different frequencies either monthly, every 3 months, or every 6 months.

There are also a number of antiandrogens available on the market. The most commonly used one is bicalutamide. It is generally the best tolerated and given once daily, as opposed to the other 2, which are either given twice or 3 times daily.

Dr. Nickols. We typically add ADT to radiation for patients with high-risk prostate cancer, defined as any of the following: A PSA ≥ 20, clinical T3 or higher disease, or Gleason score of ≥ 8. The addition of ADT to radiation in high-risk patients improves overall survival, prostate cancer survival, and biochemical recurrence-free survival. The backbone of this hormone therapy is usually a GnRH analogue like leuprolide.

The data are extensive, including many large phase 3 randomized trials of patients with highrisk prostate cancer treated with radiation plus or minus androgen suppression. Many of these trials were led by the big cooperative trial groups: the Radiation Therapy Oncology Group (RTOG), the European Organisation for Research and Treatment of Cancer (EORTC), and others. Looking
at all of the data, the answer to the general question of whether hormone therapy is beneficial is yes. The unknown question is what is the optimal duration for this concurrent and adjuvant hormone therapy. The optimal duration is probably somewhere between 1 and 3 years. That’s a large range, and clearly preferences of the patient and the comorbidities play a role in the decision of duration. The radiation doses were considerably lower than what is considered standard of care at this time in the trials that have established the use of concurrent and adjuvant hormone therapy with radiation, which needs to be taken in context.

For patients with localized intermediate-risk prostate cancer, a shorter course of hormone therapy is reasonable. The RTOG 9408 and DFCI 95096 trials showed that a 4- to 6-month course of ADT with RT in mostly intermediate-risk patients was better than RT alone. However, studies looking at the different comorbidities present in these patients showed that patients with less comorbidity actually benefit more from the addition of hormone therapy, which needs to be taken into account.

The benefit to the intermediate-risk patients is probably driven by the patients with unfavorable intermediate-risk disease, for example, with the primary Gleason 4 patterns, such as Gleason 4+3 patients rather than Gleason 3+4, patients with higher volume of prostate cancer, patients with multiple intermediate-risk features, etc. For the truly favorable intermediate-risk patients, low-volume disease, low PSA, and Gleason 3+4 pattern, the added value of concurrent ADT may be small.

The mechanism of why ADT may contribute to radiation efficacy may be explained by direct radio-sensitization: the transcription factor androgen receptor activates expression of many genes involved in DNA repair. Interfere with that, and you sensitize to radiation.

Dr. Graff. Of note, we don’t use ADT as the primary treatment for localized prostate cancer. This is for use in combination with radiation, in people with positive lymph nodes after surgery and in people with incurable prostate cancer.

Dr. Nickols. The question of whether or not to treat patients with localized high-risk prostate cancer with hormone therapy alone has been answered: The SPCG-7 and NCIC CTG PR3/MRC PR07 trials proved that adding radiation to long-term ADT improved survival in these patients.

The DFCI 95096 trial also showed that patients with a high level of comorbidities benefitted the least from concurrent hormone therapy; cardiovascular risks from the hormone therapy can offset the anticancer effect in these patients.

Analyses of the large randomized trials of radiation with or without hormones looking at the question of whether or not there was increased cardiovascular mortality in the patients that had hormone therapy did not show more cardiovascular mortality. Importantly, those trials were not enriched for patients with comorbidities that would set them up for this risk. One needs to weigh the benefits of adding hormones to radiation against the risks on a patient-to-patient basis.

Dr. Aronson. Another scenario where we used ADT is for patients whose cancer progressed after primary therapy; for example, when radical prostatectomy and RT are not successful for a patient. We see patients on a regular basis with a rising PSA after primary therapy. Our main goal is to avoid giving ADT to these patients as long as possible and only use it when it is clearly indicated.

The best measure that we typically use is the PSA doubling time. If the PSA doubling time, for example, is > 1 year, than we feel more confident in holding off on starting ADT and instead just monitoring the PSA. Adverse effects (AEs) of ADT are dramatic. We know that patients can get significant fatigue, gain weight, lose muscle mass, have an increased risk of diabetes mellitus, get hot flashes, and develop impotence and loss of libido. And now there are emerging data on an increased risk of Alzheimer disease. We use ADT but only when clearly indicated.

When I start patients on ADT, in addition to explaining the AEs, I also strongly suggest that, if their health allows, they walk at a brisk rate for at least 30 minutes daily and get on a regular weight training or a resistance training program to try to maintain muscle mass. They need to watch their diet more carefully because they are at increased risk for weight gain. And if they also can do balancing exercises, that would also be ideal. Typically, we also start patients on calcium and vitamin D as there is a risk for bone loss and osteoporosis, and we monitor their bone density.

Dr. Nickols. There’s another role for ADT. In patients who have a PSA recurrence after surgery, RT directed to the prostate bed and/or pelvic nodes is a potential curative therapy. There’s now some emerging evidence that analogous to the definitive radiation setting, the addition of hormone therapy to salvage radiation may be of value.

There were 2 recent trials published. The RTOG-9601 trial showed a benefit to the addition of bicalutamide for patients who had rising PSA after a surgery and were randomized to radiation that was directed to the prostate bed plus or minus 2 years of bicalutamide. The second trial, GETUG-AFU 16, was similar except that in this case the hormone therapy used was 6 months of the GnRH analogue leuprolide. The RTOG-9601 trial had positive outcomes in multiple endpoints, including survival. The GETUG trial is not as mature but had a biochemical improvement.

I don’t think the interpretation of this should be to use hormones with salvage radiation all the time. Importantly, in the RTOG 9601 trial, the patients that had the greatest benefit to the addition of concurrent hormone therapy were those that had a PSA of higher than 0.5 or 0.7. Most patients who get salvage radiation now get it at a much lower PSA, so we probably don’t want to overinterpret that data. And, of course, we have to wait for the GETUG-AFU data to mature more to see if there’s any hard clinical endpoints met
there. Notably, the incidence of gynecomastia in the bicalutamide arm of RTOG 9601 was near 70%. I discuss the addition of hormones with my patients who are getting salvage radiation and usually recommend it to the ones who have the high-risk features, those who would have gotten the concurrent hormones in the definitive setting, those with a PSA greater than 0.5 at the time of salvage, and those with a rapid PSA doubling time.

Dr. Houranieh. Androgen deprivation therapy includes use of LHRH agonists, like leuprolide and antiandrogens like bicalutamide. Some of the short-term AEs from androgen deprivation that we counsel patients on are things like tumor flare, hot flashes, erectile dysfunction, and injection site reactions. Some of the more long-term complications that we touch upon are osteoporosis, obesity, insulin resistance, increased risk of diabetes mellitus and cardiovascular events. We counsel patients on these adverse reactions and do our best with monitoring and prevention.

Dr. Nickols. The ProtecT trial also had some valuable patient-reported outcomes that were very carefully tracked. It confirmed what we already believe. The patients that had primary RT had the greatest negative impact on bowel function and on urinary irritative and obstructive symptoms. The patients who had surgery had the greatest negative impact on sexual function and on urinary incontinence. Obviously, active surveillance had the benefit of avoiding or postponing AEs of local therapy.

You can break up RT for localized disease, into 2 general approaches. The first is external beam radiation. This can be delivered as intensity-modulated radiotherapy (IMRT), which is the most common approach right now, typically stretched over more than 2 months of daily treatments. In addition, there is a newer technique called stereotactic body radiation therapy (SBRT), which has been applied to localized prostate cancer now for more than a decade. It’s efficacy was demonstrated first in low-risk patients as normally is the case. It has the advantage of convenience; it is just 5 treatment days total, which can be accomplished in a couple of weeks. And its convenient for patients who are commuting some distance. That’s really important for veterans, as radiotherapy is not available at all VAs.

At the West LA VAMC, we offer SBRT as a standard treatment for men with low and favorable intermediate risk prostate cancer. In addition, we offer it in the context of a clinical trial for patients with unfavorable intermediate- and high-risk prostate cancer.

The other type of radiation therapy is brachytherapy in which the radiation is temporarily or permanently inserted into the target, the prostate. It is a good stand-alone option for men with low- or intermediate-risk prostate cancer. It has the advantage of being relatively fast in that it is done in a day, although it is more invasive than IMRT or SBRT, and certain anatomic features of the prostate and the patient’s baseline urinary function can limit its appropriateness in some patients.

There are some recent data of interest for the combination of brachytherapy and externalbeam radiation therapy (EBRT). The recently reported ASCENDE-RT trial randomized mostly high-risk patients to either EBRT with 1 year of androgen suppression or EBRT with a boost of brachytherapy to the prostate and 1 year of ADT.

The arm that got the brachytherapy boost actually had half the biochemical recurrence of the EBRT alone but had double the rate of grade 2 acute genitourinary toxicity and triple the rate of grade 3. Metastasis-free survival and other hard clinical endpoints will need longer follow-up, but the biochemical control was quite high: It was about 80% at 10 years out.

Dr. Aronson. For surgical approaches, many VAs now have the da Vinci robot system (Sunnyvale, CA). When we look at the key results, which examine cancer care and AEs, such as incontinence and impotence, there actually is no clear advantage over the open procedure that we previously used. That being said, with the robotic surgery, because we do it laparoscopically, there’s significantly less blood loss. The magnification is such that it is much easier to do the surgery. It’s also much easier on the surgeon’s body, given that you’re in an anatomically, ergonomically good position, and patients go home much sooner, typically on postoperative day 1 or postoperative day 2 with less morbidity following the procedure and a much quicker recovery.

Precision Medicine

Dr. Graff. Prostate cancer may not be cured, even after the best attempts at surgery or radiation. The medical oncologist is probably most utilized with people with incurable prostate cancer. Once it’s incurable, it develops tumors in the bones and lymph nodes most commonly, and we call it metastatic prostate cancer.

Right now we use mostly a once-size-fits-all approach. Everyone initially gets some form of castration therapy, usually medical castration with LHRH agonists. However, prostate cancer invariably becomes resistant to those maneuvers. We call that castration-resistant prostate cancer. That opens the door to 6 other treatments that can prolong survival in prostate cancer. Two of the treatments are hormonal (enzalutamide and abiraterone), 2 are chemotherapy (docetaxel and cabazitaxel), 1 is IV radiation with radium-223, and 1 is an immunotherapy (sipuleucel-T).

At this point, there’s not a lot of guidance about what to use when except that each of these therapies has unique AEs, so we may not use one of the therapies because it causes a lot of fatigue or it could cause seizures, for example, in a patient at risk for those. Sometimes the therapies are inappropriate. For example, with radium, you wouldn’t give it to a patient with a tumor in the liver.

We don’t have readily available companion diagnostics to help us narrow the selection. In 2015, there was an article in Cell that looked at men with metastatic castration-resistant prostate cancer. The tumors were biopsied and analyzed, and we found some surprising things, including certain mutations called DNA repair defects that could make them susceptible to a drug already approved in ovarian cancer, such as olaparib and rucaparib.

A subsequent study in the New England Journal of Medicine looked at patients with advanced prostate cancer whose cancers have these DNA repair defects. Those cancers were susceptible to the PARP (poly ADP ribose polymerase) inhibitor olaparib. That’s an example of where looking and sequencing a tumor could lead to a treatment selection. The PARP inhibitors are not yet approved in prostate cancer, but the Prostate Cancer Foundation is interested in supporting research that could help deliver appropriate therapies to veterans in particular whose cancers have certain markers.

So, we are biopsying patients’ tumors, looking at the mutations in their germline DNA, and matching patients to treatments and vice versa. The DNA repair defects is the one that’s probably under most active evaluation right now. Another example of a biomarker is the AR-V7, which is a mutation in the androgen receptor that renders the cancer resistant to enzalutamide and abiraterone.

Also, I have a study of pembrolizumab which is a PD-1 inhibitor, and I’ve seen some very good responses to that therapy. And we’re not yet sure how to identify prospectively those patients who are likely to respond.

Use of Imaging

Dr. Nickols. The sensitivity of technetium-99m bone scans and CT (computed tomography) scans is not good enough. Many patients that we classify as M0, but with clear evidence of disease with a rising PSA, will be more accurately classified as M1 when the imaging allows this to be the case.

I think prostate-specific membrane antigen positron emission tomography (PET), which is not approved at this time, is going to be of value. A lot of data are coming out of Europe and in the recurrence setting show that PET imaging can detect metastatic sites at PSA values as low as 0.2 with the per lesion sensitivity around 80% and a specificity upward of 97%. This is clearly far and away much better than anything we have now.

There’s going to be a whole cohort of patients that we literally can’t see now, patients with essentially minimally metastatic disease, and they will be revealed when the imaging gets there. And the question is what to do for these patients. Treating patients with a heavy metastatic disease burden is much different from treating patients who may have just one or a few areas of disease outside of their prostate. And we need new strategies for these patients. We are now looking at new treatment regimens for patients with limited metastatic disease burden. I think this is going to be important going forward.

It’s also worth asking: What is the role of local therapy in patients with advanced prostate cancer, patients with metastatic disease? If you look at the patients who were in a lot of the old trials, for example, the NCIC trial, that was adding radiation to hormone therapy for high-risk patients, about 25% of patients in that trial had a PSA > 50. That’s a lot. Many of those patients probably had occult metastases. And there are trials now looking at the role of local therapy in metastatic patients.

Another area of interest is precision oncology, which Dr. Graff touched on, is starting to play a big role in the metastatic setting, but what about the local setting? There are now genomic classifiers available to help with risk assessments, but we don’t yet have much in the way of predictive tools that help guide specific therapies in the localized setting. We know that patients, for example, who have germline BRCA1 or 2 mutations have a worse outcome, period, after local therapy; and right now it may play some into treatment decisions, but we don’t have tailored therapy yet in the localized setting at the molecular level. And I think this is something that we need to start looking at.

Dr. Aronson. The VA is a very rich environment for performing clinical research as well as translational research (bench to bedside). And for example, at the West Los Angeles VAMC, I think one of the key steps that we have taken, moving forward is now our urology, radiation oncology, and hematology-oncology research groups have now merged together. This allows us to not only combine our administrative resources but to really improve the ability for us to perform highquality research in our veterans. And so that’s a model which I think other VAs might consider pursuing, depending upon their circumstances.

Author Disclosures
Dr. Graff has received research support from Sanofi, Astellas, Merck, Janssen, and Bristol Myers Squibb; an honorarium from Astellas; travel support from Clovis and Sanofi; and has consulted for Bayer and Dendreon. No other authors report actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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Early Treatment and Diagnosis

Dr. Ascensão. An area that is becoming very important is identifying and separating smoldering multiple myeloma (SMM) from multiple myeloma (MM) and determining when to start treatment. At the Washington DC VAMC (DCVAMC) we started early on bisphosphonates and thalidomide without much benefit, but perhaps we were treating the wrong disease.

Dr. Mehta. Identifying patients as early as possible is often the best way to start. Treating early disease is easier than treating late disease, and it avoids all the complications. The problem is we don’t want to treat too many people because some of the people with SMM will never develop overt MM and, therefore, may not need treatment. We don’t have benign treatment yet. Whatever treatment we decide to use is going to carry adverse effects and toxicity.

So the trick is identifying those patients with SMM who are likely to progress in a finite period and, therefore, can be helped by treating early to avoid the complications of late diagnosis. We know that early treatment for patients with high-risk SMM helps. In a report from Lancet Oncology, early treatment with lenalidomide and dexamethasone reduces time to progression.¹ There are other reports that treating early reduces time to progression.

So how do we identify those patients who are going to progress? We have a few clues. We know that patients who have a myeloma spike of > 1.5 g/dL are more likely to progress than others…The more discordant the / ratio from 1:1, the higher the risk for progression. And if that ratio is 1:100 or more, that would be a risk factor for progression.

We know from the work of Mayo Clinic researchers that if there are ≥ 60% of plasma cells in the bone marrow then it is a risk factor for progression. And we know from early studies that magnetic resonance imaging (MRI) detection of bone lesions, even long before they become detectable by X-ray, also is a risk factor for rapid development to myeloma.

...Methods such as genotyping, which we do here at the University of Arkansas for Medical Sciences, even in patients with MGUS (monoclonal gammopathy of undetermined significance), can identify high-risk patients, but that is not the standard of care yet. But it may become the standard of care in the days to come.

Another thing to think about for MGUS patients: Are there ways to identify what causes MGUS patients to evolve to SMM and then to overt myeloma, and to develop means of interrupting the progression cascade? There have been clinical trials on treatments (eg, bisphosphonates, thalidomide, aspirin, and cyclooxygenase inhibitors), but we haven’t found any safe, good treatment to prevent progression yet. With better technologies, we may be able to do that.

Dr. Ascensão. At the DCVAMC often we receive consults for a patient who had a little anemia, diabetes, renal disease, and the serum protein electrophoresis reveals a very small peak. How often should you follow patients? Do you do a complete workup the moment you see an MGUS or do you wait until they reach SMM?

Dr. Mehta. I don’t think every patient needs a complete workup. If you have obviously identifiable reasons for the anemia or the renal failure, then it’s less likely to be suspicious for myeloma. But patients with M spikes > 1 g/dL deserve a workup with a bone marrow aspirate and biopsy and at least bone X-rays, although MRIs would be even better.

I would differentiate based on the amount of M protein. Higher M protein patients deserve to have at least a bone marrow aspirate and bone study. Patients
with M protein > 1g/dL deserve to be seen every 3 to 4 months. I see patients with tiny little peaks every 6 months. And then, after 1 or 2 years, I turn over their care to the primary care doctor to follow. If we had research protocols to look at those patients and find the methods for progression, which I had at one point, then of course, we could see them more often and try to unravel the mystery.

Use of Imaging

Dr. Ascensão. That’s pretty close to what we do at DCVAMC. What do you think is the role for a bone survey as opposed to MRIs and positron emission tomography (PET) scans in this setting?

Dr. Mehta. In the real world X-rays are more accessible and much less expensive. So for the patient with very low risk who doesn’t have any complaints and
who has a low M spike, I think a bone survey is adequate. But you need about 30% to 40% bone destruction before you’re going to find anything on the X-ray.
MRIs are much more sensitive, plus they tell you about bone marrow involvement, but that should be reserved for the patient who has symptoms or a high
M protein. At Central Arkansas Veterans Healthcare System we simply can’t get PET scans for myeloma patients. At the myeloma center across the street from us, PET scans are used for routine evaluations.

Dr. Chauncey. I agree with Dr. Mehta. At VA Puget Sound Healthcare System (VAPSHCS) there isn’t a problem getting PET scans, but we probably get far fewer
scans than Arkansas. I still like the skeletal survey because it directs you where to look for potential pathologic fracture. It’s definitely not as sensitive as the dedicated myeloma MRI, but it’s a lot easier to get at VAPSHCS, especially as a screening tool.

Dr. Ascensão. Right, I believe there are some issues about the number of osteolytic lesions that may drive diagnosis.

Dr. Mehta. For patients with high M protein, I always request MRI. But the correlation is poorer in patients who have lower M protein. I try to limit it to the patients who have symptoms or high M protein, but I don’t have any evidence-based data to prove that’s the right way.

Dr. Ascensão. If you were going to start treatment of SMM that you believe is evolving to a more regular myeloma, do you do anything different than you would for any of the patients that you have identified as having active myeloma? Do you have different protocols for those patients as opposed to patients who present de novo with active myeloma?

Dr. Mehta. Those patients should be treated with the same drugs, an IMiD and a steroid. And the question is plus or minus a proteasome inhibitor. Studies have shown that an IMiD with a steroid gets much better results than using observation alone. Whether you would get even better results with the proteasome inhibitor remains to be seen. Maybe we can do that study.

Dr. Chauncey. We strive to identify high-risk SMM patients and treat them accordingly. Alternatively, physicians are pulling the trigger for therapy earlier and earlier and when they come for transplant with a diagnosis of MM, it is critical to review the initial diagnostic information. Most transplant centers have experience with this phenomena and know that they don’t want to transplant a non-high-risk SMM or any MGUS. However, by the time the patient is referred for transplantation, the initial clinical data are sometimes obscured or inaccessible.

Dr. Ascensão. We also look into the bone bearing areas, which allows us to make sure that if the patient has hip problems, we can work on how to approach them, whether we want to radiate those patients to prevent fractures.

Use of Bisphosphonates

Dr. Cosgriff. Myeloma metastasizes to bone, and it is one of the common sites of metastatic disease. It poses some interesting complications, whether it is from hypercalcemia due to metastatic sites, or pain syndromes. Bisphosphonates are indicated for myeloma, and they have been for years. Interestingly, unlike some of the other disease, the use of bisphosphonates induces apoptosis in myeloma. So we have seen some disease control with these agents.

The 2 bisphosphonates that are available for use are pamidronate and zoledronic acid. At the VA Portland Health Care System (VAPORHCS), we have been
using pamidronate exclusively for individuals with myeloma. There was a 2003 paper that evaluated the use of bisphosphonates for skeletal-related events in myeloma and in patients with metastatic breast cancer.2 In the subset analysis of myeloma patients with the bisphosphonates, there was no difference between pamidronate and zoledronic acid.

At the time, zoledronic acid was significantly more expensive than pamidronate, and so VAPORHCS opted to use pamidronate as a cost-saving measure. But there are the other reasons for picking pamidronate: Zoledronic acid has some dose recommendations and guidelines for individuals with renal failure, which is often a significant problem in patients with myeloma as well. To get around dose adjustments that need to be made for zoledronic acid, VAPORHCS switched to pamidronate, which is looser with the recommendations on renal failure.

Earlier use criteria, like the National Comprehensive Cancer Network guidelines, stated that if the renal failure was due to the disease itself and not some other outlying factor, a full 90-mg dose of pamidronate could still be used. That comment has since been removed. We still pay attention to it and reduce pamidronate dosing to 60 mg for patients with renal failure.

The prices for zoledronic acid have dropped significantly since it became a generic. The nice thing about zoledronic acid is that it has a short infusion time of 15 minutes. As chair space becomes a problem—VAPHCS has significant issues with that—zoledronic acid looks more and more attractive. The FDA label states that pamidronate should be infused over 4 hours, but VAPHCS typically has been infusing it for 3 hours.

It should be noted that denosumab (XGEVA), a monoclonal antibody that also is targeted for hypercalcemia, has been specifically excluded for myeloma. It
has no FDA indication for myeloma. It does have an indication for hypercalcemia. Whether or not you can state that the patient with myeloma is hypercalcemic, and that’s the reason you want to use it, it starts crossing into some gray area. The drug is still significantly more expensive and it seems to have similar efficacy rates compared with both pamidronate and zoledronic acid, so VAPHCS limits its use to individuals who would otherwise be contraindicated to zoledronic acid or pamidronate due to renal failure.

Dr. Ascensão. How often do you give it, every month, every 3 months?

Dr. Cosgriff. Currently, VAPORHCS is giving bisphosphonates every month whether in the chemotherapy unit or in the short stay unit. We are starting to reevaluate that. I have heard some emerging data that suggest we can use it once a quarter and get the same results. Those data are still emerging. It would be nice to be able to reduce the infusion frequency. But bisphosphonates adhere to bone and get incorporated into the bone matrix and stay there for an extended period of time, upwards of 6 months to a year, as with zoledronic acid.

Osteonecrosis

Dr. Ascensão. Do you require dental clearance prior to first dose?

Dr. Cosgriff. Bisphosphonates have a warning for 2% incidence of osteonecrosis of the jaw. Risk factors for the development of osteonecrosis of the jaw include poor dentition or major dental work, like extractions and illfitting dentures but not necessarily root canals. Ill-fitting dentures tend to rub on the gums and irritate the bone layer underneath. It’s the irritation of the bone that’s the biggest risk factor for osteonecrosis of the jaw.

We require that patients see the dentist because we’ve had individuals develop osteonecrosis eventhough we thought they had good dentition. If a patient is seeing a dentist outside of the VA system, we ask them to notify their dentist that they’re receiving bisphosphonates. Because of the risk and because we’ve had some individuals with good dentition develop it, VAPORHCS requires all patients, particularly those who are receiving zoledronic acid, to have dental evaluations. Denosumab also has a listed 2% incidence of osteonecrosis of the jaw, so those individuals also need to be evaluated by our dental service.

Dr. Ascensão. The DCVAMC has the same problem. I have a patient that presented primarily with a plasmacytoma, and we tried to get him to see the dentist. The dentist said, ‘You’ve got to get your teeth pulled.’ The patient has tried to see outside dentists and is finding all kinds of excuses because he would like to have implants.

Dr. Cosgriff. Anytime that you somehow damage or irritate that bone, that becomes a risk factor for the development of osteonecrosis. And for those individuals, we delay the bisphosphonate. If they’re having pain syndrome, we try to support them with opiates. We would love to be able to use nonsteroidal anti-inflammatory drugs—they have really good efficacy against bone pain—but renal function and renal failures prevent the use of those in a majority of patients. We start bisphosphonates as soon as dental clears them.

Dr. Mehta. Isn’t there a contraindication for denosumab and some evidence that it may worsen MM outcomes?

Dr. Cosgriff. When the drug first came on the market, it specifically stated in the package insert that it is not to be used in MM (it doesn’t state it specifically anymore). There is a thought that maybe some underlying mechanism exists that might stimulate some of the myeloma problems, which is why I get a little concerned when people say, “Well, I’m using it for hypercalcemia, I’m not using it to treat or to prevent a skeletal-related event in patients with myeloma.” That becomes a gray area and in that type of situation, I would recommend treating the hypercalcemia with a single dose and then switching the
patient to a bisphosphonate.

Dr. Mehta. And of course, bisphosphonates also lower calcium. They can be used to treat hypercalcemia.

Dr. Cosgriff. Yes. Zoledronic acid does have limitations in renal failure, though pamidronate doesn’t have quite the same limitations. The VAPORHCS tries to
use exclusively for hypercalcemia as well. The data show that when using zoledronic acid compared with pamidronate, you end up with the same outcomes as far as hypercalcemia. The zoledronic acid onset of action is a little faster, around 12 to 24 hours vs 48 to 72 hours with pamidronate, but you can get around that by using calcitonin over a short period; 48 hours is typically the maximum efficacy for calcitonin in treating hypercalcemia. So we use pamidronate in place of that, supplementing with calcitonin.

The result is that at 7 days, pamidronate and zoledronic acid show the same efficacy rates for treating hypercalcemia. But the renal function sometimes prevents us from doing that. Denosumab does become an option for hypercalcemia, but again, I caution against its use for treating hypercalcemia in patients with myeloma due to the risk of advancing the myeloma.

Bone Marrow Transplant

Dr. Ascensão. Do you transplant for 1 or 2 bone marrows? What’s the best maintenance regimen postallograft, and when do you start? Do you use lenalidomide the first month of the transplant or do you wait until day 100?

Dr. Chauncey. From my perspective, hematopoietic stem cell transplantation has never really lost prominence. It is true that the concept of marrow transplantation for MM has been around for more than 20 years for those patients with first best response (Note that I’ll use best response rather than first remission). The concept was developed in an era when we had much less effective therapy, and in comparative trials, progressionfree survival was consistently superior and occasionally, overall survival was better with transplantation. As treatments got better, responses got better, and there were regular questions as to whether we still needed transplantation. But the data show that as responses got better, the progression-free survivals continued to improve, and transplantation still adds something to initial therapy.

Probably the most current data are from the Dana Farber- IFM trial for which Nikhil Munshi, MD, is an investigator. The trial includes induction with lenalidomide/bortezomib/dexamethasone, which is one of the more aggressive induction regimens. When upfront transplant vs delayed transplant are compared, it seems the preliminary data still favor having an upfront transplant after initial induction therapy.

The consensus is that autologous transplantation adds to the better response that we see with better induction therapy. Overall survival has become a less accessible endpoint since the initial trials, and that’s really a consequence of having better salvage therapy, and the confounding effects of subsequent treatments. We have so many options for salvage therapy that it’s now very hard to look at overall survival as an endpoint in trials of initial therapy.

A sometimes contentious question when it comes to payers, and less so in the VA, is how many transplants to do as part of initial therapy? Little Rock and the French did some of the pioneering work on tandem transplants. The BMT CTN 0702–StaMINA trial looks at this directly, and is mature and should be presented soon [Editorial Note: Preliminary results were presented at the American Society of Hematology meeting on December 6, 2016].

The approach at VAPSHCS and most other transplant centers has typically been to harvest a sufficient quantity of peripheral blood stem cells to do 2 transplants. If less than a very good partial response is achieved after the first transplant, then we do a second transplant in tandem fashion.

One exception would be for plasma cell leukemia, which is very aggressive. In that case, we would routinely perform tandem transplantation. We are unlikely to ever have a randomized trial that compares 1 vs 2 transplants in that particular setting.

Another question is whether a second autologous transplantation can be useful in a nontandem fashion, and there is a large amount of retrospective data about its use as salvage treatment. In eras when there were not as many effective therapies, salvage autologous transplant was more attractive. As new therapies came along, its use has somewhat waned, but there’s been renewed interest because dose-intensive melphalan with autologous rescue is relatively safe and not cross-resistant to other therapies. It also offers the option of a drug holiday after the transplant, whereas salvage drug therapy is typically continuous.

There is no universal agreement on nontandem second transplantation, there are no consistent algorithms to say when it is appropriate, but it’s worth discussing with the transplant programs, especially if there is a lot of toxicity with current salvage therapy.

The last question is the role of allogeneic transplantation, and while I’m generally a proponent of allogeneic transplantation for many diseases, in spite of some really significant efforts, the majority of allogeneic data for MM has not been very positive. The large BMT-CTN 0102 trial compared tandem autologous transplant at first response to a single autologous transplantation followed by reduced-intensity autologous transplantation from a matched sibling. This study was limited in part by enrollment bias, but the published results did not favor an allogeneic approach.³ Although there was less relapse in the allogeneic setting, the mortality of allogeneic transplant was not overcome by the decrease in relapse. Neither progression-free or overall survivals at 3 years were better in the allogeneic group.

Despite small studies showing feasibility and promising results, it’s currently very hard to advocate for allogeneic transplantation in MM. There are certainly centers that continue to have their own approach, with some in the U.S. that are pioneering tweaks on allogeneic regimens and graft engineering, but the data are typically small and anecdotal. That doesn’t mean that there won’t ultimately be a better way to do allogeneic transplantation in MM, but rather that we don’t currently know the best way to approach this strategy.

Next Steps in Myeloma Treatment

Dr. Ascensão. There are some people who are now starting to talk about a cure for myeloma. I’m not sure we’re there yet. Certainly, it’s a chronic disease that, if we can take care of the complications and maybe by starting treatment early. I’m not sure Agent Orange-exposed patients do better or worse. That’s something that needs to be researched if we can find a way to compare within this group and within the type of treatment that patients get.

Is it reasonable to start looking for minimal residual disease in cells? Should we shoot for the best response? I think one of the points that Dr. Chauncey made a number of times, and I agree, is that our patient population may not be able to tolerate some of the more aggressive therapies. Perhaps we need to find a slightly different version of this algorithm for VA patients.

Dr. Chauncey. There’s a diverse biology for both veterans and nonveterans alike. There are patients for whom a deeper response will lead to longer remission and better survival, and there are others whose disease will smolder with a lower tumor burden and not progress quickly. A lot of the early gene expression profiling data on this comes from Little Rock. Unfortunately, determination of an individual’s biology is not readily accessible in the clinic, and we are typically unable to clearly define each patient’s inherent disease biology.

Dr. Mehta. We just don’t have the answers as to exactly what to do with the information that we get except watch more closely and treat a little bit earlier. We don’t even know the significance of minimal residue disease and how often to test for it and if it correlates truly with longer-term survival. These are great research questions. We need to accumulate the data and try to analyze it. We need to participate in the big data programs.

Dr. Ascensão. The other thing, of course, is now we have new immunotherapy approaches beyond transplant, which includes some of the checkpoint inhibitors and there’s some exciting data coming out. So I think the future looks good.

We all are committed to treating our patients, our veterans, to the best of our abilities. And I think the VA has done a very good job in allowing us to do this for our patients and allowing us to provide the best treatments available out there.

Click here to read the digital edition.

Early Treatment and Diagnosis

Dr. Ascensão. An area that is becoming very important is identifying and separating smoldering multiple myeloma (SMM) from multiple myeloma (MM) and determining when to start treatment. At the Washington DC VAMC (DCVAMC) we started early on bisphosphonates and thalidomide without much benefit, but perhaps we were treating the wrong disease.

Dr. Mehta. Identifying patients as early as possible is often the best way to start. Treating early disease is easier than treating late disease, and it avoids all the complications. The problem is we don’t want to treat too many people because some of the people with SMM will never develop overt MM and, therefore, may not need treatment. We don’t have benign treatment yet. Whatever treatment we decide to use is going to carry adverse effects and toxicity.

So the trick is identifying those patients with SMM who are likely to progress in a finite period and, therefore, can be helped by treating early to avoid the complications of late diagnosis. We know that early treatment for patients with high-risk SMM helps. In a report from Lancet Oncology, early treatment with lenalidomide and dexamethasone reduces time to progression.¹ There are other reports that treating early reduces time to progression.

So how do we identify those patients who are going to progress? We have a few clues. We know that patients who have a myeloma spike of > 1.5 g/dL are more likely to progress than others…The more discordant the / ratio from 1:1, the higher the risk for progression. And if that ratio is 1:100 or more, that would be a risk factor for progression.

We know from the work of Mayo Clinic researchers that if there are ≥ 60% of plasma cells in the bone marrow then it is a risk factor for progression. And we know from early studies that magnetic resonance imaging (MRI) detection of bone lesions, even long before they become detectable by X-ray, also is a risk factor for rapid development to myeloma.

...Methods such as genotyping, which we do here at the University of Arkansas for Medical Sciences, even in patients with MGUS (monoclonal gammopathy of undetermined significance), can identify high-risk patients, but that is not the standard of care yet. But it may become the standard of care in the days to come.

Another thing to think about for MGUS patients: Are there ways to identify what causes MGUS patients to evolve to SMM and then to overt myeloma, and to develop means of interrupting the progression cascade? There have been clinical trials on treatments (eg, bisphosphonates, thalidomide, aspirin, and cyclooxygenase inhibitors), but we haven’t found any safe, good treatment to prevent progression yet. With better technologies, we may be able to do that.

Dr. Ascensão. At the DCVAMC often we receive consults for a patient who had a little anemia, diabetes, renal disease, and the serum protein electrophoresis reveals a very small peak. How often should you follow patients? Do you do a complete workup the moment you see an MGUS or do you wait until they reach SMM?

Dr. Mehta. I don’t think every patient needs a complete workup. If you have obviously identifiable reasons for the anemia or the renal failure, then it’s less likely to be suspicious for myeloma. But patients with M spikes > 1 g/dL deserve a workup with a bone marrow aspirate and biopsy and at least bone X-rays, although MRIs would be even better.

I would differentiate based on the amount of M protein. Higher M protein patients deserve to have at least a bone marrow aspirate and bone study. Patients
with M protein > 1g/dL deserve to be seen every 3 to 4 months. I see patients with tiny little peaks every 6 months. And then, after 1 or 2 years, I turn over their care to the primary care doctor to follow. If we had research protocols to look at those patients and find the methods for progression, which I had at one point, then of course, we could see them more often and try to unravel the mystery.

Use of Imaging

Dr. Ascensão. That’s pretty close to what we do at DCVAMC. What do you think is the role for a bone survey as opposed to MRIs and positron emission tomography (PET) scans in this setting?

Dr. Mehta. In the real world X-rays are more accessible and much less expensive. So for the patient with very low risk who doesn’t have any complaints and
who has a low M spike, I think a bone survey is adequate. But you need about 30% to 40% bone destruction before you’re going to find anything on the X-ray.
MRIs are much more sensitive, plus they tell you about bone marrow involvement, but that should be reserved for the patient who has symptoms or a high
M protein. At Central Arkansas Veterans Healthcare System we simply can’t get PET scans for myeloma patients. At the myeloma center across the street from us, PET scans are used for routine evaluations.

Dr. Chauncey. I agree with Dr. Mehta. At VA Puget Sound Healthcare System (VAPSHCS) there isn’t a problem getting PET scans, but we probably get far fewer
scans than Arkansas. I still like the skeletal survey because it directs you where to look for potential pathologic fracture. It’s definitely not as sensitive as the dedicated myeloma MRI, but it’s a lot easier to get at VAPSHCS, especially as a screening tool.

Dr. Ascensão. Right, I believe there are some issues about the number of osteolytic lesions that may drive diagnosis.

Dr. Mehta. For patients with high M protein, I always request MRI. But the correlation is poorer in patients who have lower M protein. I try to limit it to the patients who have symptoms or high M protein, but I don’t have any evidence-based data to prove that’s the right way.

Dr. Ascensão. If you were going to start treatment of SMM that you believe is evolving to a more regular myeloma, do you do anything different than you would for any of the patients that you have identified as having active myeloma? Do you have different protocols for those patients as opposed to patients who present de novo with active myeloma?

Dr. Mehta. Those patients should be treated with the same drugs, an IMiD and a steroid. And the question is plus or minus a proteasome inhibitor. Studies have shown that an IMiD with a steroid gets much better results than using observation alone. Whether you would get even better results with the proteasome inhibitor remains to be seen. Maybe we can do that study.

Dr. Chauncey. We strive to identify high-risk SMM patients and treat them accordingly. Alternatively, physicians are pulling the trigger for therapy earlier and earlier and when they come for transplant with a diagnosis of MM, it is critical to review the initial diagnostic information. Most transplant centers have experience with this phenomena and know that they don’t want to transplant a non-high-risk SMM or any MGUS. However, by the time the patient is referred for transplantation, the initial clinical data are sometimes obscured or inaccessible.

Dr. Ascensão. We also look into the bone bearing areas, which allows us to make sure that if the patient has hip problems, we can work on how to approach them, whether we want to radiate those patients to prevent fractures.

Use of Bisphosphonates

Dr. Cosgriff. Myeloma metastasizes to bone, and it is one of the common sites of metastatic disease. It poses some interesting complications, whether it is from hypercalcemia due to metastatic sites, or pain syndromes. Bisphosphonates are indicated for myeloma, and they have been for years. Interestingly, unlike some of the other disease, the use of bisphosphonates induces apoptosis in myeloma. So we have seen some disease control with these agents.

The 2 bisphosphonates that are available for use are pamidronate and zoledronic acid. At the VA Portland Health Care System (VAPORHCS), we have been
using pamidronate exclusively for individuals with myeloma. There was a 2003 paper that evaluated the use of bisphosphonates for skeletal-related events in myeloma and in patients with metastatic breast cancer.2 In the subset analysis of myeloma patients with the bisphosphonates, there was no difference between pamidronate and zoledronic acid.

At the time, zoledronic acid was significantly more expensive than pamidronate, and so VAPORHCS opted to use pamidronate as a cost-saving measure. But there are the other reasons for picking pamidronate: Zoledronic acid has some dose recommendations and guidelines for individuals with renal failure, which is often a significant problem in patients with myeloma as well. To get around dose adjustments that need to be made for zoledronic acid, VAPORHCS switched to pamidronate, which is looser with the recommendations on renal failure.

Earlier use criteria, like the National Comprehensive Cancer Network guidelines, stated that if the renal failure was due to the disease itself and not some other outlying factor, a full 90-mg dose of pamidronate could still be used. That comment has since been removed. We still pay attention to it and reduce pamidronate dosing to 60 mg for patients with renal failure.

The prices for zoledronic acid have dropped significantly since it became a generic. The nice thing about zoledronic acid is that it has a short infusion time of 15 minutes. As chair space becomes a problem—VAPHCS has significant issues with that—zoledronic acid looks more and more attractive. The FDA label states that pamidronate should be infused over 4 hours, but VAPHCS typically has been infusing it for 3 hours.

It should be noted that denosumab (XGEVA), a monoclonal antibody that also is targeted for hypercalcemia, has been specifically excluded for myeloma. It
has no FDA indication for myeloma. It does have an indication for hypercalcemia. Whether or not you can state that the patient with myeloma is hypercalcemic, and that’s the reason you want to use it, it starts crossing into some gray area. The drug is still significantly more expensive and it seems to have similar efficacy rates compared with both pamidronate and zoledronic acid, so VAPHCS limits its use to individuals who would otherwise be contraindicated to zoledronic acid or pamidronate due to renal failure.

Dr. Ascensão. How often do you give it, every month, every 3 months?

Dr. Cosgriff. Currently, VAPORHCS is giving bisphosphonates every month whether in the chemotherapy unit or in the short stay unit. We are starting to reevaluate that. I have heard some emerging data that suggest we can use it once a quarter and get the same results. Those data are still emerging. It would be nice to be able to reduce the infusion frequency. But bisphosphonates adhere to bone and get incorporated into the bone matrix and stay there for an extended period of time, upwards of 6 months to a year, as with zoledronic acid.

Osteonecrosis

Dr. Ascensão. Do you require dental clearance prior to first dose?

Dr. Cosgriff. Bisphosphonates have a warning for 2% incidence of osteonecrosis of the jaw. Risk factors for the development of osteonecrosis of the jaw include poor dentition or major dental work, like extractions and illfitting dentures but not necessarily root canals. Ill-fitting dentures tend to rub on the gums and irritate the bone layer underneath. It’s the irritation of the bone that’s the biggest risk factor for osteonecrosis of the jaw.

We require that patients see the dentist because we’ve had individuals develop osteonecrosis eventhough we thought they had good dentition. If a patient is seeing a dentist outside of the VA system, we ask them to notify their dentist that they’re receiving bisphosphonates. Because of the risk and because we’ve had some individuals with good dentition develop it, VAPORHCS requires all patients, particularly those who are receiving zoledronic acid, to have dental evaluations. Denosumab also has a listed 2% incidence of osteonecrosis of the jaw, so those individuals also need to be evaluated by our dental service.

Dr. Ascensão. The DCVAMC has the same problem. I have a patient that presented primarily with a plasmacytoma, and we tried to get him to see the dentist. The dentist said, ‘You’ve got to get your teeth pulled.’ The patient has tried to see outside dentists and is finding all kinds of excuses because he would like to have implants.

Dr. Cosgriff. Anytime that you somehow damage or irritate that bone, that becomes a risk factor for the development of osteonecrosis. And for those individuals, we delay the bisphosphonate. If they’re having pain syndrome, we try to support them with opiates. We would love to be able to use nonsteroidal anti-inflammatory drugs—they have really good efficacy against bone pain—but renal function and renal failures prevent the use of those in a majority of patients. We start bisphosphonates as soon as dental clears them.

Dr. Mehta. Isn’t there a contraindication for denosumab and some evidence that it may worsen MM outcomes?

Dr. Cosgriff. When the drug first came on the market, it specifically stated in the package insert that it is not to be used in MM (it doesn’t state it specifically anymore). There is a thought that maybe some underlying mechanism exists that might stimulate some of the myeloma problems, which is why I get a little concerned when people say, “Well, I’m using it for hypercalcemia, I’m not using it to treat or to prevent a skeletal-related event in patients with myeloma.” That becomes a gray area and in that type of situation, I would recommend treating the hypercalcemia with a single dose and then switching the
patient to a bisphosphonate.

Dr. Mehta. And of course, bisphosphonates also lower calcium. They can be used to treat hypercalcemia.

Dr. Cosgriff. Yes. Zoledronic acid does have limitations in renal failure, though pamidronate doesn’t have quite the same limitations. The VAPORHCS tries to
use exclusively for hypercalcemia as well. The data show that when using zoledronic acid compared with pamidronate, you end up with the same outcomes as far as hypercalcemia. The zoledronic acid onset of action is a little faster, around 12 to 24 hours vs 48 to 72 hours with pamidronate, but you can get around that by using calcitonin over a short period; 48 hours is typically the maximum efficacy for calcitonin in treating hypercalcemia. So we use pamidronate in place of that, supplementing with calcitonin.

The result is that at 7 days, pamidronate and zoledronic acid show the same efficacy rates for treating hypercalcemia. But the renal function sometimes prevents us from doing that. Denosumab does become an option for hypercalcemia, but again, I caution against its use for treating hypercalcemia in patients with myeloma due to the risk of advancing the myeloma.

Bone Marrow Transplant

Dr. Ascensão. Do you transplant for 1 or 2 bone marrows? What’s the best maintenance regimen postallograft, and when do you start? Do you use lenalidomide the first month of the transplant or do you wait until day 100?

Dr. Chauncey. From my perspective, hematopoietic stem cell transplantation has never really lost prominence. It is true that the concept of marrow transplantation for MM has been around for more than 20 years for those patients with first best response (Note that I’ll use best response rather than first remission). The concept was developed in an era when we had much less effective therapy, and in comparative trials, progressionfree survival was consistently superior and occasionally, overall survival was better with transplantation. As treatments got better, responses got better, and there were regular questions as to whether we still needed transplantation. But the data show that as responses got better, the progression-free survivals continued to improve, and transplantation still adds something to initial therapy.

Probably the most current data are from the Dana Farber- IFM trial for which Nikhil Munshi, MD, is an investigator. The trial includes induction with lenalidomide/bortezomib/dexamethasone, which is one of the more aggressive induction regimens. When upfront transplant vs delayed transplant are compared, it seems the preliminary data still favor having an upfront transplant after initial induction therapy.

The consensus is that autologous transplantation adds to the better response that we see with better induction therapy. Overall survival has become a less accessible endpoint since the initial trials, and that’s really a consequence of having better salvage therapy, and the confounding effects of subsequent treatments. We have so many options for salvage therapy that it’s now very hard to look at overall survival as an endpoint in trials of initial therapy.

A sometimes contentious question when it comes to payers, and less so in the VA, is how many transplants to do as part of initial therapy? Little Rock and the French did some of the pioneering work on tandem transplants. The BMT CTN 0702–StaMINA trial looks at this directly, and is mature and should be presented soon [Editorial Note: Preliminary results were presented at the American Society of Hematology meeting on December 6, 2016].

The approach at VAPSHCS and most other transplant centers has typically been to harvest a sufficient quantity of peripheral blood stem cells to do 2 transplants. If less than a very good partial response is achieved after the first transplant, then we do a second transplant in tandem fashion.

One exception would be for plasma cell leukemia, which is very aggressive. In that case, we would routinely perform tandem transplantation. We are unlikely to ever have a randomized trial that compares 1 vs 2 transplants in that particular setting.

Another question is whether a second autologous transplantation can be useful in a nontandem fashion, and there is a large amount of retrospective data about its use as salvage treatment. In eras when there were not as many effective therapies, salvage autologous transplant was more attractive. As new therapies came along, its use has somewhat waned, but there’s been renewed interest because dose-intensive melphalan with autologous rescue is relatively safe and not cross-resistant to other therapies. It also offers the option of a drug holiday after the transplant, whereas salvage drug therapy is typically continuous.

There is no universal agreement on nontandem second transplantation, there are no consistent algorithms to say when it is appropriate, but it’s worth discussing with the transplant programs, especially if there is a lot of toxicity with current salvage therapy.

The last question is the role of allogeneic transplantation, and while I’m generally a proponent of allogeneic transplantation for many diseases, in spite of some really significant efforts, the majority of allogeneic data for MM has not been very positive. The large BMT-CTN 0102 trial compared tandem autologous transplant at first response to a single autologous transplantation followed by reduced-intensity autologous transplantation from a matched sibling. This study was limited in part by enrollment bias, but the published results did not favor an allogeneic approach.³ Although there was less relapse in the allogeneic setting, the mortality of allogeneic transplant was not overcome by the decrease in relapse. Neither progression-free or overall survivals at 3 years were better in the allogeneic group.

Despite small studies showing feasibility and promising results, it’s currently very hard to advocate for allogeneic transplantation in MM. There are certainly centers that continue to have their own approach, with some in the U.S. that are pioneering tweaks on allogeneic regimens and graft engineering, but the data are typically small and anecdotal. That doesn’t mean that there won’t ultimately be a better way to do allogeneic transplantation in MM, but rather that we don’t currently know the best way to approach this strategy.

Next Steps in Myeloma Treatment

Dr. Ascensão. There are some people who are now starting to talk about a cure for myeloma. I’m not sure we’re there yet. Certainly, it’s a chronic disease that, if we can take care of the complications and maybe by starting treatment early. I’m not sure Agent Orange-exposed patients do better or worse. That’s something that needs to be researched if we can find a way to compare within this group and within the type of treatment that patients get.

Is it reasonable to start looking for minimal residual disease in cells? Should we shoot for the best response? I think one of the points that Dr. Chauncey made a number of times, and I agree, is that our patient population may not be able to tolerate some of the more aggressive therapies. Perhaps we need to find a slightly different version of this algorithm for VA patients.

Dr. Chauncey. There’s a diverse biology for both veterans and nonveterans alike. There are patients for whom a deeper response will lead to longer remission and better survival, and there are others whose disease will smolder with a lower tumor burden and not progress quickly. A lot of the early gene expression profiling data on this comes from Little Rock. Unfortunately, determination of an individual’s biology is not readily accessible in the clinic, and we are typically unable to clearly define each patient’s inherent disease biology.

Dr. Mehta. We just don’t have the answers as to exactly what to do with the information that we get except watch more closely and treat a little bit earlier. We don’t even know the significance of minimal residue disease and how often to test for it and if it correlates truly with longer-term survival. These are great research questions. We need to accumulate the data and try to analyze it. We need to participate in the big data programs.

Dr. Ascensão. The other thing, of course, is now we have new immunotherapy approaches beyond transplant, which includes some of the checkpoint inhibitors and there’s some exciting data coming out. So I think the future looks good.

We all are committed to treating our patients, our veterans, to the best of our abilities. And I think the VA has done a very good job in allowing us to do this for our patients and allowing us to provide the best treatments available out there.

Click here to read the digital edition.

Early Treatment and Diagnosis

Dr. Ascensão. An area that is becoming very important is identifying and separating smoldering multiple myeloma (SMM) from multiple myeloma (MM) and determining when to start treatment. At the Washington DC VAMC (DCVAMC) we started early on bisphosphonates and thalidomide without much benefit, but perhaps we were treating the wrong disease.

Dr. Mehta. Identifying patients as early as possible is often the best way to start. Treating early disease is easier than treating late disease, and it avoids all the complications. The problem is we don’t want to treat too many people because some of the people with SMM will never develop overt MM and, therefore, may not need treatment. We don’t have benign treatment yet. Whatever treatment we decide to use is going to carry adverse effects and toxicity.

So the trick is identifying those patients with SMM who are likely to progress in a finite period and, therefore, can be helped by treating early to avoid the complications of late diagnosis. We know that early treatment for patients with high-risk SMM helps. In a report from Lancet Oncology, early treatment with lenalidomide and dexamethasone reduces time to progression.¹ There are other reports that treating early reduces time to progression.

So how do we identify those patients who are going to progress? We have a few clues. We know that patients who have a myeloma spike of > 1.5 g/dL are more likely to progress than others…The more discordant the / ratio from 1:1, the higher the risk for progression. And if that ratio is 1:100 or more, that would be a risk factor for progression.

We know from the work of Mayo Clinic researchers that if there are ≥ 60% of plasma cells in the bone marrow then it is a risk factor for progression. And we know from early studies that magnetic resonance imaging (MRI) detection of bone lesions, even long before they become detectable by X-ray, also is a risk factor for rapid development to myeloma.

...Methods such as genotyping, which we do here at the University of Arkansas for Medical Sciences, even in patients with MGUS (monoclonal gammopathy of undetermined significance), can identify high-risk patients, but that is not the standard of care yet. But it may become the standard of care in the days to come.

Another thing to think about for MGUS patients: Are there ways to identify what causes MGUS patients to evolve to SMM and then to overt myeloma, and to develop means of interrupting the progression cascade? There have been clinical trials on treatments (eg, bisphosphonates, thalidomide, aspirin, and cyclooxygenase inhibitors), but we haven’t found any safe, good treatment to prevent progression yet. With better technologies, we may be able to do that.

Dr. Ascensão. At the DCVAMC often we receive consults for a patient who had a little anemia, diabetes, renal disease, and the serum protein electrophoresis reveals a very small peak. How often should you follow patients? Do you do a complete workup the moment you see an MGUS or do you wait until they reach SMM?

Dr. Mehta. I don’t think every patient needs a complete workup. If you have obviously identifiable reasons for the anemia or the renal failure, then it’s less likely to be suspicious for myeloma. But patients with M spikes > 1 g/dL deserve a workup with a bone marrow aspirate and biopsy and at least bone X-rays, although MRIs would be even better.

I would differentiate based on the amount of M protein. Higher M protein patients deserve to have at least a bone marrow aspirate and bone study. Patients
with M protein > 1g/dL deserve to be seen every 3 to 4 months. I see patients with tiny little peaks every 6 months. And then, after 1 or 2 years, I turn over their care to the primary care doctor to follow. If we had research protocols to look at those patients and find the methods for progression, which I had at one point, then of course, we could see them more often and try to unravel the mystery.

Use of Imaging

Dr. Ascensão. That’s pretty close to what we do at DCVAMC. What do you think is the role for a bone survey as opposed to MRIs and positron emission tomography (PET) scans in this setting?

Dr. Mehta. In the real world X-rays are more accessible and much less expensive. So for the patient with very low risk who doesn’t have any complaints and
who has a low M spike, I think a bone survey is adequate. But you need about 30% to 40% bone destruction before you’re going to find anything on the X-ray.
MRIs are much more sensitive, plus they tell you about bone marrow involvement, but that should be reserved for the patient who has symptoms or a high
M protein. At Central Arkansas Veterans Healthcare System we simply can’t get PET scans for myeloma patients. At the myeloma center across the street from us, PET scans are used for routine evaluations.

Dr. Chauncey. I agree with Dr. Mehta. At VA Puget Sound Healthcare System (VAPSHCS) there isn’t a problem getting PET scans, but we probably get far fewer
scans than Arkansas. I still like the skeletal survey because it directs you where to look for potential pathologic fracture. It’s definitely not as sensitive as the dedicated myeloma MRI, but it’s a lot easier to get at VAPSHCS, especially as a screening tool.

Dr. Ascensão. Right, I believe there are some issues about the number of osteolytic lesions that may drive diagnosis.

Dr. Mehta. For patients with high M protein, I always request MRI. But the correlation is poorer in patients who have lower M protein. I try to limit it to the patients who have symptoms or high M protein, but I don’t have any evidence-based data to prove that’s the right way.

Dr. Ascensão. If you were going to start treatment of SMM that you believe is evolving to a more regular myeloma, do you do anything different than you would for any of the patients that you have identified as having active myeloma? Do you have different protocols for those patients as opposed to patients who present de novo with active myeloma?

Dr. Mehta. Those patients should be treated with the same drugs, an IMiD and a steroid. And the question is plus or minus a proteasome inhibitor. Studies have shown that an IMiD with a steroid gets much better results than using observation alone. Whether you would get even better results with the proteasome inhibitor remains to be seen. Maybe we can do that study.

Dr. Chauncey. We strive to identify high-risk SMM patients and treat them accordingly. Alternatively, physicians are pulling the trigger for therapy earlier and earlier and when they come for transplant with a diagnosis of MM, it is critical to review the initial diagnostic information. Most transplant centers have experience with this phenomena and know that they don’t want to transplant a non-high-risk SMM or any MGUS. However, by the time the patient is referred for transplantation, the initial clinical data are sometimes obscured or inaccessible.

Dr. Ascensão. We also look into the bone bearing areas, which allows us to make sure that if the patient has hip problems, we can work on how to approach them, whether we want to radiate those patients to prevent fractures.

Use of Bisphosphonates

Dr. Cosgriff. Myeloma metastasizes to bone, and it is one of the common sites of metastatic disease. It poses some interesting complications, whether it is from hypercalcemia due to metastatic sites, or pain syndromes. Bisphosphonates are indicated for myeloma, and they have been for years. Interestingly, unlike some of the other disease, the use of bisphosphonates induces apoptosis in myeloma. So we have seen some disease control with these agents.

The 2 bisphosphonates that are available for use are pamidronate and zoledronic acid. At the VA Portland Health Care System (VAPORHCS), we have been
using pamidronate exclusively for individuals with myeloma. There was a 2003 paper that evaluated the use of bisphosphonates for skeletal-related events in myeloma and in patients with metastatic breast cancer.2 In the subset analysis of myeloma patients with the bisphosphonates, there was no difference between pamidronate and zoledronic acid.

At the time, zoledronic acid was significantly more expensive than pamidronate, and so VAPORHCS opted to use pamidronate as a cost-saving measure. But there are the other reasons for picking pamidronate: Zoledronic acid has some dose recommendations and guidelines for individuals with renal failure, which is often a significant problem in patients with myeloma as well. To get around dose adjustments that need to be made for zoledronic acid, VAPORHCS switched to pamidronate, which is looser with the recommendations on renal failure.

Earlier use criteria, like the National Comprehensive Cancer Network guidelines, stated that if the renal failure was due to the disease itself and not some other outlying factor, a full 90-mg dose of pamidronate could still be used. That comment has since been removed. We still pay attention to it and reduce pamidronate dosing to 60 mg for patients with renal failure.

The prices for zoledronic acid have dropped significantly since it became a generic. The nice thing about zoledronic acid is that it has a short infusion time of 15 minutes. As chair space becomes a problem—VAPHCS has significant issues with that—zoledronic acid looks more and more attractive. The FDA label states that pamidronate should be infused over 4 hours, but VAPHCS typically has been infusing it for 3 hours.

It should be noted that denosumab (XGEVA), a monoclonal antibody that also is targeted for hypercalcemia, has been specifically excluded for myeloma. It
has no FDA indication for myeloma. It does have an indication for hypercalcemia. Whether or not you can state that the patient with myeloma is hypercalcemic, and that’s the reason you want to use it, it starts crossing into some gray area. The drug is still significantly more expensive and it seems to have similar efficacy rates compared with both pamidronate and zoledronic acid, so VAPHCS limits its use to individuals who would otherwise be contraindicated to zoledronic acid or pamidronate due to renal failure.

Dr. Ascensão. How often do you give it, every month, every 3 months?

Dr. Cosgriff. Currently, VAPORHCS is giving bisphosphonates every month whether in the chemotherapy unit or in the short stay unit. We are starting to reevaluate that. I have heard some emerging data that suggest we can use it once a quarter and get the same results. Those data are still emerging. It would be nice to be able to reduce the infusion frequency. But bisphosphonates adhere to bone and get incorporated into the bone matrix and stay there for an extended period of time, upwards of 6 months to a year, as with zoledronic acid.

Osteonecrosis

Dr. Ascensão. Do you require dental clearance prior to first dose?

Dr. Cosgriff. Bisphosphonates have a warning for 2% incidence of osteonecrosis of the jaw. Risk factors for the development of osteonecrosis of the jaw include poor dentition or major dental work, like extractions and illfitting dentures but not necessarily root canals. Ill-fitting dentures tend to rub on the gums and irritate the bone layer underneath. It’s the irritation of the bone that’s the biggest risk factor for osteonecrosis of the jaw.

We require that patients see the dentist because we’ve had individuals develop osteonecrosis eventhough we thought they had good dentition. If a patient is seeing a dentist outside of the VA system, we ask them to notify their dentist that they’re receiving bisphosphonates. Because of the risk and because we’ve had some individuals with good dentition develop it, VAPORHCS requires all patients, particularly those who are receiving zoledronic acid, to have dental evaluations. Denosumab also has a listed 2% incidence of osteonecrosis of the jaw, so those individuals also need to be evaluated by our dental service.

Dr. Ascensão. The DCVAMC has the same problem. I have a patient that presented primarily with a plasmacytoma, and we tried to get him to see the dentist. The dentist said, ‘You’ve got to get your teeth pulled.’ The patient has tried to see outside dentists and is finding all kinds of excuses because he would like to have implants.

Dr. Cosgriff. Anytime that you somehow damage or irritate that bone, that becomes a risk factor for the development of osteonecrosis. And for those individuals, we delay the bisphosphonate. If they’re having pain syndrome, we try to support them with opiates. We would love to be able to use nonsteroidal anti-inflammatory drugs—they have really good efficacy against bone pain—but renal function and renal failures prevent the use of those in a majority of patients. We start bisphosphonates as soon as dental clears them.

Dr. Mehta. Isn’t there a contraindication for denosumab and some evidence that it may worsen MM outcomes?

Dr. Cosgriff. When the drug first came on the market, it specifically stated in the package insert that it is not to be used in MM (it doesn’t state it specifically anymore). There is a thought that maybe some underlying mechanism exists that might stimulate some of the myeloma problems, which is why I get a little concerned when people say, “Well, I’m using it for hypercalcemia, I’m not using it to treat or to prevent a skeletal-related event in patients with myeloma.” That becomes a gray area and in that type of situation, I would recommend treating the hypercalcemia with a single dose and then switching the
patient to a bisphosphonate.

Dr. Mehta. And of course, bisphosphonates also lower calcium. They can be used to treat hypercalcemia.

Dr. Cosgriff. Yes. Zoledronic acid does have limitations in renal failure, though pamidronate doesn’t have quite the same limitations. The VAPORHCS tries to
use exclusively for hypercalcemia as well. The data show that when using zoledronic acid compared with pamidronate, you end up with the same outcomes as far as hypercalcemia. The zoledronic acid onset of action is a little faster, around 12 to 24 hours vs 48 to 72 hours with pamidronate, but you can get around that by using calcitonin over a short period; 48 hours is typically the maximum efficacy for calcitonin in treating hypercalcemia. So we use pamidronate in place of that, supplementing with calcitonin.

The result is that at 7 days, pamidronate and zoledronic acid show the same efficacy rates for treating hypercalcemia. But the renal function sometimes prevents us from doing that. Denosumab does become an option for hypercalcemia, but again, I caution against its use for treating hypercalcemia in patients with myeloma due to the risk of advancing the myeloma.

Bone Marrow Transplant

Dr. Ascensão. Do you transplant for 1 or 2 bone marrows? What’s the best maintenance regimen postallograft, and when do you start? Do you use lenalidomide the first month of the transplant or do you wait until day 100?

Dr. Chauncey. From my perspective, hematopoietic stem cell transplantation has never really lost prominence. It is true that the concept of marrow transplantation for MM has been around for more than 20 years for those patients with first best response (Note that I’ll use best response rather than first remission). The concept was developed in an era when we had much less effective therapy, and in comparative trials, progressionfree survival was consistently superior and occasionally, overall survival was better with transplantation. As treatments got better, responses got better, and there were regular questions as to whether we still needed transplantation. But the data show that as responses got better, the progression-free survivals continued to improve, and transplantation still adds something to initial therapy.

Probably the most current data are from the Dana Farber- IFM trial for which Nikhil Munshi, MD, is an investigator. The trial includes induction with lenalidomide/bortezomib/dexamethasone, which is one of the more aggressive induction regimens. When upfront transplant vs delayed transplant are compared, it seems the preliminary data still favor having an upfront transplant after initial induction therapy.

The consensus is that autologous transplantation adds to the better response that we see with better induction therapy. Overall survival has become a less accessible endpoint since the initial trials, and that’s really a consequence of having better salvage therapy, and the confounding effects of subsequent treatments. We have so many options for salvage therapy that it’s now very hard to look at overall survival as an endpoint in trials of initial therapy.

A sometimes contentious question when it comes to payers, and less so in the VA, is how many transplants to do as part of initial therapy? Little Rock and the French did some of the pioneering work on tandem transplants. The BMT CTN 0702–StaMINA trial looks at this directly, and is mature and should be presented soon [Editorial Note: Preliminary results were presented at the American Society of Hematology meeting on December 6, 2016].

The approach at VAPSHCS and most other transplant centers has typically been to harvest a sufficient quantity of peripheral blood stem cells to do 2 transplants. If less than a very good partial response is achieved after the first transplant, then we do a second transplant in tandem fashion.

One exception would be for plasma cell leukemia, which is very aggressive. In that case, we would routinely perform tandem transplantation. We are unlikely to ever have a randomized trial that compares 1 vs 2 transplants in that particular setting.

Another question is whether a second autologous transplantation can be useful in a nontandem fashion, and there is a large amount of retrospective data about its use as salvage treatment. In eras when there were not as many effective therapies, salvage autologous transplant was more attractive. As new therapies came along, its use has somewhat waned, but there’s been renewed interest because dose-intensive melphalan with autologous rescue is relatively safe and not cross-resistant to other therapies. It also offers the option of a drug holiday after the transplant, whereas salvage drug therapy is typically continuous.

There is no universal agreement on nontandem second transplantation, there are no consistent algorithms to say when it is appropriate, but it’s worth discussing with the transplant programs, especially if there is a lot of toxicity with current salvage therapy.

The last question is the role of allogeneic transplantation, and while I’m generally a proponent of allogeneic transplantation for many diseases, in spite of some really significant efforts, the majority of allogeneic data for MM has not been very positive. The large BMT-CTN 0102 trial compared tandem autologous transplant at first response to a single autologous transplantation followed by reduced-intensity autologous transplantation from a matched sibling. This study was limited in part by enrollment bias, but the published results did not favor an allogeneic approach.³ Although there was less relapse in the allogeneic setting, the mortality of allogeneic transplant was not overcome by the decrease in relapse. Neither progression-free or overall survivals at 3 years were better in the allogeneic group.

Despite small studies showing feasibility and promising results, it’s currently very hard to advocate for allogeneic transplantation in MM. There are certainly centers that continue to have their own approach, with some in the U.S. that are pioneering tweaks on allogeneic regimens and graft engineering, but the data are typically small and anecdotal. That doesn’t mean that there won’t ultimately be a better way to do allogeneic transplantation in MM, but rather that we don’t currently know the best way to approach this strategy.

Next Steps in Myeloma Treatment

Dr. Ascensão. There are some people who are now starting to talk about a cure for myeloma. I’m not sure we’re there yet. Certainly, it’s a chronic disease that, if we can take care of the complications and maybe by starting treatment early. I’m not sure Agent Orange-exposed patients do better or worse. That’s something that needs to be researched if we can find a way to compare within this group and within the type of treatment that patients get.

Is it reasonable to start looking for minimal residual disease in cells? Should we shoot for the best response? I think one of the points that Dr. Chauncey made a number of times, and I agree, is that our patient population may not be able to tolerate some of the more aggressive therapies. Perhaps we need to find a slightly different version of this algorithm for VA patients.

Dr. Chauncey. There’s a diverse biology for both veterans and nonveterans alike. There are patients for whom a deeper response will lead to longer remission and better survival, and there are others whose disease will smolder with a lower tumor burden and not progress quickly. A lot of the early gene expression profiling data on this comes from Little Rock. Unfortunately, determination of an individual’s biology is not readily accessible in the clinic, and we are typically unable to clearly define each patient’s inherent disease biology.

Dr. Mehta. We just don’t have the answers as to exactly what to do with the information that we get except watch more closely and treat a little bit earlier. We don’t even know the significance of minimal residue disease and how often to test for it and if it correlates truly with longer-term survival. These are great research questions. We need to accumulate the data and try to analyze it. We need to participate in the big data programs.

Dr. Ascensão. The other thing, of course, is now we have new immunotherapy approaches beyond transplant, which includes some of the checkpoint inhibitors and there’s some exciting data coming out. So I think the future looks good.

We all are committed to treating our patients, our veterans, to the best of our abilities. And I think the VA has done a very good job in allowing us to do this for our patients and allowing us to provide the best treatments available out there.

Click here to read the digital edition.

The following is a lightly edited transcript of a portion of a teleconference discussion on treating patients with multiple myeloma in the VHA. The conclusion will be published in the August special issue. For more information and to listen to the conversation, visit FedPrac.com/AVAHOupdates.

Biology of Multiple Myeloma

Dr. Munshi. There are many new advances in understanding of basic molecular and genomic changes in multiple myeloma (MM) that involve signaling pathways that drive MM. We have many drugs that target signaling pathways and the number of newer mutational changes that are identified could have therapeutic as well as prognostic significance.

One of the important findings is the lack of specific myeloma-related mutations. Unlike Waldenström macroglobulinemia, which has about 90% patients with Myd88 mutation, in myeloma we do not see that. The mutation frequency, at the maximum, is in the range of 20% for any one gene, and the 3 to 4 most common genes mutated are KRAS, NRAS, BRAF, and P53.

Importantly, if we look at RAS and RAF combined, they target the MEK pathway. So, almost 45% patients have a mutation affecting the MEK pathway, and potentially we can use drugs in the future to see if MEK inhibitors will provide some benefit. And there are anecdotal reports and 1 medium-sized study that has used either a pure MEK inhibitor or a BRAF inhibitor with responses in MM patients. This is a very exciting new area of development.

The second important biological feature in myeloma is clonal shifts. You see multiple clones even at the time of diagnosis. The clonal complexity increases and different clones shift over time with treatment, various other interventions, and changes in myeloma growth patterns. In the future, we cannot just do genomic or cytogenetic analysis one time and sit on it. Over the course of the disease, we may have to repeat it to see if a new clone has evolved. Low-grade or low-risk disease can become a high-grade disease over time.

What is becoming apparent is that sometimes a clone that has almost disappeared reappears after 3, 4, or 5 years. The patient can become resistant to a drug that he or she previously was responsive to with the emergenceof a resistant clone. Three or 4 years later the old sensitive clone can reappear and again be sensitive to the drug that it was not responsive to. The patient may be able to use the same drug again down the line and/or consider similar pathways for targeting. This is one of the major advances that is happening now and is going to inform how we treat patients and how we evaluate patients.

Dr. Mehta. Dr. Munshi, is this going to become “big data?” Are we going to get a lot of information about the molecular changes and findings in our patients not only over time with the evolution of the disease, but also with treatment with various combinations and single agents? Do you think that we at the VA would be able to contribute to some type of banking of material with reference labs that can help to interpret all of the data that we’re going to be able to generate?

Tissue Banking

Dr. Munshi. I think that’s a very important and interesting question. Some mechanisms should be developed so we could not only bank, but also study these genomic patterns. From the VA point of view, there would be some peculiarities that we should understand. One is the age of the patient population—veterans usually end up being older. Number 2, we know the disease is more common in the African American population, and we need to understand why. Tissue banking may help us compare the genomic differences and similarities to understand who may be predisposed to increased frequency of myeloma.

Finally, we still have to keep Agent Orange in mind. Although it is becoming quite an old exposure, a lot of times myeloma occurs. There is a recent paper in JAMA Oncology that showed that incidence of MGUS [monoclonal gammopathy of undetermined significance] is higher in people who are exposed to Agent Orange. Tissue banking to understand that also would be extremely important, and the banked tissue should be processed to understand what’s happening at the molecular level.

Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.

Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.

Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?

Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.

How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.

Relapse

Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.

Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.

Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.

Immune System

Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?

Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.

The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.

The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.

Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”

Standard of Therapy

Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?

Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.

An alternative people use that has a financial difference is to use a proteasome inhibitor with cyclophosphamide and dexamethasone, a VCD-like regimen. The study is going to use ixazomib, cyclophosphamide, and dexamethasone followed by ixazomib maintenance. That’s the usual induction regimen.

The question is do we do this differently whether the patient is high risk or low risk? My personal bias in the answer is, not really. At the beginning, we will present the best treatment for the patient’s health. If they are older patients with a lot of comorbidities, which is more important, we can use weekly bortezomib instead of using the full dose. We can use subcutaneous weekly bortezomib or a similar 3-drug regimen. And so high risk or low risk doesn’t change how we’re doing the beginning.

The place where the risk stratification comes into the picture is if patients get a transplant. We are beginning to do posttransplant consolidation, and that’s where we would add 2 cycles of consolidation. If consolidation is not done, for high-risk patients one may do maintenance with 2 drugs like bortezomib and lenalidomide alone; whereas in a low-risk patient, you could do lenalidomide only and not use bortezomib with it. This is the impact of risk stratification as far as what we do. It comes more at the later time rather than earlier time point.

Dr. Mehta. There are still a lot of unanswered questions. One area where I think the VA is very good at becoming involved, if we choose to do so, would be some of the drug dosings. For example, dexamethasone used to be used in high dose and the ECOG study showed that you can use it in lower dose weekly rather than 4 days on, 4 days off. The Myeloma In VA (MIVA) group led by Dr. Munshi did a study looking at different doses of lenalidomide. There’s still unanswered questions even in this standard of care regimen that we use where we could try to make the regimen more tolerable for patients.

Dr. Roodman. RVd (modified RVD) has been piloted by Dr. Noopur Raje at Mass General, but I don’t think it’s a large study. She uses it in older patients. To follow-up on what you said, which I think is a really great idea, we could look at RVd as well as 2 doses of dexamethasone, or use oral proteasome antagonists instead.

Dr. Mehta. Yes, to reduce the neurotoxicity.

Dr. Roodman. That is correct. But I think the VA is set up to look at those kinds of questions because most of our patients are older.

Dr. Mehta. They have all the comorbidities.

Dr. Chauncey. We have what we think is an optimal regimen for an optimal patient, and then we have what we often see in the clinic. I’m not sure of the quantitative VA demographics, but if you look at the U.S. myeloma population, the median age is 70 years. While a triplet like
RVd or a carfilzomib-based triplet is probably optimal based on depth of response and the theoretical aspect of suppression of all subclones, it’s not really an accessible regimen for many patients that I see in clinic who are not transplant eligible.

For the nontransplant patients and more frail patients, the doublets or the cyclophosphamide/bortezomib/dexamethasone are reasonable options. I know there are proponents saying that everybody should get RVd or dose-attenuated RVd; I don’t think that’s practical for many of the patients that we see in our clinics.

Dr. Mehta. Why is it not practical in most of your patients? Because they have to come once a week to the clinic?

Dr. Chauncey. That’s part of it, but I find that it’s often too intense with excessive toxicity. The patients are older with comorbidities and they have more limited physiologic reserve. Part of it is coming to clinic, and that’s where all oral regimens such as Rd are useful. I don’t know that if you have an older patient and you see a good response that you’re tracking in terms of their Mspike (monoclonal protein) and their CRAB criteria, that everybody requires the aggressive approach of RVd or a similar triplet with a proteasome inhibitor, an IMiD [immunomodulator drug], and a steroid as induction therapy.

This is true even for some of the older patients who come to autologous transplantation. The data we talk about are in a younger group of patients who can tolerate the full dose of those regimens. The all-oral regimens are attractive, but it’s also quite a financial burden, maybe not to an individual patient, but certainly to the whole health care system. I’m not sure if there is a depth or durability of response advantage for the oral proteasome inhibitor over those available as IV or subcutaneous dosing.

Pricing

Dr. Ascensão. It’s interesting you bring that up because at the Washington DC VAMC, ixazomib may be priced similarly to bortezomib.

Dr. Chauncey. Well that would be very good and very interesting. It’s possible the federal pricing would make it a lot more attractive. It’s not the case outside of the VA, but there the cost burden for oral medication is often shifted to the patient.

Dr. Cosgriff. The price of carfilzomib is about $7,000 to $9,000 per month or per cycle. When we priced ixazomib here in Portland, it actually was more expensive than bortezomib, but it was cheaper than carfilzomib.

Dr. Mehta. If we can do a drug company-sponsored study, the ixazomib people would surely be interested in its usefulness as a triplet in VA patients. It also would be good for the VA patient because you don’t have to come once a week and it has much less neurotoxicity compared to the other proteasome inhibitors, which is a big problem.

Dr. Chauncey. That would be a great study to offer the right patient. I see a lot of myeloma patients in clinic that aren’t really eligible for transplantation. Many of those patients do well on doublet therapy, though they will often require dose adjustments, both down and up, as well as tracking disease status.

Dr. Cosgriff. In Portland, we’re using a lenalidomidebased regimen as a first-line therapy. We’re starting to see more and more individuals starting RVD upfront. There are some select individuals who have diabetic neuropathy or something like that, who may go on just
a lenalidomide plus dexamethasone, leaving out the bortezomib because of neuropathy issues.

Our second-line choice at this point in time has been carfilzomib, but with ixazomib being a cheaper option, we may actually consider switching over to that as a second-line choice. When you look at the clinical trials they cite in the product literature, the grade 1 neuropathy is about 18% with ixazomib and 14% with the placebo arm, so it does add some peripheral neuropathy. Maybe not as much as we would think.

While these oral agents and all-oral regimens are nice to have, we still bring in the patients for clinic and for monitoring of white blood count. It doesn’t necessarily decrease the burden of clinic visits. We still have to get lab draws. Yes, the patient is not sitting in a chair waiting for the bortezomib infusion to be mixed by the pharmacy, but we still have considerations for travel and those types of things.

We treat the entire state of Oregon and parts of southwest Washington. Fortunately, we have community-based outpatient clinics (CBOCs) and VAMCs in other areas of the state, and we also utilize places like Walla Walla and Spokane, Washington, where we can draw and check labs remotely, which decreases the travel burden, but it still is a burden to the patient to actually go in for lab tests. We’re not looking at ixazomib as a first line currently.

We’re going to wait for data to be published on ixazomib in the first line. In a couple of presentations, researchers have suggested that if you tease the data, ixazomib may be inferior to bortezomib in the first-line setting. It will be interesting to see what the data say for that as far as a first-line setting choice.

Dr. Chauncey. I second what Dr. Cosgriff said. You can’t just give patients 3 bottles of pills and say, “See you in 3 months.” Here in the Northwest we cover large rural areas, and there are many CBOCs whose labs feed directly into our CPRS (Computerized Patient Record System) so it’s very accessible and easy to follow patients that come in less frequently, but that doesn’t change the need for regular clinical follow-up. The other thing I’d say is the noncomparative data of carfilzomib/lenalidomide/dexamethasone (CRD) is quite compelling in terms of depth and duration of response. We usually don’t want to accept convenience over efficacy. Whether that durability translates long term, we don’t really know, but I think right now, CRD is the best available regimen, again, with the caveat that it’s not really accessible to patients of all ages and performance status.

Dr. Ascensão. At the Washington DC VAMC in our first cycle it is day 1, 4, 8, and 11 with bortezomib, but after that we go pretty much to weekly bortezomib. We also tend to use what I would call lower dose 20 mg dexamethasone in patients over the age of 70 years. And we feel that it is a lot less toxic. We use subcutaneous bortezomib for pretty much everybody else.

Managing Adverse Effects

Dr. Chauncey. I think we’re all using subcutaneous bortezomib at this point. Dexamethasone doesn’t get a lot of independent attention, but there’s no question that, as Dr. Mehta mentioned, the older regimen that we used, the dose-dense dexamethasone of the VAD regimen, was
quite disabling. In addition to obvious hyperglycemia, there were psychiatric problems and, ultimately, profound steroid myopathy that seemed to affect patients in variable fashion. Different patients seem to be more or less susceptible, but after a couple of cycles, it starts to kick in and is progressive.

So we’ve since abandoned those massive doses. But when you look at the ECOG study (E4A03) that really defined the lower dose (40 mg weekly), there’s no question the higher dose was more toxic but also more effective in terms of disease response. While there are many older patients that I would start with a lower dose of dexamethasone, whether it’s with lenalidomide or bortezomib, I keep in mind there can be a steep dose response curve for dexamethasone. If you’re giving 20 mg and you’re not getting the response you need, then you increase the dose. There is definitely a dose response, but the higher doses are just not as well tolerated.

Dr. Cosgriff. I don’t know if other institutions are doing it, but instead of doing 40 mg as a single dose because of patient performance status, providers in Portland will prescribe 20 mg on days 1, 2, 8, 9, 15, and 16. They’ll break up that 40 mg dose and give it that way.

Dr. Chauncey. I don’t know if that strategy is biologically equivalent in terms of antimyeloma activity or less toxic in terms of myopathy. There’s almost always some disease marker to track, so that whether you’re using the serum free-light chain assay or serum protein electrophoresis, you can see if the strategy you’re using is working in real time.

Dr. Cosgriff. I’ve never known whether it’s been shown to be more efficacious or if it’s just a way of getting around some of the adverse effects. However, it does pose some alternate challenges. With higher doses of steroids, you’re looking at 2 days where the patient can become hyperglycemic, if not, a little bit longer.

The other thing with it is that adding on that extra day of dexamethasone can interfere with some other drugs and some other therapies. In individuals who have had a deep vein thrombosis for whatever reason and they’re on warfarin, now we have an agent that really screws up our warfarin monitoring. We would have to consider switching them to another agent.

Thrombosis

Dr. Mehta. It’s also prothrombotic.

Dr. Chauncey. If you actually ask the patient, independent of the hyperglycemia, independent of the myopathy, independent of psychosis, but just quality of life, they’ll typically tell you that the on-and-off of steroids is the worst part of the regimen. It’s often the roller coaster ride of short-term hypomania followed by dysphoria.

Dr. Mehta. And the lack of sleep. They describe it as being out of their skin.

Dr. Chauncey. They are. And as soon as they stop, often there is a depression.

Dr. Mehta. It is very, very difficult. And some actually develop psychosis.

Dr. Ascensão. We all use some form of acyclovir or its derivative for the prevention of shingles in patients exposed to the proteasome inhibitors. We use aspirin, usually low dose (81 mg), for deep vein thrombosis prophylaxis. But is anybody using other anticoagulants or putting everybody prophylactically on proton-pump inhibitors (PPIs) or just seeing how people do first and then adjusting?

Dr. Chauncey. I typically use conventional dose aspirin, and if there’s breakthrough thrombosis, the first response should be that it is not the best regimen for this patient. Sometimes you have to go back to it, and if someone’s an anticoagulation candidate, then full anticoagulation is
needed if that’s the best regimen. Usually if there’s a breakthrough thrombosis, it is a deal breaker, and you’re ready to move on to a nonthrombogenic regimen.

There has been an observation (there is some biological basis to back this up) that if you give bortezomib with an IMiD, the regimen became less thrombogenic than with the IMiD and dexamethasone alone.

Dr. Ascensão. On aspirin, even if they’re on an IMiD plus a proteasome inhibitor, I just don’t know that the data are good enough for us to avoid it at this point in time. And I don’t necessarily put people on a PPI unless they’ve got added gastrointestinal problems and unless they have associated heartburn or dyspepsia symptoms.

Dr. Mehta. I use low-dose aspirin in every patient. And if they breakthrough, they go on full anticoagulation usually with a new oral anticoagulant. I use PPIs only if needed, although most of them do need it, and, of course, bisphosphonates so the bone protective aspect.

Click to read the digital edition.

The following is a lightly edited transcript of a portion of a teleconference discussion on treating patients with multiple myeloma in the VHA. The conclusion will be published in the August special issue. For more information and to listen to the conversation, visit FedPrac.com/AVAHOupdates.

Biology of Multiple Myeloma

Dr. Munshi. There are many new advances in understanding of basic molecular and genomic changes in multiple myeloma (MM) that involve signaling pathways that drive MM. We have many drugs that target signaling pathways and the number of newer mutational changes that are identified could have therapeutic as well as prognostic significance.

One of the important findings is the lack of specific myeloma-related mutations. Unlike Waldenström macroglobulinemia, which has about 90% patients with Myd88 mutation, in myeloma we do not see that. The mutation frequency, at the maximum, is in the range of 20% for any one gene, and the 3 to 4 most common genes mutated are KRAS, NRAS, BRAF, and P53.

Importantly, if we look at RAS and RAF combined, they target the MEK pathway. So, almost 45% patients have a mutation affecting the MEK pathway, and potentially we can use drugs in the future to see if MEK inhibitors will provide some benefit. And there are anecdotal reports and 1 medium-sized study that has used either a pure MEK inhibitor or a BRAF inhibitor with responses in MM patients. This is a very exciting new area of development.

The second important biological feature in myeloma is clonal shifts. You see multiple clones even at the time of diagnosis. The clonal complexity increases and different clones shift over time with treatment, various other interventions, and changes in myeloma growth patterns. In the future, we cannot just do genomic or cytogenetic analysis one time and sit on it. Over the course of the disease, we may have to repeat it to see if a new clone has evolved. Low-grade or low-risk disease can become a high-grade disease over time.

What is becoming apparent is that sometimes a clone that has almost disappeared reappears after 3, 4, or 5 years. The patient can become resistant to a drug that he or she previously was responsive to with the emergenceof a resistant clone. Three or 4 years later the old sensitive clone can reappear and again be sensitive to the drug that it was not responsive to. The patient may be able to use the same drug again down the line and/or consider similar pathways for targeting. This is one of the major advances that is happening now and is going to inform how we treat patients and how we evaluate patients.

Dr. Mehta. Dr. Munshi, is this going to become “big data?” Are we going to get a lot of information about the molecular changes and findings in our patients not only over time with the evolution of the disease, but also with treatment with various combinations and single agents? Do you think that we at the VA would be able to contribute to some type of banking of material with reference labs that can help to interpret all of the data that we’re going to be able to generate?

Tissue Banking

Dr. Munshi. I think that’s a very important and interesting question. Some mechanisms should be developed so we could not only bank, but also study these genomic patterns. From the VA point of view, there would be some peculiarities that we should understand. One is the age of the patient population—veterans usually end up being older. Number 2, we know the disease is more common in the African American population, and we need to understand why. Tissue banking may help us compare the genomic differences and similarities to understand who may be predisposed to increased frequency of myeloma.

Finally, we still have to keep Agent Orange in mind. Although it is becoming quite an old exposure, a lot of times myeloma occurs. There is a recent paper in JAMA Oncology that showed that incidence of MGUS [monoclonal gammopathy of undetermined significance] is higher in people who are exposed to Agent Orange. Tissue banking to understand that also would be extremely important, and the banked tissue should be processed to understand what’s happening at the molecular level.

Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.

Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.

Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?

Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.

How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.

Relapse

Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.

Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.

Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.

Immune System

Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?

Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.

The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.

The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.

Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”

Standard of Therapy

Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?

Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.

An alternative people use that has a financial difference is to use a proteasome inhibitor with cyclophosphamide and dexamethasone, a VCD-like regimen. The study is going to use ixazomib, cyclophosphamide, and dexamethasone followed by ixazomib maintenance. That’s the usual induction regimen.

The question is do we do this differently whether the patient is high risk or low risk? My personal bias in the answer is, not really. At the beginning, we will present the best treatment for the patient’s health. If they are older patients with a lot of comorbidities, which is more important, we can use weekly bortezomib instead of using the full dose. We can use subcutaneous weekly bortezomib or a similar 3-drug regimen. And so high risk or low risk doesn’t change how we’re doing the beginning.

The place where the risk stratification comes into the picture is if patients get a transplant. We are beginning to do posttransplant consolidation, and that’s where we would add 2 cycles of consolidation. If consolidation is not done, for high-risk patients one may do maintenance with 2 drugs like bortezomib and lenalidomide alone; whereas in a low-risk patient, you could do lenalidomide only and not use bortezomib with it. This is the impact of risk stratification as far as what we do. It comes more at the later time rather than earlier time point.

Dr. Mehta. There are still a lot of unanswered questions. One area where I think the VA is very good at becoming involved, if we choose to do so, would be some of the drug dosings. For example, dexamethasone used to be used in high dose and the ECOG study showed that you can use it in lower dose weekly rather than 4 days on, 4 days off. The Myeloma In VA (MIVA) group led by Dr. Munshi did a study looking at different doses of lenalidomide. There’s still unanswered questions even in this standard of care regimen that we use where we could try to make the regimen more tolerable for patients.

Dr. Roodman. RVd (modified RVD) has been piloted by Dr. Noopur Raje at Mass General, but I don’t think it’s a large study. She uses it in older patients. To follow-up on what you said, which I think is a really great idea, we could look at RVd as well as 2 doses of dexamethasone, or use oral proteasome antagonists instead.

Dr. Mehta. Yes, to reduce the neurotoxicity.

Dr. Roodman. That is correct. But I think the VA is set up to look at those kinds of questions because most of our patients are older.

Dr. Mehta. They have all the comorbidities.

Dr. Chauncey. We have what we think is an optimal regimen for an optimal patient, and then we have what we often see in the clinic. I’m not sure of the quantitative VA demographics, but if you look at the U.S. myeloma population, the median age is 70 years. While a triplet like
RVd or a carfilzomib-based triplet is probably optimal based on depth of response and the theoretical aspect of suppression of all subclones, it’s not really an accessible regimen for many patients that I see in clinic who are not transplant eligible.

For the nontransplant patients and more frail patients, the doublets or the cyclophosphamide/bortezomib/dexamethasone are reasonable options. I know there are proponents saying that everybody should get RVd or dose-attenuated RVd; I don’t think that’s practical for many of the patients that we see in our clinics.

Dr. Mehta. Why is it not practical in most of your patients? Because they have to come once a week to the clinic?

Dr. Chauncey. That’s part of it, but I find that it’s often too intense with excessive toxicity. The patients are older with comorbidities and they have more limited physiologic reserve. Part of it is coming to clinic, and that’s where all oral regimens such as Rd are useful. I don’t know that if you have an older patient and you see a good response that you’re tracking in terms of their Mspike (monoclonal protein) and their CRAB criteria, that everybody requires the aggressive approach of RVd or a similar triplet with a proteasome inhibitor, an IMiD [immunomodulator drug], and a steroid as induction therapy.

This is true even for some of the older patients who come to autologous transplantation. The data we talk about are in a younger group of patients who can tolerate the full dose of those regimens. The all-oral regimens are attractive, but it’s also quite a financial burden, maybe not to an individual patient, but certainly to the whole health care system. I’m not sure if there is a depth or durability of response advantage for the oral proteasome inhibitor over those available as IV or subcutaneous dosing.

Pricing

Dr. Ascensão. It’s interesting you bring that up because at the Washington DC VAMC, ixazomib may be priced similarly to bortezomib.

Dr. Chauncey. Well that would be very good and very interesting. It’s possible the federal pricing would make it a lot more attractive. It’s not the case outside of the VA, but there the cost burden for oral medication is often shifted to the patient.

Dr. Cosgriff. The price of carfilzomib is about $7,000 to $9,000 per month or per cycle. When we priced ixazomib here in Portland, it actually was more expensive than bortezomib, but it was cheaper than carfilzomib.

Dr. Mehta. If we can do a drug company-sponsored study, the ixazomib people would surely be interested in its usefulness as a triplet in VA patients. It also would be good for the VA patient because you don’t have to come once a week and it has much less neurotoxicity compared to the other proteasome inhibitors, which is a big problem.

Dr. Chauncey. That would be a great study to offer the right patient. I see a lot of myeloma patients in clinic that aren’t really eligible for transplantation. Many of those patients do well on doublet therapy, though they will often require dose adjustments, both down and up, as well as tracking disease status.

Dr. Cosgriff. In Portland, we’re using a lenalidomidebased regimen as a first-line therapy. We’re starting to see more and more individuals starting RVD upfront. There are some select individuals who have diabetic neuropathy or something like that, who may go on just
a lenalidomide plus dexamethasone, leaving out the bortezomib because of neuropathy issues.

Our second-line choice at this point in time has been carfilzomib, but with ixazomib being a cheaper option, we may actually consider switching over to that as a second-line choice. When you look at the clinical trials they cite in the product literature, the grade 1 neuropathy is about 18% with ixazomib and 14% with the placebo arm, so it does add some peripheral neuropathy. Maybe not as much as we would think.

While these oral agents and all-oral regimens are nice to have, we still bring in the patients for clinic and for monitoring of white blood count. It doesn’t necessarily decrease the burden of clinic visits. We still have to get lab draws. Yes, the patient is not sitting in a chair waiting for the bortezomib infusion to be mixed by the pharmacy, but we still have considerations for travel and those types of things.

We treat the entire state of Oregon and parts of southwest Washington. Fortunately, we have community-based outpatient clinics (CBOCs) and VAMCs in other areas of the state, and we also utilize places like Walla Walla and Spokane, Washington, where we can draw and check labs remotely, which decreases the travel burden, but it still is a burden to the patient to actually go in for lab tests. We’re not looking at ixazomib as a first line currently.

We’re going to wait for data to be published on ixazomib in the first line. In a couple of presentations, researchers have suggested that if you tease the data, ixazomib may be inferior to bortezomib in the first-line setting. It will be interesting to see what the data say for that as far as a first-line setting choice.

Dr. Chauncey. I second what Dr. Cosgriff said. You can’t just give patients 3 bottles of pills and say, “See you in 3 months.” Here in the Northwest we cover large rural areas, and there are many CBOCs whose labs feed directly into our CPRS (Computerized Patient Record System) so it’s very accessible and easy to follow patients that come in less frequently, but that doesn’t change the need for regular clinical follow-up. The other thing I’d say is the noncomparative data of carfilzomib/lenalidomide/dexamethasone (CRD) is quite compelling in terms of depth and duration of response. We usually don’t want to accept convenience over efficacy. Whether that durability translates long term, we don’t really know, but I think right now, CRD is the best available regimen, again, with the caveat that it’s not really accessible to patients of all ages and performance status.

Dr. Ascensão. At the Washington DC VAMC in our first cycle it is day 1, 4, 8, and 11 with bortezomib, but after that we go pretty much to weekly bortezomib. We also tend to use what I would call lower dose 20 mg dexamethasone in patients over the age of 70 years. And we feel that it is a lot less toxic. We use subcutaneous bortezomib for pretty much everybody else.

Managing Adverse Effects

Dr. Chauncey. I think we’re all using subcutaneous bortezomib at this point. Dexamethasone doesn’t get a lot of independent attention, but there’s no question that, as Dr. Mehta mentioned, the older regimen that we used, the dose-dense dexamethasone of the VAD regimen, was
quite disabling. In addition to obvious hyperglycemia, there were psychiatric problems and, ultimately, profound steroid myopathy that seemed to affect patients in variable fashion. Different patients seem to be more or less susceptible, but after a couple of cycles, it starts to kick in and is progressive.

So we’ve since abandoned those massive doses. But when you look at the ECOG study (E4A03) that really defined the lower dose (40 mg weekly), there’s no question the higher dose was more toxic but also more effective in terms of disease response. While there are many older patients that I would start with a lower dose of dexamethasone, whether it’s with lenalidomide or bortezomib, I keep in mind there can be a steep dose response curve for dexamethasone. If you’re giving 20 mg and you’re not getting the response you need, then you increase the dose. There is definitely a dose response, but the higher doses are just not as well tolerated.

Dr. Cosgriff. I don’t know if other institutions are doing it, but instead of doing 40 mg as a single dose because of patient performance status, providers in Portland will prescribe 20 mg on days 1, 2, 8, 9, 15, and 16. They’ll break up that 40 mg dose and give it that way.

Dr. Chauncey. I don’t know if that strategy is biologically equivalent in terms of antimyeloma activity or less toxic in terms of myopathy. There’s almost always some disease marker to track, so that whether you’re using the serum free-light chain assay or serum protein electrophoresis, you can see if the strategy you’re using is working in real time.

Dr. Cosgriff. I’ve never known whether it’s been shown to be more efficacious or if it’s just a way of getting around some of the adverse effects. However, it does pose some alternate challenges. With higher doses of steroids, you’re looking at 2 days where the patient can become hyperglycemic, if not, a little bit longer.

The other thing with it is that adding on that extra day of dexamethasone can interfere with some other drugs and some other therapies. In individuals who have had a deep vein thrombosis for whatever reason and they’re on warfarin, now we have an agent that really screws up our warfarin monitoring. We would have to consider switching them to another agent.

Thrombosis

Dr. Mehta. It’s also prothrombotic.

Dr. Chauncey. If you actually ask the patient, independent of the hyperglycemia, independent of the myopathy, independent of psychosis, but just quality of life, they’ll typically tell you that the on-and-off of steroids is the worst part of the regimen. It’s often the roller coaster ride of short-term hypomania followed by dysphoria.

Dr. Mehta. And the lack of sleep. They describe it as being out of their skin.

Dr. Chauncey. They are. And as soon as they stop, often there is a depression.

Dr. Mehta. It is very, very difficult. And some actually develop psychosis.

Dr. Ascensão. We all use some form of acyclovir or its derivative for the prevention of shingles in patients exposed to the proteasome inhibitors. We use aspirin, usually low dose (81 mg), for deep vein thrombosis prophylaxis. But is anybody using other anticoagulants or putting everybody prophylactically on proton-pump inhibitors (PPIs) or just seeing how people do first and then adjusting?

Dr. Chauncey. I typically use conventional dose aspirin, and if there’s breakthrough thrombosis, the first response should be that it is not the best regimen for this patient. Sometimes you have to go back to it, and if someone’s an anticoagulation candidate, then full anticoagulation is
needed if that’s the best regimen. Usually if there’s a breakthrough thrombosis, it is a deal breaker, and you’re ready to move on to a nonthrombogenic regimen.

There has been an observation (there is some biological basis to back this up) that if you give bortezomib with an IMiD, the regimen became less thrombogenic than with the IMiD and dexamethasone alone.

Dr. Ascensão. On aspirin, even if they’re on an IMiD plus a proteasome inhibitor, I just don’t know that the data are good enough for us to avoid it at this point in time. And I don’t necessarily put people on a PPI unless they’ve got added gastrointestinal problems and unless they have associated heartburn or dyspepsia symptoms.

Dr. Mehta. I use low-dose aspirin in every patient. And if they breakthrough, they go on full anticoagulation usually with a new oral anticoagulant. I use PPIs only if needed, although most of them do need it, and, of course, bisphosphonates so the bone protective aspect.

Click to read the digital edition.

The following is a lightly edited transcript of a portion of a teleconference discussion on treating patients with multiple myeloma in the VHA. The conclusion will be published in the August special issue. For more information and to listen to the conversation, visit FedPrac.com/AVAHOupdates.

Biology of Multiple Myeloma

Dr. Munshi. There are many new advances in understanding of basic molecular and genomic changes in multiple myeloma (MM) that involve signaling pathways that drive MM. We have many drugs that target signaling pathways and the number of newer mutational changes that are identified could have therapeutic as well as prognostic significance.

One of the important findings is the lack of specific myeloma-related mutations. Unlike Waldenström macroglobulinemia, which has about 90% patients with Myd88 mutation, in myeloma we do not see that. The mutation frequency, at the maximum, is in the range of 20% for any one gene, and the 3 to 4 most common genes mutated are KRAS, NRAS, BRAF, and P53.

Importantly, if we look at RAS and RAF combined, they target the MEK pathway. So, almost 45% patients have a mutation affecting the MEK pathway, and potentially we can use drugs in the future to see if MEK inhibitors will provide some benefit. And there are anecdotal reports and 1 medium-sized study that has used either a pure MEK inhibitor or a BRAF inhibitor with responses in MM patients. This is a very exciting new area of development.

The second important biological feature in myeloma is clonal shifts. You see multiple clones even at the time of diagnosis. The clonal complexity increases and different clones shift over time with treatment, various other interventions, and changes in myeloma growth patterns. In the future, we cannot just do genomic or cytogenetic analysis one time and sit on it. Over the course of the disease, we may have to repeat it to see if a new clone has evolved. Low-grade or low-risk disease can become a high-grade disease over time.

What is becoming apparent is that sometimes a clone that has almost disappeared reappears after 3, 4, or 5 years. The patient can become resistant to a drug that he or she previously was responsive to with the emergenceof a resistant clone. Three or 4 years later the old sensitive clone can reappear and again be sensitive to the drug that it was not responsive to. The patient may be able to use the same drug again down the line and/or consider similar pathways for targeting. This is one of the major advances that is happening now and is going to inform how we treat patients and how we evaluate patients.

Dr. Mehta. Dr. Munshi, is this going to become “big data?” Are we going to get a lot of information about the molecular changes and findings in our patients not only over time with the evolution of the disease, but also with treatment with various combinations and single agents? Do you think that we at the VA would be able to contribute to some type of banking of material with reference labs that can help to interpret all of the data that we’re going to be able to generate?

Tissue Banking

Dr. Munshi. I think that’s a very important and interesting question. Some mechanisms should be developed so we could not only bank, but also study these genomic patterns. From the VA point of view, there would be some peculiarities that we should understand. One is the age of the patient population—veterans usually end up being older. Number 2, we know the disease is more common in the African American population, and we need to understand why. Tissue banking may help us compare the genomic differences and similarities to understand who may be predisposed to increased frequency of myeloma.

Finally, we still have to keep Agent Orange in mind. Although it is becoming quite an old exposure, a lot of times myeloma occurs. There is a recent paper in JAMA Oncology that showed that incidence of MGUS [monoclonal gammopathy of undetermined significance] is higher in people who are exposed to Agent Orange. Tissue banking to understand that also would be extremely important, and the banked tissue should be processed to understand what’s happening at the molecular level.

Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.

Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.

Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?

Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.

How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.

Relapse

Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.

Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.

Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.

Immune System

Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?

Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.

The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.

The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.

Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”

Standard of Therapy

Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?

Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.

An alternative people use that has a financial difference is to use a proteasome inhibitor with cyclophosphamide and dexamethasone, a VCD-like regimen. The study is going to use ixazomib, cyclophosphamide, and dexamethasone followed by ixazomib maintenance. That’s the usual induction regimen.

The question is do we do this differently whether the patient is high risk or low risk? My personal bias in the answer is, not really. At the beginning, we will present the best treatment for the patient’s health. If they are older patients with a lot of comorbidities, which is more important, we can use weekly bortezomib instead of using the full dose. We can use subcutaneous weekly bortezomib or a similar 3-drug regimen. And so high risk or low risk doesn’t change how we’re doing the beginning.

The place where the risk stratification comes into the picture is if patients get a transplant. We are beginning to do posttransplant consolidation, and that’s where we would add 2 cycles of consolidation. If consolidation is not done, for high-risk patients one may do maintenance with 2 drugs like bortezomib and lenalidomide alone; whereas in a low-risk patient, you could do lenalidomide only and not use bortezomib with it. This is the impact of risk stratification as far as what we do. It comes more at the later time rather than earlier time point.

Dr. Mehta. There are still a lot of unanswered questions. One area where I think the VA is very good at becoming involved, if we choose to do so, would be some of the drug dosings. For example, dexamethasone used to be used in high dose and the ECOG study showed that you can use it in lower dose weekly rather than 4 days on, 4 days off. The Myeloma In VA (MIVA) group led by Dr. Munshi did a study looking at different doses of lenalidomide. There’s still unanswered questions even in this standard of care regimen that we use where we could try to make the regimen more tolerable for patients.

Dr. Roodman. RVd (modified RVD) has been piloted by Dr. Noopur Raje at Mass General, but I don’t think it’s a large study. She uses it in older patients. To follow-up on what you said, which I think is a really great idea, we could look at RVd as well as 2 doses of dexamethasone, or use oral proteasome antagonists instead.

Dr. Mehta. Yes, to reduce the neurotoxicity.

Dr. Roodman. That is correct. But I think the VA is set up to look at those kinds of questions because most of our patients are older.

Dr. Mehta. They have all the comorbidities.

Dr. Chauncey. We have what we think is an optimal regimen for an optimal patient, and then we have what we often see in the clinic. I’m not sure of the quantitative VA demographics, but if you look at the U.S. myeloma population, the median age is 70 years. While a triplet like
RVd or a carfilzomib-based triplet is probably optimal based on depth of response and the theoretical aspect of suppression of all subclones, it’s not really an accessible regimen for many patients that I see in clinic who are not transplant eligible.

For the nontransplant patients and more frail patients, the doublets or the cyclophosphamide/bortezomib/dexamethasone are reasonable options. I know there are proponents saying that everybody should get RVd or dose-attenuated RVd; I don’t think that’s practical for many of the patients that we see in our clinics.

Dr. Mehta. Why is it not practical in most of your patients? Because they have to come once a week to the clinic?

Dr. Chauncey. That’s part of it, but I find that it’s often too intense with excessive toxicity. The patients are older with comorbidities and they have more limited physiologic reserve. Part of it is coming to clinic, and that’s where all oral regimens such as Rd are useful. I don’t know that if you have an older patient and you see a good response that you’re tracking in terms of their Mspike (monoclonal protein) and their CRAB criteria, that everybody requires the aggressive approach of RVd or a similar triplet with a proteasome inhibitor, an IMiD [immunomodulator drug], and a steroid as induction therapy.

This is true even for some of the older patients who come to autologous transplantation. The data we talk about are in a younger group of patients who can tolerate the full dose of those regimens. The all-oral regimens are attractive, but it’s also quite a financial burden, maybe not to an individual patient, but certainly to the whole health care system. I’m not sure if there is a depth or durability of response advantage for the oral proteasome inhibitor over those available as IV or subcutaneous dosing.

Pricing

Dr. Ascensão. It’s interesting you bring that up because at the Washington DC VAMC, ixazomib may be priced similarly to bortezomib.

Dr. Chauncey. Well that would be very good and very interesting. It’s possible the federal pricing would make it a lot more attractive. It’s not the case outside of the VA, but there the cost burden for oral medication is often shifted to the patient.

Dr. Cosgriff. The price of carfilzomib is about $7,000 to $9,000 per month or per cycle. When we priced ixazomib here in Portland, it actually was more expensive than bortezomib, but it was cheaper than carfilzomib.

Dr. Mehta. If we can do a drug company-sponsored study, the ixazomib people would surely be interested in its usefulness as a triplet in VA patients. It also would be good for the VA patient because you don’t have to come once a week and it has much less neurotoxicity compared to the other proteasome inhibitors, which is a big problem.

Dr. Chauncey. That would be a great study to offer the right patient. I see a lot of myeloma patients in clinic that aren’t really eligible for transplantation. Many of those patients do well on doublet therapy, though they will often require dose adjustments, both down and up, as well as tracking disease status.

Dr. Cosgriff. In Portland, we’re using a lenalidomidebased regimen as a first-line therapy. We’re starting to see more and more individuals starting RVD upfront. There are some select individuals who have diabetic neuropathy or something like that, who may go on just
a lenalidomide plus dexamethasone, leaving out the bortezomib because of neuropathy issues.

Our second-line choice at this point in time has been carfilzomib, but with ixazomib being a cheaper option, we may actually consider switching over to that as a second-line choice. When you look at the clinical trials they cite in the product literature, the grade 1 neuropathy is about 18% with ixazomib and 14% with the placebo arm, so it does add some peripheral neuropathy. Maybe not as much as we would think.

While these oral agents and all-oral regimens are nice to have, we still bring in the patients for clinic and for monitoring of white blood count. It doesn’t necessarily decrease the burden of clinic visits. We still have to get lab draws. Yes, the patient is not sitting in a chair waiting for the bortezomib infusion to be mixed by the pharmacy, but we still have considerations for travel and those types of things.

We treat the entire state of Oregon and parts of southwest Washington. Fortunately, we have community-based outpatient clinics (CBOCs) and VAMCs in other areas of the state, and we also utilize places like Walla Walla and Spokane, Washington, where we can draw and check labs remotely, which decreases the travel burden, but it still is a burden to the patient to actually go in for lab tests. We’re not looking at ixazomib as a first line currently.

We’re going to wait for data to be published on ixazomib in the first line. In a couple of presentations, researchers have suggested that if you tease the data, ixazomib may be inferior to bortezomib in the first-line setting. It will be interesting to see what the data say for that as far as a first-line setting choice.

Dr. Chauncey. I second what Dr. Cosgriff said. You can’t just give patients 3 bottles of pills and say, “See you in 3 months.” Here in the Northwest we cover large rural areas, and there are many CBOCs whose labs feed directly into our CPRS (Computerized Patient Record System) so it’s very accessible and easy to follow patients that come in less frequently, but that doesn’t change the need for regular clinical follow-up. The other thing I’d say is the noncomparative data of carfilzomib/lenalidomide/dexamethasone (CRD) is quite compelling in terms of depth and duration of response. We usually don’t want to accept convenience over efficacy. Whether that durability translates long term, we don’t really know, but I think right now, CRD is the best available regimen, again, with the caveat that it’s not really accessible to patients of all ages and performance status.

Dr. Ascensão. At the Washington DC VAMC in our first cycle it is day 1, 4, 8, and 11 with bortezomib, but after that we go pretty much to weekly bortezomib. We also tend to use what I would call lower dose 20 mg dexamethasone in patients over the age of 70 years. And we feel that it is a lot less toxic. We use subcutaneous bortezomib for pretty much everybody else.

Managing Adverse Effects

Dr. Chauncey. I think we’re all using subcutaneous bortezomib at this point. Dexamethasone doesn’t get a lot of independent attention, but there’s no question that, as Dr. Mehta mentioned, the older regimen that we used, the dose-dense dexamethasone of the VAD regimen, was
quite disabling. In addition to obvious hyperglycemia, there were psychiatric problems and, ultimately, profound steroid myopathy that seemed to affect patients in variable fashion. Different patients seem to be more or less susceptible, but after a couple of cycles, it starts to kick in and is progressive.

So we’ve since abandoned those massive doses. But when you look at the ECOG study (E4A03) that really defined the lower dose (40 mg weekly), there’s no question the higher dose was more toxic but also more effective in terms of disease response. While there are many older patients that I would start with a lower dose of dexamethasone, whether it’s with lenalidomide or bortezomib, I keep in mind there can be a steep dose response curve for dexamethasone. If you’re giving 20 mg and you’re not getting the response you need, then you increase the dose. There is definitely a dose response, but the higher doses are just not as well tolerated.

Dr. Cosgriff. I don’t know if other institutions are doing it, but instead of doing 40 mg as a single dose because of patient performance status, providers in Portland will prescribe 20 mg on days 1, 2, 8, 9, 15, and 16. They’ll break up that 40 mg dose and give it that way.

Dr. Chauncey. I don’t know if that strategy is biologically equivalent in terms of antimyeloma activity or less toxic in terms of myopathy. There’s almost always some disease marker to track, so that whether you’re using the serum free-light chain assay or serum protein electrophoresis, you can see if the strategy you’re using is working in real time.

Dr. Cosgriff. I’ve never known whether it’s been shown to be more efficacious or if it’s just a way of getting around some of the adverse effects. However, it does pose some alternate challenges. With higher doses of steroids, you’re looking at 2 days where the patient can become hyperglycemic, if not, a little bit longer.

The other thing with it is that adding on that extra day of dexamethasone can interfere with some other drugs and some other therapies. In individuals who have had a deep vein thrombosis for whatever reason and they’re on warfarin, now we have an agent that really screws up our warfarin monitoring. We would have to consider switching them to another agent.

Thrombosis

Dr. Mehta. It’s also prothrombotic.

Dr. Chauncey. If you actually ask the patient, independent of the hyperglycemia, independent of the myopathy, independent of psychosis, but just quality of life, they’ll typically tell you that the on-and-off of steroids is the worst part of the regimen. It’s often the roller coaster ride of short-term hypomania followed by dysphoria.

Dr. Mehta. And the lack of sleep. They describe it as being out of their skin.

Dr. Chauncey. They are. And as soon as they stop, often there is a depression.

Dr. Mehta. It is very, very difficult. And some actually develop psychosis.

Dr. Ascensão. We all use some form of acyclovir or its derivative for the prevention of shingles in patients exposed to the proteasome inhibitors. We use aspirin, usually low dose (81 mg), for deep vein thrombosis prophylaxis. But is anybody using other anticoagulants or putting everybody prophylactically on proton-pump inhibitors (PPIs) or just seeing how people do first and then adjusting?

Dr. Chauncey. I typically use conventional dose aspirin, and if there’s breakthrough thrombosis, the first response should be that it is not the best regimen for this patient. Sometimes you have to go back to it, and if someone’s an anticoagulation candidate, then full anticoagulation is
needed if that’s the best regimen. Usually if there’s a breakthrough thrombosis, it is a deal breaker, and you’re ready to move on to a nonthrombogenic regimen.

There has been an observation (there is some biological basis to back this up) that if you give bortezomib with an IMiD, the regimen became less thrombogenic than with the IMiD and dexamethasone alone.

Dr. Ascensão. On aspirin, even if they’re on an IMiD plus a proteasome inhibitor, I just don’t know that the data are good enough for us to avoid it at this point in time. And I don’t necessarily put people on a PPI unless they’ve got added gastrointestinal problems and unless they have associated heartburn or dyspepsia symptoms.

Dr. Mehta. I use low-dose aspirin in every patient. And if they breakthrough, they go on full anticoagulation usually with a new oral anticoagulant. I use PPIs only if needed, although most of them do need it, and, of course, bisphosphonates so the bone protective aspect.

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