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Precision medicine: A new approach to AML, other blood cancers
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
Study supports changing classification of renal cell carcinoma
, according to a population-level cohort study published in Cancer.
While patients with lymph node–negative stage III disease had superior overall survival at 5 years, survival rates were similar between patients with node–positive stage III disease and stage IV disease. This supports reclassifying stage III node-positive RCC to stage IV, according to researchers.
“Prior institutional studies have indicated that, among patients with stage III disease, those with lymph node disease have worse oncologic outcomes and experience survival that is similar to that of patients with American Joint Committee on Cancer (AJCC) stage IV disease,” wrote Arnav Srivastava, MD, of Rutgers Cancer Institute of New Jersey, New Brunswick, and colleagues.
The researchers used data from the National Cancer Database to identify patients with AJCC stage III or stage IV RCC who had undergone nephrectomy and lymph node dissection.
The cohort included 8,988 patients, 6,587 of whom had node–negative stage III disease, 2,218 of whom had node–positive stage III disease, and 183 of whom had stage IV metastatic disease. The researchers compared relative survival between staging groups.
The 5-year overall survival rate was 61.9% in patients with node–negative stage III RCC (95% confidence interval, 60.3%-63.4%), 22.7% in patients with node-positive stage III RCC (95% CI, 20.6%-24.9%), and 15.6% in patients with stage IV RCC (95% CI, 11.1%-23.8%).
“Patients with lymph node–positive stage III disease and those with stage IV disease were found to have overlapping 95% CIs when measuring 5-year survival; both demonstrated similar mortality,” the researchers reported. They further noted that these findings remained unchanged when patients were stratified by clear cell and non–clear cell histology.
In an accompanying editorial, Daniel D. Shapiro, MD, of the University of Texas MD Anderson Cancer Center, Houston, and E. Jason Abel, MD, of the University of Wisconsin–Madison, said the study results suggest the clinical phenotype of patients with isolated lymph node metastases is different from other stage III RCCs.
“Future editions of the AJCC staging system [should] recognize the increased risk with [lymph node–positive stage III] tumors and consider reclassification of [these] tumors as stage IV tumors so that baseline risks are more accurately measured in these rare populations,” they recommended.
Dr. Srivastava and colleagues acknowledged that two key limitations of the study were the retrospective design and the absence of data on other survival measures, such as metastasis-free and cancer-specific survival.
“Despite these limitations, we believe the current study was able to significantly build on prior work recommending the reclassification of lymph node–positive RCC as stage IV cancer,” they concluded.
The National Cancer Institute supported the study. Some study authors disclosed relationships with pharmaceutical companies and other organizations for work performed outside of the current study. The editorial authors disclosed no conflicts of interest.
SOURCE: Srivastava A et al. Cancer. 2020 Jul 1;126(13):2991-3001.
, according to a population-level cohort study published in Cancer.
While patients with lymph node–negative stage III disease had superior overall survival at 5 years, survival rates were similar between patients with node–positive stage III disease and stage IV disease. This supports reclassifying stage III node-positive RCC to stage IV, according to researchers.
“Prior institutional studies have indicated that, among patients with stage III disease, those with lymph node disease have worse oncologic outcomes and experience survival that is similar to that of patients with American Joint Committee on Cancer (AJCC) stage IV disease,” wrote Arnav Srivastava, MD, of Rutgers Cancer Institute of New Jersey, New Brunswick, and colleagues.
The researchers used data from the National Cancer Database to identify patients with AJCC stage III or stage IV RCC who had undergone nephrectomy and lymph node dissection.
The cohort included 8,988 patients, 6,587 of whom had node–negative stage III disease, 2,218 of whom had node–positive stage III disease, and 183 of whom had stage IV metastatic disease. The researchers compared relative survival between staging groups.
The 5-year overall survival rate was 61.9% in patients with node–negative stage III RCC (95% confidence interval, 60.3%-63.4%), 22.7% in patients with node-positive stage III RCC (95% CI, 20.6%-24.9%), and 15.6% in patients with stage IV RCC (95% CI, 11.1%-23.8%).
“Patients with lymph node–positive stage III disease and those with stage IV disease were found to have overlapping 95% CIs when measuring 5-year survival; both demonstrated similar mortality,” the researchers reported. They further noted that these findings remained unchanged when patients were stratified by clear cell and non–clear cell histology.
In an accompanying editorial, Daniel D. Shapiro, MD, of the University of Texas MD Anderson Cancer Center, Houston, and E. Jason Abel, MD, of the University of Wisconsin–Madison, said the study results suggest the clinical phenotype of patients with isolated lymph node metastases is different from other stage III RCCs.
“Future editions of the AJCC staging system [should] recognize the increased risk with [lymph node–positive stage III] tumors and consider reclassification of [these] tumors as stage IV tumors so that baseline risks are more accurately measured in these rare populations,” they recommended.
Dr. Srivastava and colleagues acknowledged that two key limitations of the study were the retrospective design and the absence of data on other survival measures, such as metastasis-free and cancer-specific survival.
“Despite these limitations, we believe the current study was able to significantly build on prior work recommending the reclassification of lymph node–positive RCC as stage IV cancer,” they concluded.
The National Cancer Institute supported the study. Some study authors disclosed relationships with pharmaceutical companies and other organizations for work performed outside of the current study. The editorial authors disclosed no conflicts of interest.
SOURCE: Srivastava A et al. Cancer. 2020 Jul 1;126(13):2991-3001.
, according to a population-level cohort study published in Cancer.
While patients with lymph node–negative stage III disease had superior overall survival at 5 years, survival rates were similar between patients with node–positive stage III disease and stage IV disease. This supports reclassifying stage III node-positive RCC to stage IV, according to researchers.
“Prior institutional studies have indicated that, among patients with stage III disease, those with lymph node disease have worse oncologic outcomes and experience survival that is similar to that of patients with American Joint Committee on Cancer (AJCC) stage IV disease,” wrote Arnav Srivastava, MD, of Rutgers Cancer Institute of New Jersey, New Brunswick, and colleagues.
The researchers used data from the National Cancer Database to identify patients with AJCC stage III or stage IV RCC who had undergone nephrectomy and lymph node dissection.
The cohort included 8,988 patients, 6,587 of whom had node–negative stage III disease, 2,218 of whom had node–positive stage III disease, and 183 of whom had stage IV metastatic disease. The researchers compared relative survival between staging groups.
The 5-year overall survival rate was 61.9% in patients with node–negative stage III RCC (95% confidence interval, 60.3%-63.4%), 22.7% in patients with node-positive stage III RCC (95% CI, 20.6%-24.9%), and 15.6% in patients with stage IV RCC (95% CI, 11.1%-23.8%).
“Patients with lymph node–positive stage III disease and those with stage IV disease were found to have overlapping 95% CIs when measuring 5-year survival; both demonstrated similar mortality,” the researchers reported. They further noted that these findings remained unchanged when patients were stratified by clear cell and non–clear cell histology.
In an accompanying editorial, Daniel D. Shapiro, MD, of the University of Texas MD Anderson Cancer Center, Houston, and E. Jason Abel, MD, of the University of Wisconsin–Madison, said the study results suggest the clinical phenotype of patients with isolated lymph node metastases is different from other stage III RCCs.
“Future editions of the AJCC staging system [should] recognize the increased risk with [lymph node–positive stage III] tumors and consider reclassification of [these] tumors as stage IV tumors so that baseline risks are more accurately measured in these rare populations,” they recommended.
Dr. Srivastava and colleagues acknowledged that two key limitations of the study were the retrospective design and the absence of data on other survival measures, such as metastasis-free and cancer-specific survival.
“Despite these limitations, we believe the current study was able to significantly build on prior work recommending the reclassification of lymph node–positive RCC as stage IV cancer,” they concluded.
The National Cancer Institute supported the study. Some study authors disclosed relationships with pharmaceutical companies and other organizations for work performed outside of the current study. The editorial authors disclosed no conflicts of interest.
SOURCE: Srivastava A et al. Cancer. 2020 Jul 1;126(13):2991-3001.
FROM CANCER
Preoperative nivo/ipi yields high response rate in early-stage colon cancer
Preoperative nivolumab plus ipilimumab appears safe and feasible for patients with early-stage colon cancer, according to researchers.
The combination produced few grade 3/4 toxicities in a phase 2 trial. It also produced pathological responses in 100% of patients with mismatch repair-deficient (dMMR) tumors and in 27% of patients with MMR-proficient (pMMR) tumors. Myriam Chalabi, MD, of the Netherlands Cancer Institute in Amsterdam, and colleagues reported these results in Nature Medicine.
The open-label, exploratory trial included 40 patients with resectable, early-stage colon adenocarcinoma, 21 of whom had dMMR tumors and 20 of whom had pMMR tumors (1 patient had both tumor types). The patients underwent surgery within 6 weeks of study enrollment.
Prior to surgery, patients received ipilimumab (1 mg/kg) on day 1 plus nivolumab (3 mg/kg) on days 1 and 15. Those with pMMR tumors also received celecoxib (200 mg) from day 1 until the day leading up to surgery. The primary endpoints were safety and feasibility. Efficacy was evaluated using histopathological response.Grade 3-4 treatment‐related adverse events (AEs) were reported in 5 patients (13%). These AEs included rash, colitis, and asymptomatic rises in laboratory parameters. Grade 3 surgery-related AEs occurred in 8 patients (20%).
“This treatment is both safe and feasible, with few treatment-related AEs and without compromising surgery,” the authors wrote.
There were 35 patients evaluable for response. Among patients with dMMR tumors, pathological responses occurred in 100% (n = 20), major pathological responses (<10% residual vital tumor) occurred in 95% (n = 19), and complete responses occurred in 60% (n = 12).
Among patients with pMMR tumors, 27% (n = 4) had a pathological response, 20% (n = 3) had a major pathological response, and 7% (n = 1) had a partial response.
The researchers acknowledged that the small sample size and short duration of postoperative follow-up were key limitations of this study, but they said this combination should be studied further.
“Neoadjuvant immunotherapy in early-stage colon cancers warrants further research and, when validated in larger studies with longer follow-up, may become a new standard of care in dMMR and possibly a subgroup of pMMR colon cancers,” the authors concluded.
This study was sponsored by the Netherlands Cancer Institute in collaboration with Bristol-Myers Squibb. Authors reported financial relationships with Bristol-Myers Squibb and many other companies.
SOURCE: Chalabi M et al. Nat Med. 2020 Apr 6. doi: 10.1038/s41591-020-0805-8.
Preoperative nivolumab plus ipilimumab appears safe and feasible for patients with early-stage colon cancer, according to researchers.
The combination produced few grade 3/4 toxicities in a phase 2 trial. It also produced pathological responses in 100% of patients with mismatch repair-deficient (dMMR) tumors and in 27% of patients with MMR-proficient (pMMR) tumors. Myriam Chalabi, MD, of the Netherlands Cancer Institute in Amsterdam, and colleagues reported these results in Nature Medicine.
The open-label, exploratory trial included 40 patients with resectable, early-stage colon adenocarcinoma, 21 of whom had dMMR tumors and 20 of whom had pMMR tumors (1 patient had both tumor types). The patients underwent surgery within 6 weeks of study enrollment.
Prior to surgery, patients received ipilimumab (1 mg/kg) on day 1 plus nivolumab (3 mg/kg) on days 1 and 15. Those with pMMR tumors also received celecoxib (200 mg) from day 1 until the day leading up to surgery. The primary endpoints were safety and feasibility. Efficacy was evaluated using histopathological response.Grade 3-4 treatment‐related adverse events (AEs) were reported in 5 patients (13%). These AEs included rash, colitis, and asymptomatic rises in laboratory parameters. Grade 3 surgery-related AEs occurred in 8 patients (20%).
“This treatment is both safe and feasible, with few treatment-related AEs and without compromising surgery,” the authors wrote.
There were 35 patients evaluable for response. Among patients with dMMR tumors, pathological responses occurred in 100% (n = 20), major pathological responses (<10% residual vital tumor) occurred in 95% (n = 19), and complete responses occurred in 60% (n = 12).
Among patients with pMMR tumors, 27% (n = 4) had a pathological response, 20% (n = 3) had a major pathological response, and 7% (n = 1) had a partial response.
The researchers acknowledged that the small sample size and short duration of postoperative follow-up were key limitations of this study, but they said this combination should be studied further.
“Neoadjuvant immunotherapy in early-stage colon cancers warrants further research and, when validated in larger studies with longer follow-up, may become a new standard of care in dMMR and possibly a subgroup of pMMR colon cancers,” the authors concluded.
This study was sponsored by the Netherlands Cancer Institute in collaboration with Bristol-Myers Squibb. Authors reported financial relationships with Bristol-Myers Squibb and many other companies.
SOURCE: Chalabi M et al. Nat Med. 2020 Apr 6. doi: 10.1038/s41591-020-0805-8.
Preoperative nivolumab plus ipilimumab appears safe and feasible for patients with early-stage colon cancer, according to researchers.
The combination produced few grade 3/4 toxicities in a phase 2 trial. It also produced pathological responses in 100% of patients with mismatch repair-deficient (dMMR) tumors and in 27% of patients with MMR-proficient (pMMR) tumors. Myriam Chalabi, MD, of the Netherlands Cancer Institute in Amsterdam, and colleagues reported these results in Nature Medicine.
The open-label, exploratory trial included 40 patients with resectable, early-stage colon adenocarcinoma, 21 of whom had dMMR tumors and 20 of whom had pMMR tumors (1 patient had both tumor types). The patients underwent surgery within 6 weeks of study enrollment.
Prior to surgery, patients received ipilimumab (1 mg/kg) on day 1 plus nivolumab (3 mg/kg) on days 1 and 15. Those with pMMR tumors also received celecoxib (200 mg) from day 1 until the day leading up to surgery. The primary endpoints were safety and feasibility. Efficacy was evaluated using histopathological response.Grade 3-4 treatment‐related adverse events (AEs) were reported in 5 patients (13%). These AEs included rash, colitis, and asymptomatic rises in laboratory parameters. Grade 3 surgery-related AEs occurred in 8 patients (20%).
“This treatment is both safe and feasible, with few treatment-related AEs and without compromising surgery,” the authors wrote.
There were 35 patients evaluable for response. Among patients with dMMR tumors, pathological responses occurred in 100% (n = 20), major pathological responses (<10% residual vital tumor) occurred in 95% (n = 19), and complete responses occurred in 60% (n = 12).
Among patients with pMMR tumors, 27% (n = 4) had a pathological response, 20% (n = 3) had a major pathological response, and 7% (n = 1) had a partial response.
The researchers acknowledged that the small sample size and short duration of postoperative follow-up were key limitations of this study, but they said this combination should be studied further.
“Neoadjuvant immunotherapy in early-stage colon cancers warrants further research and, when validated in larger studies with longer follow-up, may become a new standard of care in dMMR and possibly a subgroup of pMMR colon cancers,” the authors concluded.
This study was sponsored by the Netherlands Cancer Institute in collaboration with Bristol-Myers Squibb. Authors reported financial relationships with Bristol-Myers Squibb and many other companies.
SOURCE: Chalabi M et al. Nat Med. 2020 Apr 6. doi: 10.1038/s41591-020-0805-8.
FROM NATURE MEDICINE
Guidelines for radiotherapy in prostate cancer during the pandemic
The framework involves using remote visits via telemedicine, avoiding radiotherapy in applicable cases, deferring radiotherapy as appropriate, and shortening the fractionation schedule of treatment based on safety and efficacy parameters.
Nicholas G. Zaorsky, MD, of Penn State Cancer Institute in Hershey, Pennsylvania, and colleagues described the framework and recommendations in Advances in Radiation Oncology.
The authors systematically reviewed the body of literature for evidence pertaining to the safe use of telemedicine, avoidance or deferral of radiotherapy, and optimal use of androgen deprivation therapy for patients with prostate cancer. The team also reviewed best practices for patients undergoing radiotherapy based on disease risk.
Based on their findings, Dr. Zaorsky and colleagues recommended that, during the pandemic, all consultations and return visits become telehealth visits. “Very few prostate cancer patients require an in-person visit during a pandemic,” the authors wrote.
Lower-risk disease
Dr. Zaorsky and colleagues recommended avoiding radiotherapy in patients with very-low-, low-, and favorable intermediate-risk disease. The authors said data suggest that, in general, treatment can be safely deferred in these patients “until after pandemic-related restrictions have been lifted.” However, this recommendation presumes the pandemic will wane over the next 12 months.
“I reassure my patients with very-low- and low-risk prostate cancer that the preferred, evidence-based treatment for patients in these categories is active surveillance,” said study author Amar U. Kishan, MD, of the University of California, Los Angeles.
“If surveillance is an option, then delaying treatment must be reasonable [during the pandemic],” he added. “For favorable intermediate-risk disease, I [review] the data supporting this approach and discuss that short delays are very unlikely to compromise outcomes.”
Higher-risk disease
The authors recommended deferral of radiotherapy for 4-6 months in patients with higher-risk disease, which includes those with unfavorable intermediate-risk, high-risk, very-high-risk, clinical node-positive, oligometastatic, and low-volume M1 disease, as well as patients who have undergone prostatectomy.
The authors noted that in-person consultations and return visits should be converted to “timely remote telehealth visits” for these patients. After these patients have started treatment, androgen deprivation therapy “can allow for further deferral of radiotherapy as necessary based on the nature of the ongoing epidemic.”
In cases where radiotherapy cannot be deferred safely, “the shortest fractionation schedule should be adopted that has evidence of safety and efficacy,” the authors wrote.
They acknowledged that these recommendations are only applicable to patients not infected with COVID-19. In cases of suspected or confirmed COVID-19, local institutional policies and practices should be followed.
The authors further explained that, due to the rapidly evolving nature of the COVID-19 pandemic, state and federal guidelines should be followed when made available.
The authors reported having no conflicts of interest. No funding sources were reported.
SOURCE: Zaorsky NG et al. Adv Radiat Oncol. 2020 Apr 1. doi: 10.1016/j.adro.2020.03.010.
The framework involves using remote visits via telemedicine, avoiding radiotherapy in applicable cases, deferring radiotherapy as appropriate, and shortening the fractionation schedule of treatment based on safety and efficacy parameters.
Nicholas G. Zaorsky, MD, of Penn State Cancer Institute in Hershey, Pennsylvania, and colleagues described the framework and recommendations in Advances in Radiation Oncology.
The authors systematically reviewed the body of literature for evidence pertaining to the safe use of telemedicine, avoidance or deferral of radiotherapy, and optimal use of androgen deprivation therapy for patients with prostate cancer. The team also reviewed best practices for patients undergoing radiotherapy based on disease risk.
Based on their findings, Dr. Zaorsky and colleagues recommended that, during the pandemic, all consultations and return visits become telehealth visits. “Very few prostate cancer patients require an in-person visit during a pandemic,” the authors wrote.
Lower-risk disease
Dr. Zaorsky and colleagues recommended avoiding radiotherapy in patients with very-low-, low-, and favorable intermediate-risk disease. The authors said data suggest that, in general, treatment can be safely deferred in these patients “until after pandemic-related restrictions have been lifted.” However, this recommendation presumes the pandemic will wane over the next 12 months.
“I reassure my patients with very-low- and low-risk prostate cancer that the preferred, evidence-based treatment for patients in these categories is active surveillance,” said study author Amar U. Kishan, MD, of the University of California, Los Angeles.
“If surveillance is an option, then delaying treatment must be reasonable [during the pandemic],” he added. “For favorable intermediate-risk disease, I [review] the data supporting this approach and discuss that short delays are very unlikely to compromise outcomes.”
Higher-risk disease
The authors recommended deferral of radiotherapy for 4-6 months in patients with higher-risk disease, which includes those with unfavorable intermediate-risk, high-risk, very-high-risk, clinical node-positive, oligometastatic, and low-volume M1 disease, as well as patients who have undergone prostatectomy.
The authors noted that in-person consultations and return visits should be converted to “timely remote telehealth visits” for these patients. After these patients have started treatment, androgen deprivation therapy “can allow for further deferral of radiotherapy as necessary based on the nature of the ongoing epidemic.”
In cases where radiotherapy cannot be deferred safely, “the shortest fractionation schedule should be adopted that has evidence of safety and efficacy,” the authors wrote.
They acknowledged that these recommendations are only applicable to patients not infected with COVID-19. In cases of suspected or confirmed COVID-19, local institutional policies and practices should be followed.
The authors further explained that, due to the rapidly evolving nature of the COVID-19 pandemic, state and federal guidelines should be followed when made available.
The authors reported having no conflicts of interest. No funding sources were reported.
SOURCE: Zaorsky NG et al. Adv Radiat Oncol. 2020 Apr 1. doi: 10.1016/j.adro.2020.03.010.
The framework involves using remote visits via telemedicine, avoiding radiotherapy in applicable cases, deferring radiotherapy as appropriate, and shortening the fractionation schedule of treatment based on safety and efficacy parameters.
Nicholas G. Zaorsky, MD, of Penn State Cancer Institute in Hershey, Pennsylvania, and colleagues described the framework and recommendations in Advances in Radiation Oncology.
The authors systematically reviewed the body of literature for evidence pertaining to the safe use of telemedicine, avoidance or deferral of radiotherapy, and optimal use of androgen deprivation therapy for patients with prostate cancer. The team also reviewed best practices for patients undergoing radiotherapy based on disease risk.
Based on their findings, Dr. Zaorsky and colleagues recommended that, during the pandemic, all consultations and return visits become telehealth visits. “Very few prostate cancer patients require an in-person visit during a pandemic,” the authors wrote.
Lower-risk disease
Dr. Zaorsky and colleagues recommended avoiding radiotherapy in patients with very-low-, low-, and favorable intermediate-risk disease. The authors said data suggest that, in general, treatment can be safely deferred in these patients “until after pandemic-related restrictions have been lifted.” However, this recommendation presumes the pandemic will wane over the next 12 months.
“I reassure my patients with very-low- and low-risk prostate cancer that the preferred, evidence-based treatment for patients in these categories is active surveillance,” said study author Amar U. Kishan, MD, of the University of California, Los Angeles.
“If surveillance is an option, then delaying treatment must be reasonable [during the pandemic],” he added. “For favorable intermediate-risk disease, I [review] the data supporting this approach and discuss that short delays are very unlikely to compromise outcomes.”
Higher-risk disease
The authors recommended deferral of radiotherapy for 4-6 months in patients with higher-risk disease, which includes those with unfavorable intermediate-risk, high-risk, very-high-risk, clinical node-positive, oligometastatic, and low-volume M1 disease, as well as patients who have undergone prostatectomy.
The authors noted that in-person consultations and return visits should be converted to “timely remote telehealth visits” for these patients. After these patients have started treatment, androgen deprivation therapy “can allow for further deferral of radiotherapy as necessary based on the nature of the ongoing epidemic.”
In cases where radiotherapy cannot be deferred safely, “the shortest fractionation schedule should be adopted that has evidence of safety and efficacy,” the authors wrote.
They acknowledged that these recommendations are only applicable to patients not infected with COVID-19. In cases of suspected or confirmed COVID-19, local institutional policies and practices should be followed.
The authors further explained that, due to the rapidly evolving nature of the COVID-19 pandemic, state and federal guidelines should be followed when made available.
The authors reported having no conflicts of interest. No funding sources were reported.
SOURCE: Zaorsky NG et al. Adv Radiat Oncol. 2020 Apr 1. doi: 10.1016/j.adro.2020.03.010.
FROM ADVANCES IN RADIATION ONCOLOGY
CNS cancer outcomes worse for black and Hispanic children
according to a study published in Scientific Reports.
While prior studies have shown the effects of racial/ethnic and socioeconomic risk factors on treatment outcomes in adult cancer populations, less is known about how these factors impact children with CNS cancers, explained study author Robert Fineberg, MD, of St. Anthony North Health Campus in Westminster, Colo., and colleagues.
The authors conducted their study to examine the effects of demographic and socioeconomic factors on survival in pediatric CNS cancers. Using data from the Surveillance, Epidemiology, and End Results database, the researchers identified 1,881 patients with CNS tumors, including both spinal and cranial neoplasms.
Data collection encompassed patient characteristics, socioeconomic parameters, tumor characteristics, treatment, and year of diagnosis. The primary outcomes were overall survival and disease stage at diagnosis.
Most patients were white (78.15%) and non-Hispanic (72.09%). The most common brain tumors were gliomas (n = 788), ependymomas (n = 418), and medulloblastomas (n = 393).
On multivariable analysis, the researchers found that black and Hispanic patients had worse survival, compared with white patients (hazard ratio, 1.39; P = .0014) and non-Hispanic patients (HR, 1.36; P = .0002).
After adjustment for socioeconomic parameters and treatment, the hazard ratios for both Hispanic (HR, 1.29; P = .0051) and black patients (HR, 1.29; P = .0206) slightly declined, but the differences remained significant.
On stratified analysis, poorer survival rates were observed for black and Hispanic patients with both metastatic and localized disease at diagnosis, compared with white non-Hispanic patients. However, after adjustment for mediating factors, the difference did not remain significant for black patients (P = .1026).
“Our findings on extent of disease at diagnosis demonstrated that neither black race nor Hispanic ethnicity increased the chance of metastatic disease at presentation when controlling for mediating variables,” the authors wrote. “These data suggest that racial and ethnic disparities appear to be partially explained by postdiagnosis mediating factors that may fall in the pathway between race/ethnicity and poorer survival.”
The researchers acknowledged that a key limitation of this study was the exclusion of insurance status because of incomplete access for some patients. As a result, potential associations between insurance and survival or extent of disease could not be determined.
“To better understand underlying causes that contribute to the disparity of outcomes in pediatric brain tumors, patient-level data should be utilized in future studies to investigate both biological factors and pre/postdiagnosis treatment gaps in the care of children diagnosed with CNS tumors in the hopes of improving outcomes,” the authors wrote.
In the meantime, collaboration among physicians could help improve outcomes for these patients, according to study author Adam Green, MD, of the University of Colorado at Denver in Aurora.
“[Clinicians] should establish good working relationships with pediatric oncology and neuro-oncology physicians in their community, and they should ask questions early of those teams when they have patients they’re concerned about,” Dr. Green said. “They can [ensure] that patients of minority race/ethnicity, nonprivate health insurance, and lower socioeconomic status have easy and timely access to appointments.”
This research was supported, in part, by grant funding from the National Institutes of Health. The authors reported having no conflicts of interest.
SOURCE: Fineberg R et al. Scientific Reports. 2020 Mar 12. doi: 10.1038/s41598-020-61237-2.
according to a study published in Scientific Reports.
While prior studies have shown the effects of racial/ethnic and socioeconomic risk factors on treatment outcomes in adult cancer populations, less is known about how these factors impact children with CNS cancers, explained study author Robert Fineberg, MD, of St. Anthony North Health Campus in Westminster, Colo., and colleagues.
The authors conducted their study to examine the effects of demographic and socioeconomic factors on survival in pediatric CNS cancers. Using data from the Surveillance, Epidemiology, and End Results database, the researchers identified 1,881 patients with CNS tumors, including both spinal and cranial neoplasms.
Data collection encompassed patient characteristics, socioeconomic parameters, tumor characteristics, treatment, and year of diagnosis. The primary outcomes were overall survival and disease stage at diagnosis.
Most patients were white (78.15%) and non-Hispanic (72.09%). The most common brain tumors were gliomas (n = 788), ependymomas (n = 418), and medulloblastomas (n = 393).
On multivariable analysis, the researchers found that black and Hispanic patients had worse survival, compared with white patients (hazard ratio, 1.39; P = .0014) and non-Hispanic patients (HR, 1.36; P = .0002).
After adjustment for socioeconomic parameters and treatment, the hazard ratios for both Hispanic (HR, 1.29; P = .0051) and black patients (HR, 1.29; P = .0206) slightly declined, but the differences remained significant.
On stratified analysis, poorer survival rates were observed for black and Hispanic patients with both metastatic and localized disease at diagnosis, compared with white non-Hispanic patients. However, after adjustment for mediating factors, the difference did not remain significant for black patients (P = .1026).
“Our findings on extent of disease at diagnosis demonstrated that neither black race nor Hispanic ethnicity increased the chance of metastatic disease at presentation when controlling for mediating variables,” the authors wrote. “These data suggest that racial and ethnic disparities appear to be partially explained by postdiagnosis mediating factors that may fall in the pathway between race/ethnicity and poorer survival.”
The researchers acknowledged that a key limitation of this study was the exclusion of insurance status because of incomplete access for some patients. As a result, potential associations between insurance and survival or extent of disease could not be determined.
“To better understand underlying causes that contribute to the disparity of outcomes in pediatric brain tumors, patient-level data should be utilized in future studies to investigate both biological factors and pre/postdiagnosis treatment gaps in the care of children diagnosed with CNS tumors in the hopes of improving outcomes,” the authors wrote.
In the meantime, collaboration among physicians could help improve outcomes for these patients, according to study author Adam Green, MD, of the University of Colorado at Denver in Aurora.
“[Clinicians] should establish good working relationships with pediatric oncology and neuro-oncology physicians in their community, and they should ask questions early of those teams when they have patients they’re concerned about,” Dr. Green said. “They can [ensure] that patients of minority race/ethnicity, nonprivate health insurance, and lower socioeconomic status have easy and timely access to appointments.”
This research was supported, in part, by grant funding from the National Institutes of Health. The authors reported having no conflicts of interest.
SOURCE: Fineberg R et al. Scientific Reports. 2020 Mar 12. doi: 10.1038/s41598-020-61237-2.
according to a study published in Scientific Reports.
While prior studies have shown the effects of racial/ethnic and socioeconomic risk factors on treatment outcomes in adult cancer populations, less is known about how these factors impact children with CNS cancers, explained study author Robert Fineberg, MD, of St. Anthony North Health Campus in Westminster, Colo., and colleagues.
The authors conducted their study to examine the effects of demographic and socioeconomic factors on survival in pediatric CNS cancers. Using data from the Surveillance, Epidemiology, and End Results database, the researchers identified 1,881 patients with CNS tumors, including both spinal and cranial neoplasms.
Data collection encompassed patient characteristics, socioeconomic parameters, tumor characteristics, treatment, and year of diagnosis. The primary outcomes were overall survival and disease stage at diagnosis.
Most patients were white (78.15%) and non-Hispanic (72.09%). The most common brain tumors were gliomas (n = 788), ependymomas (n = 418), and medulloblastomas (n = 393).
On multivariable analysis, the researchers found that black and Hispanic patients had worse survival, compared with white patients (hazard ratio, 1.39; P = .0014) and non-Hispanic patients (HR, 1.36; P = .0002).
After adjustment for socioeconomic parameters and treatment, the hazard ratios for both Hispanic (HR, 1.29; P = .0051) and black patients (HR, 1.29; P = .0206) slightly declined, but the differences remained significant.
On stratified analysis, poorer survival rates were observed for black and Hispanic patients with both metastatic and localized disease at diagnosis, compared with white non-Hispanic patients. However, after adjustment for mediating factors, the difference did not remain significant for black patients (P = .1026).
“Our findings on extent of disease at diagnosis demonstrated that neither black race nor Hispanic ethnicity increased the chance of metastatic disease at presentation when controlling for mediating variables,” the authors wrote. “These data suggest that racial and ethnic disparities appear to be partially explained by postdiagnosis mediating factors that may fall in the pathway between race/ethnicity and poorer survival.”
The researchers acknowledged that a key limitation of this study was the exclusion of insurance status because of incomplete access for some patients. As a result, potential associations between insurance and survival or extent of disease could not be determined.
“To better understand underlying causes that contribute to the disparity of outcomes in pediatric brain tumors, patient-level data should be utilized in future studies to investigate both biological factors and pre/postdiagnosis treatment gaps in the care of children diagnosed with CNS tumors in the hopes of improving outcomes,” the authors wrote.
In the meantime, collaboration among physicians could help improve outcomes for these patients, according to study author Adam Green, MD, of the University of Colorado at Denver in Aurora.
“[Clinicians] should establish good working relationships with pediatric oncology and neuro-oncology physicians in their community, and they should ask questions early of those teams when they have patients they’re concerned about,” Dr. Green said. “They can [ensure] that patients of minority race/ethnicity, nonprivate health insurance, and lower socioeconomic status have easy and timely access to appointments.”
This research was supported, in part, by grant funding from the National Institutes of Health. The authors reported having no conflicts of interest.
SOURCE: Fineberg R et al. Scientific Reports. 2020 Mar 12. doi: 10.1038/s41598-020-61237-2.
FROM SCIENTIFIC REPORTS
Combo maintenance boosts PFS, not OS, in advanced NSCLC
(NSCLC).
However, the addition of pemetrexed to bevacizumab maintenance improved OS for patients with wild-type EGFR, reported Takashi Seto, MD, of the National Kyushu Cancer Center, Japan, and colleagues. Their report was published in the Journal of Clinical Oncology.
The researchers conducted a phase 3 trial of 599 patients with previously untreated, advanced nonsquamous NSCLC. Patients were randomly allocated to receive maintenance with either pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) or bevacizumab alone (15 mg/kg once every 3 weeks).
Prior to starting maintenance, patients received induction with carboplatin, pemetrexed, and bevacizumab. Both interventions were maintained until unacceptable toxicity, disease progression, death, or withdrawal for other reasons.
The primary outcome was OS, measured from the time of randomization until death from any cause. Secondary outcomes included PFS and safety.
Survival
Overall, there was no significant difference in OS between the treatment arms. The median OS was 23.3 months in the pemetrexed-bevacizumab arm and 19.6 months in the bevacizumab arm (hazard ratio, 0.87; P = .069).
However, OS was significantly prolonged for patients with wild-type EGFR who received pemetrexed plus bevacizumab. The median OS was 23.3 months in the pemetrexed-bevacizumab arm and 18.8 months in the bevacizumab arm (HR, 0.82; P = .020).
For the entire cohort, PFS was significantly better in the pemetrexed-bevacizumab arm. The median PFS was 5.7 months in the pemetrexed-bevacizumab arm and 4.0 months in the bevacizumab arm (HR, 0.67; P < .001).
Safety
In the pemetrexed-bevacizumab arm, the most common grade 3 or higher adverse events were low neutrophil count (14.0%), hypertension (11.7%), and low white blood cell count (5.4%).
Treatment-related deaths occurred in four patients receiving pemetrexed-bevacizumab maintenance. The causes of death were interstitial pneumonitis (n = 2), alveolar hemorrhage, and lung infection.
“The safety profile obtained in this study was predictable and similar to previous reports,” the researchers wrote. They acknowledged that bevacizumab-induced hypertension was commonly observed but was not problematic from a clinical perspective.
Based on these results, the researchers concluded that pemetrexed plus bevacizumab maintenance is “useful” in patients with advanced nonsquamous NSCLC, especially in patients with wild-type EGFR.
This study was supported, in part, by Eli Lilly Japan KK. The authors disclosed financial affiliations with Eli Lilly and other companies.
SOURCE: Seto T et al. J Clin Oncol. 2020 Mar 10;38(8):793-803.
(NSCLC).
However, the addition of pemetrexed to bevacizumab maintenance improved OS for patients with wild-type EGFR, reported Takashi Seto, MD, of the National Kyushu Cancer Center, Japan, and colleagues. Their report was published in the Journal of Clinical Oncology.
The researchers conducted a phase 3 trial of 599 patients with previously untreated, advanced nonsquamous NSCLC. Patients were randomly allocated to receive maintenance with either pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) or bevacizumab alone (15 mg/kg once every 3 weeks).
Prior to starting maintenance, patients received induction with carboplatin, pemetrexed, and bevacizumab. Both interventions were maintained until unacceptable toxicity, disease progression, death, or withdrawal for other reasons.
The primary outcome was OS, measured from the time of randomization until death from any cause. Secondary outcomes included PFS and safety.
Survival
Overall, there was no significant difference in OS between the treatment arms. The median OS was 23.3 months in the pemetrexed-bevacizumab arm and 19.6 months in the bevacizumab arm (hazard ratio, 0.87; P = .069).
However, OS was significantly prolonged for patients with wild-type EGFR who received pemetrexed plus bevacizumab. The median OS was 23.3 months in the pemetrexed-bevacizumab arm and 18.8 months in the bevacizumab arm (HR, 0.82; P = .020).
For the entire cohort, PFS was significantly better in the pemetrexed-bevacizumab arm. The median PFS was 5.7 months in the pemetrexed-bevacizumab arm and 4.0 months in the bevacizumab arm (HR, 0.67; P < .001).
Safety
In the pemetrexed-bevacizumab arm, the most common grade 3 or higher adverse events were low neutrophil count (14.0%), hypertension (11.7%), and low white blood cell count (5.4%).
Treatment-related deaths occurred in four patients receiving pemetrexed-bevacizumab maintenance. The causes of death were interstitial pneumonitis (n = 2), alveolar hemorrhage, and lung infection.
“The safety profile obtained in this study was predictable and similar to previous reports,” the researchers wrote. They acknowledged that bevacizumab-induced hypertension was commonly observed but was not problematic from a clinical perspective.
Based on these results, the researchers concluded that pemetrexed plus bevacizumab maintenance is “useful” in patients with advanced nonsquamous NSCLC, especially in patients with wild-type EGFR.
This study was supported, in part, by Eli Lilly Japan KK. The authors disclosed financial affiliations with Eli Lilly and other companies.
SOURCE: Seto T et al. J Clin Oncol. 2020 Mar 10;38(8):793-803.
(NSCLC).
However, the addition of pemetrexed to bevacizumab maintenance improved OS for patients with wild-type EGFR, reported Takashi Seto, MD, of the National Kyushu Cancer Center, Japan, and colleagues. Their report was published in the Journal of Clinical Oncology.
The researchers conducted a phase 3 trial of 599 patients with previously untreated, advanced nonsquamous NSCLC. Patients were randomly allocated to receive maintenance with either pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) or bevacizumab alone (15 mg/kg once every 3 weeks).
Prior to starting maintenance, patients received induction with carboplatin, pemetrexed, and bevacizumab. Both interventions were maintained until unacceptable toxicity, disease progression, death, or withdrawal for other reasons.
The primary outcome was OS, measured from the time of randomization until death from any cause. Secondary outcomes included PFS and safety.
Survival
Overall, there was no significant difference in OS between the treatment arms. The median OS was 23.3 months in the pemetrexed-bevacizumab arm and 19.6 months in the bevacizumab arm (hazard ratio, 0.87; P = .069).
However, OS was significantly prolonged for patients with wild-type EGFR who received pemetrexed plus bevacizumab. The median OS was 23.3 months in the pemetrexed-bevacizumab arm and 18.8 months in the bevacizumab arm (HR, 0.82; P = .020).
For the entire cohort, PFS was significantly better in the pemetrexed-bevacizumab arm. The median PFS was 5.7 months in the pemetrexed-bevacizumab arm and 4.0 months in the bevacizumab arm (HR, 0.67; P < .001).
Safety
In the pemetrexed-bevacizumab arm, the most common grade 3 or higher adverse events were low neutrophil count (14.0%), hypertension (11.7%), and low white blood cell count (5.4%).
Treatment-related deaths occurred in four patients receiving pemetrexed-bevacizumab maintenance. The causes of death were interstitial pneumonitis (n = 2), alveolar hemorrhage, and lung infection.
“The safety profile obtained in this study was predictable and similar to previous reports,” the researchers wrote. They acknowledged that bevacizumab-induced hypertension was commonly observed but was not problematic from a clinical perspective.
Based on these results, the researchers concluded that pemetrexed plus bevacizumab maintenance is “useful” in patients with advanced nonsquamous NSCLC, especially in patients with wild-type EGFR.
This study was supported, in part, by Eli Lilly Japan KK. The authors disclosed financial affiliations with Eli Lilly and other companies.
SOURCE: Seto T et al. J Clin Oncol. 2020 Mar 10;38(8):793-803.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Antidepressant could treat recurrent prostate cancer
“We sought to investigate if phenelzine would exert an anticancer effect demonstrated by decreasing PSA [prostate-specific antigen] values in biochemically recurrent prostate cancer patients,” study author Mitchell E. Gross, MD, PhD, of the University of Southern California, Los Angeles, and colleagues wrote. Their findings were published in Prostate Cancer and Prostatic Diseases.
The single-arm study included 20 patients with biochemically recurrent, nonmetastatic, castrate-sensitive prostate cancer who received primary treatment with either radical prostatectomy (n = 18) or radiotherapy (n = 2). Study subjects had normal levels of free testosterone (50 ng/dL or above) and showed no evidence of metastatic disease on bone and CT imaging.
With respect to dosing, 18 patients were successfully titrated to the target dose of 30 mg of oral phenelzine twice daily. Five of these patients subsequently had their dose increased to 45 mg twice daily. Each dosing cycle was 28 days, with escalations occurring during the first 2 weeks of therapy.
Therapy was continued until disease progression, patient preference, therapy interruption of more than 2 weeks from study-related toxicity, or physician decision.
The primary outcome measured was PSA reduction of at least 50% from baseline. Psychiatric outcomes were also evaluated using the Hospital Anxiety and Depression Scale.
The median treatment duration was 326 days (range, 40-954 days). Among 20 evaluable patients, 5 patients (25%) achieved a PSA reduction of at least 30% from baseline, and 2 patients (10%) achieved a reduction of at least 50% from baseline.
At 12 weeks, 17 patients were still on treatment. Four patients (24%) had PSA reductions of at least 30%, and one patient (6%) had a PSA reduction of at least 50%.
The most common grade 2 or higher phenelzine-related adverse effects were dizziness (35%), hypertension (30%), and edema (10%). Serious toxicities included one case of grade 4 hypertension and two cases of grade 3 syncope, which required treatment discontinuation.
With respect to mood outcomes, Hospital Anxiety and Depression Scale scores showed a significant decline in anxiety symptoms but no difference in depressive symptoms.
The researchers acknowledged that two key limitations of this study were the small sample size and the absence of a placebo arm. Hence, the results may not accurately reflect long-term clinically relevant outcomes, such as overall survival or disease progression.
“Further studies would be needed to determine if [monoamine oxidase inhibitors], used alone or in combination with other agents, may delay clinical progression and metastasis,” the researchers concluded.
This study was funded by the USC-Taiwan Center for Translational Research and the National Cancer Institute. Some of the authors disclosed financial affiliations with Amgen, Astellas, AstraZeneca, Bayer, and other companies.
SOURCE: Gross ME et al. Prostate Cancer Prostatic Dis. 2020 Mar 3. doi: 10.1038/s41391-020-0211-9.
“We sought to investigate if phenelzine would exert an anticancer effect demonstrated by decreasing PSA [prostate-specific antigen] values in biochemically recurrent prostate cancer patients,” study author Mitchell E. Gross, MD, PhD, of the University of Southern California, Los Angeles, and colleagues wrote. Their findings were published in Prostate Cancer and Prostatic Diseases.
The single-arm study included 20 patients with biochemically recurrent, nonmetastatic, castrate-sensitive prostate cancer who received primary treatment with either radical prostatectomy (n = 18) or radiotherapy (n = 2). Study subjects had normal levels of free testosterone (50 ng/dL or above) and showed no evidence of metastatic disease on bone and CT imaging.
With respect to dosing, 18 patients were successfully titrated to the target dose of 30 mg of oral phenelzine twice daily. Five of these patients subsequently had their dose increased to 45 mg twice daily. Each dosing cycle was 28 days, with escalations occurring during the first 2 weeks of therapy.
Therapy was continued until disease progression, patient preference, therapy interruption of more than 2 weeks from study-related toxicity, or physician decision.
The primary outcome measured was PSA reduction of at least 50% from baseline. Psychiatric outcomes were also evaluated using the Hospital Anxiety and Depression Scale.
The median treatment duration was 326 days (range, 40-954 days). Among 20 evaluable patients, 5 patients (25%) achieved a PSA reduction of at least 30% from baseline, and 2 patients (10%) achieved a reduction of at least 50% from baseline.
At 12 weeks, 17 patients were still on treatment. Four patients (24%) had PSA reductions of at least 30%, and one patient (6%) had a PSA reduction of at least 50%.
The most common grade 2 or higher phenelzine-related adverse effects were dizziness (35%), hypertension (30%), and edema (10%). Serious toxicities included one case of grade 4 hypertension and two cases of grade 3 syncope, which required treatment discontinuation.
With respect to mood outcomes, Hospital Anxiety and Depression Scale scores showed a significant decline in anxiety symptoms but no difference in depressive symptoms.
The researchers acknowledged that two key limitations of this study were the small sample size and the absence of a placebo arm. Hence, the results may not accurately reflect long-term clinically relevant outcomes, such as overall survival or disease progression.
“Further studies would be needed to determine if [monoamine oxidase inhibitors], used alone or in combination with other agents, may delay clinical progression and metastasis,” the researchers concluded.
This study was funded by the USC-Taiwan Center for Translational Research and the National Cancer Institute. Some of the authors disclosed financial affiliations with Amgen, Astellas, AstraZeneca, Bayer, and other companies.
SOURCE: Gross ME et al. Prostate Cancer Prostatic Dis. 2020 Mar 3. doi: 10.1038/s41391-020-0211-9.
“We sought to investigate if phenelzine would exert an anticancer effect demonstrated by decreasing PSA [prostate-specific antigen] values in biochemically recurrent prostate cancer patients,” study author Mitchell E. Gross, MD, PhD, of the University of Southern California, Los Angeles, and colleagues wrote. Their findings were published in Prostate Cancer and Prostatic Diseases.
The single-arm study included 20 patients with biochemically recurrent, nonmetastatic, castrate-sensitive prostate cancer who received primary treatment with either radical prostatectomy (n = 18) or radiotherapy (n = 2). Study subjects had normal levels of free testosterone (50 ng/dL or above) and showed no evidence of metastatic disease on bone and CT imaging.
With respect to dosing, 18 patients were successfully titrated to the target dose of 30 mg of oral phenelzine twice daily. Five of these patients subsequently had their dose increased to 45 mg twice daily. Each dosing cycle was 28 days, with escalations occurring during the first 2 weeks of therapy.
Therapy was continued until disease progression, patient preference, therapy interruption of more than 2 weeks from study-related toxicity, or physician decision.
The primary outcome measured was PSA reduction of at least 50% from baseline. Psychiatric outcomes were also evaluated using the Hospital Anxiety and Depression Scale.
The median treatment duration was 326 days (range, 40-954 days). Among 20 evaluable patients, 5 patients (25%) achieved a PSA reduction of at least 30% from baseline, and 2 patients (10%) achieved a reduction of at least 50% from baseline.
At 12 weeks, 17 patients were still on treatment. Four patients (24%) had PSA reductions of at least 30%, and one patient (6%) had a PSA reduction of at least 50%.
The most common grade 2 or higher phenelzine-related adverse effects were dizziness (35%), hypertension (30%), and edema (10%). Serious toxicities included one case of grade 4 hypertension and two cases of grade 3 syncope, which required treatment discontinuation.
With respect to mood outcomes, Hospital Anxiety and Depression Scale scores showed a significant decline in anxiety symptoms but no difference in depressive symptoms.
The researchers acknowledged that two key limitations of this study were the small sample size and the absence of a placebo arm. Hence, the results may not accurately reflect long-term clinically relevant outcomes, such as overall survival or disease progression.
“Further studies would be needed to determine if [monoamine oxidase inhibitors], used alone or in combination with other agents, may delay clinical progression and metastasis,” the researchers concluded.
This study was funded by the USC-Taiwan Center for Translational Research and the National Cancer Institute. Some of the authors disclosed financial affiliations with Amgen, Astellas, AstraZeneca, Bayer, and other companies.
SOURCE: Gross ME et al. Prostate Cancer Prostatic Dis. 2020 Mar 3. doi: 10.1038/s41391-020-0211-9.
FROM PROSTATE CANCER AND PROSTATIC DISEASES
HRQOL deteriorates after disease progression in metastatic cancer
, results of an observational study suggest.
The findings highlight the importance of patient-relevant outcomes when evaluating novel therapies for patients with metastatic cancers, according to Norbert Marschner, MD, of Praxis für interdisziplinäre onkologie und hämatologie in Freiburg, Germany, and colleagues. The researchers reported the findings in JAMA Network Open.
They used four nationwide German registries to evaluate the association of disease progression with HRQOL in patients receiving systemic therapy for metastatic colorectal, lung, pancreatic, or breast cancer.
The analysis included 2,314 adults with documented disease progression across 203 institutions in Germany. Data collection occurred during routine follow-up visits at participating centers during 2011-2018.
Various patient-reported outcome questionnaires were used to measure HRQOL and symptom severity among participants. For the present study, the team enrolled patients at the start of any systemic palliative treatment, defined as targeted therapy, chemotherapy, or endocrine therapy.
Mixed-model analyses of more than 8,000 questionnaires showed that the first disease progression was associated with significant deterioration in 37 of 45 HRQOL scales overall, 17 of which were considered clinically meaningful.
With respect to cancer type, significant worsening after the first progression occurred in 12 of 14 colorectal cancer HRQOL scales, 11 of 14 lung cancer scales, 10 of 10 pancreatic cancer scales, and 4 of 7 breast cancer scales.
The deterioration in global HRQOL associated with the first progression was of greatest magnitude in lung cancer (6.7 points; P < .001), followed by pancreatic cancer (5.4 points; P < .001), colorectal cancer (3.5 points; P = .002), and breast cancer (2.4 points; P = .001).
The researchers also found that 38 of 45 HRQOL scales showed a greater degree of worsening after the second disease progression than after the first. They observed significant worsening after the second disease progression in 32 of 45 HRQOL scales, and all 32 were considered clinically meaningful.
The researchers acknowledged that a key limitation of this study was the observational design. As a result, the study did not include specifications related to tumor assessment, such as frequency, timing, or criteria.
“We suggest that progression-related endpoints in metastatic breast, colorectal, lung, or pancreatic cancer should be considered when evaluating the benefit of novel treatments, in addition to survival, morbidity, and HRQOL outcomes,” the researchers concluded.
The registries used in this study are funded by iOMEDICO and industry sponsors. The authors disclosed relationships with iOMEDICO and several pharmaceutical companies.
SOURCE: Marschner N et al. JAMA Netw Open. 2020 Mar 10. doi: 10.1001/jamanetworkopen.2020.0643.
, results of an observational study suggest.
The findings highlight the importance of patient-relevant outcomes when evaluating novel therapies for patients with metastatic cancers, according to Norbert Marschner, MD, of Praxis für interdisziplinäre onkologie und hämatologie in Freiburg, Germany, and colleagues. The researchers reported the findings in JAMA Network Open.
They used four nationwide German registries to evaluate the association of disease progression with HRQOL in patients receiving systemic therapy for metastatic colorectal, lung, pancreatic, or breast cancer.
The analysis included 2,314 adults with documented disease progression across 203 institutions in Germany. Data collection occurred during routine follow-up visits at participating centers during 2011-2018.
Various patient-reported outcome questionnaires were used to measure HRQOL and symptom severity among participants. For the present study, the team enrolled patients at the start of any systemic palliative treatment, defined as targeted therapy, chemotherapy, or endocrine therapy.
Mixed-model analyses of more than 8,000 questionnaires showed that the first disease progression was associated with significant deterioration in 37 of 45 HRQOL scales overall, 17 of which were considered clinically meaningful.
With respect to cancer type, significant worsening after the first progression occurred in 12 of 14 colorectal cancer HRQOL scales, 11 of 14 lung cancer scales, 10 of 10 pancreatic cancer scales, and 4 of 7 breast cancer scales.
The deterioration in global HRQOL associated with the first progression was of greatest magnitude in lung cancer (6.7 points; P < .001), followed by pancreatic cancer (5.4 points; P < .001), colorectal cancer (3.5 points; P = .002), and breast cancer (2.4 points; P = .001).
The researchers also found that 38 of 45 HRQOL scales showed a greater degree of worsening after the second disease progression than after the first. They observed significant worsening after the second disease progression in 32 of 45 HRQOL scales, and all 32 were considered clinically meaningful.
The researchers acknowledged that a key limitation of this study was the observational design. As a result, the study did not include specifications related to tumor assessment, such as frequency, timing, or criteria.
“We suggest that progression-related endpoints in metastatic breast, colorectal, lung, or pancreatic cancer should be considered when evaluating the benefit of novel treatments, in addition to survival, morbidity, and HRQOL outcomes,” the researchers concluded.
The registries used in this study are funded by iOMEDICO and industry sponsors. The authors disclosed relationships with iOMEDICO and several pharmaceutical companies.
SOURCE: Marschner N et al. JAMA Netw Open. 2020 Mar 10. doi: 10.1001/jamanetworkopen.2020.0643.
, results of an observational study suggest.
The findings highlight the importance of patient-relevant outcomes when evaluating novel therapies for patients with metastatic cancers, according to Norbert Marschner, MD, of Praxis für interdisziplinäre onkologie und hämatologie in Freiburg, Germany, and colleagues. The researchers reported the findings in JAMA Network Open.
They used four nationwide German registries to evaluate the association of disease progression with HRQOL in patients receiving systemic therapy for metastatic colorectal, lung, pancreatic, or breast cancer.
The analysis included 2,314 adults with documented disease progression across 203 institutions in Germany. Data collection occurred during routine follow-up visits at participating centers during 2011-2018.
Various patient-reported outcome questionnaires were used to measure HRQOL and symptom severity among participants. For the present study, the team enrolled patients at the start of any systemic palliative treatment, defined as targeted therapy, chemotherapy, or endocrine therapy.
Mixed-model analyses of more than 8,000 questionnaires showed that the first disease progression was associated with significant deterioration in 37 of 45 HRQOL scales overall, 17 of which were considered clinically meaningful.
With respect to cancer type, significant worsening after the first progression occurred in 12 of 14 colorectal cancer HRQOL scales, 11 of 14 lung cancer scales, 10 of 10 pancreatic cancer scales, and 4 of 7 breast cancer scales.
The deterioration in global HRQOL associated with the first progression was of greatest magnitude in lung cancer (6.7 points; P < .001), followed by pancreatic cancer (5.4 points; P < .001), colorectal cancer (3.5 points; P = .002), and breast cancer (2.4 points; P = .001).
The researchers also found that 38 of 45 HRQOL scales showed a greater degree of worsening after the second disease progression than after the first. They observed significant worsening after the second disease progression in 32 of 45 HRQOL scales, and all 32 were considered clinically meaningful.
The researchers acknowledged that a key limitation of this study was the observational design. As a result, the study did not include specifications related to tumor assessment, such as frequency, timing, or criteria.
“We suggest that progression-related endpoints in metastatic breast, colorectal, lung, or pancreatic cancer should be considered when evaluating the benefit of novel treatments, in addition to survival, morbidity, and HRQOL outcomes,” the researchers concluded.
The registries used in this study are funded by iOMEDICO and industry sponsors. The authors disclosed relationships with iOMEDICO and several pharmaceutical companies.
SOURCE: Marschner N et al. JAMA Netw Open. 2020 Mar 10. doi: 10.1001/jamanetworkopen.2020.0643.
FROM JAMA NETWORK OPEN
Colorectal cancer burden rises in younger age groups
Current trends in the incidence and mortality of colorectal cancer (CRC) in the United States suggest CRC will become a disease that largely affects young and middle-aged adults, according to a report published in CA: A Cancer Journal for Clinicians.
As the second leading cause of cancer-related death in the United States, and with modifiable risk factors accounting for over 50% of cases and deaths, CRC is largely a preventable disease, explained study author Rebecca L. Siegel, of the American Cancer Society, and colleagues.
According to the investigators, CRC incidence dropped by 3.3% per year from 2011 through 2016 among individuals aged 65 years or older, but the opposite was observed for those aged 50-64 years, with rates increasing by 1% per year. The increase was even greater for those younger than 50 years, with an increase of 2.2% per year.
The CRC incidence from 2012 through 2016 was highest among Alaska Natives (89 cases per 100,000 persons) and lowest among Asian/Pacific Islanders (30 cases per 100,000 persons).
“CRC has been the most commonly diagnosed cancer in Alaska Natives since the early 1970s for reasons that are unknown but may include a higher prevalence of risk factors,” the investigators wrote.
The risk of developing CRC is related to several factors, including obesity, vitamin D deficiency, diabetes, smoking, and other dietary factors, the team further explained.
Among those aged 65 years or older, CRC death rates decreased by 3% per year from 2008 through 2017. For those aged 50-64 years, death rates dropped by 0.6% per year. In contrast, death rates rose by 1.3% per year for those younger than 50 years.
“The uptick in young adults, which is most rapid among non-Hispanic whites (2% per year), began around 2004 and was preceded by declines of 1% to 2% per year since at least 1975,” the investigators wrote.
The reduction in incidence and mortality among older adults is partially attributable to higher uptake of CRC screening. According to recent data, CRC screening rates were lower for those aged 50-64 years compared with individuals aged 65 years and older.
Based on current recommendations from the American Cancer Society, CRC screening should begin at age 45, with some higher-risk patients starting at age 40.
“Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults,” the investigators concluded.
The authors disclosed financial affiliations with the American Cancer Society, which funded the study, as well as Array Biopharma, Bayer, RGenix, Tesaro, and Seattle Genetics.
SOURCE: Siegel RL et al. CA Cancer J Clin. 2020 Mar 5. doi: 10.3322/caac.21601.
Current trends in the incidence and mortality of colorectal cancer (CRC) in the United States suggest CRC will become a disease that largely affects young and middle-aged adults, according to a report published in CA: A Cancer Journal for Clinicians.
As the second leading cause of cancer-related death in the United States, and with modifiable risk factors accounting for over 50% of cases and deaths, CRC is largely a preventable disease, explained study author Rebecca L. Siegel, of the American Cancer Society, and colleagues.
According to the investigators, CRC incidence dropped by 3.3% per year from 2011 through 2016 among individuals aged 65 years or older, but the opposite was observed for those aged 50-64 years, with rates increasing by 1% per year. The increase was even greater for those younger than 50 years, with an increase of 2.2% per year.
The CRC incidence from 2012 through 2016 was highest among Alaska Natives (89 cases per 100,000 persons) and lowest among Asian/Pacific Islanders (30 cases per 100,000 persons).
“CRC has been the most commonly diagnosed cancer in Alaska Natives since the early 1970s for reasons that are unknown but may include a higher prevalence of risk factors,” the investigators wrote.
The risk of developing CRC is related to several factors, including obesity, vitamin D deficiency, diabetes, smoking, and other dietary factors, the team further explained.
Among those aged 65 years or older, CRC death rates decreased by 3% per year from 2008 through 2017. For those aged 50-64 years, death rates dropped by 0.6% per year. In contrast, death rates rose by 1.3% per year for those younger than 50 years.
“The uptick in young adults, which is most rapid among non-Hispanic whites (2% per year), began around 2004 and was preceded by declines of 1% to 2% per year since at least 1975,” the investigators wrote.
The reduction in incidence and mortality among older adults is partially attributable to higher uptake of CRC screening. According to recent data, CRC screening rates were lower for those aged 50-64 years compared with individuals aged 65 years and older.
Based on current recommendations from the American Cancer Society, CRC screening should begin at age 45, with some higher-risk patients starting at age 40.
“Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults,” the investigators concluded.
The authors disclosed financial affiliations with the American Cancer Society, which funded the study, as well as Array Biopharma, Bayer, RGenix, Tesaro, and Seattle Genetics.
SOURCE: Siegel RL et al. CA Cancer J Clin. 2020 Mar 5. doi: 10.3322/caac.21601.
Current trends in the incidence and mortality of colorectal cancer (CRC) in the United States suggest CRC will become a disease that largely affects young and middle-aged adults, according to a report published in CA: A Cancer Journal for Clinicians.
As the second leading cause of cancer-related death in the United States, and with modifiable risk factors accounting for over 50% of cases and deaths, CRC is largely a preventable disease, explained study author Rebecca L. Siegel, of the American Cancer Society, and colleagues.
According to the investigators, CRC incidence dropped by 3.3% per year from 2011 through 2016 among individuals aged 65 years or older, but the opposite was observed for those aged 50-64 years, with rates increasing by 1% per year. The increase was even greater for those younger than 50 years, with an increase of 2.2% per year.
The CRC incidence from 2012 through 2016 was highest among Alaska Natives (89 cases per 100,000 persons) and lowest among Asian/Pacific Islanders (30 cases per 100,000 persons).
“CRC has been the most commonly diagnosed cancer in Alaska Natives since the early 1970s for reasons that are unknown but may include a higher prevalence of risk factors,” the investigators wrote.
The risk of developing CRC is related to several factors, including obesity, vitamin D deficiency, diabetes, smoking, and other dietary factors, the team further explained.
Among those aged 65 years or older, CRC death rates decreased by 3% per year from 2008 through 2017. For those aged 50-64 years, death rates dropped by 0.6% per year. In contrast, death rates rose by 1.3% per year for those younger than 50 years.
“The uptick in young adults, which is most rapid among non-Hispanic whites (2% per year), began around 2004 and was preceded by declines of 1% to 2% per year since at least 1975,” the investigators wrote.
The reduction in incidence and mortality among older adults is partially attributable to higher uptake of CRC screening. According to recent data, CRC screening rates were lower for those aged 50-64 years compared with individuals aged 65 years and older.
Based on current recommendations from the American Cancer Society, CRC screening should begin at age 45, with some higher-risk patients starting at age 40.
“Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults,” the investigators concluded.
The authors disclosed financial affiliations with the American Cancer Society, which funded the study, as well as Array Biopharma, Bayer, RGenix, Tesaro, and Seattle Genetics.
SOURCE: Siegel RL et al. CA Cancer J Clin. 2020 Mar 5. doi: 10.3322/caac.21601.
FROM CA: A CANCER JOURNAL FOR CLINICIANS
Bevacizumab/pembrolizumab deemed safe and active in mRCC
The combination of bevacizumab and pembrolizumab demonstrated acceptable safety and activity in patients with metastatic renal cell carcinoma (mRCC) in a phase 1b/2 study, according to researchers.
Grade 3-4 adverse events were seen in 45% of patients, which “compares favorably” with other combinations of immune checkpoint inhibitors and tyrosine kinase inhibitors, according to study author Arkadiusz Z. Dudek, MD, PhD, of HealthPartners Regions Cancer Care Center in St. Paul, Minn. and colleagues. Their report was published in the Journal of Clinical Oncology.
Phase 1b
The phase 1b portion of the study included 13 patients with clear cell mRCC that relapsed after or was refractory to multiple prior lines of therapy. The patients’ median age was 55 years (range, 33-68 years), and most were men (84.6%).
The patients received infusions of pembrolizumab at 200 mg plus bevacizumab at 10 mg/kg or 15 mg/kg every 3 weeks. The primary objective of the phase 1b component was to determine safety and identify the maximum tolerated dose of the combination.
The overall response rate was 41.7%. Five patients had partial responses, six had stable disease, one had progressive disease, and one was not evaluable.
The median progression-free survival was 9.9 months, and the median overall survival was 17.9 months. No dose-limiting toxicities were observed.
Phase 2
The phase 2 component included 48 patients with clear cell mRCC, all of whom were treatment naive. Their median age was 61 years (range, 42-84 years), and most were men (68.8%).
Based on the phase 1b data, the phase 2 dose of bevacizumab was 15 mg/kg every 3 weeks.
After a median time on treatment of 298 days, the overall response rate was 60.9%. One patient achieved a complete response, and two patients had complete responses in target lesions. Of the remaining patients, 25 achieved partial responses, 18 had stable disease, and 2 were unevaluable.
The median progression-free survival was 20.7 months, and the median overall survival was not reached at 28.3 months.
Safety
In the combined safety analysis, the most frequent treatment-related grade 3 adverse events were hypertension (25%), proteinuria (10%), adrenal insufficiency (6.7%), and pain/headaches (5.0%).
The most common grade 3 immune-related adverse events were adrenal insufficiency (6.7%), pneumonitis (3.3%), hepatitis (1.7%), skin rash (1.7%), gastritis (1.7%), hypothyroidism (1.7%), and oral mucositis (1.7%).
Two grade 4 adverse events (hyponatremia and duodenal ulcer) were reported. There were no treatment-related grade 5 events.
“The combination of 200 mg of pembrolizumab and a 15-mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC,” the authors wrote. “[The combination] could be further tested in patient populations where TKIs [tyrosine kinase inhibitors] are not well tolerated and can cause early treatment discontinuation.”
This study was funded by Merck. The authors disclosed financial affiliations with Merck and other companies.
SOURCE: Dudek AZ et al. J Clin Oncol. 2020 Feb 25. doi: 10.1200/JCO.19.02394.
The combination of bevacizumab and pembrolizumab demonstrated acceptable safety and activity in patients with metastatic renal cell carcinoma (mRCC) in a phase 1b/2 study, according to researchers.
Grade 3-4 adverse events were seen in 45% of patients, which “compares favorably” with other combinations of immune checkpoint inhibitors and tyrosine kinase inhibitors, according to study author Arkadiusz Z. Dudek, MD, PhD, of HealthPartners Regions Cancer Care Center in St. Paul, Minn. and colleagues. Their report was published in the Journal of Clinical Oncology.
Phase 1b
The phase 1b portion of the study included 13 patients with clear cell mRCC that relapsed after or was refractory to multiple prior lines of therapy. The patients’ median age was 55 years (range, 33-68 years), and most were men (84.6%).
The patients received infusions of pembrolizumab at 200 mg plus bevacizumab at 10 mg/kg or 15 mg/kg every 3 weeks. The primary objective of the phase 1b component was to determine safety and identify the maximum tolerated dose of the combination.
The overall response rate was 41.7%. Five patients had partial responses, six had stable disease, one had progressive disease, and one was not evaluable.
The median progression-free survival was 9.9 months, and the median overall survival was 17.9 months. No dose-limiting toxicities were observed.
Phase 2
The phase 2 component included 48 patients with clear cell mRCC, all of whom were treatment naive. Their median age was 61 years (range, 42-84 years), and most were men (68.8%).
Based on the phase 1b data, the phase 2 dose of bevacizumab was 15 mg/kg every 3 weeks.
After a median time on treatment of 298 days, the overall response rate was 60.9%. One patient achieved a complete response, and two patients had complete responses in target lesions. Of the remaining patients, 25 achieved partial responses, 18 had stable disease, and 2 were unevaluable.
The median progression-free survival was 20.7 months, and the median overall survival was not reached at 28.3 months.
Safety
In the combined safety analysis, the most frequent treatment-related grade 3 adverse events were hypertension (25%), proteinuria (10%), adrenal insufficiency (6.7%), and pain/headaches (5.0%).
The most common grade 3 immune-related adverse events were adrenal insufficiency (6.7%), pneumonitis (3.3%), hepatitis (1.7%), skin rash (1.7%), gastritis (1.7%), hypothyroidism (1.7%), and oral mucositis (1.7%).
Two grade 4 adverse events (hyponatremia and duodenal ulcer) were reported. There were no treatment-related grade 5 events.
“The combination of 200 mg of pembrolizumab and a 15-mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC,” the authors wrote. “[The combination] could be further tested in patient populations where TKIs [tyrosine kinase inhibitors] are not well tolerated and can cause early treatment discontinuation.”
This study was funded by Merck. The authors disclosed financial affiliations with Merck and other companies.
SOURCE: Dudek AZ et al. J Clin Oncol. 2020 Feb 25. doi: 10.1200/JCO.19.02394.
The combination of bevacizumab and pembrolizumab demonstrated acceptable safety and activity in patients with metastatic renal cell carcinoma (mRCC) in a phase 1b/2 study, according to researchers.
Grade 3-4 adverse events were seen in 45% of patients, which “compares favorably” with other combinations of immune checkpoint inhibitors and tyrosine kinase inhibitors, according to study author Arkadiusz Z. Dudek, MD, PhD, of HealthPartners Regions Cancer Care Center in St. Paul, Minn. and colleagues. Their report was published in the Journal of Clinical Oncology.
Phase 1b
The phase 1b portion of the study included 13 patients with clear cell mRCC that relapsed after or was refractory to multiple prior lines of therapy. The patients’ median age was 55 years (range, 33-68 years), and most were men (84.6%).
The patients received infusions of pembrolizumab at 200 mg plus bevacizumab at 10 mg/kg or 15 mg/kg every 3 weeks. The primary objective of the phase 1b component was to determine safety and identify the maximum tolerated dose of the combination.
The overall response rate was 41.7%. Five patients had partial responses, six had stable disease, one had progressive disease, and one was not evaluable.
The median progression-free survival was 9.9 months, and the median overall survival was 17.9 months. No dose-limiting toxicities were observed.
Phase 2
The phase 2 component included 48 patients with clear cell mRCC, all of whom were treatment naive. Their median age was 61 years (range, 42-84 years), and most were men (68.8%).
Based on the phase 1b data, the phase 2 dose of bevacizumab was 15 mg/kg every 3 weeks.
After a median time on treatment of 298 days, the overall response rate was 60.9%. One patient achieved a complete response, and two patients had complete responses in target lesions. Of the remaining patients, 25 achieved partial responses, 18 had stable disease, and 2 were unevaluable.
The median progression-free survival was 20.7 months, and the median overall survival was not reached at 28.3 months.
Safety
In the combined safety analysis, the most frequent treatment-related grade 3 adverse events were hypertension (25%), proteinuria (10%), adrenal insufficiency (6.7%), and pain/headaches (5.0%).
The most common grade 3 immune-related adverse events were adrenal insufficiency (6.7%), pneumonitis (3.3%), hepatitis (1.7%), skin rash (1.7%), gastritis (1.7%), hypothyroidism (1.7%), and oral mucositis (1.7%).
Two grade 4 adverse events (hyponatremia and duodenal ulcer) were reported. There were no treatment-related grade 5 events.
“The combination of 200 mg of pembrolizumab and a 15-mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC,” the authors wrote. “[The combination] could be further tested in patient populations where TKIs [tyrosine kinase inhibitors] are not well tolerated and can cause early treatment discontinuation.”
This study was funded by Merck. The authors disclosed financial affiliations with Merck and other companies.
SOURCE: Dudek AZ et al. J Clin Oncol. 2020 Feb 25. doi: 10.1200/JCO.19.02394.
FROM THE JOURNAL OF CLINICAL ONCOLOGY