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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Optimal adjuvant endocrine therapy use in breast cancer remains elusive
Appropriate use of adjuvant endocrine therapy for breast cancer improved over a 10-year period, but optimal use has not been achieved, according to findings from a retrospective review of more than 980,000 women with stages I-III breast cancer.
As a result, an estimated 14,630 lives were unnecessarily lost during the study period, according to Bobby M. Daly, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues.
Of the 981,729 women in the National Cancer Database from Jan. 1, 2004, to Dec. 31, 2013, who received all or part of their care at the reporting institution and who met eligibility criteria, 818,435 had hormone receptor positive (HR+) disease and 163,294 had hormone receptor negative (HR-) disease.
The percentage of HR+ patients receiving adjuvant endocrine therapy (AET) increased from 69.8% in 2004 to 82.4% in 2013 (annual percentage change, 1.51%), and the percentage of HR- patients decreased from 5.2% to 3.4% during the same time period (annual percentage change, -0.17%), the authors reported online Feb. 2 in JAMA Oncology (2017 Feb 2. doi: 10.1001jamaoncol.2016.6380).
Notably, receipt of AET varied significantly by age, race, geographic location, and receptor status. For example, more than 80% of those aged 50-69 years received AET, compared with 79.1% of those younger than age 40 years and 60.5% of those 80 years or older. African American and Hispanic patients were less likely than non-Hispanic white patients to receive AET (76.4% and 75.9% vs. 79.0%, respectively). The latter finding could be an important contributing factor to the racial disparity in breast cancer survival, the authors noted.
Facility factors also played a role in AET receipt; the rate of receipt varied substantially by facility volume and geographic location.
“We found that facilities in west south central states and low-volume institutions were more likely to misuse and underuse AET,” the investigators wrote, noting that these deficits could affect breast cancer mortality, as geographic differences in such mortality are well documented.
AET receipt also varied based on hormone receptor status, tumor size, and local treatment. Surgery and radiotherapy were the factors most significantly associated with appropriate AET receipt, with only 45% of those who underwent lumpectomy without radiotherapy receiving AET, compared with 90.1% of those receiving postmastectomy radiotherapy, 85.5% in those with postlumpectomy radiotherapy, and 73.2% of those with mastectomy alone.
Women included in this study were age 18 years or older (mean age, 60.8 years). Those undergoing surgery but receiving no neoadjuvant systemic treatment were eligible. Those with prior cancer diagnoses or with missing hormone receptor or AET status were excluded.
Based on recent trial results, the American Society of Clinical Oncology updated treatment guidelines in 2016 to recommend ovarian suppression for 5 years in combination with AET for high-risk premenopausal women, and AET alone both for women with stage I breast cancers that don’t warrant chemotherapy and for node-negative cancers of 1.0 cm or less.
“Similarly, the National Quality Forum (cancer measure 0220) endorsed tamoxifen or a third-generation aromatase inhibitor (considered or administered) within 1 year of diagnosis as a marker of quality care for patients with HR+ American Joint Committee on Cancer stage T1cN0M0, II, or III disease,” the researchers wrote. Studies demonstrated benefit with AET even in those with node-negative cancers of 1.0 cm or less, they added.
Improving adherence to these guidelines has lifesaving potential. In the current cohort, receipt of AET was associated with a 29% relative risk reduction in mortality, after adjusting for numerous patient, disease, and facility-related factors. This suggests that if all women with HR+ disease received AET in concordance with guidelines, 14,630 more lives would have been saved over the 10-year study period, the investigators said.
As for approaches that could help improve the appropriate use of AET, the findings of this cohort study support those from previous studies suggesting that a team-based approach is of benefit.
The finding that local treatments are key factors associated with appropriate AET use suggests that patients who undergo radiotherapy may be more likely to receive standard-of-care therapy in general, the authors explained, adding that “with more physicians involved in a patient’s care, these patients would be more likely to be recommended for guideline concordant care.
“Facilitation of multidisciplinary team-based care may help optimize guideline-concordant treatment by ensuring patients are not lost to follow-up and are recommended for evidence-based care,” the study authors concluded.
Their hope is that with the coming launch of the Medicare Access and Chip Reauthorization Act and value-based reimbursement, efforts will be made to close the quality gap affecting patients in certain age groups, racial minority groups, and geographic regions, and to thereby prevent the loss of lives.
MACRA may boost outcomes
In an interview, Dr. Daly said he believes the coming changes with respect to value-based reimbursement will indeed have an important impact on outcomes.
“The oncology care model, for example, mandates that physicians document that they are providing guideline-concordant care,” said Dr. Daly, assistant attending physician at Memorial Sloan Kettering Cancer Center. “There are also new technologies such as oncology clinical pathways ... that also try to ensure that all patients are receiving care according to guidelines.”
Further, the increasing use of team-based approaches to care and the incorporation of “tumor boards” might explain the growth in optimal AET usage seen in this cohort.
Dr. Daly said he was surprised to find that certain patient groups were being left behind, such as those with estrogen receptor-negative/progesterone receptor-positive disease, African American patients, and younger and older patients, who were less likely to receive AET.
“I think that helps us also focus on patient populations we can target to make sure they are receiving optimal care,” he said, stressing that the findings have important policy implications for figuring out why those patients are being left behind, and raising the standard of care for all patients.
“We are making great strides to providing appropriate guideline-concordant care for breast cancer patients, but there’s still room to improve,” he said.
Dr. Daly serves as a director of and receives compensation from Quadrant Holdings. Frontline Medical News is a subsidiary of Quadrant Holdings. Dr. Daly also reported financial relationships with CVS Health, Johnson & Johnson, McKesson, and Walgreens Boots Alliance.
Appropriate use of adjuvant endocrine therapy for breast cancer improved over a 10-year period, but optimal use has not been achieved, according to findings from a retrospective review of more than 980,000 women with stages I-III breast cancer.
As a result, an estimated 14,630 lives were unnecessarily lost during the study period, according to Bobby M. Daly, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues.
Of the 981,729 women in the National Cancer Database from Jan. 1, 2004, to Dec. 31, 2013, who received all or part of their care at the reporting institution and who met eligibility criteria, 818,435 had hormone receptor positive (HR+) disease and 163,294 had hormone receptor negative (HR-) disease.
The percentage of HR+ patients receiving adjuvant endocrine therapy (AET) increased from 69.8% in 2004 to 82.4% in 2013 (annual percentage change, 1.51%), and the percentage of HR- patients decreased from 5.2% to 3.4% during the same time period (annual percentage change, -0.17%), the authors reported online Feb. 2 in JAMA Oncology (2017 Feb 2. doi: 10.1001jamaoncol.2016.6380).
Notably, receipt of AET varied significantly by age, race, geographic location, and receptor status. For example, more than 80% of those aged 50-69 years received AET, compared with 79.1% of those younger than age 40 years and 60.5% of those 80 years or older. African American and Hispanic patients were less likely than non-Hispanic white patients to receive AET (76.4% and 75.9% vs. 79.0%, respectively). The latter finding could be an important contributing factor to the racial disparity in breast cancer survival, the authors noted.
Facility factors also played a role in AET receipt; the rate of receipt varied substantially by facility volume and geographic location.
“We found that facilities in west south central states and low-volume institutions were more likely to misuse and underuse AET,” the investigators wrote, noting that these deficits could affect breast cancer mortality, as geographic differences in such mortality are well documented.
AET receipt also varied based on hormone receptor status, tumor size, and local treatment. Surgery and radiotherapy were the factors most significantly associated with appropriate AET receipt, with only 45% of those who underwent lumpectomy without radiotherapy receiving AET, compared with 90.1% of those receiving postmastectomy radiotherapy, 85.5% in those with postlumpectomy radiotherapy, and 73.2% of those with mastectomy alone.
Women included in this study were age 18 years or older (mean age, 60.8 years). Those undergoing surgery but receiving no neoadjuvant systemic treatment were eligible. Those with prior cancer diagnoses or with missing hormone receptor or AET status were excluded.
Based on recent trial results, the American Society of Clinical Oncology updated treatment guidelines in 2016 to recommend ovarian suppression for 5 years in combination with AET for high-risk premenopausal women, and AET alone both for women with stage I breast cancers that don’t warrant chemotherapy and for node-negative cancers of 1.0 cm or less.
“Similarly, the National Quality Forum (cancer measure 0220) endorsed tamoxifen or a third-generation aromatase inhibitor (considered or administered) within 1 year of diagnosis as a marker of quality care for patients with HR+ American Joint Committee on Cancer stage T1cN0M0, II, or III disease,” the researchers wrote. Studies demonstrated benefit with AET even in those with node-negative cancers of 1.0 cm or less, they added.
Improving adherence to these guidelines has lifesaving potential. In the current cohort, receipt of AET was associated with a 29% relative risk reduction in mortality, after adjusting for numerous patient, disease, and facility-related factors. This suggests that if all women with HR+ disease received AET in concordance with guidelines, 14,630 more lives would have been saved over the 10-year study period, the investigators said.
As for approaches that could help improve the appropriate use of AET, the findings of this cohort study support those from previous studies suggesting that a team-based approach is of benefit.
The finding that local treatments are key factors associated with appropriate AET use suggests that patients who undergo radiotherapy may be more likely to receive standard-of-care therapy in general, the authors explained, adding that “with more physicians involved in a patient’s care, these patients would be more likely to be recommended for guideline concordant care.
“Facilitation of multidisciplinary team-based care may help optimize guideline-concordant treatment by ensuring patients are not lost to follow-up and are recommended for evidence-based care,” the study authors concluded.
Their hope is that with the coming launch of the Medicare Access and Chip Reauthorization Act and value-based reimbursement, efforts will be made to close the quality gap affecting patients in certain age groups, racial minority groups, and geographic regions, and to thereby prevent the loss of lives.
MACRA may boost outcomes
In an interview, Dr. Daly said he believes the coming changes with respect to value-based reimbursement will indeed have an important impact on outcomes.
“The oncology care model, for example, mandates that physicians document that they are providing guideline-concordant care,” said Dr. Daly, assistant attending physician at Memorial Sloan Kettering Cancer Center. “There are also new technologies such as oncology clinical pathways ... that also try to ensure that all patients are receiving care according to guidelines.”
Further, the increasing use of team-based approaches to care and the incorporation of “tumor boards” might explain the growth in optimal AET usage seen in this cohort.
Dr. Daly said he was surprised to find that certain patient groups were being left behind, such as those with estrogen receptor-negative/progesterone receptor-positive disease, African American patients, and younger and older patients, who were less likely to receive AET.
“I think that helps us also focus on patient populations we can target to make sure they are receiving optimal care,” he said, stressing that the findings have important policy implications for figuring out why those patients are being left behind, and raising the standard of care for all patients.
“We are making great strides to providing appropriate guideline-concordant care for breast cancer patients, but there’s still room to improve,” he said.
Dr. Daly serves as a director of and receives compensation from Quadrant Holdings. Frontline Medical News is a subsidiary of Quadrant Holdings. Dr. Daly also reported financial relationships with CVS Health, Johnson & Johnson, McKesson, and Walgreens Boots Alliance.
Appropriate use of adjuvant endocrine therapy for breast cancer improved over a 10-year period, but optimal use has not been achieved, according to findings from a retrospective review of more than 980,000 women with stages I-III breast cancer.
As a result, an estimated 14,630 lives were unnecessarily lost during the study period, according to Bobby M. Daly, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues.
Of the 981,729 women in the National Cancer Database from Jan. 1, 2004, to Dec. 31, 2013, who received all or part of their care at the reporting institution and who met eligibility criteria, 818,435 had hormone receptor positive (HR+) disease and 163,294 had hormone receptor negative (HR-) disease.
The percentage of HR+ patients receiving adjuvant endocrine therapy (AET) increased from 69.8% in 2004 to 82.4% in 2013 (annual percentage change, 1.51%), and the percentage of HR- patients decreased from 5.2% to 3.4% during the same time period (annual percentage change, -0.17%), the authors reported online Feb. 2 in JAMA Oncology (2017 Feb 2. doi: 10.1001jamaoncol.2016.6380).
Notably, receipt of AET varied significantly by age, race, geographic location, and receptor status. For example, more than 80% of those aged 50-69 years received AET, compared with 79.1% of those younger than age 40 years and 60.5% of those 80 years or older. African American and Hispanic patients were less likely than non-Hispanic white patients to receive AET (76.4% and 75.9% vs. 79.0%, respectively). The latter finding could be an important contributing factor to the racial disparity in breast cancer survival, the authors noted.
Facility factors also played a role in AET receipt; the rate of receipt varied substantially by facility volume and geographic location.
“We found that facilities in west south central states and low-volume institutions were more likely to misuse and underuse AET,” the investigators wrote, noting that these deficits could affect breast cancer mortality, as geographic differences in such mortality are well documented.
AET receipt also varied based on hormone receptor status, tumor size, and local treatment. Surgery and radiotherapy were the factors most significantly associated with appropriate AET receipt, with only 45% of those who underwent lumpectomy without radiotherapy receiving AET, compared with 90.1% of those receiving postmastectomy radiotherapy, 85.5% in those with postlumpectomy radiotherapy, and 73.2% of those with mastectomy alone.
Women included in this study were age 18 years or older (mean age, 60.8 years). Those undergoing surgery but receiving no neoadjuvant systemic treatment were eligible. Those with prior cancer diagnoses or with missing hormone receptor or AET status were excluded.
Based on recent trial results, the American Society of Clinical Oncology updated treatment guidelines in 2016 to recommend ovarian suppression for 5 years in combination with AET for high-risk premenopausal women, and AET alone both for women with stage I breast cancers that don’t warrant chemotherapy and for node-negative cancers of 1.0 cm or less.
“Similarly, the National Quality Forum (cancer measure 0220) endorsed tamoxifen or a third-generation aromatase inhibitor (considered or administered) within 1 year of diagnosis as a marker of quality care for patients with HR+ American Joint Committee on Cancer stage T1cN0M0, II, or III disease,” the researchers wrote. Studies demonstrated benefit with AET even in those with node-negative cancers of 1.0 cm or less, they added.
Improving adherence to these guidelines has lifesaving potential. In the current cohort, receipt of AET was associated with a 29% relative risk reduction in mortality, after adjusting for numerous patient, disease, and facility-related factors. This suggests that if all women with HR+ disease received AET in concordance with guidelines, 14,630 more lives would have been saved over the 10-year study period, the investigators said.
As for approaches that could help improve the appropriate use of AET, the findings of this cohort study support those from previous studies suggesting that a team-based approach is of benefit.
The finding that local treatments are key factors associated with appropriate AET use suggests that patients who undergo radiotherapy may be more likely to receive standard-of-care therapy in general, the authors explained, adding that “with more physicians involved in a patient’s care, these patients would be more likely to be recommended for guideline concordant care.
“Facilitation of multidisciplinary team-based care may help optimize guideline-concordant treatment by ensuring patients are not lost to follow-up and are recommended for evidence-based care,” the study authors concluded.
Their hope is that with the coming launch of the Medicare Access and Chip Reauthorization Act and value-based reimbursement, efforts will be made to close the quality gap affecting patients in certain age groups, racial minority groups, and geographic regions, and to thereby prevent the loss of lives.
MACRA may boost outcomes
In an interview, Dr. Daly said he believes the coming changes with respect to value-based reimbursement will indeed have an important impact on outcomes.
“The oncology care model, for example, mandates that physicians document that they are providing guideline-concordant care,” said Dr. Daly, assistant attending physician at Memorial Sloan Kettering Cancer Center. “There are also new technologies such as oncology clinical pathways ... that also try to ensure that all patients are receiving care according to guidelines.”
Further, the increasing use of team-based approaches to care and the incorporation of “tumor boards” might explain the growth in optimal AET usage seen in this cohort.
Dr. Daly said he was surprised to find that certain patient groups were being left behind, such as those with estrogen receptor-negative/progesterone receptor-positive disease, African American patients, and younger and older patients, who were less likely to receive AET.
“I think that helps us also focus on patient populations we can target to make sure they are receiving optimal care,” he said, stressing that the findings have important policy implications for figuring out why those patients are being left behind, and raising the standard of care for all patients.
“We are making great strides to providing appropriate guideline-concordant care for breast cancer patients, but there’s still room to improve,” he said.
Dr. Daly serves as a director of and receives compensation from Quadrant Holdings. Frontline Medical News is a subsidiary of Quadrant Holdings. Dr. Daly also reported financial relationships with CVS Health, Johnson & Johnson, McKesson, and Walgreens Boots Alliance.
FROM JAMA ONCOLOGY
Key clinical point:
Major finding: Receipt of AET was associated with a 29% relative risk reduction in mortality; use of AET in concordance with guidelines would have saved an estimated 14,630 additional lives over 10 years.
Data source: A retrospective cohort study of 981,729 women with breast cancer.
Disclosures: Dr. Daly serves as a director of and receives compensation from Quadrant Holdings. Frontline Medical News is a subsidiary of Quadrant Holdings. Dr. Daly also reported financial relationships with CVS Health, Johnson & Johnson, McKesson, and Walgreens Boots Alliance.
Cabozantinib shows promise for carcinoid tumors, pNET
SAN FRANCISCO – Treatment with cabozantinib was associated with objective tumor responses and encouraging progression-free survival in patients with advanced carcinoid and pancreatic neuroendocrine tumors in a two-cohort phase II trial.
Of 41 patients in the carcinoid tumor cohort, 6 achieved RECIST-defined partial response (objective response rate, 15%), and 26 had stable disease. Median progression-free survival was 31.4 months.
Of 20 patients in the pancreatic neuroendocrine tumors (pNET) cohort, 3 achieved a partial response (objective response rate, 15%), and 15 had stable disease. Median progression-free survival was 21.8 months, Jennifer A. Chan, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Although dose reduction was common – occurring in 81% of 53 patients who completed at least one treatment cycle – treatment was tolerable, said Dr. Chan of Dana-Farber Cancer Institute, Boston.
Study patients had progressive, well-differentiated grade 1-2 carcinoid tumors or pNET, and were treated with 60 mg of oral cabozantinib daily. There were no limits on prior therapy, and patients were restaged every 2 months for the first 6 months, then every 3 months thereafter.
The 41 patients with carcinoid tumors had a median age of 63 years and ECOG performance status of 0 or 1. Only 20 patients were enrolled in the pNET group, because accrual was halted, in part because of funding considerations. Patients in that group had a median age of 55 years, and also had ECOG performance status of 0 or 1, Dr. Chan said.
Carcinoid tumor patients completed a median of 8 28-day treatment cycles (range, 0-44), and pNET patients completed a median of 10 cycles (range, 0-25).
The most common reasons for discontinuation were progression or death in 51% of patients, withdrawal of consent or investigator decision in 28%, and adverse events in 21%, she noted.
The most common grade 3/4 toxicities included hypertension in 13% of patients, hypophosphatemia in 11%, and diarrhea in 10%.
Unexpected grade 3/4 events included heart failure and autoimmune hemolytic anemia, which each occurred in 1 patient.
This phase II study was initiated in light of promising preclinical work, Dr. Chan said.
“There has been much progress in recent years in the treatment of advanced neuroendocrine tumors,” she said. “The VEGF pathway inhibitors have been demonstrated to show activity, and the tyrosine kinase inhibitor sunitinib is approved for patients with progressive pancreatic neuroendocrine tumors.”
Recent studies also suggest that inhibition of MET may be an effective treatment strategy. MET activation has been shown to be associated with tumor growth, expression of MET has been observed in a significant proportion of neuroendocrine tumors, and increased expression of MET has been associated with decreased overall survival in pancreatic neuroendocrine tumors, she noted.
“Cabozantinib is a tyrosine kinase inhibitor that targets multiple receptors, including the VEGF receptors MET, ASL, and RET,” Dr. Chan explained. “It improves progression-free survival in advanced renal cell carcinoma in the first-line setting, compared with sunitinib, and also in the second-line setting, compared with everolimus in patients previously treated with anti-angiogenic therapy.” Cabozantinib is also approved for use in patients with progressive, metastatic medullary thyroid carcinoma, she added.
In preclinical models of neuroendocrine tumors, cabozantinib inhibited cell viability, and in a mouse model it decreased metastasis and invasion of pNET.
The current findings provide further evidence of cabozantinib’s safety and efficacy, Dr. Chan said. The progression-free survival in this phase II study is of particularly interest in the context of historical results, she added.
“Recognizing the limitations of interpreting progression-free survival data in an uncontrolled phase II trial, as well as comparing data to previous clinical trials, the progression-free survival results that we observed do appear encouraging,” she said. “It will be important to confirm the activity of cabozantinib in a randomized phase III setting.”
Dr. Chan reported having stock or other ownership interests in Merck; having a consulting or advisory role with Bayer, Ipsen, Novartis, Pfizer, and Pozen; and receiving research funding from Novartis and Sanofi.
SAN FRANCISCO – Treatment with cabozantinib was associated with objective tumor responses and encouraging progression-free survival in patients with advanced carcinoid and pancreatic neuroendocrine tumors in a two-cohort phase II trial.
Of 41 patients in the carcinoid tumor cohort, 6 achieved RECIST-defined partial response (objective response rate, 15%), and 26 had stable disease. Median progression-free survival was 31.4 months.
Of 20 patients in the pancreatic neuroendocrine tumors (pNET) cohort, 3 achieved a partial response (objective response rate, 15%), and 15 had stable disease. Median progression-free survival was 21.8 months, Jennifer A. Chan, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Although dose reduction was common – occurring in 81% of 53 patients who completed at least one treatment cycle – treatment was tolerable, said Dr. Chan of Dana-Farber Cancer Institute, Boston.
Study patients had progressive, well-differentiated grade 1-2 carcinoid tumors or pNET, and were treated with 60 mg of oral cabozantinib daily. There were no limits on prior therapy, and patients were restaged every 2 months for the first 6 months, then every 3 months thereafter.
The 41 patients with carcinoid tumors had a median age of 63 years and ECOG performance status of 0 or 1. Only 20 patients were enrolled in the pNET group, because accrual was halted, in part because of funding considerations. Patients in that group had a median age of 55 years, and also had ECOG performance status of 0 or 1, Dr. Chan said.
Carcinoid tumor patients completed a median of 8 28-day treatment cycles (range, 0-44), and pNET patients completed a median of 10 cycles (range, 0-25).
The most common reasons for discontinuation were progression or death in 51% of patients, withdrawal of consent or investigator decision in 28%, and adverse events in 21%, she noted.
The most common grade 3/4 toxicities included hypertension in 13% of patients, hypophosphatemia in 11%, and diarrhea in 10%.
Unexpected grade 3/4 events included heart failure and autoimmune hemolytic anemia, which each occurred in 1 patient.
This phase II study was initiated in light of promising preclinical work, Dr. Chan said.
“There has been much progress in recent years in the treatment of advanced neuroendocrine tumors,” she said. “The VEGF pathway inhibitors have been demonstrated to show activity, and the tyrosine kinase inhibitor sunitinib is approved for patients with progressive pancreatic neuroendocrine tumors.”
Recent studies also suggest that inhibition of MET may be an effective treatment strategy. MET activation has been shown to be associated with tumor growth, expression of MET has been observed in a significant proportion of neuroendocrine tumors, and increased expression of MET has been associated with decreased overall survival in pancreatic neuroendocrine tumors, she noted.
“Cabozantinib is a tyrosine kinase inhibitor that targets multiple receptors, including the VEGF receptors MET, ASL, and RET,” Dr. Chan explained. “It improves progression-free survival in advanced renal cell carcinoma in the first-line setting, compared with sunitinib, and also in the second-line setting, compared with everolimus in patients previously treated with anti-angiogenic therapy.” Cabozantinib is also approved for use in patients with progressive, metastatic medullary thyroid carcinoma, she added.
In preclinical models of neuroendocrine tumors, cabozantinib inhibited cell viability, and in a mouse model it decreased metastasis and invasion of pNET.
The current findings provide further evidence of cabozantinib’s safety and efficacy, Dr. Chan said. The progression-free survival in this phase II study is of particularly interest in the context of historical results, she added.
“Recognizing the limitations of interpreting progression-free survival data in an uncontrolled phase II trial, as well as comparing data to previous clinical trials, the progression-free survival results that we observed do appear encouraging,” she said. “It will be important to confirm the activity of cabozantinib in a randomized phase III setting.”
Dr. Chan reported having stock or other ownership interests in Merck; having a consulting or advisory role with Bayer, Ipsen, Novartis, Pfizer, and Pozen; and receiving research funding from Novartis and Sanofi.
SAN FRANCISCO – Treatment with cabozantinib was associated with objective tumor responses and encouraging progression-free survival in patients with advanced carcinoid and pancreatic neuroendocrine tumors in a two-cohort phase II trial.
Of 41 patients in the carcinoid tumor cohort, 6 achieved RECIST-defined partial response (objective response rate, 15%), and 26 had stable disease. Median progression-free survival was 31.4 months.
Of 20 patients in the pancreatic neuroendocrine tumors (pNET) cohort, 3 achieved a partial response (objective response rate, 15%), and 15 had stable disease. Median progression-free survival was 21.8 months, Jennifer A. Chan, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Although dose reduction was common – occurring in 81% of 53 patients who completed at least one treatment cycle – treatment was tolerable, said Dr. Chan of Dana-Farber Cancer Institute, Boston.
Study patients had progressive, well-differentiated grade 1-2 carcinoid tumors or pNET, and were treated with 60 mg of oral cabozantinib daily. There were no limits on prior therapy, and patients were restaged every 2 months for the first 6 months, then every 3 months thereafter.
The 41 patients with carcinoid tumors had a median age of 63 years and ECOG performance status of 0 or 1. Only 20 patients were enrolled in the pNET group, because accrual was halted, in part because of funding considerations. Patients in that group had a median age of 55 years, and also had ECOG performance status of 0 or 1, Dr. Chan said.
Carcinoid tumor patients completed a median of 8 28-day treatment cycles (range, 0-44), and pNET patients completed a median of 10 cycles (range, 0-25).
The most common reasons for discontinuation were progression or death in 51% of patients, withdrawal of consent or investigator decision in 28%, and adverse events in 21%, she noted.
The most common grade 3/4 toxicities included hypertension in 13% of patients, hypophosphatemia in 11%, and diarrhea in 10%.
Unexpected grade 3/4 events included heart failure and autoimmune hemolytic anemia, which each occurred in 1 patient.
This phase II study was initiated in light of promising preclinical work, Dr. Chan said.
“There has been much progress in recent years in the treatment of advanced neuroendocrine tumors,” she said. “The VEGF pathway inhibitors have been demonstrated to show activity, and the tyrosine kinase inhibitor sunitinib is approved for patients with progressive pancreatic neuroendocrine tumors.”
Recent studies also suggest that inhibition of MET may be an effective treatment strategy. MET activation has been shown to be associated with tumor growth, expression of MET has been observed in a significant proportion of neuroendocrine tumors, and increased expression of MET has been associated with decreased overall survival in pancreatic neuroendocrine tumors, she noted.
“Cabozantinib is a tyrosine kinase inhibitor that targets multiple receptors, including the VEGF receptors MET, ASL, and RET,” Dr. Chan explained. “It improves progression-free survival in advanced renal cell carcinoma in the first-line setting, compared with sunitinib, and also in the second-line setting, compared with everolimus in patients previously treated with anti-angiogenic therapy.” Cabozantinib is also approved for use in patients with progressive, metastatic medullary thyroid carcinoma, she added.
In preclinical models of neuroendocrine tumors, cabozantinib inhibited cell viability, and in a mouse model it decreased metastasis and invasion of pNET.
The current findings provide further evidence of cabozantinib’s safety and efficacy, Dr. Chan said. The progression-free survival in this phase II study is of particularly interest in the context of historical results, she added.
“Recognizing the limitations of interpreting progression-free survival data in an uncontrolled phase II trial, as well as comparing data to previous clinical trials, the progression-free survival results that we observed do appear encouraging,” she said. “It will be important to confirm the activity of cabozantinib in a randomized phase III setting.”
Dr. Chan reported having stock or other ownership interests in Merck; having a consulting or advisory role with Bayer, Ipsen, Novartis, Pfizer, and Pozen; and receiving research funding from Novartis and Sanofi.
Key clinical point:
Major finding: The objective response rate was 15% in both groups; median progression-free survival was 31.4 and 21.8 months in the carcinoid and pNET groups, respectively.
Data source: A phase II trial involving 61 patients.
Disclosures: Dr. Chan reported having stock or other ownership interests in Merck; having a consulting or advisory role with Bayer, Ipsen, Novartis, Pfizer, and Pozen; and receiving research funding from Novartis and Sanofi.
Nivolumab shows promise for pretreated advanced HCC
SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.
Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
In all, 262 patients with histologically confirmed advanced disease not amenable to curative resection were treated across the CheckMate 040 dose-escalation phase (phase I), which evaluated 0.1-10 mg/kg of nivolumab given every 2 weeks, and the dose-expansion phase (phase II), which involved nivolumab at a dose of 3 mg/kg every 2 weeks in four cohorts: sorafenib naive/intolerant patients, sorafenib progressors, hepatitis C virus-infected patients, and hepatitis B virus-infected patients.
“Because of the inflammation that often afflicts the liver, we were very afraid of precipitating hyper-acute or fulminant hepatitis in these patients, and that was the reason we undertook a very careful dose escalation,” Dr. Melero said, adding that due to efficacy and safety results in the dose escalation phase, the 3-mg/kg dose used in other clinical trials was expanded to all subjects, including uninfected patients and those with HCV or HBV infection.
In regard to safety and tolerability – the primary endpoint of phase I – grade 3/4 treatment-related adverse events occurred in 20% of patients. No maximum tolerated dose was reached during dose escalation, Dr. Melero said.
The most common reason for treatment discontinuation was disease progression; very few patients discontinued for toxicity, he said, noting that “the safety profile was very consistent with what has been reported in other indications.”
In fact, most grade 3/4 events involved laboratory abnormalities without clinical repercussions, he said.
The safety profile in phase II was consistent with that observed in phase I, and no differences in safety were seen in the three categories of hepatocellular carcinoma patients in the study.
In regard to objective response – the primary endpoint of phase II – the investigator-assessed rates were 16.2% in phase I and 18.6% in phase II, and the rates assessed by blinded independent central review were 18.9% and 14.5% in the phases, respectively. Based on imaging assessed using modified RESIST criteria, the rates were 21.6% and 18.6%, respectively.
The median duration of response was 17.1 months in phase I, and had not yet been reached in phase II, Dr. Melero said, adding that in uninfected patients, an “important number of patients developed stable disease that was durable.”
This also was seen in patients with chronic hepatitis, he noted.
“We believe that stabilization of disease is a driver of survival, because we have seen that in dose escalation, 45% of patients were alive 18 months after treatment onset, and at last data base log [in dose escalation], 71% were alive 9 months after starting treatment,” he said.
Of note, objective response rates were similar in patients treated with sorafenib and in those who received nivolumab as first-line treatment, and they were similar regardless of tumor programmed death-ligand 1 (PD-L1) expression.
Quality of life, as reported by patients via EQ-5D questionnaire, remained stable over time.
Study subjects had a median age of 63 years, and were heavily pretreated – most often by sorafenib.
Hepatocellular carcinoma diagnosed at advanced stages has a poor prognosis, and those who progress on sorafenib – the only systemic therapy option in such patients – have few options, Dr. Melero said.
Nivolumab, which has been shown to restore T-cell–mediated antitumor activity, has demonstrated clinical and survival benefit in a number of tumor types.
The current findings suggest that it also is a promising alternative for advanced hepatocellular carcinoma.
“Nivolumab demonstrated objective responses and long-term survival in both sorafenib-experienced and sorafenib-naive patients. Nivolumab monotherapy provided early, stable and durable responses when they took place, efficacy was observed irrespective of chronic viral infection by hepatitis viruses, and responses were also observed in PD-L1-negative cases upon examination of biopsies,” he concluded, noting that a randomized phase III trial comparing nivolumab with systemic sorafenib is ongoing.
CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.
Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
In all, 262 patients with histologically confirmed advanced disease not amenable to curative resection were treated across the CheckMate 040 dose-escalation phase (phase I), which evaluated 0.1-10 mg/kg of nivolumab given every 2 weeks, and the dose-expansion phase (phase II), which involved nivolumab at a dose of 3 mg/kg every 2 weeks in four cohorts: sorafenib naive/intolerant patients, sorafenib progressors, hepatitis C virus-infected patients, and hepatitis B virus-infected patients.
“Because of the inflammation that often afflicts the liver, we were very afraid of precipitating hyper-acute or fulminant hepatitis in these patients, and that was the reason we undertook a very careful dose escalation,” Dr. Melero said, adding that due to efficacy and safety results in the dose escalation phase, the 3-mg/kg dose used in other clinical trials was expanded to all subjects, including uninfected patients and those with HCV or HBV infection.
In regard to safety and tolerability – the primary endpoint of phase I – grade 3/4 treatment-related adverse events occurred in 20% of patients. No maximum tolerated dose was reached during dose escalation, Dr. Melero said.
The most common reason for treatment discontinuation was disease progression; very few patients discontinued for toxicity, he said, noting that “the safety profile was very consistent with what has been reported in other indications.”
In fact, most grade 3/4 events involved laboratory abnormalities without clinical repercussions, he said.
The safety profile in phase II was consistent with that observed in phase I, and no differences in safety were seen in the three categories of hepatocellular carcinoma patients in the study.
In regard to objective response – the primary endpoint of phase II – the investigator-assessed rates were 16.2% in phase I and 18.6% in phase II, and the rates assessed by blinded independent central review were 18.9% and 14.5% in the phases, respectively. Based on imaging assessed using modified RESIST criteria, the rates were 21.6% and 18.6%, respectively.
The median duration of response was 17.1 months in phase I, and had not yet been reached in phase II, Dr. Melero said, adding that in uninfected patients, an “important number of patients developed stable disease that was durable.”
This also was seen in patients with chronic hepatitis, he noted.
“We believe that stabilization of disease is a driver of survival, because we have seen that in dose escalation, 45% of patients were alive 18 months after treatment onset, and at last data base log [in dose escalation], 71% were alive 9 months after starting treatment,” he said.
Of note, objective response rates were similar in patients treated with sorafenib and in those who received nivolumab as first-line treatment, and they were similar regardless of tumor programmed death-ligand 1 (PD-L1) expression.
Quality of life, as reported by patients via EQ-5D questionnaire, remained stable over time.
Study subjects had a median age of 63 years, and were heavily pretreated – most often by sorafenib.
Hepatocellular carcinoma diagnosed at advanced stages has a poor prognosis, and those who progress on sorafenib – the only systemic therapy option in such patients – have few options, Dr. Melero said.
Nivolumab, which has been shown to restore T-cell–mediated antitumor activity, has demonstrated clinical and survival benefit in a number of tumor types.
The current findings suggest that it also is a promising alternative for advanced hepatocellular carcinoma.
“Nivolumab demonstrated objective responses and long-term survival in both sorafenib-experienced and sorafenib-naive patients. Nivolumab monotherapy provided early, stable and durable responses when they took place, efficacy was observed irrespective of chronic viral infection by hepatitis viruses, and responses were also observed in PD-L1-negative cases upon examination of biopsies,” he concluded, noting that a randomized phase III trial comparing nivolumab with systemic sorafenib is ongoing.
CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.
Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
In all, 262 patients with histologically confirmed advanced disease not amenable to curative resection were treated across the CheckMate 040 dose-escalation phase (phase I), which evaluated 0.1-10 mg/kg of nivolumab given every 2 weeks, and the dose-expansion phase (phase II), which involved nivolumab at a dose of 3 mg/kg every 2 weeks in four cohorts: sorafenib naive/intolerant patients, sorafenib progressors, hepatitis C virus-infected patients, and hepatitis B virus-infected patients.
“Because of the inflammation that often afflicts the liver, we were very afraid of precipitating hyper-acute or fulminant hepatitis in these patients, and that was the reason we undertook a very careful dose escalation,” Dr. Melero said, adding that due to efficacy and safety results in the dose escalation phase, the 3-mg/kg dose used in other clinical trials was expanded to all subjects, including uninfected patients and those with HCV or HBV infection.
In regard to safety and tolerability – the primary endpoint of phase I – grade 3/4 treatment-related adverse events occurred in 20% of patients. No maximum tolerated dose was reached during dose escalation, Dr. Melero said.
The most common reason for treatment discontinuation was disease progression; very few patients discontinued for toxicity, he said, noting that “the safety profile was very consistent with what has been reported in other indications.”
In fact, most grade 3/4 events involved laboratory abnormalities without clinical repercussions, he said.
The safety profile in phase II was consistent with that observed in phase I, and no differences in safety were seen in the three categories of hepatocellular carcinoma patients in the study.
In regard to objective response – the primary endpoint of phase II – the investigator-assessed rates were 16.2% in phase I and 18.6% in phase II, and the rates assessed by blinded independent central review were 18.9% and 14.5% in the phases, respectively. Based on imaging assessed using modified RESIST criteria, the rates were 21.6% and 18.6%, respectively.
The median duration of response was 17.1 months in phase I, and had not yet been reached in phase II, Dr. Melero said, adding that in uninfected patients, an “important number of patients developed stable disease that was durable.”
This also was seen in patients with chronic hepatitis, he noted.
“We believe that stabilization of disease is a driver of survival, because we have seen that in dose escalation, 45% of patients were alive 18 months after treatment onset, and at last data base log [in dose escalation], 71% were alive 9 months after starting treatment,” he said.
Of note, objective response rates were similar in patients treated with sorafenib and in those who received nivolumab as first-line treatment, and they were similar regardless of tumor programmed death-ligand 1 (PD-L1) expression.
Quality of life, as reported by patients via EQ-5D questionnaire, remained stable over time.
Study subjects had a median age of 63 years, and were heavily pretreated – most often by sorafenib.
Hepatocellular carcinoma diagnosed at advanced stages has a poor prognosis, and those who progress on sorafenib – the only systemic therapy option in such patients – have few options, Dr. Melero said.
Nivolumab, which has been shown to restore T-cell–mediated antitumor activity, has demonstrated clinical and survival benefit in a number of tumor types.
The current findings suggest that it also is a promising alternative for advanced hepatocellular carcinoma.
“Nivolumab demonstrated objective responses and long-term survival in both sorafenib-experienced and sorafenib-naive patients. Nivolumab monotherapy provided early, stable and durable responses when they took place, efficacy was observed irrespective of chronic viral infection by hepatitis viruses, and responses were also observed in PD-L1-negative cases upon examination of biopsies,” he concluded, noting that a randomized phase III trial comparing nivolumab with systemic sorafenib is ongoing.
CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Investigator-assessed objective response rates were 16.2% in phase I and 18.6% in phase II.
Data source: The CheckMate 040 phase I and phase II clinical studies involving 262 patients.
Disclosures: CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
Adjuvant GEMOX disappoints for localized biliary tract cancer
SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.
Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.
Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.
Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.
In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.
The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.
The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.
“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”
Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.
“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.
“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.
Dr. Edeline reported having no disclosures.
SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.
Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.
Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.
Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.
In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.
The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.
The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.
“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”
Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.
“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.
“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.
Dr. Edeline reported having no disclosures.
SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.
Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.
Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.
Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.
In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.
The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.
The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.
“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”
Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.
“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.
“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.
Dr. Edeline reported having no disclosures.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Relapse-free survival at 4 years was 39.3% and 33.2% with GEMOX and surveillance, respectively.
Data source: The randomized, phase III PRODIGE 12-ACCORD 18 trial.
Disclosures: Dr. Edeline reported having no disclosures.
Bursectomy provides no benefit over omentectomy for gastric cancers
SAN FRANCISCO – Bursectomy was not found to be superior to omentectomy for improving survival in patients with subserosal/serosal gastric cancer in a Japanese randomized phase III study.
The procedure – the dissection of the peritoneal lining covering the pancreas and anterior plane of the transverse mesocolon to prevent peritoneal metastasis – was common worldwide and considered standard in Japan from the 1950s until the mid-1990s, but was replaced by omentectomy following publication of reports questioning its value, according to Masanori Terashima, MD, of Shizuoka Cancer Center, Nagaizumi, Japan.
However, interest in bursectomy was rekindled when a 2012 noninferiority phase II study suggested that bursectomy may improve survival; the authors concluded that it should not be abandoned as a futile procedure until more definitive data could be obtained (Gastric Cancer. 2012;15[1]:42-8).
“So based on this result, [Japanese Clinical Oncology Group] conducted a large-scale randomized phase III trial [JCOG1001] to evaluate the efficacy of bursectomy. The objective of this study was to confirm the superiority of bursectomy for clinical T3 or clinical T4a gastric cancer patients in terms of overall survival,” Dr. Terashima said at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
At a planned interim analysis when 522 patients had been enrolled, the Data and Safety Monitoring Committee approved continued enrollment. However, at a second interim analysis when 54% of expected events had been observed, the committee recommended early release of the survival results because “there was little possibility of demonstration of the superiority of bursectomy,” he said.
Overall 3-year survival was 83.3% among 601 patients in the bursectomy arm, compared with 86% in 600 patients in the nonbursectomy arm (hazard ratio, 1.07). The predictive probability of superiority of bursectomy was 12.7%.
Study subjects were adults aged 20-80 years (median of 65-66 years) with histologically proven adenocarcinoma of the stomach and clinical T3 or T4 disease. They enrolled from 57 institutions and were intraoperatively randomized to the bursectomy or nonbursectomy arm after confirmation of tumor stage. All received adjuvant chemotherapy with S-1 for 1 year for pathologic stage II/III disease.
Patients with bulky nodal metastases, Borrmann type 4 and 8 cm or larger Borrmann type 3 tumors were excluded, as their poor prognosis made them candidates for other clinical trials, Dr. Terashima said.
Patients’ background and operative procedures were well balanced between the arms, he noted.
For those in the bursectomy group, operation time was longer (median, 254 vs. 222 minutes), and blood loss was larger (330 vs. 230 mL), although the incidence of blood transfusion was not significantly different between the groups (4.5% vs. 4.8%).
The incidence of grade 3 or higher complications was slightly higher in the bursectomy arm (13.3% vs. 11.6%). This was due largely to the incidence of pancreatic fistulas, which was nearly double in the bursectomy arm (4.8% vs. 2.5% ).
Mortality was “quite low” in both groups (0.2 vs. 0.8%).
“There was no significant difference in overall survival between the arms. Bursectomy seemed to be a bit inferior to the nonbursectomy arm. Relapse-free survival also demonstrated no significant difference between the arms. Again, bursectomy seemed to be a bit worse than nonbursectomy,” he said.
The most common site of recurrence for all patient was the peritoneum, with 63 and 56 patients in the bursectomy and nonbursectomy arms, respectively, experiencing peritoneal recurrence.
“We could not detect any subgroup who may have a benefit from bursectomy,” Dr. Terashima said.
“Bursectomy is not recommended as a standard treatment for clinical T3 or clinical T4 gastric cancer, while complete omentectomy remains a part of standard procedure,” he concluded.
Dr. Terashima reported receiving honoraria, and/or research funding from Chugai Pharma, Eisai; Lilly, Otsuka, Taiho Pharmaceutical, Takeda, and Yakult Honsha.
SAN FRANCISCO – Bursectomy was not found to be superior to omentectomy for improving survival in patients with subserosal/serosal gastric cancer in a Japanese randomized phase III study.
The procedure – the dissection of the peritoneal lining covering the pancreas and anterior plane of the transverse mesocolon to prevent peritoneal metastasis – was common worldwide and considered standard in Japan from the 1950s until the mid-1990s, but was replaced by omentectomy following publication of reports questioning its value, according to Masanori Terashima, MD, of Shizuoka Cancer Center, Nagaizumi, Japan.
However, interest in bursectomy was rekindled when a 2012 noninferiority phase II study suggested that bursectomy may improve survival; the authors concluded that it should not be abandoned as a futile procedure until more definitive data could be obtained (Gastric Cancer. 2012;15[1]:42-8).
“So based on this result, [Japanese Clinical Oncology Group] conducted a large-scale randomized phase III trial [JCOG1001] to evaluate the efficacy of bursectomy. The objective of this study was to confirm the superiority of bursectomy for clinical T3 or clinical T4a gastric cancer patients in terms of overall survival,” Dr. Terashima said at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
At a planned interim analysis when 522 patients had been enrolled, the Data and Safety Monitoring Committee approved continued enrollment. However, at a second interim analysis when 54% of expected events had been observed, the committee recommended early release of the survival results because “there was little possibility of demonstration of the superiority of bursectomy,” he said.
Overall 3-year survival was 83.3% among 601 patients in the bursectomy arm, compared with 86% in 600 patients in the nonbursectomy arm (hazard ratio, 1.07). The predictive probability of superiority of bursectomy was 12.7%.
Study subjects were adults aged 20-80 years (median of 65-66 years) with histologically proven adenocarcinoma of the stomach and clinical T3 or T4 disease. They enrolled from 57 institutions and were intraoperatively randomized to the bursectomy or nonbursectomy arm after confirmation of tumor stage. All received adjuvant chemotherapy with S-1 for 1 year for pathologic stage II/III disease.
Patients with bulky nodal metastases, Borrmann type 4 and 8 cm or larger Borrmann type 3 tumors were excluded, as their poor prognosis made them candidates for other clinical trials, Dr. Terashima said.
Patients’ background and operative procedures were well balanced between the arms, he noted.
For those in the bursectomy group, operation time was longer (median, 254 vs. 222 minutes), and blood loss was larger (330 vs. 230 mL), although the incidence of blood transfusion was not significantly different between the groups (4.5% vs. 4.8%).
The incidence of grade 3 or higher complications was slightly higher in the bursectomy arm (13.3% vs. 11.6%). This was due largely to the incidence of pancreatic fistulas, which was nearly double in the bursectomy arm (4.8% vs. 2.5% ).
Mortality was “quite low” in both groups (0.2 vs. 0.8%).
“There was no significant difference in overall survival between the arms. Bursectomy seemed to be a bit inferior to the nonbursectomy arm. Relapse-free survival also demonstrated no significant difference between the arms. Again, bursectomy seemed to be a bit worse than nonbursectomy,” he said.
The most common site of recurrence for all patient was the peritoneum, with 63 and 56 patients in the bursectomy and nonbursectomy arms, respectively, experiencing peritoneal recurrence.
“We could not detect any subgroup who may have a benefit from bursectomy,” Dr. Terashima said.
“Bursectomy is not recommended as a standard treatment for clinical T3 or clinical T4 gastric cancer, while complete omentectomy remains a part of standard procedure,” he concluded.
Dr. Terashima reported receiving honoraria, and/or research funding from Chugai Pharma, Eisai; Lilly, Otsuka, Taiho Pharmaceutical, Takeda, and Yakult Honsha.
SAN FRANCISCO – Bursectomy was not found to be superior to omentectomy for improving survival in patients with subserosal/serosal gastric cancer in a Japanese randomized phase III study.
The procedure – the dissection of the peritoneal lining covering the pancreas and anterior plane of the transverse mesocolon to prevent peritoneal metastasis – was common worldwide and considered standard in Japan from the 1950s until the mid-1990s, but was replaced by omentectomy following publication of reports questioning its value, according to Masanori Terashima, MD, of Shizuoka Cancer Center, Nagaizumi, Japan.
However, interest in bursectomy was rekindled when a 2012 noninferiority phase II study suggested that bursectomy may improve survival; the authors concluded that it should not be abandoned as a futile procedure until more definitive data could be obtained (Gastric Cancer. 2012;15[1]:42-8).
“So based on this result, [Japanese Clinical Oncology Group] conducted a large-scale randomized phase III trial [JCOG1001] to evaluate the efficacy of bursectomy. The objective of this study was to confirm the superiority of bursectomy for clinical T3 or clinical T4a gastric cancer patients in terms of overall survival,” Dr. Terashima said at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
At a planned interim analysis when 522 patients had been enrolled, the Data and Safety Monitoring Committee approved continued enrollment. However, at a second interim analysis when 54% of expected events had been observed, the committee recommended early release of the survival results because “there was little possibility of demonstration of the superiority of bursectomy,” he said.
Overall 3-year survival was 83.3% among 601 patients in the bursectomy arm, compared with 86% in 600 patients in the nonbursectomy arm (hazard ratio, 1.07). The predictive probability of superiority of bursectomy was 12.7%.
Study subjects were adults aged 20-80 years (median of 65-66 years) with histologically proven adenocarcinoma of the stomach and clinical T3 or T4 disease. They enrolled from 57 institutions and were intraoperatively randomized to the bursectomy or nonbursectomy arm after confirmation of tumor stage. All received adjuvant chemotherapy with S-1 for 1 year for pathologic stage II/III disease.
Patients with bulky nodal metastases, Borrmann type 4 and 8 cm or larger Borrmann type 3 tumors were excluded, as their poor prognosis made them candidates for other clinical trials, Dr. Terashima said.
Patients’ background and operative procedures were well balanced between the arms, he noted.
For those in the bursectomy group, operation time was longer (median, 254 vs. 222 minutes), and blood loss was larger (330 vs. 230 mL), although the incidence of blood transfusion was not significantly different between the groups (4.5% vs. 4.8%).
The incidence of grade 3 or higher complications was slightly higher in the bursectomy arm (13.3% vs. 11.6%). This was due largely to the incidence of pancreatic fistulas, which was nearly double in the bursectomy arm (4.8% vs. 2.5% ).
Mortality was “quite low” in both groups (0.2 vs. 0.8%).
“There was no significant difference in overall survival between the arms. Bursectomy seemed to be a bit inferior to the nonbursectomy arm. Relapse-free survival also demonstrated no significant difference between the arms. Again, bursectomy seemed to be a bit worse than nonbursectomy,” he said.
The most common site of recurrence for all patient was the peritoneum, with 63 and 56 patients in the bursectomy and nonbursectomy arms, respectively, experiencing peritoneal recurrence.
“We could not detect any subgroup who may have a benefit from bursectomy,” Dr. Terashima said.
“Bursectomy is not recommended as a standard treatment for clinical T3 or clinical T4 gastric cancer, while complete omentectomy remains a part of standard procedure,” he concluded.
Dr. Terashima reported receiving honoraria, and/or research funding from Chugai Pharma, Eisai; Lilly, Otsuka, Taiho Pharmaceutical, Takeda, and Yakult Honsha.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Overall 3-year survival was 83.3% and 86% in the bursectomy and nonbursectomy arms, respectively (hazard ratio, 1.07).
Data source: The randomized phase III JCOG1001 trial with more than 1,200 subjects.
Disclosures: Dr. Terashima reported receiving honoraria, and/or research funding from Chugai Pharma, Eisai; Lilly, Otsuka, Taiho Pharmaceutical, Takeda, and Yakult Honsha.
Everolimus fails in pretreated gastric cancer
SAN FRANCISCO – Adding everolimus to paclitaxel failed to significantly improve outcomes in pretreated patients with gastric or esophagogastric junction adenocarcinoma in a German randomized phase III study.
Median overall survival in the double-blind multicenter study (RADPAC) was 6.12 months among 150 patients randomized to receive treatment with paclitaxel plus everolimus as 2nd, 3rd, or 4th line therapy, and 5.03 months among those who received paclitaxel and placebo (hazard ratio, 0.93), Salah-Eddin Al-Batran, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Median progression-free survival was 2.20 vs. 2.07 months in the treatment and placebo groups, respectively (hazard ratio, 0.88), said Dr. Al-Batran of Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany.
Study subjects had a mean age of 62 years and had progressed after treatment with a fluoropyrimidine/platinum-containing regimen. All had at least one, and a maximum of three prior lines of therapy (median of two in both groups).
Of note, accrual was slow and was stopped early, largely because of the very-high rate of taxane use for first-line treatment, but also because combination ramucirumab/paclitaxel was approved during the course of the study, Dr. Al-Batran said.
The treatment and placebo groups were well balanced. Treatment included 80 mg/m2 of paclitaxel on days 1, 8 and 15, plus placebo or 10 mg of everolimus daily on days 1-28, repeated every 28 days. Dose adjustment was more common in the treatment group (26% vs. 13%) but cumulative doses were similar in the groups.
Also, more patients in the everolimus group discontinued treatment for toxicity (11% vs. 5%). However, the only toxicity that was significantly increased was grade 3-5 oral mucositis in the treatment group (13% vs. 1% in the placebo group).
Gastric cancer is aggressive and difficult to treat, with median survival of only 9-11 months, Dr. Al-Batran said, adding that at the time the RADPAC study was initiated, no treatments had been approved for patients who failed first-line therapy, although agents like paclitaxel and irinotecan were in use.
He and his colleagues sought to evaluate everolimus, because 50%-60% of gastric cancers are driven by dysregulation in the P13k/Akt/mTOR pathway – a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, and because everolimus – an oral mTOR inhibitor – showed efficacy in preclinical models of gastric cancer.
In the phase III GRANITE-1 trial, it was associated with trends toward improved progression-free survival and overall survival, compared with best supportive care, he noted.
Subgroup analyses in the current trial suggested that patients with prior taxane use derived greater benefit from everolimus. Overall survival in those patients, who comprised about half of the study population, was 6 months vs. 4 months with placebo; the difference did not reach statistical significance, but showed a strong trend in that direction (P = .072). Progression-free survival was, however, significantly greater with everolimus than with placebo (2.66 vs. 1.81 months; HR, 0.50) in those with prior taxane use.
“Interestingly, the very few patients having ECOG performance status of 2 really performed very poorly,” Dr. Al-Batran said, explaining that those patients had better outcomes with paclitaxel monotherapy.
“So, in conclusion, everolimus combined with paclitaxel improved outcomes as compared with paclitaxel alone in the intention to treat population. However, activity was seen in the taxane pretreated subgroup. Biomarker studies could attempt to identify a subgroup with more benefit, as we see some activity, but this activity is not enough,” he concluded.
Dr. Al-Batran reported receiving honoraria, serving as a consultant or advisor, receiving research funding from, and/or being on the speakers’ bureau for Celgene, Hospira, Lilly, Medac, Merck, Roche, Sanofi, Vifor, and Nordic Bioscience.
SAN FRANCISCO – Adding everolimus to paclitaxel failed to significantly improve outcomes in pretreated patients with gastric or esophagogastric junction adenocarcinoma in a German randomized phase III study.
Median overall survival in the double-blind multicenter study (RADPAC) was 6.12 months among 150 patients randomized to receive treatment with paclitaxel plus everolimus as 2nd, 3rd, or 4th line therapy, and 5.03 months among those who received paclitaxel and placebo (hazard ratio, 0.93), Salah-Eddin Al-Batran, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Median progression-free survival was 2.20 vs. 2.07 months in the treatment and placebo groups, respectively (hazard ratio, 0.88), said Dr. Al-Batran of Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany.
Study subjects had a mean age of 62 years and had progressed after treatment with a fluoropyrimidine/platinum-containing regimen. All had at least one, and a maximum of three prior lines of therapy (median of two in both groups).
Of note, accrual was slow and was stopped early, largely because of the very-high rate of taxane use for first-line treatment, but also because combination ramucirumab/paclitaxel was approved during the course of the study, Dr. Al-Batran said.
The treatment and placebo groups were well balanced. Treatment included 80 mg/m2 of paclitaxel on days 1, 8 and 15, plus placebo or 10 mg of everolimus daily on days 1-28, repeated every 28 days. Dose adjustment was more common in the treatment group (26% vs. 13%) but cumulative doses were similar in the groups.
Also, more patients in the everolimus group discontinued treatment for toxicity (11% vs. 5%). However, the only toxicity that was significantly increased was grade 3-5 oral mucositis in the treatment group (13% vs. 1% in the placebo group).
Gastric cancer is aggressive and difficult to treat, with median survival of only 9-11 months, Dr. Al-Batran said, adding that at the time the RADPAC study was initiated, no treatments had been approved for patients who failed first-line therapy, although agents like paclitaxel and irinotecan were in use.
He and his colleagues sought to evaluate everolimus, because 50%-60% of gastric cancers are driven by dysregulation in the P13k/Akt/mTOR pathway – a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, and because everolimus – an oral mTOR inhibitor – showed efficacy in preclinical models of gastric cancer.
In the phase III GRANITE-1 trial, it was associated with trends toward improved progression-free survival and overall survival, compared with best supportive care, he noted.
Subgroup analyses in the current trial suggested that patients with prior taxane use derived greater benefit from everolimus. Overall survival in those patients, who comprised about half of the study population, was 6 months vs. 4 months with placebo; the difference did not reach statistical significance, but showed a strong trend in that direction (P = .072). Progression-free survival was, however, significantly greater with everolimus than with placebo (2.66 vs. 1.81 months; HR, 0.50) in those with prior taxane use.
“Interestingly, the very few patients having ECOG performance status of 2 really performed very poorly,” Dr. Al-Batran said, explaining that those patients had better outcomes with paclitaxel monotherapy.
“So, in conclusion, everolimus combined with paclitaxel improved outcomes as compared with paclitaxel alone in the intention to treat population. However, activity was seen in the taxane pretreated subgroup. Biomarker studies could attempt to identify a subgroup with more benefit, as we see some activity, but this activity is not enough,” he concluded.
Dr. Al-Batran reported receiving honoraria, serving as a consultant or advisor, receiving research funding from, and/or being on the speakers’ bureau for Celgene, Hospira, Lilly, Medac, Merck, Roche, Sanofi, Vifor, and Nordic Bioscience.
SAN FRANCISCO – Adding everolimus to paclitaxel failed to significantly improve outcomes in pretreated patients with gastric or esophagogastric junction adenocarcinoma in a German randomized phase III study.
Median overall survival in the double-blind multicenter study (RADPAC) was 6.12 months among 150 patients randomized to receive treatment with paclitaxel plus everolimus as 2nd, 3rd, or 4th line therapy, and 5.03 months among those who received paclitaxel and placebo (hazard ratio, 0.93), Salah-Eddin Al-Batran, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Median progression-free survival was 2.20 vs. 2.07 months in the treatment and placebo groups, respectively (hazard ratio, 0.88), said Dr. Al-Batran of Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany.
Study subjects had a mean age of 62 years and had progressed after treatment with a fluoropyrimidine/platinum-containing regimen. All had at least one, and a maximum of three prior lines of therapy (median of two in both groups).
Of note, accrual was slow and was stopped early, largely because of the very-high rate of taxane use for first-line treatment, but also because combination ramucirumab/paclitaxel was approved during the course of the study, Dr. Al-Batran said.
The treatment and placebo groups were well balanced. Treatment included 80 mg/m2 of paclitaxel on days 1, 8 and 15, plus placebo or 10 mg of everolimus daily on days 1-28, repeated every 28 days. Dose adjustment was more common in the treatment group (26% vs. 13%) but cumulative doses were similar in the groups.
Also, more patients in the everolimus group discontinued treatment for toxicity (11% vs. 5%). However, the only toxicity that was significantly increased was grade 3-5 oral mucositis in the treatment group (13% vs. 1% in the placebo group).
Gastric cancer is aggressive and difficult to treat, with median survival of only 9-11 months, Dr. Al-Batran said, adding that at the time the RADPAC study was initiated, no treatments had been approved for patients who failed first-line therapy, although agents like paclitaxel and irinotecan were in use.
He and his colleagues sought to evaluate everolimus, because 50%-60% of gastric cancers are driven by dysregulation in the P13k/Akt/mTOR pathway – a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, and because everolimus – an oral mTOR inhibitor – showed efficacy in preclinical models of gastric cancer.
In the phase III GRANITE-1 trial, it was associated with trends toward improved progression-free survival and overall survival, compared with best supportive care, he noted.
Subgroup analyses in the current trial suggested that patients with prior taxane use derived greater benefit from everolimus. Overall survival in those patients, who comprised about half of the study population, was 6 months vs. 4 months with placebo; the difference did not reach statistical significance, but showed a strong trend in that direction (P = .072). Progression-free survival was, however, significantly greater with everolimus than with placebo (2.66 vs. 1.81 months; HR, 0.50) in those with prior taxane use.
“Interestingly, the very few patients having ECOG performance status of 2 really performed very poorly,” Dr. Al-Batran said, explaining that those patients had better outcomes with paclitaxel monotherapy.
“So, in conclusion, everolimus combined with paclitaxel improved outcomes as compared with paclitaxel alone in the intention to treat population. However, activity was seen in the taxane pretreated subgroup. Biomarker studies could attempt to identify a subgroup with more benefit, as we see some activity, but this activity is not enough,” he concluded.
Dr. Al-Batran reported receiving honoraria, serving as a consultant or advisor, receiving research funding from, and/or being on the speakers’ bureau for Celgene, Hospira, Lilly, Medac, Merck, Roche, Sanofi, Vifor, and Nordic Bioscience.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Median overall survival was 6.12 vs. 5.03 months with paclitaxel plus everolimus vs. placebo (hazard ratio, 0.93).
Data source: The randomized phase III RADPAC study of 300 patients.
Disclosures: Dr. Al-Batran reported receiving honoraria, serving as a consultant or advisor, receiving research funding from, and/or being on the speakers’ bureau for Celgene, Hospira, Lilly, Medac, Merck, Roche, Sanofi, Vifor, and Nordic Bioscience.
Ramucirumab benefits gastric cancer patients across age groups
SAN FRANCISCO – Patients with metastatic gastric or gastroesophageal junction adenocarcinoma benefit from treatment with ramucirumab regardless of their age, according to findings from an exploratory subgroup analysis of the phase III RAINBOW and REGARD studies.
The findings, which show at least a trend toward improvements in most age categories, are important given that nearly two-thirds of patients with these cancers are diagnosed at over age 65 years, and more than half of those are over age 75 years, Kei Muro, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
“At the other end of the age spectrum, there is evidence that young age can also be an unfavorable prognostic characteristic for gastric cancer,” said Dr. Muro of Aichi Cancer Center Hospital in Nagoya, Japan.
Both RAINBOW and REGARD demonstrated statistically significant and clinically meaningful overall and progression-free survival benefits and acceptable and manageable toxicity with ramucirumab among patients with advanced gastric cancer who were randomized, in the second-line treatment setting, to receive active treatment with the fully humanized monoclonal antibody directed against vascular endothelial growth factor receptor–2 or placebo.
RAINBOW subjects were randomized 1:1 to receive 8 mg/kg of ramucirumab plus paclitaxel, or placebo plus paclitaxel. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 months for treatment vs. 4.2 months for placebo (hazard ratio, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
The corresponding median overall survival rates for those aged 45-70 (225 and 230 patients in the groups, respectively), 70 or older (68 patients in each group), and 75 or older (20 and 16 patients in the groups, respectively) were 9.6 vs. 7.6 months (HR, 0.860), 10.8 vs. 8.6 months (HR, 0.881), and 11.0 vs. 11.0 months (HR, 0.971). The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 4.6 vs. 2.8 months (HR, 0.649), 4.7 vs. 2.9 months (HR, 0.676), and 4.2 vs. 2.8 months (HR, 0.330).
REGARD subjects were randomized 2:1 to receive 8 mg/kg of ramucirumab plus best supportive care, or placebo plus best supportive care. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 vs. 4.2 months for treatment vs. placebo (HR, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
Among REGARD subjects aged 45 years or less (28 and 12 patients in the groups, respectively), the median overall survival was 5.8 vs. 2.9 months for treatment vs. placebo (HR, 0.586), and the median progression-free survival was 1.9 vs. 1.4 months (HR, 0.270).
The corresponding median overall survival rates for those aged 45-70 (166 and 70 patients in the groups, respectively), 70 or older (44 and 35 patients in the groups, respectively), and 75 or older (21 and 13 patients in the groups, respectively) were 4.9 vs. 4.1 months (HR, 0.780), 5.9 vs. 3.8 months (HR, 0.730), and 9.3 vs. 5.1 months (HR, 0.588).
The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 2.2 vs. 1.3 months (HR, 0.451), 2.1 vs. 1.4 months (HR, 0.559), 2.8 vs. 1.4 (HR, 0.420).
Baseline characteristics were generally well balanced between arms in each of the age subgroups, Dr. Muro said, noting that no obvious patterns for differential risks in terms of efficacy and adverse events of any grade or of grade 3 or greater were seen according to age. Discontinuation rates for adverse events were similar across different age groups, and quality of life, as determined by global health status, was satisfactory in all age groups.
“Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of ramucirumab for the treatment of our patients with gastric cancer irrespective of age,” he concluded.
RAINBOW was funded by Eli Lilly. REGARD was funded by ImClone Systems. Dr. Muro reported receiving honoraria from Chugai Pharma, Merck Serono, Taiho Pharmaceutical, Takeda, Eli Lilly, and Yakult Honsha, as well as serving in a consulting or an advisory role for Ono, Merck Serono, and Eli Lilly, and receiving research funding from MSD, Daiichi Sankyo, Ono, Eisai, Pfizer, Chugai, Dainippon Sumitomo, Merck Serono, Janssen Pharmaceutical K.K., AstraZeneca, GlaxoSmithKline, and Kyowa Hakko Kirin.
SAN FRANCISCO – Patients with metastatic gastric or gastroesophageal junction adenocarcinoma benefit from treatment with ramucirumab regardless of their age, according to findings from an exploratory subgroup analysis of the phase III RAINBOW and REGARD studies.
The findings, which show at least a trend toward improvements in most age categories, are important given that nearly two-thirds of patients with these cancers are diagnosed at over age 65 years, and more than half of those are over age 75 years, Kei Muro, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
“At the other end of the age spectrum, there is evidence that young age can also be an unfavorable prognostic characteristic for gastric cancer,” said Dr. Muro of Aichi Cancer Center Hospital in Nagoya, Japan.
Both RAINBOW and REGARD demonstrated statistically significant and clinically meaningful overall and progression-free survival benefits and acceptable and manageable toxicity with ramucirumab among patients with advanced gastric cancer who were randomized, in the second-line treatment setting, to receive active treatment with the fully humanized monoclonal antibody directed against vascular endothelial growth factor receptor–2 or placebo.
RAINBOW subjects were randomized 1:1 to receive 8 mg/kg of ramucirumab plus paclitaxel, or placebo plus paclitaxel. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 months for treatment vs. 4.2 months for placebo (hazard ratio, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
The corresponding median overall survival rates for those aged 45-70 (225 and 230 patients in the groups, respectively), 70 or older (68 patients in each group), and 75 or older (20 and 16 patients in the groups, respectively) were 9.6 vs. 7.6 months (HR, 0.860), 10.8 vs. 8.6 months (HR, 0.881), and 11.0 vs. 11.0 months (HR, 0.971). The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 4.6 vs. 2.8 months (HR, 0.649), 4.7 vs. 2.9 months (HR, 0.676), and 4.2 vs. 2.8 months (HR, 0.330).
REGARD subjects were randomized 2:1 to receive 8 mg/kg of ramucirumab plus best supportive care, or placebo plus best supportive care. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 vs. 4.2 months for treatment vs. placebo (HR, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
Among REGARD subjects aged 45 years or less (28 and 12 patients in the groups, respectively), the median overall survival was 5.8 vs. 2.9 months for treatment vs. placebo (HR, 0.586), and the median progression-free survival was 1.9 vs. 1.4 months (HR, 0.270).
The corresponding median overall survival rates for those aged 45-70 (166 and 70 patients in the groups, respectively), 70 or older (44 and 35 patients in the groups, respectively), and 75 or older (21 and 13 patients in the groups, respectively) were 4.9 vs. 4.1 months (HR, 0.780), 5.9 vs. 3.8 months (HR, 0.730), and 9.3 vs. 5.1 months (HR, 0.588).
The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 2.2 vs. 1.3 months (HR, 0.451), 2.1 vs. 1.4 months (HR, 0.559), 2.8 vs. 1.4 (HR, 0.420).
Baseline characteristics were generally well balanced between arms in each of the age subgroups, Dr. Muro said, noting that no obvious patterns for differential risks in terms of efficacy and adverse events of any grade or of grade 3 or greater were seen according to age. Discontinuation rates for adverse events were similar across different age groups, and quality of life, as determined by global health status, was satisfactory in all age groups.
“Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of ramucirumab for the treatment of our patients with gastric cancer irrespective of age,” he concluded.
RAINBOW was funded by Eli Lilly. REGARD was funded by ImClone Systems. Dr. Muro reported receiving honoraria from Chugai Pharma, Merck Serono, Taiho Pharmaceutical, Takeda, Eli Lilly, and Yakult Honsha, as well as serving in a consulting or an advisory role for Ono, Merck Serono, and Eli Lilly, and receiving research funding from MSD, Daiichi Sankyo, Ono, Eisai, Pfizer, Chugai, Dainippon Sumitomo, Merck Serono, Janssen Pharmaceutical K.K., AstraZeneca, GlaxoSmithKline, and Kyowa Hakko Kirin.
SAN FRANCISCO – Patients with metastatic gastric or gastroesophageal junction adenocarcinoma benefit from treatment with ramucirumab regardless of their age, according to findings from an exploratory subgroup analysis of the phase III RAINBOW and REGARD studies.
The findings, which show at least a trend toward improvements in most age categories, are important given that nearly two-thirds of patients with these cancers are diagnosed at over age 65 years, and more than half of those are over age 75 years, Kei Muro, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
“At the other end of the age spectrum, there is evidence that young age can also be an unfavorable prognostic characteristic for gastric cancer,” said Dr. Muro of Aichi Cancer Center Hospital in Nagoya, Japan.
Both RAINBOW and REGARD demonstrated statistically significant and clinically meaningful overall and progression-free survival benefits and acceptable and manageable toxicity with ramucirumab among patients with advanced gastric cancer who were randomized, in the second-line treatment setting, to receive active treatment with the fully humanized monoclonal antibody directed against vascular endothelial growth factor receptor–2 or placebo.
RAINBOW subjects were randomized 1:1 to receive 8 mg/kg of ramucirumab plus paclitaxel, or placebo plus paclitaxel. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 months for treatment vs. 4.2 months for placebo (hazard ratio, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
The corresponding median overall survival rates for those aged 45-70 (225 and 230 patients in the groups, respectively), 70 or older (68 patients in each group), and 75 or older (20 and 16 patients in the groups, respectively) were 9.6 vs. 7.6 months (HR, 0.860), 10.8 vs. 8.6 months (HR, 0.881), and 11.0 vs. 11.0 months (HR, 0.971). The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 4.6 vs. 2.8 months (HR, 0.649), 4.7 vs. 2.9 months (HR, 0.676), and 4.2 vs. 2.8 months (HR, 0.330).
REGARD subjects were randomized 2:1 to receive 8 mg/kg of ramucirumab plus best supportive care, or placebo plus best supportive care. Among those aged 45 years or less (37 patients in each group), the median overall survival was 9.0 vs. 4.2 months for treatment vs. placebo (HR, 0.555), and the median progression-free survival was 3.9 vs. 2.8 months (HR, 0.299).
Among REGARD subjects aged 45 years or less (28 and 12 patients in the groups, respectively), the median overall survival was 5.8 vs. 2.9 months for treatment vs. placebo (HR, 0.586), and the median progression-free survival was 1.9 vs. 1.4 months (HR, 0.270).
The corresponding median overall survival rates for those aged 45-70 (166 and 70 patients in the groups, respectively), 70 or older (44 and 35 patients in the groups, respectively), and 75 or older (21 and 13 patients in the groups, respectively) were 4.9 vs. 4.1 months (HR, 0.780), 5.9 vs. 3.8 months (HR, 0.730), and 9.3 vs. 5.1 months (HR, 0.588).
The corresponding progression-free survival rates for those aged 45-70, 70 or older, and 75 or older were 2.2 vs. 1.3 months (HR, 0.451), 2.1 vs. 1.4 months (HR, 0.559), 2.8 vs. 1.4 (HR, 0.420).
Baseline characteristics were generally well balanced between arms in each of the age subgroups, Dr. Muro said, noting that no obvious patterns for differential risks in terms of efficacy and adverse events of any grade or of grade 3 or greater were seen according to age. Discontinuation rates for adverse events were similar across different age groups, and quality of life, as determined by global health status, was satisfactory in all age groups.
“Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of ramucirumab for the treatment of our patients with gastric cancer irrespective of age,” he concluded.
RAINBOW was funded by Eli Lilly. REGARD was funded by ImClone Systems. Dr. Muro reported receiving honoraria from Chugai Pharma, Merck Serono, Taiho Pharmaceutical, Takeda, Eli Lilly, and Yakult Honsha, as well as serving in a consulting or an advisory role for Ono, Merck Serono, and Eli Lilly, and receiving research funding from MSD, Daiichi Sankyo, Ono, Eisai, Pfizer, Chugai, Dainippon Sumitomo, Merck Serono, Janssen Pharmaceutical K.K., AstraZeneca, GlaxoSmithKline, and Kyowa Hakko Kirin.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Among patients 45-70 years and 70 and older, the hazard ratios for overall survival were 0.860 and 0.881 with ramucirumab vs. placebo in RAINBOW, and 0.780 and 0.730 in REGARD
Data source: The phase III RAINBOW and REGARD trials, including a total of more than 1,000 patients.
Disclosures: Dr. Muro reported receiving honoraria from Chugai Pharma, Merck Serono, Taiho Pharmaceutical, Takeda, Eli Lilly, and Yakult Honsha, as well as serving in a consulting or an advisory role for Ono, Merck Serono, and Eli Lilly, and receiving research funding from MSD, Daiichi Sankyo, Ono, Eisai, Pfizer, Chugai, Dainippon Sumitomo, Merck Serono, Janssen Pharmaceutical K.K., AstraZeneca, GlaxoSmithKline, and Kyowa Hakko Kirin.
Ohio progestogen program reduced early preterm births
A statewide progestogen promotion program that aimed to reduce early premature births in Ohio by 10% is exceeding its goals, thanks to a joint effort of maternity hospitals and clinics, Ohio’s Medicaid program, Medicaid insurers, and service agencies.
The organizations joined forces via the Ohio Perinatal Quality Collaborative (PQC) beginning in 2014, and by February 2016 a sustained reduction in singleton births before 32 weeks of gestation was evident. The reduction was particularly pronounced among women with a prior preterm birth, African American women, and women on Medicaid, with reductions of 20.5%, 20.3%, and 17.1%, respectively, according to Jay D. Iams, MD, the obstetrics lead for the collaborative and emeritus professor at Ohio State University; Mary S. Applegate, MD, medical director for the Ohio Department of Medicaid; and their colleagues.
What was the key driver of their success? A collaborative effort among local- and system-level organizations and individuals to overcome the numerous barriers to providing the preventive, highly effective progestogen treatments to at-risk women, according to Dr. Iams and Dr. Applegate.
“Ohio has one of the worst rates of infant mortality and a high rate of premature birth – especially very early premature birth [before 32 weeks],” Dr. Iams said in an interview.
Those very early births account for more than half of infants who die before their first birthday, so while 13% may seem like a small number, it has the potential to have a very large effect on long-term health and infant mortality, he said.
The Ohio program was developed in the wake of practice guidelines from the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists, both issued in 2012, on the use of progestogens to reduce the incidence of preterm birth (Am J Obstet Gynecol 2012;206:376-86 and Obstet Gynecol 2012;120:964-73).
Large, high-quality, randomized placebo-controlled trials supported the use of 17-alpha hydroxyprogesterone caproate (17-p) injections or progesterone administered vaginally, and the Ohio Department of Medicaid and Ohio Department of Health asked the Ohio PQC – a volunteer network of stakeholders dedicated to improving perinatal health outcomes – to design a statewide quality improvement project to promote progestogen prescribing for eligible women.
To facilitate identification and management of women at risk for preterm birth, clinicians were asked to notify the Ohio Medicaid agency when a patient became pregnant so that a care manager could be assigned to help remove barriers to care.
“It turned out that piece of it was key,” she said. “It was the communication between these two, and then just dealing with whatever the issues were that actually made the difference.”
Care managers helped the patients navigate the system by notifying the county to make sure they didn’t “fall off Medicaid,” by addressing transportation issues to ensure patients could get to their weekly treatment visits, and by addressing cultural issues, for instance.
“It never really occurred to clinicians that Medicaid could actually be helpful in finding women and actually doing the right thing for them,” Dr. Applegate said, explaining that most only thought of Medicaid as “after the fact ... the doctors do what they need to and afterward we pay claims.”
“So this was kind of a new concept to them,” she added.
In fact, a quality improvement plan was structured on the managed care plan side, just like one was structured on the clinical side, she said. “In essence we have these parallel systems that were actually connecting, identifying barriers as we went,” Dr. Applegate said.
In the article in Obstetrics & Gynecology, the investigators describe the quality improvement processes, including training, evidence reviews, and strategy sharing. Steps toward efficient identification of eligible patients and prescription of progestogens were developed, and participating sites were encouraged to follow them.
At the system level, efforts focused on maintaining the patient’s Medicaid coverage, expanding eligibility for Medicaid, and streamlining forms and processes to improve efficiency and improve data collection.
The effects of these cumulative efforts emerged over time, with the drop in early premature births becoming apparent about 16-18 months after the project started. The investigators reviewed other possible causes for the decrease, such as an increase in the rate of cervical cerclage, but confirmed that the change was likely the result of the progestogen promotion program, Dr. Iams said.
In all, 2,562 women were eligible for progestogen at participating clinics between Jan. 1, 2014, and Nov. 30, 2015. Most (93%) were eligible because of a prior preterm birth, and the remainder had a short cervix on ultrasound. A progestogen was prescribed at or before 20 6/7 weeks of gestation in 64%, and at or before 24 6/7 weeks gestation in 72%. Injections were prescribed in 65%, and vaginal preparations in 30%; 5% were prescribed both or had no documentation of the formulation.
The progestogen program had no effect on the overall rate of births before 37 weeks. “So we can’t say that we changed the prematurity rate, but we changed the rate of births that are most likely to result in infant death and we were pretty excited about that,” Dr. Iams said.
Next steps for the program include expansion to rural areas and development of an electronic notification system to further streamline communication between the various players (pharmacies, insurance companies, Medicaid, etc.). Dr. Applegate said she also hopes to harness the lessons of this program for use in other high-risk scenarios, such as pregnancies complicated by substance abuse.
As for whether other states will follow Ohio’s lead, Dr. Iams said almost all the states are involved in quality improvement efforts, including several with programs similar to Ohio’s.
In fact, the Centers for Disease Control and Prevention is currently providing support to PQCs in California, Illinois, Massachusetts, North Carolina, and New York, in addition to the Ohio PQC, according to Zsakeba Henderson, MD, a medical officer on the CDC division of reproductive health in Atlanta.
“CDC has developed a resource guide to help develop and advance the work of state PQCs, and in collaboration with March of Dimes has spearheaded the development and launch of the National Network of Perinatal Quality Collaboratives,” she said. “This network is a consultative resource for state PQCs, with a mission is to support the development and enhance the ability of state perinatal quality collaboratives to make measurable improvements in statewide maternal and infant health care and health outcomes.”
Dr. Applegate stressed the importance of collaboration in achieving results.
“I think the message is you can’t do it in a silo. It really has taken this collaborative and fairly comprehensive approach to understand not only how complex the system is, but how complicated people’s lives are. You just have to hang in there over lots and lots of weeks to get the outcome you want,” she said, adding that the effort is well worth it.
“These are babies that are born weighing less than a pound and a half. When we’re helping them be born closer to term that changes the next 60 years of their life,” she said. “It totally changes not just that baby’s life, but the hardship that comes to that family as well, so the impact is actually huge.”
A statewide progestogen promotion program that aimed to reduce early premature births in Ohio by 10% is exceeding its goals, thanks to a joint effort of maternity hospitals and clinics, Ohio’s Medicaid program, Medicaid insurers, and service agencies.
The organizations joined forces via the Ohio Perinatal Quality Collaborative (PQC) beginning in 2014, and by February 2016 a sustained reduction in singleton births before 32 weeks of gestation was evident. The reduction was particularly pronounced among women with a prior preterm birth, African American women, and women on Medicaid, with reductions of 20.5%, 20.3%, and 17.1%, respectively, according to Jay D. Iams, MD, the obstetrics lead for the collaborative and emeritus professor at Ohio State University; Mary S. Applegate, MD, medical director for the Ohio Department of Medicaid; and their colleagues.
What was the key driver of their success? A collaborative effort among local- and system-level organizations and individuals to overcome the numerous barriers to providing the preventive, highly effective progestogen treatments to at-risk women, according to Dr. Iams and Dr. Applegate.
“Ohio has one of the worst rates of infant mortality and a high rate of premature birth – especially very early premature birth [before 32 weeks],” Dr. Iams said in an interview.
Those very early births account for more than half of infants who die before their first birthday, so while 13% may seem like a small number, it has the potential to have a very large effect on long-term health and infant mortality, he said.
The Ohio program was developed in the wake of practice guidelines from the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists, both issued in 2012, on the use of progestogens to reduce the incidence of preterm birth (Am J Obstet Gynecol 2012;206:376-86 and Obstet Gynecol 2012;120:964-73).
Large, high-quality, randomized placebo-controlled trials supported the use of 17-alpha hydroxyprogesterone caproate (17-p) injections or progesterone administered vaginally, and the Ohio Department of Medicaid and Ohio Department of Health asked the Ohio PQC – a volunteer network of stakeholders dedicated to improving perinatal health outcomes – to design a statewide quality improvement project to promote progestogen prescribing for eligible women.
To facilitate identification and management of women at risk for preterm birth, clinicians were asked to notify the Ohio Medicaid agency when a patient became pregnant so that a care manager could be assigned to help remove barriers to care.
“It turned out that piece of it was key,” she said. “It was the communication between these two, and then just dealing with whatever the issues were that actually made the difference.”
Care managers helped the patients navigate the system by notifying the county to make sure they didn’t “fall off Medicaid,” by addressing transportation issues to ensure patients could get to their weekly treatment visits, and by addressing cultural issues, for instance.
“It never really occurred to clinicians that Medicaid could actually be helpful in finding women and actually doing the right thing for them,” Dr. Applegate said, explaining that most only thought of Medicaid as “after the fact ... the doctors do what they need to and afterward we pay claims.”
“So this was kind of a new concept to them,” she added.
In fact, a quality improvement plan was structured on the managed care plan side, just like one was structured on the clinical side, she said. “In essence we have these parallel systems that were actually connecting, identifying barriers as we went,” Dr. Applegate said.
In the article in Obstetrics & Gynecology, the investigators describe the quality improvement processes, including training, evidence reviews, and strategy sharing. Steps toward efficient identification of eligible patients and prescription of progestogens were developed, and participating sites were encouraged to follow them.
At the system level, efforts focused on maintaining the patient’s Medicaid coverage, expanding eligibility for Medicaid, and streamlining forms and processes to improve efficiency and improve data collection.
The effects of these cumulative efforts emerged over time, with the drop in early premature births becoming apparent about 16-18 months after the project started. The investigators reviewed other possible causes for the decrease, such as an increase in the rate of cervical cerclage, but confirmed that the change was likely the result of the progestogen promotion program, Dr. Iams said.
In all, 2,562 women were eligible for progestogen at participating clinics between Jan. 1, 2014, and Nov. 30, 2015. Most (93%) were eligible because of a prior preterm birth, and the remainder had a short cervix on ultrasound. A progestogen was prescribed at or before 20 6/7 weeks of gestation in 64%, and at or before 24 6/7 weeks gestation in 72%. Injections were prescribed in 65%, and vaginal preparations in 30%; 5% were prescribed both or had no documentation of the formulation.
The progestogen program had no effect on the overall rate of births before 37 weeks. “So we can’t say that we changed the prematurity rate, but we changed the rate of births that are most likely to result in infant death and we were pretty excited about that,” Dr. Iams said.
Next steps for the program include expansion to rural areas and development of an electronic notification system to further streamline communication between the various players (pharmacies, insurance companies, Medicaid, etc.). Dr. Applegate said she also hopes to harness the lessons of this program for use in other high-risk scenarios, such as pregnancies complicated by substance abuse.
As for whether other states will follow Ohio’s lead, Dr. Iams said almost all the states are involved in quality improvement efforts, including several with programs similar to Ohio’s.
In fact, the Centers for Disease Control and Prevention is currently providing support to PQCs in California, Illinois, Massachusetts, North Carolina, and New York, in addition to the Ohio PQC, according to Zsakeba Henderson, MD, a medical officer on the CDC division of reproductive health in Atlanta.
“CDC has developed a resource guide to help develop and advance the work of state PQCs, and in collaboration with March of Dimes has spearheaded the development and launch of the National Network of Perinatal Quality Collaboratives,” she said. “This network is a consultative resource for state PQCs, with a mission is to support the development and enhance the ability of state perinatal quality collaboratives to make measurable improvements in statewide maternal and infant health care and health outcomes.”
Dr. Applegate stressed the importance of collaboration in achieving results.
“I think the message is you can’t do it in a silo. It really has taken this collaborative and fairly comprehensive approach to understand not only how complex the system is, but how complicated people’s lives are. You just have to hang in there over lots and lots of weeks to get the outcome you want,” she said, adding that the effort is well worth it.
“These are babies that are born weighing less than a pound and a half. When we’re helping them be born closer to term that changes the next 60 years of their life,” she said. “It totally changes not just that baby’s life, but the hardship that comes to that family as well, so the impact is actually huge.”
A statewide progestogen promotion program that aimed to reduce early premature births in Ohio by 10% is exceeding its goals, thanks to a joint effort of maternity hospitals and clinics, Ohio’s Medicaid program, Medicaid insurers, and service agencies.
The organizations joined forces via the Ohio Perinatal Quality Collaborative (PQC) beginning in 2014, and by February 2016 a sustained reduction in singleton births before 32 weeks of gestation was evident. The reduction was particularly pronounced among women with a prior preterm birth, African American women, and women on Medicaid, with reductions of 20.5%, 20.3%, and 17.1%, respectively, according to Jay D. Iams, MD, the obstetrics lead for the collaborative and emeritus professor at Ohio State University; Mary S. Applegate, MD, medical director for the Ohio Department of Medicaid; and their colleagues.
What was the key driver of their success? A collaborative effort among local- and system-level organizations and individuals to overcome the numerous barriers to providing the preventive, highly effective progestogen treatments to at-risk women, according to Dr. Iams and Dr. Applegate.
“Ohio has one of the worst rates of infant mortality and a high rate of premature birth – especially very early premature birth [before 32 weeks],” Dr. Iams said in an interview.
Those very early births account for more than half of infants who die before their first birthday, so while 13% may seem like a small number, it has the potential to have a very large effect on long-term health and infant mortality, he said.
The Ohio program was developed in the wake of practice guidelines from the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists, both issued in 2012, on the use of progestogens to reduce the incidence of preterm birth (Am J Obstet Gynecol 2012;206:376-86 and Obstet Gynecol 2012;120:964-73).
Large, high-quality, randomized placebo-controlled trials supported the use of 17-alpha hydroxyprogesterone caproate (17-p) injections or progesterone administered vaginally, and the Ohio Department of Medicaid and Ohio Department of Health asked the Ohio PQC – a volunteer network of stakeholders dedicated to improving perinatal health outcomes – to design a statewide quality improvement project to promote progestogen prescribing for eligible women.
To facilitate identification and management of women at risk for preterm birth, clinicians were asked to notify the Ohio Medicaid agency when a patient became pregnant so that a care manager could be assigned to help remove barriers to care.
“It turned out that piece of it was key,” she said. “It was the communication between these two, and then just dealing with whatever the issues were that actually made the difference.”
Care managers helped the patients navigate the system by notifying the county to make sure they didn’t “fall off Medicaid,” by addressing transportation issues to ensure patients could get to their weekly treatment visits, and by addressing cultural issues, for instance.
“It never really occurred to clinicians that Medicaid could actually be helpful in finding women and actually doing the right thing for them,” Dr. Applegate said, explaining that most only thought of Medicaid as “after the fact ... the doctors do what they need to and afterward we pay claims.”
“So this was kind of a new concept to them,” she added.
In fact, a quality improvement plan was structured on the managed care plan side, just like one was structured on the clinical side, she said. “In essence we have these parallel systems that were actually connecting, identifying barriers as we went,” Dr. Applegate said.
In the article in Obstetrics & Gynecology, the investigators describe the quality improvement processes, including training, evidence reviews, and strategy sharing. Steps toward efficient identification of eligible patients and prescription of progestogens were developed, and participating sites were encouraged to follow them.
At the system level, efforts focused on maintaining the patient’s Medicaid coverage, expanding eligibility for Medicaid, and streamlining forms and processes to improve efficiency and improve data collection.
The effects of these cumulative efforts emerged over time, with the drop in early premature births becoming apparent about 16-18 months after the project started. The investigators reviewed other possible causes for the decrease, such as an increase in the rate of cervical cerclage, but confirmed that the change was likely the result of the progestogen promotion program, Dr. Iams said.
In all, 2,562 women were eligible for progestogen at participating clinics between Jan. 1, 2014, and Nov. 30, 2015. Most (93%) were eligible because of a prior preterm birth, and the remainder had a short cervix on ultrasound. A progestogen was prescribed at or before 20 6/7 weeks of gestation in 64%, and at or before 24 6/7 weeks gestation in 72%. Injections were prescribed in 65%, and vaginal preparations in 30%; 5% were prescribed both or had no documentation of the formulation.
The progestogen program had no effect on the overall rate of births before 37 weeks. “So we can’t say that we changed the prematurity rate, but we changed the rate of births that are most likely to result in infant death and we were pretty excited about that,” Dr. Iams said.
Next steps for the program include expansion to rural areas and development of an electronic notification system to further streamline communication between the various players (pharmacies, insurance companies, Medicaid, etc.). Dr. Applegate said she also hopes to harness the lessons of this program for use in other high-risk scenarios, such as pregnancies complicated by substance abuse.
As for whether other states will follow Ohio’s lead, Dr. Iams said almost all the states are involved in quality improvement efforts, including several with programs similar to Ohio’s.
In fact, the Centers for Disease Control and Prevention is currently providing support to PQCs in California, Illinois, Massachusetts, North Carolina, and New York, in addition to the Ohio PQC, according to Zsakeba Henderson, MD, a medical officer on the CDC division of reproductive health in Atlanta.
“CDC has developed a resource guide to help develop and advance the work of state PQCs, and in collaboration with March of Dimes has spearheaded the development and launch of the National Network of Perinatal Quality Collaboratives,” she said. “This network is a consultative resource for state PQCs, with a mission is to support the development and enhance the ability of state perinatal quality collaboratives to make measurable improvements in statewide maternal and infant health care and health outcomes.”
Dr. Applegate stressed the importance of collaboration in achieving results.
“I think the message is you can’t do it in a silo. It really has taken this collaborative and fairly comprehensive approach to understand not only how complex the system is, but how complicated people’s lives are. You just have to hang in there over lots and lots of weeks to get the outcome you want,” she said, adding that the effort is well worth it.
“These are babies that are born weighing less than a pound and a half. When we’re helping them be born closer to term that changes the next 60 years of their life,” she said. “It totally changes not just that baby’s life, but the hardship that comes to that family as well, so the impact is actually huge.”
Nivolumab safe, effective for salvage in advanced gastric cancer
SAN FRANCISCO – The human monoclonal IgG4 antibody nivolumab was safe and effective as a salvage treatment for patients in a randomized phase III trial who failed standard chemotherapy for advanced gastric or gastroesophageal junction cancer.
Nivolumab, which blocks the human programmed cell death-1 receptor, was superior to placebo with respect to overall survival, progression-free survival, and overall response rate, Yoon-Koo Kang, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
For the study (ONO-4538), 493 patients with ECOG performance status of 0-1 and unresectable advanced or recurrent advanced gastric or gastroesophageal cancer who failed 2 or more prior chemotherapy regimens were randomized to receive placebo or nivolumab in a 2:1 ratio. Nivolumab treatment was associated with significantly improved median overall survival at the time of data cut-off 5.6 months after the last patient was randomized (5.32 months vs. 4.14 months with placebo; hazard ratio, 0.63), said Dr. Kang of Asan Medical Center, University of Ulsan, Seoul, Korea.
The overall survival rate at 12 months was 26.6% vs. 10.9%, respectively, he said.
The overall response rate was 11.2% vs. 0%, and median progression-free survival was 1.61 months vs. 1.45 months (hazard ratio, 0.60) with nivolumab vs. placebo, respectively.
“Median duration of response was 9.53 months,” he said.
Study subjects were adults aged 20 years or older who were enrolled from 49 centers in Japan, Korea, and Taiwan. The 330 patients in the nivolumab group received 3 mg/kg every 2 weeks until toxicity became unacceptable or disease progressed. Treatment-related adverse events occurred in 42.7% vs. 26.7% of nivolumab and placebo group patients, respectively, and grade 3 or greater events occurred in 11.5% vs. 5.5%, respectively.
Grade 3 or 4 events reported in more than 2% of patients were diarrhea, fatigue, decreased appetite, pyrexia, and increased AST and ALT in the treatment group, and fatigue and decreased appetite in the placebo group. The rates of discontinuation of active treatment due to drug-related adverse events were similar at 2.7% and 2.5% in the groups, respectively, he said, noting that the safety profile was consistent with findings in prior studies involving patients with solid tumors.
The findings demonstrate a clinical benefit with nivolumab in pretreated advanced or recurrent gastric cancer, and establish a strong basis for conducting additional studies of the drug in such patients, he concluded.
ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.
SAN FRANCISCO – The human monoclonal IgG4 antibody nivolumab was safe and effective as a salvage treatment for patients in a randomized phase III trial who failed standard chemotherapy for advanced gastric or gastroesophageal junction cancer.
Nivolumab, which blocks the human programmed cell death-1 receptor, was superior to placebo with respect to overall survival, progression-free survival, and overall response rate, Yoon-Koo Kang, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
For the study (ONO-4538), 493 patients with ECOG performance status of 0-1 and unresectable advanced or recurrent advanced gastric or gastroesophageal cancer who failed 2 or more prior chemotherapy regimens were randomized to receive placebo or nivolumab in a 2:1 ratio. Nivolumab treatment was associated with significantly improved median overall survival at the time of data cut-off 5.6 months after the last patient was randomized (5.32 months vs. 4.14 months with placebo; hazard ratio, 0.63), said Dr. Kang of Asan Medical Center, University of Ulsan, Seoul, Korea.
The overall survival rate at 12 months was 26.6% vs. 10.9%, respectively, he said.
The overall response rate was 11.2% vs. 0%, and median progression-free survival was 1.61 months vs. 1.45 months (hazard ratio, 0.60) with nivolumab vs. placebo, respectively.
“Median duration of response was 9.53 months,” he said.
Study subjects were adults aged 20 years or older who were enrolled from 49 centers in Japan, Korea, and Taiwan. The 330 patients in the nivolumab group received 3 mg/kg every 2 weeks until toxicity became unacceptable or disease progressed. Treatment-related adverse events occurred in 42.7% vs. 26.7% of nivolumab and placebo group patients, respectively, and grade 3 or greater events occurred in 11.5% vs. 5.5%, respectively.
Grade 3 or 4 events reported in more than 2% of patients were diarrhea, fatigue, decreased appetite, pyrexia, and increased AST and ALT in the treatment group, and fatigue and decreased appetite in the placebo group. The rates of discontinuation of active treatment due to drug-related adverse events were similar at 2.7% and 2.5% in the groups, respectively, he said, noting that the safety profile was consistent with findings in prior studies involving patients with solid tumors.
The findings demonstrate a clinical benefit with nivolumab in pretreated advanced or recurrent gastric cancer, and establish a strong basis for conducting additional studies of the drug in such patients, he concluded.
ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.
SAN FRANCISCO – The human monoclonal IgG4 antibody nivolumab was safe and effective as a salvage treatment for patients in a randomized phase III trial who failed standard chemotherapy for advanced gastric or gastroesophageal junction cancer.
Nivolumab, which blocks the human programmed cell death-1 receptor, was superior to placebo with respect to overall survival, progression-free survival, and overall response rate, Yoon-Koo Kang, MD, reported at the symposium sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
For the study (ONO-4538), 493 patients with ECOG performance status of 0-1 and unresectable advanced or recurrent advanced gastric or gastroesophageal cancer who failed 2 or more prior chemotherapy regimens were randomized to receive placebo or nivolumab in a 2:1 ratio. Nivolumab treatment was associated with significantly improved median overall survival at the time of data cut-off 5.6 months after the last patient was randomized (5.32 months vs. 4.14 months with placebo; hazard ratio, 0.63), said Dr. Kang of Asan Medical Center, University of Ulsan, Seoul, Korea.
The overall survival rate at 12 months was 26.6% vs. 10.9%, respectively, he said.
The overall response rate was 11.2% vs. 0%, and median progression-free survival was 1.61 months vs. 1.45 months (hazard ratio, 0.60) with nivolumab vs. placebo, respectively.
“Median duration of response was 9.53 months,” he said.
Study subjects were adults aged 20 years or older who were enrolled from 49 centers in Japan, Korea, and Taiwan. The 330 patients in the nivolumab group received 3 mg/kg every 2 weeks until toxicity became unacceptable or disease progressed. Treatment-related adverse events occurred in 42.7% vs. 26.7% of nivolumab and placebo group patients, respectively, and grade 3 or greater events occurred in 11.5% vs. 5.5%, respectively.
Grade 3 or 4 events reported in more than 2% of patients were diarrhea, fatigue, decreased appetite, pyrexia, and increased AST and ALT in the treatment group, and fatigue and decreased appetite in the placebo group. The rates of discontinuation of active treatment due to drug-related adverse events were similar at 2.7% and 2.5% in the groups, respectively, he said, noting that the safety profile was consistent with findings in prior studies involving patients with solid tumors.
The findings demonstrate a clinical benefit with nivolumab in pretreated advanced or recurrent gastric cancer, and establish a strong basis for conducting additional studies of the drug in such patients, he concluded.
ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: The overall survival rate at 12 months was 26.6% vs. 10.9% with nivolumab vs. placebo, respectively.
Data source: The randomized phase III ONO-4538 trial.
Disclosures: ONO-4538 was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Dr. Kang reported a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical, and research funding from Bayer, Novartis, and Roche/Genentech.
PET-directed induction therapy improves esophageal cancer outcomes
SAN FRANCISCO – The use of positron emission tomography to assess esophageal tumor response to induction chemotherapy and to guide a regimen change in those who failed to respond was associated with an improved pathologic complete response (pCR) rate in patients in a phase II randomized trial.
Of 257 patients with esophageal and gastroesophageal junction (GEJ) adenocarcinomas who were randomized after a baseline PET scan to receive induction chemotherapy with either modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) on days 1, 15, and 29, or carboplatin/paclitaxel (CP) on days 1, 8, 22, and 29, 39 patients and 49 patients, respectively, were found on a repeat PET scan performed between days 36 and 42 after initiation of therapy to be nonresponders. Those patients were switched to the alternative regimen during preoperative chemoradiation therapy (CRT). Eligible subjects underwent surgical resection 6 weeks after CRT. The pCR rate after surgery among those who were switched because of initial nonresponse was 18%, compared with an expected rate of 5% based on data from prior studies in which chemotherapy was not changed in nonresponders. The rate was 26% in PET responders, Karyn A. Goodman, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology..
“Preoperative chemoradiotherapy is an accepted standard of care for patients with operable esophageal or gastroesophageal junction adenocarcinoma, but even with this aggressive approach, 5-year overall survival rates are on the order of 40%-50%, and most patients die of systemic disease. Optimal systemic therapy for esophageal and gastroesophageal junction cancers remains undefined, so better methods to identify effective therapies are needed,” she said.
Based on findings from the German, phase II, multicenter MUNICON trial, which showed that early PET responders to chemotherapy had significantly better event-free survival than did PET nonresponders (30 vs. 14 months), and that immediate surgical resection among those identified as nonresponders was also associated with improved outcomes, Dr. Goodman and her colleagues “set out to do CALGB 80803 [the current trial] to evaluate the use of early assessment of chemotherapy responsiveness by PET imaging to direct further therapy … with the goal of improving treatment responses,” she said.
Among secondary CALGB 80803 endpoints was the PET response in the treatment arms.
The rate of response to induction chemotherapy was 57% in the FOLFOX group, and 50% in the CP group. The nonresponders were switched to the alternate regimen, and 84% of patients went on to surgery.
The overall pCR rate after surgery was 19% for those who switched from FOLFOX to CP, and 17% for those who switched from CP to FOLFOX.
“The efficacy criteria for changing therapy was met for both induction arms,” she said.
“Of note, patients who were PET responders who had induction and concurrent FOLFOX had a pCR rate of almost 38%. The pCR rate for patients who started on the induction FOLFOX arm was 31%, and for those who started on the induction CP arm it was 14%, and for all patients enrolled on the study, the pCR rate was 22.7%” she said.
PET scans are routinely used to guide therapy decisions in patients with lymphoma, but are only beginning to be explored for this purpose in solid tumors. CALGB 80803 is among the first to show the benefit of PET imaging in directing presurgery treatment decisions for esophageal cancer.
“We’ve shown that a short course of induction chemotherapy followed by early response assessment using PET imaging to determine whether to switch from ineffective therapy to alternative chemotherapy during preoperative chemoradiation for PET nonresponders is feasible for esophageal and GEJ cancers,” she said, adding that the findings demonstrate a benefit with “a new paradigm of using metabolic imaging … to individualize multimodality therapy and improve outcomes in this poor-prognosis population.”
Further, while the study was not powered for a head-to-head comparison of FOLFOX and CP, the “very promising” 38% pCR rate with FOLFOX induction and concurrent therapy is hypothesis generating, she said.
“How these improvements in pCR translate into survival benefit will be determined with longer follow-up,” she added, noting in response to a question about whether these findings will change practice that “this is really the first step in the process. If we can improve outcomes by changing treatment early on, this should be standard of care, but we really do need to get survival outcome information.”
PET at baseline is already standard; adding another scan adds additional cost, but this potentially may be offset by the prevention of costly toxicities and other problems that have to be addressed, she said, concluding that “going forward, early-response assessment using PET imaging can be incorporated into studies to identify more effective new regimens for esophageal and GEJ cancers.”
During a preconference press cast on the findings, press cast moderator Nancy Baxter, MD, of ASCO said that PET scans may prove to be a valuable tool for fine-tuning the use of chemotherapy for esophageal cancer, and for maximizing the benefit of chemotherapy for each patient.
“This is heartening evidence for a new approach to treating a disease where innovation is sorely needed,” she said.
CALGB 80803 was funded by grants from the National Cancer Institute. Dr. Goodman and Dr. Baxter reported having no disclosures.
SAN FRANCISCO – The use of positron emission tomography to assess esophageal tumor response to induction chemotherapy and to guide a regimen change in those who failed to respond was associated with an improved pathologic complete response (pCR) rate in patients in a phase II randomized trial.
Of 257 patients with esophageal and gastroesophageal junction (GEJ) adenocarcinomas who were randomized after a baseline PET scan to receive induction chemotherapy with either modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) on days 1, 15, and 29, or carboplatin/paclitaxel (CP) on days 1, 8, 22, and 29, 39 patients and 49 patients, respectively, were found on a repeat PET scan performed between days 36 and 42 after initiation of therapy to be nonresponders. Those patients were switched to the alternative regimen during preoperative chemoradiation therapy (CRT). Eligible subjects underwent surgical resection 6 weeks after CRT. The pCR rate after surgery among those who were switched because of initial nonresponse was 18%, compared with an expected rate of 5% based on data from prior studies in which chemotherapy was not changed in nonresponders. The rate was 26% in PET responders, Karyn A. Goodman, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology..
“Preoperative chemoradiotherapy is an accepted standard of care for patients with operable esophageal or gastroesophageal junction adenocarcinoma, but even with this aggressive approach, 5-year overall survival rates are on the order of 40%-50%, and most patients die of systemic disease. Optimal systemic therapy for esophageal and gastroesophageal junction cancers remains undefined, so better methods to identify effective therapies are needed,” she said.
Based on findings from the German, phase II, multicenter MUNICON trial, which showed that early PET responders to chemotherapy had significantly better event-free survival than did PET nonresponders (30 vs. 14 months), and that immediate surgical resection among those identified as nonresponders was also associated with improved outcomes, Dr. Goodman and her colleagues “set out to do CALGB 80803 [the current trial] to evaluate the use of early assessment of chemotherapy responsiveness by PET imaging to direct further therapy … with the goal of improving treatment responses,” she said.
Among secondary CALGB 80803 endpoints was the PET response in the treatment arms.
The rate of response to induction chemotherapy was 57% in the FOLFOX group, and 50% in the CP group. The nonresponders were switched to the alternate regimen, and 84% of patients went on to surgery.
The overall pCR rate after surgery was 19% for those who switched from FOLFOX to CP, and 17% for those who switched from CP to FOLFOX.
“The efficacy criteria for changing therapy was met for both induction arms,” she said.
“Of note, patients who were PET responders who had induction and concurrent FOLFOX had a pCR rate of almost 38%. The pCR rate for patients who started on the induction FOLFOX arm was 31%, and for those who started on the induction CP arm it was 14%, and for all patients enrolled on the study, the pCR rate was 22.7%” she said.
PET scans are routinely used to guide therapy decisions in patients with lymphoma, but are only beginning to be explored for this purpose in solid tumors. CALGB 80803 is among the first to show the benefit of PET imaging in directing presurgery treatment decisions for esophageal cancer.
“We’ve shown that a short course of induction chemotherapy followed by early response assessment using PET imaging to determine whether to switch from ineffective therapy to alternative chemotherapy during preoperative chemoradiation for PET nonresponders is feasible for esophageal and GEJ cancers,” she said, adding that the findings demonstrate a benefit with “a new paradigm of using metabolic imaging … to individualize multimodality therapy and improve outcomes in this poor-prognosis population.”
Further, while the study was not powered for a head-to-head comparison of FOLFOX and CP, the “very promising” 38% pCR rate with FOLFOX induction and concurrent therapy is hypothesis generating, she said.
“How these improvements in pCR translate into survival benefit will be determined with longer follow-up,” she added, noting in response to a question about whether these findings will change practice that “this is really the first step in the process. If we can improve outcomes by changing treatment early on, this should be standard of care, but we really do need to get survival outcome information.”
PET at baseline is already standard; adding another scan adds additional cost, but this potentially may be offset by the prevention of costly toxicities and other problems that have to be addressed, she said, concluding that “going forward, early-response assessment using PET imaging can be incorporated into studies to identify more effective new regimens for esophageal and GEJ cancers.”
During a preconference press cast on the findings, press cast moderator Nancy Baxter, MD, of ASCO said that PET scans may prove to be a valuable tool for fine-tuning the use of chemotherapy for esophageal cancer, and for maximizing the benefit of chemotherapy for each patient.
“This is heartening evidence for a new approach to treating a disease where innovation is sorely needed,” she said.
CALGB 80803 was funded by grants from the National Cancer Institute. Dr. Goodman and Dr. Baxter reported having no disclosures.
SAN FRANCISCO – The use of positron emission tomography to assess esophageal tumor response to induction chemotherapy and to guide a regimen change in those who failed to respond was associated with an improved pathologic complete response (pCR) rate in patients in a phase II randomized trial.
Of 257 patients with esophageal and gastroesophageal junction (GEJ) adenocarcinomas who were randomized after a baseline PET scan to receive induction chemotherapy with either modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) on days 1, 15, and 29, or carboplatin/paclitaxel (CP) on days 1, 8, 22, and 29, 39 patients and 49 patients, respectively, were found on a repeat PET scan performed between days 36 and 42 after initiation of therapy to be nonresponders. Those patients were switched to the alternative regimen during preoperative chemoradiation therapy (CRT). Eligible subjects underwent surgical resection 6 weeks after CRT. The pCR rate after surgery among those who were switched because of initial nonresponse was 18%, compared with an expected rate of 5% based on data from prior studies in which chemotherapy was not changed in nonresponders. The rate was 26% in PET responders, Karyn A. Goodman, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology..
“Preoperative chemoradiotherapy is an accepted standard of care for patients with operable esophageal or gastroesophageal junction adenocarcinoma, but even with this aggressive approach, 5-year overall survival rates are on the order of 40%-50%, and most patients die of systemic disease. Optimal systemic therapy for esophageal and gastroesophageal junction cancers remains undefined, so better methods to identify effective therapies are needed,” she said.
Based on findings from the German, phase II, multicenter MUNICON trial, which showed that early PET responders to chemotherapy had significantly better event-free survival than did PET nonresponders (30 vs. 14 months), and that immediate surgical resection among those identified as nonresponders was also associated with improved outcomes, Dr. Goodman and her colleagues “set out to do CALGB 80803 [the current trial] to evaluate the use of early assessment of chemotherapy responsiveness by PET imaging to direct further therapy … with the goal of improving treatment responses,” she said.
Among secondary CALGB 80803 endpoints was the PET response in the treatment arms.
The rate of response to induction chemotherapy was 57% in the FOLFOX group, and 50% in the CP group. The nonresponders were switched to the alternate regimen, and 84% of patients went on to surgery.
The overall pCR rate after surgery was 19% for those who switched from FOLFOX to CP, and 17% for those who switched from CP to FOLFOX.
“The efficacy criteria for changing therapy was met for both induction arms,” she said.
“Of note, patients who were PET responders who had induction and concurrent FOLFOX had a pCR rate of almost 38%. The pCR rate for patients who started on the induction FOLFOX arm was 31%, and for those who started on the induction CP arm it was 14%, and for all patients enrolled on the study, the pCR rate was 22.7%” she said.
PET scans are routinely used to guide therapy decisions in patients with lymphoma, but are only beginning to be explored for this purpose in solid tumors. CALGB 80803 is among the first to show the benefit of PET imaging in directing presurgery treatment decisions for esophageal cancer.
“We’ve shown that a short course of induction chemotherapy followed by early response assessment using PET imaging to determine whether to switch from ineffective therapy to alternative chemotherapy during preoperative chemoradiation for PET nonresponders is feasible for esophageal and GEJ cancers,” she said, adding that the findings demonstrate a benefit with “a new paradigm of using metabolic imaging … to individualize multimodality therapy and improve outcomes in this poor-prognosis population.”
Further, while the study was not powered for a head-to-head comparison of FOLFOX and CP, the “very promising” 38% pCR rate with FOLFOX induction and concurrent therapy is hypothesis generating, she said.
“How these improvements in pCR translate into survival benefit will be determined with longer follow-up,” she added, noting in response to a question about whether these findings will change practice that “this is really the first step in the process. If we can improve outcomes by changing treatment early on, this should be standard of care, but we really do need to get survival outcome information.”
PET at baseline is already standard; adding another scan adds additional cost, but this potentially may be offset by the prevention of costly toxicities and other problems that have to be addressed, she said, concluding that “going forward, early-response assessment using PET imaging can be incorporated into studies to identify more effective new regimens for esophageal and GEJ cancers.”
During a preconference press cast on the findings, press cast moderator Nancy Baxter, MD, of ASCO said that PET scans may prove to be a valuable tool for fine-tuning the use of chemotherapy for esophageal cancer, and for maximizing the benefit of chemotherapy for each patient.
“This is heartening evidence for a new approach to treating a disease where innovation is sorely needed,” she said.
CALGB 80803 was funded by grants from the National Cancer Institute. Dr. Goodman and Dr. Baxter reported having no disclosures.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: The pathologic completer response rate among PET nonresponders who switched therapies was 18% vs. an expected rate of 5%.
Data source: The phase II randomized CALGB 80803 of 257 esophageal and GEJ cancer patients.
Disclosures: CALGB 80803 was funded by grants from the National Cancer Institute. Dr. Goodman and Dr. Baxter reported having no disclosures.