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For patients with completely or near-completely resected pancreatic ductal adenocarcinoma, adjuvant therapy with a modified FOLFIRINOX regimen was associated with significantly better 3-year disease-free survival and overall survival compared with gemcitabine, results of the phase 3 randomized PRODIGE 24 trial showed.
At a median follow-up of 33.6 months, median disease-free survival was 21.6 months for 247 patients assigned to receive adjuvant modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), compared with 12.8 months for 246 patients randomized to receive gemcitabine.
The median overall survival was 54.4 months for patients treated with FOLFIRINOX, vs. 35 months for patients treated with gemcitabine, a difference that translated into a hazard ratio (HR) of 0.65 (P = .003) for the combination regimen, reported Thierry Conroy, MD, of Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France, and colleagues in the Canadian Cancer Trials Group and Unicancer-GI-PRODIGE Group.
“The disease-free survival benefit with modified FOLFIRINOX was significant in the majority of subgroups, including subgroups of patients with adverse prognostic factors (i.e., T3 or T4 tumor status, positive lymph nodes, or R1 resection),” they wrote. The report is in The New England Journal of Medicine.
The survival advantage with FOLFIRINOX came at the cost of more frequent adverse events, however, although the only treatment-related death occurred in a patient treated with gemcitabine.
A previous randomized trial by the PRODIGE group showed a survival advantage of FOLFIRINOX over gemcitabine in patients with metastatic pancreatic cancer, prompting the investigators to look at the same two regimens as adjuvant therapy for patients with pancreatic cancer following R0 (clear surgical margins) or RI (minimal residual disease) resections. In the current trial, FOLFIRINOX was modified by the elimination of a bolus dose of fluorouracil to decrease hematologic toxicities and diarrhea without compromising efficacy.
In the intention-to-treat analysis, 493 patients were randomly assigned to receive either modified FOLFIRINOX, consisting of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, which was reduced to 150 mg/m2 after a protocol-specified safety analysis, leucovorin 400 mg/m2, and fluorouracil 2,400 mg/m2 every 2 weeks, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks for 24 weeks.
The disease-free survival primary endpoint and overall survival secondary endpoints were as reported before.
The 3-year overall survival rates were 63.4% with modified FOLFIRINOX, compared with 48.6% with gemcitabine.
Additional secondary endpoints also favored FOLFIRINOX, including metastasis-free survival at a median 30.4 month vs. 17.7 months, respectively, translating into a stratified HR of 0.59 (P less than .001). The 3-year metastasis-free survival rates were 48.2% vs. 30.9% for gemcitabine.
The median cancer-specific survival was not reached in the combination therapy group compared with 36.4 months with gemcitabine monotherapy, a difference that translated into a stratified HR for death from the treated cancer or treatment-related complications of 0.63 (P = .003).
The safety analysis included data on 238 patients treated with FOLFIRINOX and 241 with gemcitabine.
Grade 3 or 4 adverse events occurred in 75.9% of patients treated with modified FOLFIRINOX and 52.9% of patients treated with gemcitabine. The single treatment-related death was from interstitial pneumonitis in a patient treated with gemcitabine.
Grade 3 or 4 diarrhea, increase in the gamma-glutamyltransferase level, paresthesia, fatigue, sensory peripheral neuropathy, nausea, vomiting, abdominal pain, and mucositis were all significantly more frequent with modified FOLFIRINOX.
Slightly more than half (56.8%) of patients in the FOLFIRINOX arm received granulocyte-colony stimulating factor support as either primary prophylaxis or therapy for uncomplicated neutropenia, with no delays in treatment.
The investigators acknowledged that although “disease-free survival is not validated as a surrogate endpoint for overall survival in trials of adjuvant therapy for pancreatic cancer, this criterion was robust and correlated with overall survival.”
The study was supported by R&D Unicancer, which received a grant from Chugai Pharmaceutical the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group Pancreatic Adenocarcinoma part of the trial was supported by a Program Grant from the Canadian Cancer Society and by grants from 7 Days in May. Dr. Conroy disclosed receiving travel grants form Roche.
SOURCE: Conroy T et al. N Engl J Med. 2018 Dec 19;379:2395-406.
Is surgery followed by 6 months of adjuvant chemotherapy the appropriate sequence in patients with a disease that may be systemic at diagnosis? Can we further improve outcomes by delivering modified FOLFIRINOX before surgery? The administration of preoperative chemotherapy has several theoretical advantages, including maximizing the potential for an R0 resection by downstaging tumor; treating micrometastatic disease early, thus selecting patients whose disease responds to therapy, while sparing from surgery those whose disease will inevitably progress; and administering chemotherapy when patients are more likely to have fewer or less serious side effects. Retrospective data suggest that neoadjuvant treatment may lead to results that are superior to those with a surgery-first approach, and prospective, randomized trials ought to evaluate this further.
Is there a role for radiation therapy in this context? Will it decrease the incidence of local recurrence among patients with a positive surgical margin who have systemic control with modified FOLFIRINOX therapy? Can preoperative radiotherapy increase the likelihood of an R0 resection? These, too, are questions for future randomized trials.
This trial represents the culmination of more than a decade of careful work that initially established FOLFIRINOX as a standard treatment for advanced pancreatic cancer. The remarkable results that have been achieved with adjuvant modified FOLFIRINOX therapy in the PRODIGE 24 trial have now changed the standard of care for many patients with resectable tumors. However, the majority of patients with pancreatic cancer present with far more advanced disease. For them, this remains a recalcitrant cancer.
Hedy L. Kindler, MD, is with the Section of Hematology/Oncology at the University of Chicago. Her remarks are adapted and condensed from an editorial accompanying the study. She disclosed consulting/advisory board activities for 14 companies, and institutional research funding from six companies.
Is surgery followed by 6 months of adjuvant chemotherapy the appropriate sequence in patients with a disease that may be systemic at diagnosis? Can we further improve outcomes by delivering modified FOLFIRINOX before surgery? The administration of preoperative chemotherapy has several theoretical advantages, including maximizing the potential for an R0 resection by downstaging tumor; treating micrometastatic disease early, thus selecting patients whose disease responds to therapy, while sparing from surgery those whose disease will inevitably progress; and administering chemotherapy when patients are more likely to have fewer or less serious side effects. Retrospective data suggest that neoadjuvant treatment may lead to results that are superior to those with a surgery-first approach, and prospective, randomized trials ought to evaluate this further.
Is there a role for radiation therapy in this context? Will it decrease the incidence of local recurrence among patients with a positive surgical margin who have systemic control with modified FOLFIRINOX therapy? Can preoperative radiotherapy increase the likelihood of an R0 resection? These, too, are questions for future randomized trials.
This trial represents the culmination of more than a decade of careful work that initially established FOLFIRINOX as a standard treatment for advanced pancreatic cancer. The remarkable results that have been achieved with adjuvant modified FOLFIRINOX therapy in the PRODIGE 24 trial have now changed the standard of care for many patients with resectable tumors. However, the majority of patients with pancreatic cancer present with far more advanced disease. For them, this remains a recalcitrant cancer.
Hedy L. Kindler, MD, is with the Section of Hematology/Oncology at the University of Chicago. Her remarks are adapted and condensed from an editorial accompanying the study. She disclosed consulting/advisory board activities for 14 companies, and institutional research funding from six companies.
Is surgery followed by 6 months of adjuvant chemotherapy the appropriate sequence in patients with a disease that may be systemic at diagnosis? Can we further improve outcomes by delivering modified FOLFIRINOX before surgery? The administration of preoperative chemotherapy has several theoretical advantages, including maximizing the potential for an R0 resection by downstaging tumor; treating micrometastatic disease early, thus selecting patients whose disease responds to therapy, while sparing from surgery those whose disease will inevitably progress; and administering chemotherapy when patients are more likely to have fewer or less serious side effects. Retrospective data suggest that neoadjuvant treatment may lead to results that are superior to those with a surgery-first approach, and prospective, randomized trials ought to evaluate this further.
Is there a role for radiation therapy in this context? Will it decrease the incidence of local recurrence among patients with a positive surgical margin who have systemic control with modified FOLFIRINOX therapy? Can preoperative radiotherapy increase the likelihood of an R0 resection? These, too, are questions for future randomized trials.
This trial represents the culmination of more than a decade of careful work that initially established FOLFIRINOX as a standard treatment for advanced pancreatic cancer. The remarkable results that have been achieved with adjuvant modified FOLFIRINOX therapy in the PRODIGE 24 trial have now changed the standard of care for many patients with resectable tumors. However, the majority of patients with pancreatic cancer present with far more advanced disease. For them, this remains a recalcitrant cancer.
Hedy L. Kindler, MD, is with the Section of Hematology/Oncology at the University of Chicago. Her remarks are adapted and condensed from an editorial accompanying the study. She disclosed consulting/advisory board activities for 14 companies, and institutional research funding from six companies.
For patients with completely or near-completely resected pancreatic ductal adenocarcinoma, adjuvant therapy with a modified FOLFIRINOX regimen was associated with significantly better 3-year disease-free survival and overall survival compared with gemcitabine, results of the phase 3 randomized PRODIGE 24 trial showed.
At a median follow-up of 33.6 months, median disease-free survival was 21.6 months for 247 patients assigned to receive adjuvant modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), compared with 12.8 months for 246 patients randomized to receive gemcitabine.
The median overall survival was 54.4 months for patients treated with FOLFIRINOX, vs. 35 months for patients treated with gemcitabine, a difference that translated into a hazard ratio (HR) of 0.65 (P = .003) for the combination regimen, reported Thierry Conroy, MD, of Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France, and colleagues in the Canadian Cancer Trials Group and Unicancer-GI-PRODIGE Group.
“The disease-free survival benefit with modified FOLFIRINOX was significant in the majority of subgroups, including subgroups of patients with adverse prognostic factors (i.e., T3 or T4 tumor status, positive lymph nodes, or R1 resection),” they wrote. The report is in The New England Journal of Medicine.
The survival advantage with FOLFIRINOX came at the cost of more frequent adverse events, however, although the only treatment-related death occurred in a patient treated with gemcitabine.
A previous randomized trial by the PRODIGE group showed a survival advantage of FOLFIRINOX over gemcitabine in patients with metastatic pancreatic cancer, prompting the investigators to look at the same two regimens as adjuvant therapy for patients with pancreatic cancer following R0 (clear surgical margins) or RI (minimal residual disease) resections. In the current trial, FOLFIRINOX was modified by the elimination of a bolus dose of fluorouracil to decrease hematologic toxicities and diarrhea without compromising efficacy.
In the intention-to-treat analysis, 493 patients were randomly assigned to receive either modified FOLFIRINOX, consisting of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, which was reduced to 150 mg/m2 after a protocol-specified safety analysis, leucovorin 400 mg/m2, and fluorouracil 2,400 mg/m2 every 2 weeks, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks for 24 weeks.
The disease-free survival primary endpoint and overall survival secondary endpoints were as reported before.
The 3-year overall survival rates were 63.4% with modified FOLFIRINOX, compared with 48.6% with gemcitabine.
Additional secondary endpoints also favored FOLFIRINOX, including metastasis-free survival at a median 30.4 month vs. 17.7 months, respectively, translating into a stratified HR of 0.59 (P less than .001). The 3-year metastasis-free survival rates were 48.2% vs. 30.9% for gemcitabine.
The median cancer-specific survival was not reached in the combination therapy group compared with 36.4 months with gemcitabine monotherapy, a difference that translated into a stratified HR for death from the treated cancer or treatment-related complications of 0.63 (P = .003).
The safety analysis included data on 238 patients treated with FOLFIRINOX and 241 with gemcitabine.
Grade 3 or 4 adverse events occurred in 75.9% of patients treated with modified FOLFIRINOX and 52.9% of patients treated with gemcitabine. The single treatment-related death was from interstitial pneumonitis in a patient treated with gemcitabine.
Grade 3 or 4 diarrhea, increase in the gamma-glutamyltransferase level, paresthesia, fatigue, sensory peripheral neuropathy, nausea, vomiting, abdominal pain, and mucositis were all significantly more frequent with modified FOLFIRINOX.
Slightly more than half (56.8%) of patients in the FOLFIRINOX arm received granulocyte-colony stimulating factor support as either primary prophylaxis or therapy for uncomplicated neutropenia, with no delays in treatment.
The investigators acknowledged that although “disease-free survival is not validated as a surrogate endpoint for overall survival in trials of adjuvant therapy for pancreatic cancer, this criterion was robust and correlated with overall survival.”
The study was supported by R&D Unicancer, which received a grant from Chugai Pharmaceutical the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group Pancreatic Adenocarcinoma part of the trial was supported by a Program Grant from the Canadian Cancer Society and by grants from 7 Days in May. Dr. Conroy disclosed receiving travel grants form Roche.
SOURCE: Conroy T et al. N Engl J Med. 2018 Dec 19;379:2395-406.
For patients with completely or near-completely resected pancreatic ductal adenocarcinoma, adjuvant therapy with a modified FOLFIRINOX regimen was associated with significantly better 3-year disease-free survival and overall survival compared with gemcitabine, results of the phase 3 randomized PRODIGE 24 trial showed.
At a median follow-up of 33.6 months, median disease-free survival was 21.6 months for 247 patients assigned to receive adjuvant modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), compared with 12.8 months for 246 patients randomized to receive gemcitabine.
The median overall survival was 54.4 months for patients treated with FOLFIRINOX, vs. 35 months for patients treated with gemcitabine, a difference that translated into a hazard ratio (HR) of 0.65 (P = .003) for the combination regimen, reported Thierry Conroy, MD, of Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France, and colleagues in the Canadian Cancer Trials Group and Unicancer-GI-PRODIGE Group.
“The disease-free survival benefit with modified FOLFIRINOX was significant in the majority of subgroups, including subgroups of patients with adverse prognostic factors (i.e., T3 or T4 tumor status, positive lymph nodes, or R1 resection),” they wrote. The report is in The New England Journal of Medicine.
The survival advantage with FOLFIRINOX came at the cost of more frequent adverse events, however, although the only treatment-related death occurred in a patient treated with gemcitabine.
A previous randomized trial by the PRODIGE group showed a survival advantage of FOLFIRINOX over gemcitabine in patients with metastatic pancreatic cancer, prompting the investigators to look at the same two regimens as adjuvant therapy for patients with pancreatic cancer following R0 (clear surgical margins) or RI (minimal residual disease) resections. In the current trial, FOLFIRINOX was modified by the elimination of a bolus dose of fluorouracil to decrease hematologic toxicities and diarrhea without compromising efficacy.
In the intention-to-treat analysis, 493 patients were randomly assigned to receive either modified FOLFIRINOX, consisting of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, which was reduced to 150 mg/m2 after a protocol-specified safety analysis, leucovorin 400 mg/m2, and fluorouracil 2,400 mg/m2 every 2 weeks, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks for 24 weeks.
The disease-free survival primary endpoint and overall survival secondary endpoints were as reported before.
The 3-year overall survival rates were 63.4% with modified FOLFIRINOX, compared with 48.6% with gemcitabine.
Additional secondary endpoints also favored FOLFIRINOX, including metastasis-free survival at a median 30.4 month vs. 17.7 months, respectively, translating into a stratified HR of 0.59 (P less than .001). The 3-year metastasis-free survival rates were 48.2% vs. 30.9% for gemcitabine.
The median cancer-specific survival was not reached in the combination therapy group compared with 36.4 months with gemcitabine monotherapy, a difference that translated into a stratified HR for death from the treated cancer or treatment-related complications of 0.63 (P = .003).
The safety analysis included data on 238 patients treated with FOLFIRINOX and 241 with gemcitabine.
Grade 3 or 4 adverse events occurred in 75.9% of patients treated with modified FOLFIRINOX and 52.9% of patients treated with gemcitabine. The single treatment-related death was from interstitial pneumonitis in a patient treated with gemcitabine.
Grade 3 or 4 diarrhea, increase in the gamma-glutamyltransferase level, paresthesia, fatigue, sensory peripheral neuropathy, nausea, vomiting, abdominal pain, and mucositis were all significantly more frequent with modified FOLFIRINOX.
Slightly more than half (56.8%) of patients in the FOLFIRINOX arm received granulocyte-colony stimulating factor support as either primary prophylaxis or therapy for uncomplicated neutropenia, with no delays in treatment.
The investigators acknowledged that although “disease-free survival is not validated as a surrogate endpoint for overall survival in trials of adjuvant therapy for pancreatic cancer, this criterion was robust and correlated with overall survival.”
The study was supported by R&D Unicancer, which received a grant from Chugai Pharmaceutical the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group Pancreatic Adenocarcinoma part of the trial was supported by a Program Grant from the Canadian Cancer Society and by grants from 7 Days in May. Dr. Conroy disclosed receiving travel grants form Roche.
SOURCE: Conroy T et al. N Engl J Med. 2018 Dec 19;379:2395-406.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Modified FOLFIRINOX resulted in significantly better disease-free and overall survival compared with gemcitabine as adjuvant therapy following complete/near complete resection of pancreatic ductal adenocarcinoma.
Major finding: Median disease-free survival was 21.6 months with modified FOLFIRINOX vs. 12.8 months with gemcitabine.
Study details: Randomized phase 3 trial of 493 patients with resected pancreatic cancer.
Disclosures: The study was supported by R&D Unicancer, which received a grant from Chugai Pharmaceutical the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group Pancreatic Adenocarcinoma part of the trial was supported by a Program Grant from the Canadian Cancer Society and by grants from 7 Days in May. Dr. Conroy disclosed receiving travel grants form Roche.
Source: Conroy T et al. N Engl J Med. 2018 Dec 19 379:2395-406.