TY - JOUR
T1 - Efficacy of Preoperative mFOLFIRINOX vs mFOLFIRINOX Plus Hypofractionated Radiotherapy for Borderline Resectable Adenocarcinoma of the Pancreas
T2 - The A021501 Phase 2 Randomized Clinical Trial
AU - Katz, Matthew H.G.
AU - Shi, Qian
AU - Meyers, Jeff
AU - Herman, Joseph M.
AU - Chuong, Michael
AU - Wolpin, Brian M.
AU - Ahmad, Syed
AU - Marsh, Robert
AU - Schwartz, Larry
AU - Behr, Spencer
AU - Frankel, Wendy L.
AU - Collisson, Eric
AU - Leenstra, James
AU - Williams, Terence M.
AU - Vaccaro, Gina
AU - Venook, Alan
AU - Meyerhardt, Jeffrey A.
AU - O'reilly, Eileen M.
N1 - Funding Information:
personal fees from Yiviva, Boehringer Ingelheim, Regeneron, Hoosier Cancer Research Network, Chugai and grants from Celgene BMS, Roche/ Genentech, Janssen, and Novartis outside the
Funding Information:
This study is supported by the NCI Cancer Trials Support Unit (CTSU). IRB Approval: Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be approved to enroll patients. Study centers can check the status of their registration packets by querying the Regulatory Support System (RSS) site registration status page of the CTSU membersÕ website by entering credentials at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically load to RSS.
Funding Information:
publication was supported by the National Cancer Institute of the National Institutes of Health under Award numbers U10CA180821, U10CA180882, and U24CA196171 (to the Alliance for Clinical Trials in Oncology), UG1CA189960, UG1CA233180, UG1CA233290, UG1CA233329, UG1CA233331, and U10CA180820 (ECOG–American College of Radiology Imaging Network); U10CA180868 (NRG); and U10CA180888 (SWOG).
Funding Information:
submitted work. Dr Herman reported personal fees from Histosonics, Boston Scientific and grants from Canopy Cancer Collective outside the submitted work. Dr Chuong reported personal fees from ViewRay, Sirtex, and IBA and grants from ViewRay outside the submitted work. Dr Wolpin reported grants and personal fees from Celgene, grants from Eli Lilly, and personal fees from BioLineRx and Grail outside the submitted work. Dr Schwartz reported service for Merck, Boehringer, Regeneron, and BMS and research support from Janssen outside of this submitted work. Dr Behr reported personal fees from Novartis and GenVivo and grants from CTT outside the submitted work. Dr Collisson reported consulting fees from Pear Diagnostics, IHP Therapeutics, and Valar Labs; grants from AstraZeneca, Merck KgA, and Bayer; and stock ownership in Tatara Therapeutics, HDT Bio, Clara Health, BloodQ, and Guardant Health. Dr Vaccaro reported research support from Celgene, Incyte, and Helsinn outside the submitted work. Dr Meyerhardt reported personal fees from Merck and COTA Healthcare outside the submitted work. Dr O'Reilly reported grants from Genentech-Roche, BioNTech, Arcus, AstraZeneca, Celgene/BMS, Parker Institute, and Elicio and personal fees from Rafael Therapeutics, CytomX Therapeutics, Merck, AstraZeneca, Boehringer Ingelheim, Seagen, Ipsen, IDEAYA, Noxxon, Tyme, Thetis, Cend Therapeutics, and Novartis during the conduct of the study and personal fees from Eisai, Bayer, and Agios outside the submitted work. No other disclosures were reported.
Publisher Copyright:
© 2022 American Medical Association. All rights reserved.
PY - 2022/9
Y1 - 2022/9
N2 - Importance: National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear. Objective: To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC. Design, Setting, and Participants: This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021. Interventions: Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2over 46 hours). Main Outcomes and Measures: Each treatment arm's 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection. Results: Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively. Conclusions and Relevance: This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02839343.
AB - Importance: National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear. Objective: To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC. Design, Setting, and Participants: This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021. Interventions: Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2over 46 hours). Main Outcomes and Measures: Each treatment arm's 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection. Results: Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively. Conclusions and Relevance: This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02839343.
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U2 - 10.1001/jamaoncol.2022.2319
DO - 10.1001/jamaoncol.2022.2319
M3 - Article
C2 - 35834226
AN - SCOPUS:85134714641
SN - 2374-2437
VL - 8
SP - 1263
EP - 1270
JO - JAMA Oncology
JF - JAMA Oncology
IS - 9
ER -