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Clinical Trial
. 2022 Sep 1;8(9):1263-1270.
doi: 10.1001/jamaoncol.2022.2319.

Efficacy of Preoperative mFOLFIRINOX vs mFOLFIRINOX Plus Hypofractionated Radiotherapy for Borderline Resectable Adenocarcinoma of the Pancreas: The A021501 Phase 2 Randomized Clinical Trial

Matthew H G Katz  1 , Qian Shi  2 , Jeff Meyers  2 , Joseph M Herman  3 , Michael Chuong  4 , Brian M Wolpin  5 , Syed Ahmad  6 , Robert Marsh  7 , Larry Schwartz  8 , Spencer Behr  9 , Wendy L Frankel  10 , Eric Collisson  9 , James Leenstra  11 , Terence M Williams  12 , Gina Vaccaro  13 , Alan Venook  9 , Jeffrey A Meyerhardt  5 , Eileen M O'Reilly  14
Affiliations
Clinical Trial

Efficacy of Preoperative mFOLFIRINOX vs mFOLFIRINOX Plus Hypofractionated Radiotherapy for Borderline Resectable Adenocarcinoma of the Pancreas: The A021501 Phase 2 Randomized Clinical Trial

Matthew H G Katz et al. JAMA Oncol. .

Abstract

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/m2 over 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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shi reported personal fees from Yiviva, Boehringer Ingelheim, Regeneron, Hoosier Cancer Research Network, Chugai and grants from Celgene BMS, Roche/Genentech, Janssen, and Novartis outside the 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.

Figures

Figure 1.
Figure 1.. CONSORT Diagram of All Patients Who Were Assessed for Eligibility for the Study
aThe final 16 patients receiving treatment with modified FOLFIRINOX (mFOLFIRINOX) were not randomized owing to the mFOLFIRINOX plus radiotherapy arm closing. bThe patients’ nutrition and performance scores deteriorated.
Figure 2.
Figure 2.. Overall and Event-Free Survival of the 120 Evaluable Patients
OS indicates overall survival; RT, radiotherapy.
See this image and copyright information in PMC

Comment in

References

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