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Original Investigation
January 21, 2021

Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial

Author Affiliations
  • 1Division of Hematology and Oncology, University of Cincinnati, Cincinnati, Ohio
  • 2SWOG Statistical and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 3Cleveland Clinic, Cleveland, Ohio
  • 4University of Texas Southwestern Medical Center, Dallas
  • 5Division of Oncology, Washington University in St Louis, St Louis, Missouri
  • 6Cancer Care Specialists of Illinois, Decatur
  • 7University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle
  • 8Department of Surgery, University of California, San Diego, La Jolla
  • 9Medical Oncology, Karmanos Cancer Institute, Detroit, Michigan
  • 10Gastrointestinal Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick
JAMA Oncol. 2021;7(3):421-427. doi:10.1001/jamaoncol.2020.7328
Key Points

Question  What is the 2-year overall survival (OS) for patients with resectable pancreatic adenocarcinoma treated with perioperative chemotherapy with either mFOLFIRINOX or gemcitabine/nab-paclitaxel?

Findings  In this randomized phase 2 clinical trial, perioperative chemotherapy with either regimen led to a 2-year OS of about 47% (median OS of 23 months), which was not statistically significantly improved over historical data from adjuvant trials. We also noted 29% of enrolled patients to have ineligible disease by resectability criteria, upon central radiology review.

Meaning  This study establishes safety and efficacy parameters regarding perioperative chemotherapy for resectable pancreatic adenocarcinoma and highlights quality control lessons for future trials.

Abstract

Importance  Clinical outcomes after curative treatment of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. To assess the potential of early control of systemic disease with multiagent perioperative chemotherapy, we conducted a prospective trial.

Objective  To determine 2-year overall survival (OS) using perioperative chemotherapy for resectable PDA.

Design, Setting, and Participants  This was a randomized phase 2 trial of perioperative chemotherapy with a pick-the-winner design. It was conducted across the National Clinical Trials Network, including academic and community centers all across the US. Eligibility required patients with Zubrod Performance Score of 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease per Intergroup criteria.

Interventions  Perioperative (12 weeks preoperative, 12 weeks postoperative) chemotherapy with either fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX, arm 1) or gemcitabine/nab-paclitaxel (arm 2).

Main Outcomes and Measures  The primary outcome was 2-year overall survival (OS), using a pick-the-winner design; for 100 eligible patients, accrual up to 150 patients was planned to account for cases deemed ineligible at central radiology review.

Results  From 2015 to 2018, 147 patients were enrolled; 43 patients (29%) had ineligible disease, beyond resectability criteria, at central radiology review. There were 102 eligible and evaluable patients, 55 in arm 1 and 47 in arm 2, of whom the median (range) age was 66 (44-76) and 64 (46-76) years, respectively; 36 patients (65%) in arm 1 and 24 (51%) in arm 2 were men. In arm 1, 34 (62%) had Zubrod Performance Score of 0, while in arm 2, 31 (66%) did; and 44 (80%) in arm 1 and 39 (83%) in arm 2 had head tumors. Of 102 patients, 84% and 85% completed preoperative chemotherapy, 73% and 70% underwent resection, and 49% and 40% completed all treatment. Adverse events were expected hematologic toxic effects, fatigue, and gastrointestinal toxicities. Two-year OS was 47% (95% CI, 31%-61%) for arm 1 and 48% (95% CI, 31%-63%) for arm 2; median OS was 23.2 months (95% CI, 17.6-45.9 months) and 23.6 months (95% CI, 17.8-31.7 months). Neither arm’s 2-year OS estimate was significantly higher than the a priori threshold of 40%. Median disease-free survival after resection was 10.9 months in arm 1 and 14.2 months in arm 2.

Conclusions and Relevance  This phase 2 randomized clinical trial did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trials in resectable pancreatic cancer. Two-year OS was 47% with mFOLFIRINOX and 48% with gemcitabine/nab-paclitaxel for all eligible patients starting treatment for resectable PDA. The trial also demonstrated adequate safety and high resectability rates with perioperative chemotherapy, and challenges in quality control for resectability criteria.

Trial Registration  ClinicalTrials.gov Identifier: NCT02562716

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    1 Comment for this article
    EXPAND ALL
    Unsolved issues in establishing a perioperative treatment strategy for resectable pancreatic cancer
    Makoto Kosaka | The University of Tokyo
    We read with great interest the study by Davendra P.S. Sohal and colleagues in The JAMA Oncology [1]. Although this phase 2 trial did not have the expected outcome, we believe that there are a couple of issues to be considered. We deeply appreciate if the authors address following discussion points to understand the results better and feedback the results to clinical practice.

    First, as randomized trials investigated the efficacy of perioperative treatment in patients with pancreatic cancer, some trials have been reported such as the PRODIGE24 trial [2] and PREOPANC [3] so far. However, many of them focusing
    on postoperative interventions included only selected patients who met the conditions such as no metastatic findings after resection and successful complete resection (R0 or R1) and full recovery after surgery (WHO PS 0-1) [2]. In other words, patients in better disease control and general condition were likely to be enrolled. On the contrary, in the current study in which patients enrolled underwent neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy, we assume general conditions of the patients should be worse. Hence, how many patients met the strict criteria at the time of completion of surgery and per-protocol analysis might be provide the comparability to with the results of previous studies.
    Second, it was discussed that there were many dropouts in the surgery-only group of PREOPANC (27.6%, 35 out of 127), but this was due to metastases and locally advanced disease at the time of surgery [3]. On the other hand, patients were assessed as resectable beforehand using new strict criteria on the randomization in this trial, as many as 29.8% (14/47) of the patients dropped out through preoperative chemotherapy and could not underwent resection. In addition, dropout during postoperative chemotherapy might affect the results. We assume treatments of both two arms might not be feasible. Detailed data regarding relative dose intensity and toxicity of both preoperative and postoperative chemotherapy are of help to interpret the higher dropout rate due to preoperative deterioration compared to that in PREOPANC.
    In conclusion, the most important question is how to select the appropriate patients for neoadjuvant therapy in addition to the new criteria for resectability, considering the possibility of dropout during perioperative treatments.

    References
    [1] Sohal DPS, Duong M, Ahmad SA et al. Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2021 Jan 21:e207328. doi: 10.1001/jamaoncol.2020.7328. Epub ahead of print. PMID: 33475684; PMCID: PMC7821078.
    [2] Conroy T, Hammel P, Hebbar M et al. Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018 Dec 20;379(25):2395-2406. doi: 10.1056/NEJMoa1809775. PMID: 30575490.
    [3] Versteijne E, Suker M, Groothuis K et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020 Jun 1;38(16):1763-1773. doi: 10.1200/JCO.19.02274. Epub 2020 Feb 27. PMID: 32105518.

    Author information:
    Makoto Kosaka,1 Hiroto Ishiki M.D.,2
    1 Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan
    m.kosaka0811@gmail.com
    2Department of Palliative Medicine, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
    ishiki-tky@umin.ac.jp
    CONFLICT OF INTEREST: None Reported
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