PRODIGE 4 ACCORD 11

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Conroy T, et al. "FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer". The New England Journal of Medicine. 2011. 364(19):1817-1825.
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Clinical Question

Among fit patients with untreated metastatic pancreatic adenocarcinoma, does FOLFIRINOX prolong overall survival compared to gemcitabine alone?

Bottom Line

Among fit patients with untreated metastatic pancreatic adenocarcinoma, FOLFIRINOX significantly prolongs overall survival compared to gemcitabine alone. FOLFIRINOX is associated with improved quality of life, although the regimen is significantly more toxic than gemcitabine alone.

Major Points

Pancreatic cancer is a devastating disease, especially for the 52% of patients who have metastatic disease at the time of diagnosis.[1] For years, patients with advanced pancreatic cancer were treated with gemcitabine monotherapy based on a trial published by Burris and colleagues that demonstrated a survival benefit of gemcitabine over bolus fluorouracil (5.65 vs. 4.41 months, P=0.0025).[2] Many trials attempted to combine gemcitabine with another agent to further improve survival. Meta-analyses of trials with gemcitabine combinations in advanced pancreatic cancer failed to show significantly improved survival compared to gemcitabine alone.[3] [4] The combination of erlotinib and gemcitabine was shown to be statistically superior to gemctiabine alone and led to the FDA approval of erlotinib for patients with advanced pancreatic cancer.[5] However, this amounted to a survival benefit of only 0.33 months (6.24 vs. 5.91 months, HR 0.82, 95% CI 0.69-0.99, P=0.38), so this combination is not used in practice.[6] More recently, the 2013 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) evaluated the addition of nab-paclitaxel to gemcitabine. Nab-paclitaxel plus gemcitabine did significantly improve overall survival over gemcitabine alone (8.5 vs. 6.7 months, P<0.001), and this combination is a viable treatment option for patients with metastatic pancreatic cancer. [7][8]

Published in 2011, the PRODIGE 4/ACCORD 11 trial evaluated FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) compared to gemcitabine. The phase II portion of the trial confirmed an improved objective response rate with FOLFIRINOX in 88 patients randomized 1:1 to FOLFIRINOX or gemcitabine (32% vs. 11%). There were more than 11 objective responses to FOLFIRINOX in the phase II portion, so the trial progressed to its phase III portion in which an additional 254 patients were randomized.

Patients treated with FOLFIRINOX had improved overall survival compared to patients treated with gemcitabine, 11.1 months vs. 6.8 months (HR 0.57; 95% CI 0.45-0.73; P<0.001). The combination was far more toxic, with significantly higher rates of grade 3-4 neutropenia (46% vs. 21%), febrile neutropenia (5% vs. 1%), thrombocytopenia (9% vs. 4%), diarrhea (13% vs. 2%), and sensory neuropathy (9% vs. 0%). There was a significantly higher rate of elevated alanine aminotransferase (ALT) in patients treated with gemcitabine (21% vs. 7%). Despite being more toxic, quality of life at 6 months was better in the FOLFIRINOX arm (31% decline from baseline vs. 66% decline from baseline in the gemcitabine arm).

Of note, the patient population was relatively fit and young: patients were excluded if their Eastern Cooperative Oncology Group (ECOG) performance status (PS) was greater than 1 or if they were older than 75 years old. The patients in the MPACT study, which showed a survival benefit of gemcitabine plus nab-paclitaxel over gemcitabine alone, included patients over age 75 (10%) and worse performance status (8% with ECOG PS of 2). FOLFIRINOX in the PRODIGE 4/ACCORD 11 trial has unparalleled survival, 11.1 months compared to 8.5 months with gemcitabine plus nab-paclitaxel in the MPACT trial. No phase III trials of patients with metastatic pancreatic cancer have been able to surpass the efficacy of FOLFIRINOX in this trial.

Guidelines

NCCN Guidelines (2016, adapted):[9]

  • For patients with metastatic disease, preferred options for first-line therapy are a clinical trial, FOLFIRINOX (category 1), or gemcitabine/nab-paclitaxel (category 1).

Design

  • Phase II/III, randomized, open-label, multicenter trial
  • N=342
    • FOLFIRINOX (N=171)
    • Gemcitabine (N=171)
  • Setting: 48 centers in France
  • Enrollment: 2005-2009
  • Median follow-up: 26.6 months
  • Analysis: Intention-to-treat
  • Primary outcome: Overall survival

Population

Full eligibility criteria are available on pg 3-4 in the protocol (French).[10]

Inclusion Criteria

  • Age ≥18 years
  • ECOG PS 0-1
  • Histologically confirmed metastastic pancreatic adenocarcinoma
  • Adequate bone marrow, hepatic, and renal function

Exclusion Criteria

  • Age ≥76 years
  • Prior chemotherapy or radiation
  • Endocrine or acinar pancreatic carcinoma
  • Known brain metastases
  • History of another malignancy, active infection, significant cardiac disease, pregnancy, or breast-feeding

Baseline Characteristics

From the FOLFIRINOX group.

  • Demographics: Age 61 years, 38% female
  • Oncological data:
    • ECOG PS: 0 - 37%, 1 - 62%, 2 - 1%
    • Pancreatic tumor location: Head 39%, body 31%, tail 26%, multicentric 4%
      • Biliary stent: Yes 16%, no 84%
    • Median number metastatic sites: 2 (range 1-6)
    • CA19-9:
      • Normal: 15%
      • Elevated <59x upper limit of normal (ULN): 44%
      • Elevated ≥59x ULN: 42%
      • Unknown: 4%
  • Sites of metastasis: Liver 88%, pancreas 53%, lymph nodes 29%, lung 19%, peritoneal 19%, other 11%

Interventions

Randomization 1:1 to one of two groups:

  • FOLFIRINOX - Including the following every 2 weeks (unless delayed for grade 2-4 neutropenia or thrombocytopenia):
    • Oxaliplatin 85 mg/m2 IV
    • Leucovorin 400 mg/m2 IV
    • Irinotecan 180 mg/m2 IV
    • Fluorouracil 400 mg/m2 IV bolus
    • Fluorouracil 2400 mg/m2 IV continuous infusion over 46 hours
  • Gemcitabine 1000 mg/m2 IV on weekly for 7 weeks then 1 week off then days 1, 8, and 15 every 4 weeks
    • The dose was reduced for thrombocytopenia or reduced granulocytes
  • Patients were assessed every 2 months with imaging and CA19-9 levels. Treatment continued until disease progression or unacceptable level of adverse events; crossover was not allowed. Quality of life assessments were completed every 2 weeks using EORTC QLQ-C30 questionnaires.

Outcomes

Comparisons are FOLFIRINOX vs. gemcitabine.

Primary Outcome

Median overall survival
11.1 months vs. 6.8 months (HR 0.57; 95% CI 0.45-0.73; P<0.001)

Secondary Outcomes

Median progression-free survival
6.4 months vs. 3.3 months (HR 0.47; 95% CI 0.37-0.59; P<0.001)
Overall response rate
32% vs. 9% (P<0.001)
Worsening quality of life
Defined as a 10 point reduction in the Global Health Status/QOL score between baseline and month 6.
31% vs. 66% (HR 0.47; 95% CI 0.30-0.74; P<0.001)

Subgroup Analysis

Subgroup analysis demonstrated superior outcomes with FOLFIRINOX across all subgroups, although this was not statistically significant in 3 subgroups (patients with metachronous metastases, ≥ 3 metastatic sites, and biliary stents).

Adverse Events

Grade 3 or greater occurring in more than 5% of patients with significant difference between groups (P<0.05).
Neutropenia: 46% vs. 21%
Febrile neutropenia: 5% vs. 1%
Thrombocytopenia: 9% vs. 4%
Diarrhea: 13% vs. 2%
Sensory neuropathy: 9% vs. 0%
Elevated alanine aminotransferase (ALT): 7% vs. 21%

Criticisms

  • The trial was open-label, thus patients and physicians were not blinded to study treatments
  • The trial was conducted only in a French patient population and ethnic background of patients is not reported
  • The patient population was relatively more fit than an average population of patients with metastatic pancreatic cancer, as patients with an ECOG PS above 1 or age above 75 were excluded

Funding

  • UNICANCER, a consortium of French comprehensive cancer centers, along with public (PHRC, French Ministry of Health, French National League against Cancer) and private funding (Amgen)
  • Oxaliplatin and irinotecan were donated by Sanofi-Aventis and Pfizer, respectively
  • Authors with financial conflicts of interest

Further Reading

  1. SEER Stat Fact Sheets Pancreatic Cancer
  2. Burris HA et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 1997. 15:2403-13.
  3. Sun C et al. Does gemcitabine-based combination therapy improve the prognosis of unresectable pancreatic cancer?. World J. Gastroenterol. 2012. 18:4944-58.
  4. Ciliberto D et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur. J. Cancer 2013. 49:593-603.
  5. Erlotinib FDA Approval for Pancreatic Cancer
  6. Moore MJ et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 2007. 25:1960-6.
  7. Von Hoff DD et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 2013. 369:1691-703.
  8. FDA press release announcing approval of nab-paclitaxel for metastatic pancreatic cancer
  9. NCCN Guidelines for Pancreatic Adenocarcinoma, Version 2.2016.
  10. Protocol