RTOG 9704 a phase III study of adjuvant pre and post chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma

Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2006

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Presenter: William F. Regine
Presenter's Affiliation: University of Maryland, Baltimore, MD
Type of Session: Scientific

Background

  • Adenocarcinoma of the pancreas, even when resectable, has a poor prognosis.  Failures occur both locoregionally and systemically.
  • Adjuvant treatment of resected pancreas adenocarcinoma is controversial.  Although the ESPAC trial showed that adjuvant chemotherapy alone was superior to chemoradiation, this study has been widely criticized.
  • Chemoradiation (CRT) with 5FU has been a standard treatment in the U.S.
  • Gemcitabine (G) is active in pancreas cancer, and confers a survival benefit in the metastatic setting.
  • RTOG 9704 was designed to determine if the addition of G to postoperative adjuvant 5-FU CRT improved survival for patients with resected pancreatic adenocarcinoma.

Materials and Methods

  • Phase III Design: Intergroup (RTOG, ECOG, SWOG) trial of randomized to:
    • Pre and post CRT 5-FU (continuous infusion at 250 mg/m2/day)
    • Pre and post CRT G (1000 mg/m2 IV weekly)
  • Patients:
    • Patients with pathologic stage T1-4, N0/1, M0 pancreatic adenocarcinoma status post gross total resection. The surgeon on this study reviewed all of the operative notes and pathology reports to confirm gross total resection.
    • 2/3 were node positive
    • Accrued from 7/1998 - 7/2002
    • 538 pts were entered; 442 were eligible and analyzable
    • Major reasons for ineligibility
      • serum not sent for CA-19-9 analysis (n=22)
      • treatment starting > 8 weeks post surgery (n=19)
  • Treatment:
    • Pre CRT treatment was for 3 weeks prior to CRT.
    • Post CRT treatment was for 12 weeks after CRT.
    • CRT was 50.4 Gy 1.8 Gy/fx/day with continuous infusion 5-FU, 250 mg/m2/day during radiation
  • Stratification:
    • Nodal status (uninvolved vs. involved)
    • Primary tumor diameter (< 3 cm vs. > 3cm)
    • Surgical margins (negative vs. positive vs. unknown)
  • Endpoints:
    • Primary: Overall survival.
    • original accrual goal was 330 patients, but rapid accrual allowed an amendment to look specifically at overall survival in pancreatic head tumors

Results

  • Arms were well balanced except for T-stage (T3/4 > for G, p=0.013)
  • Overall survival:
    • G significantly improved survival in pancreatic head tumors (n=380)
    • Median survival: 18.8 months G vs. 16.7 months 5-FU
    • 3-yr survival: 31% G vs. 21% 5-FU
    • HR 0.79 (95% CI 0.63-0.99, p=0.047)
    • No significant difference when body/tail tumors included (n=442) (p=0.2)
  • Toxicity:
    • No significant difference in >Grade 3 non-hematologic toxicity
    • Grade 4 hematologic toxicity rate high in G arm
    • 14% G arm vs. 2% 5-FU arm (p<0.0001)
    • No difference in febrile neutropenia/infection.
    • Ability to complete treatment per study was similar:
      • chemo (86%, 5-FU vs. 90%, G) and RT (85%, 5-FU vs. 88%, G)

Author's Conclusions

  • The addition of G to postoperative adjuvant 5-FU CRT significantly improves survival in pts with pancreatic head adenocarcinoma.

Clinical/Scientific Implications

  • Although the optimum adjuvant treatment for resected adenocarcinoma remains controversial, this study explored the best adjuvant chemotherapy to be combined with 5-FU sensitized CRT
  • This study was designed to evaluate adenocarcinoma of the pancreatic head as a primary endpoint. In this population there was a clear advantage to G of 5-FU for pre- and post-chemotherapy that sandwiched the CRT
  • The RTOG will adopt Gemzar followed by 5-FU/XRT followed by additional Gemzar as the standard for future clinical trials of adjuvant pancreatic cancer