Intergroup RTOG 9811: Phase III Comparison of Chemoradiation With 5-FU and Mitomycin Vs. 5-FU and Cisplatin for Anal Canal Carcinoma: Impact on Disease-Free, Overall and Colostomy-Free Survival

Reviewer: Christopher Dolinsky, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 10, 2006

Presenter: L.L. Gunderson
Presenter's Affiliation: Mayo Clinic Cancer Center ? Arizona, Scottsdale, AZ
Type of Session: Scientific


  • Anal cancer is frequently a loco-regional disease
  • The RTOG 8704/ECOG 1289 study showed the superiority of RT/5-FU/Mitomycin C over RT/5FU
  • The current standard treatment of squamous cell carcinoma of the anus is concurrent chemoradiation (CRT) with 5-FU and Mitomycin-C
  • The 5-yr disease-free survival (DFS) is ~65%
  • Patients with higher T stage or clinically node-postive cancer have poorer local control and higher colostomy rates
  • Mitomycin-C has an undesirable side-effect profile, including prolonged thrombocytopenia, renal failure, and hemolytic uremic syndrome
  • The rationale for this study was to use cisplatin (CDDP)-based induction chemotherapy to shrink tumors prior to CRT in hopes of improving locoregional control
  • Preliminary results from this trial were reported at ASCO 2006, and this session updates those results

Materials and Methods

  • Phase III, multi-center trial randomized to:
    • Arm A: Standard Concurrent CRT using 5-FU (1,000mg/m2 days 1-4 and 29-32) and mitomycin (10mg/m2 days 1 and 29) with radiation (45 to 59 Gy)
    • Arm B: Induction chemotherapy using 5-FU (1,000mg/m2 days 1-4, 29-32, 57-60 and 85-88) and cisplatin (75mg/m2 on days 1, 29, 57 and 85), then later concurrent with radiation (45 to 59 Gy; start day=57)
  • Radiation was given with successive field size reductions
  • Patients:
    • Squamous cell carcinoma of the anus
    • 682 accrued, 644 analyzable
    • T stage 2 to 4
    • Any N stage
  • Stratification:
    • Gender, clinical nodal status, tumor diameter
  • Endpoints:
    • Primary: Disease-free survival (DFS)
    • Secondary: Overall survival (OS), cumulative rate of colostomy, rate of local- regional relapse, difference in toxicities


  • In a second interim analysis performed in June 2005, the data indicated that even with the full number of events, there would be no difference between the two arms
  • Patient characteristics and tumor-related factors were balanced between the two arms
  • Disease-free survival was not significantly different
    • 5-year estimated DFS was 60% for Arm A and 54% for Arm B (p=0.17)
  • Overall survival was not significantly different 
    • 5-year estimated OS was 75% for Arm A and 70% for Arm B (p=0.10)
  • Distant metastasis rates were not significantly different
    • 5-year estimated distant failure rate was 15% for Arm A and 19% for Arm B (p=0.14)
  • Colostomy rates were higher in the CDDP/5-FU induction arm:
    • 5-year colostomy rate was 10% for Arm A and 19% for arm B (p=0.02).
  • Grade 3/4 toxicity rates favored CDDP/5-FU induction arm:
    • Non-hematologic toxicity was 11% for Arm A and 10% for Arm B
    • Hematologic toxicity was 61% for Arm A and 42% for Arm B (p=0.0005)

Author's Conclusions

  • Induction 5-FU/cisplatin followed by 5-FU/cisplatin/radiation failed to improve disease-free survival compared to the standard treatment, 5-FU/mitomycin/radiation
  • Overall survival in both arms was similar
  • The colostomy rate was significantly higher in the 5-FU/cisplatin/radiation
  • Acute grade >3 hematologic toxicity was worse in the 5FU/mitomycin/radiation arm
  • Male gender, tumor size >5cm, and node positivity were all independent poor prognostic factors for disease-free survival and overall survival
  • The standard treatment arm should remain the standard

Clinical/Scientific Implications
The authors presented updated results of an important and well-designed randomized clinical trial comparing the standard of care to a widely used regimen that substitutes cisplatin for mitomycin.  Surprisingly, there was no improvement in disease-free survival with the cisplatin, and in fact, the colostomy rate was statistically significantly higher in the experimental cisplatin arm. Mitomycin's toxicity had led many physicians to use  cisplatin and 5-FU instead of mitomycin and 5-FU, but without any randomized data to support this decision. This trial really illustrates the importance of comparing treatment approaches in a randomized fashion.  The authors ultimately conclude that 5-FU and mitomycin concurrent with radiation should remain the standard of care in patients who can tolerate it, that is unless and until a different regimen is shown to be superior in a randomized clinical trial.


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