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

Background

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

Results

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.