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Intergroup RTOG 98-11: A phase III randomized study of 5-fluorouracil (5-FU), mitomycin, and radiotherapy versus 5-fluorouracil, cisplatin and radiotherapy in carcinoma of the anal canal

Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 7 de junio del 2006

Presenter: J.A. Ajani
Presenter's Affiliation: M.D. Anderson Cancer Center, Houston, TX
Type of Session: Scientific

Background

• 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%
• 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

Materials and Methods

• Phase III, multi-center randomized to:
• Arm A: Standard 5-FU/mito-C concurrent CRT
• 5-FU (1,000mg/m2 days 1-4 and 29-32) plus mitomycin (10mg/m2 days 1 and 29) and radiation (45 to 59 Gy)
• Arm B: Induction chemotherapy 5-FU/CDDP
• 5-FU (1,000mg/m2 days 1-4, 29-32, 57-60 and 85-88) plus cisplatin (75mg/m2 on days 1, 29, 57 and 85) and radiation (45 to 59 Gy; start day=57)
• Patients:
  • Squamous cell carcinoma of the anus
  • 682 accrued, 598 analyzable
• Stratification:
  • Gender, clinical nodal status, tumor diameter
• Endpoints:
  • Primary: Disease-free survival.
  • Powered (80%) to detect a 10% DFS difference

Results

• Patient characteristics were balanced between the two arms:
  • median age was 55 yrs, 69% women
  • 28% had >5 cm tumor, 26% were clinical node positive
• Disease free survival was not significantly different
  • 5-year estimated DFS was 56% for Arm A and 48% for Arm B (p=0.28)
• Overall survival (5-year estimated) was 69% for both arms (p=0.24)
• Colostomy rates were higher in the CDDP/5-FU induction arm:
  • 5-year colostomy rate was 10% for Arm A and 20% for arm B(p=0.12).
• There was no significant difference in local control (33% vs. 26%)
• Grade 3/4 toxicity rates favored CDDP/5-FU induction arm:
  • non-hematologic toxicity was 76% for Arm A and 75% for Arm B
  • hematologic toxicity was 67% for Arm A and 47% for Arm B (p=0.0004)

Author's Conclusions

• Induction 5-FU/cisplatin followed by 5-FU/cisplatin/radiation failed to improve DFS compared to the standard treatment, 5-FU/mitomycin/radiation
• The colostomy rate was higher in the 5-FU/cisplatin/radiation
• The standard treatment arm should remain the standard

Clinical/Scientific Implications

• The DFS not only was not improved by CDDP-based induction chemotherapy, but it actually trended toward the standard arm
• The colostomy rate difference hints at a difference in local control/late RT effects that favored the standard arm, although there was no statistically significant difference in local control