Background
Phase III RCT (UKCCR Anal Cancer Trial). 577 patients with squamous cell carcinoma of the anal canal. Randomized to radiation therapy (RT) alone vs combined chemoradiation (CRT) with 5-fluorouracil and mitomycin C. RT: 45 Gy to pelvis + 15–25 Gy boost (external beam or brachytherapy). CRT: same RT + 5-FU 750–1000 mg/m²/d continuous infusion days 1–4 and 29–32 + mitomycin C 12 mg/m² day 1. This landmark trial established chemoradiation as the definitive standard for anal cancer.
Interventions and follow up
Arm A: Radiation therapy alone (45 Gy + 15–25 Gy boost)
Arm B: CRT — same RT + 5-FU (days 1–4 and 29–32) + mitomycin C (day 1)
Primary endpoint: Local failure rate
mFollow up: Median 42 month
Arm B: CRT — same RT + 5-FU (days 1–4 and 29–32) + mitomycin C (day 1)
Primary endpoint: Local failure rate
mFollow up: Median 42 month
Results
Local failure at 3 years: 61% (RT alone) vs 39% (CRT), P<.0001
Anal cancer deaths: 28% (RT alone) vs 12% (CRT), P<.02
Colostomy rate: 39% vs 36% — not significantly different at early follow-up
Early morbidity: Higher in CRT arm (confluent mucositis, skin reactions)
Anal cancer deaths: 28% (RT alone) vs 12% (CRT), P<.02
Colostomy rate: 39% vs 36% — not significantly different at early follow-up
Early morbidity: Higher in CRT arm (confluent mucositis, skin reactions)
Adverse events
Main adverse events: Grade 3–4 acute morbidity significantly higher in CRT arm. Late complications similar. One treatment-related death in CRT arm from aplasia.
Conclusions
Chemoradiation with 5-FU and mitomycin C significantly reduces local failure and anal cancer–specific death compared with radiation alone, establishing CRT as the definitive standard of care for anal carcinoma.
Key Limitations
Key Limitations: Open-label design with no blinding. Colostomy rate was not significantly different at early follow-up — longer follow-up was needed to show locoregional control benefit translating to colostomy-free survival. Radiation techniques were not standardized (15–25 Gy boost range). Predates modern IMRT and staging with PET-CT.
Clinical Context
The UKCCR trial, together with the EORTC trial (Bartelink JCO 1997) and Intergroup trial (Flam JCO 1996), established 5-FU + mitomycin C + RT as the definitive standard for anal cancer — replacing surgery. All three trials showed that CRT preserves the sphincter and avoids permanent colostomy in the majority of patients. Modern practice uses IMRT (RTOG 0529) with 5-FU + MMC or capecitabine + MMC over 50–54 Gy.
References