Background
Phase III 2×2 factorial RCT (ACT II), N=940 patients with squamous cell carcinoma of the anal canal (SCCA) without involvement of the rectal mucosa. Two simultaneous randomizations: (1) mitomycin-C (MMC) vs cisplatin concurrent with 5-FU+radiotherapy; (2) maintenance 5-FU+cisplatin × 2 cycles vs observation. All patients received RT 50.4 Gy (45 Gy pelvis + 5.4 Gy boost) with continuous 5-FU infusion days 1–4 and 29–32. Enrolled 2001–2008 across UK centers.
Interventions and follow up
Arm A: Mitomycin-C 12 mg/m² day 1 + 5-FU 1000 mg/m²/day CI days 1–4 and 29–32 + RT 50.4 Gy (then randomized to maintenance or observation)
Arm B: Cisplatin 60 mg/m² days 1 and 29 + 5-FU 1000 mg/m²/day CI days 1–4 and 29–32 + RT 50.4 Gy (then randomized to maintenance or observation)
Primary endpoint: Complete response (CR) at 26 weeks
Median follow-up: 5.1 years
Arm B: Cisplatin 60 mg/m² days 1 and 29 + 5-FU 1000 mg/m²/day CI days 1–4 and 29–32 + RT 50.4 Gy (then randomized to maintenance or observation)
Primary endpoint: Complete response (CR) at 26 weeks
Median follow-up: 5.1 years
Results
CR at 26 weeks: 94.5% vs 90.5% (MMC vs cisplatin), P=.074 — not significantly different
3-year PFS (maintenance vs no maintenance): 74% vs 73%, HR 0.92 (95% CI 0.72–1.17), P=.53 — no benefit from maintenance
3-year colostomy-free survival: comparable between all groups
3-year OS: comparable between all groups
3-year PFS (maintenance vs no maintenance): 74% vs 73%, HR 0.92 (95% CI 0.72–1.17), P=.53 — no benefit from maintenance
3-year colostomy-free survival: comparable between all groups
3-year OS: comparable between all groups
Adverse events
Hematologic: Grade ≥3 acute hematologic toxicity MMC 26% vs cisplatin 13%, P<.001.
Non-hematologic: Grade ≥3 toxicity MMC 31% vs cisplatin 28%, P=.28; late toxicities and colostomy rates comparable across all four arms.
Maintenance arm: Grade ≥3 toxicity 49% vs 36% (no maintenance), P=.001, with no efficacy benefit.
Non-hematologic: Grade ≥3 toxicity MMC 31% vs cisplatin 28%, P=.28; late toxicities and colostomy rates comparable across all four arms.
Maintenance arm: Grade ≥3 toxicity 49% vs 36% (no maintenance), P=.001, with no efficacy benefit.
Conclusions
MMC and cisplatin concurrent with 5-FU+radiotherapy produced equivalent complete response rates at 26 weeks in anal canal SCCA (94.5% vs 90.5%, P=.074). Maintenance 5-FU+cisplatin provided no improvement in PFS, OS, or colostomy-free survival while adding significant toxicity. MMC-based chemoradiation remains the standard of care.
Key Limitations
Primary endpoint (CR at 26 weeks) is a surrogate — not powered as a formal non-inferiority trial for cisplatin substitution, so the equivalence interpretation is limited. Cisplatin had numerically lower hematologic toxicity but numerically lower CR rate; neither difference reached statistical significance. Maintenance 5-FU+cisplatin question is now answered definitively (no benefit). Trial predates routine HPV typing and PD-L1 assessment; ~90% of anal SCCAs are HPV-driven and highly immunogenic, motivating subsequent immunotherapy trials (POD1UM-303). The trial does not address locally recurrent or metastatic SCCA management.
Clinical Context
ACT II confirmed MMC-based chemoradiation (5-FU/MMC/RT) as the standard of care for anal canal SCCA and definitively ruled out maintenance chemotherapy — simplifying the treatment paradigm. The positive ACT I trial (1990s) established chemoradiation over RT alone; ACT II refined the regimen. MMC+5-FU+RT (50.4 Gy) remains the global standard definitive treatment for non-metastatic anal SCCA. Cisplatin may be substituted in patients with contraindications to MMC. For metastatic/advanced disease, InterAACT established carboplatin+paclitaxel as preferred, and POD1UM-303 has now added retifanlimab to that backbone.