The second anal cancer trial (ACT2): a randomised trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the anus


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David Sebag-Montefiore, Rob Glynne-Jones, Helen Meadows, Susan Wan, Latha Kadalayil, John Northover, David Cunningham, Jonathan Lederman, Roger James

On behalf of the National Cancer Research Institute and the 2nd Anal Cancer Trial Management Group, University College Clinical Trial Unit, London, UK

Abstract

Introduction
The ACT 2 trial addresses two questions: (i) does replacing concurrent MMC with cisplatin (CDDP) improve the complete response (CR) rate; (ii) does two cycles of maintenance chemotherapy after CRT reduce relapse free survival (RFS).

Method
Between 2001 and 2008, 940 patients (pts) were recruited. Pts received 5-FU (1,000mg/m2/day on d1-4 and 29-32), radiotherapy (RT) (50.4Gy in 28 fractions), and either MMC (12mg/m2, d1; n=471) or CDDP (60mg/m2 on d1 and 29; n=469). Pts were randomized to receive maintenance therapy (n=448) (two cycles of CDDP and 5-FU weeks 11 and 14) or no maintenance (n=446). Statistical power was ≥80% to detect a 5% difference in the CR rate (CDDP vs MMC), and 30% reduction in recurrence (maintenance vs none).

Results
Median age 58 yrs; 62% male; tumour site - canal (81%), margin (15%); stage T1-T2 (50%), T3-T4 (43%); node negative (62%), positive (30%). Median follow-up was 3 yrs. The CR rate was 94% MMC and 95% CDDP (p=0.53). MMC pts had more acute grade 3/4 haematological toxicities (25 vs 13%, p<0.001) but without an increase in neutropaenic sepsis (3.1 vs 3.2%, p=0.93). Non-haematologic grade 3/4 toxicities were similar (61 vs 65%, p=0.22). Preliminary analysis shows no statistically significant difference in RFS (HR 0.89, 95% CI 0.68, 1.18; p=0.42) or overall survival (HR 0.79, 95% CI 0.56,1.12; p=0.19) for the maintenance comparison.

Conclusion
ACT II is the largest trial conducted in anal cancer. High CR (95%) and RFS (75% at 3 yrs) rates were achieved with a CRT schedule using 50Gy without a gap which is now the UK standard regimen and questions the benefit of higher RT doses. There was no difference in CR rates between MMC and CDDP or in RFS rates with or without maintenance chemotherapy. 5-FU, MMC with RT remains the standard of care.