Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial

Summary

Background

Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival.

Methods

In this 2×2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m² on day 1) or cisplatin (60 mg/m² on days 1 and 29), with fluorouracil (1000 mg/m² per day on days 1–4 and 29–32) and radiotherapy (50·4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889.

Findings

We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5·1 years (IQR 3·9–6·9). 391 of 432 (90·5%) patients in the mitomycin group versus 386 of 431 (89·6%) in the cisplatin group had a complete response at 26 weeks (difference −0·9%, 95% CI −4·9 to 3·1; p=0·64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3–4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69–77; maintenance) versus 73% (95% CI 68–77; no maintenance; hazard ratio 0·95, 95% CI 0·75–1·21; p=0·70).

Interpretation

The results of our trial—the largest in anal cancer to date—show that fluorouracil and mitomycin with 50·4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK.

Funding

Cancer Research UK.

Introduction

The incidence of squamous-cell cancer of the anus is roughly 1·5 cases per 100 000 people per year worldwide (900 cases per year in the UK, 5000 in the USA), and is increasing, particularly in women.1, 2 Improving locoregional control without need for a colostomy is the primary aim of treatment. Chemoradiation became the standard of care for treatment of squamous-cell cancer of the anus after three phase 3 trials3, 4, 5 showed that radiotherapy with concurrent fluorouracil and mitomycin resulted in better local control and recurrence-free or progression-free survival than did radiotherapy alone, or radiotherapy with fluorouracil. The first UK anal cancer trial (ACT I)3, 6 showed a reduction in locoregional failure—from 59% to 36%—with this combined treatment, sustained after 13 years. However, local control was achieved in only around two-thirds of patients, with a 5-year survival of roughly 50% for mitomycin and fluorouracil plus radiotherapy; 40% of deaths were caused by distant spread.³ Although the benefits of adding mitomycin to fluorouracil and radiotherapy were established by the Radiotherapy Therapy Oncology Group 8704 trial,⁵ mitomycin can cause life-threatening toxic effects and treatment-related deaths.3, 5

ACT II was therefore designed to test whether these outcomes could be improved. The rationale for comparing cisplatin instead of mitomycin with fluorouracil-based chemoradiation was based on seemingly higher complete response rates with cisplatin,7, 8, 9 and acceptable acute toxic effects in phase 2 trials. Other randomised phase 3 trials10, 11 by the Radiotherapy Therapy Oncology Group (RTOG 98-11) and the Action Clinique Coordonees en Cancerologie Digestive (ACCORD-03), done while ACT II was being designed, were testing neoadjuvant cisplatin-based chemotherapy and dose-escalation of the radiotherapy boost. A maintenance chemotherapy schedule including cisplatin after chemoradiation was included to test whether intensifying treatment in this way would decrease the rate of distant disease and therefore improve survival. Our group previously piloted the feasibility of additional maintenance chemotherapy with three courses of fluorouracil, mitomycin, and cisplatin after chemoradiation.¹² The main objectives of ACT II were to assess whether cisplatin given concurrently with fluorouracil and radiotherapy produces a higher clinical and radiological response rate than does mitomycin, with acceptable toxic effects, and whether two courses of fluorouracil and cisplatin maintenance chemotherapy after chemoradiation improves progression-free survival (ie, improve local control or prolong survival by preventing or delaying disease dissemination).