ACT II
Needs reviewMitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial
Phase 3N = 940NCT00025090
- Population
- Patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease, from 59 centres in the UK
- Design
- Randomised, open-label, 2 × 2 factorial trial in 59 UK centres, registered at controlled-trials.com as ISRCTN26715889. 940 patients were enrolled and randomised by minimisation to four groups: mitomycin without maintenance (246), mitomycin with maintenance (226), cisplatin without maintenance (246), cisplatin with maintenance (222). All received fluorouracil (1000 mg/m2 per day on days 1-4 and 29-32) and radiotherapy (50.4 Gy in 28 daily fractions) with mitomycin (12 mg/m2 on day 1) or cisplatin (60 mg/m2 on days 1 and 29); maintenance was two courses of fluorouracil and cisplatin at weeks 11 and 14. Primary analyses were by intention to treat. Median follow-up 5.1 years (IQR 3.9-6.9).
- Primary endpoint
- Complete response of the primary tumour, Acute toxic effects, PFS
- Arms
- Mitomycin chemoradiation (all patients) (control, n = 472): Mitomycin 12 mg/m2 on day 1 with fluorouracil 1000 mg/m2 per day on days 1-4 and 29-32 and radiotherapy 50.4 Gy in 28 daily fractions; patients in this factor level were randomised with or without maintenance
- Cisplatin chemoradiation (all patients) (experimental, n = 468): 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; patients in this factor level were randomised with or without maintenance
- No maintenance chemotherapy (all patients) (control): Chemoradiation only, with mitomycin or cisplatin
- Maintenance chemotherapy (all patients) (experimental): Two courses of fluorouracil and cisplatin at weeks 11 and 14 after chemoradiation with mitomycin or cisplatin
- People
- James RD, senior author Sebag-Montefiore D
Δ Complete response of the primary tumour−0.9 pointsΔ Acute toxic effects+1 pointsPFSHR 0.95 (95% CI 0.75–1.21)Δ 36-month PFS+1 pointsColostomy-free survivalHR 1.04 (95% CI 0.82–1.31)
Show the numbers
| Endpoint | Analysis | Cisplatin chemoradiation (all patients) / Maintenance chemotherapy (all patients) | Mitomycin chemoradiation (all patients) / No maintenance chemotherapy (all patients) | Effect |
|---|---|---|---|---|
| Complete response of the primary tumour432 patients in the mitomycin group and 431 in the cisplatin group with response assessed (of 940 enrolled); the abstract states that primary analyses were by intention to treatComplete response at 26 weeks; the abstract does not state how response was assessed. | primarymedian follow-up 5.1 yearsJames 2013 | 89.6% | 90.5% | P=0.64391 of 432 patients in the mitomycin group versus 386 of 431 in the cisplatin group had a complete response at 26 weeks (difference -0.9%, 95% CI -4.9 to 3.1). Each figure pools patients randomised with and without maintenance. |
| Acute toxic effects472 patients in the mitomycin group and 468 in the cisplatin groupOverall toxic effects (acute toxic effects were a primary endpoint of the chemoradiation comparison); the abstract does not state the grade threshold of the overall figure. | primaryJames 2013 | 72% | 71% | 334 of 472 versus 337 of 468 patients; the abstract describes overall toxic effects as similar and gives no p-value. The most common grade 3-4 toxic effects, mitomycin versus cisplatin: skin 48% vs 47%, pain 26% vs 29%, haematological 26% vs 16%, gastrointestinal 16% vs 18%. |
| PFSPatients randomised to maintenance versus no maintenance chemotherapy, pooled across mitomycin and cisplatin; the abstract states that primary analyses were by intention to treat | primarymedian follow-up 5.1 yearsJames 2013 | 74% at 3 y (69–77%) | 73% at 3 y (68–77%) | HR 0.95 (95% CI 0.75–1.21)P=0.703-year progression-free survival with maintenance versus without. The abstract does not state the reference group of the hazard ratio. |
| Colostomy-free survival884 evaluable patients of 940 enrolled | exploratorymedian follow-up 5.1 yearsGlynne-Jones 2014 | — | — | HR 1.04 (95% CI 0.82–1.31)P=0.74Hazard ratio for cisplatin versus mitomycin chemoradiation in the colostomy report (884 evaluable patients). The 'exploratory' label is the closest schema category for this separate report; the abstract does not use the word. 5-year colostomy-free survival was 68% with mitomycin and maintenance, 70% with cisplatin and maintenance, 68% with mitomycin and no maintenance, and 65% with cisplatin and no maintenance. The authors conclude that neither cisplatin chemoradiation nor maintenance chemotherapy affected colostomy-free survival. 52% of pretreatment colostomies (61 of 118) were never reversed. |
| Endpoint | Analysis | Cisplatin chemoradiation (all patients) / Maintenance chemotherapy (all patients) | Mitomycin chemoradiation (all patients) / No maintenance chemotherapy (all patients) | Effect |
|---|---|---|---|---|
| Complete response of the primary tumour432 patients in the mitomycin group and 431 in the cisplatin group with response assessed (of 940 enrolled); the abstract states that primary analyses were by intention to treatComplete response at 26 weeks; the abstract does not state how response was assessed. | primarymedian follow-up 5.1 yearsJames 2013 | 89.6% | 90.5% | P=0.64391 of 432 patients in the mitomycin group versus 386 of 431 in the cisplatin group had a complete response at 26 weeks (difference -0.9%, 95% CI -4.9 to 3.1). Each figure pools patients randomised with and without maintenance. |
| Acute toxic effects472 patients in the mitomycin group and 468 in the cisplatin groupOverall toxic effects (acute toxic effects were a primary endpoint of the chemoradiation comparison); the abstract does not state the grade threshold of the overall figure. | primaryJames 2013 | 72% | 71% | 334 of 472 versus 337 of 468 patients; the abstract describes overall toxic effects as similar and gives no p-value. The most common grade 3-4 toxic effects, mitomycin versus cisplatin: skin 48% vs 47%, pain 26% vs 29%, haematological 26% vs 16%, gastrointestinal 16% vs 18%. |
| PFSPatients randomised to maintenance versus no maintenance chemotherapy, pooled across mitomycin and cisplatin; the abstract states that primary analyses were by intention to treat | primarymedian follow-up 5.1 yearsJames 2013 | 74% at 3 y (69–77%) | 73% at 3 y (68–77%) | HR 0.95 (95% CI 0.75–1.21)P=0.703-year progression-free survival with maintenance versus without. The abstract does not state the reference group of the hazard ratio. |
| Colostomy-free survival884 evaluable patients of 940 enrolled | exploratorymedian follow-up 5.1 yearsGlynne-Jones 2014 | — | — | HR 1.04 (95% CI 0.82–1.31)P=0.74Hazard ratio for cisplatin versus mitomycin chemoradiation in the colostomy report (884 evaluable patients). The 'exploratory' label is the closest schema category for this separate report; the abstract does not use the word. 5-year colostomy-free survival was 68% with mitomycin and maintenance, 70% with cisplatin and maintenance, 68% with mitomycin and no maintenance, and 65% with cisplatin and no maintenance. The authors conclude that neither cisplatin chemoradiation nor maintenance chemotherapy affected colostomy-free survival. 52% of pretreatment colostomies (61 of 118) were never reversed. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.95 | 0.75–1.21 |
| Colostomy-free survival | 1.04 | 0.82–1.31 |
Appears in
Sources
James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, et al. 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. Lancet Oncol. 2013;14(6):516-24.
Glynne-Jones R, Kadalayil L, Meadows HM, Cunningham D, Samuel L, Geh JI, et al. Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial. Ann Oncol. 2014;25(8):1616-22.