title: 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.
abstract: 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/m(2) on day 1) or cisplatin (60 mg/m(2) on days 1 and 29), with fluorouracil (1000 mg/m(2) 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Cancer Research UK.
authors.affiliation: The Kent Cancer Centre, Maidstone, UK.
authors.forename: Roger D
authors.initials: RD
authors.lastname: James
authors.forename: Robert
authors.initials: R
authors.lastname: Glynne-Jones
authors.forename: Helen M
authors.initials: HM
authors.lastname: Meadows
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Arthur Sun
authors.initials: AS
authors.lastname: Myint
authors.forename: Mark P
authors.initials: MP
authors.lastname: Saunders
authors.forename: Timothy
authors.initials: T
authors.lastname: Maughan
authors.forename: Alec
authors.initials: A
authors.lastname: McDonald
authors.forename: Sharadah
authors.initials: S
authors.lastname: Essapen
authors.forename: Martin
authors.initials: M
authors.lastname: Leslie
authors.forename: Stephen
authors.initials: S
authors.lastname: Falk
authors.forename: Charles
authors.initials: C
authors.lastname: Wilson
authors.forename: Simon
authors.initials: S
authors.lastname: Gollins
authors.forename: Rubina
authors.initials: R
authors.lastname: Begum
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ledermann
authors.forename: Latha
authors.initials: L
authors.lastname: Kadalayil
authors.forename: David
authors.initials: D
authors.lastname: Sebag-Montefiore
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001005:Anus Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local; D016016:Proportional Hazards Models; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D016685:Mitomycin; D002945:Cisplatin; D005472:Fluorouracil