title: Best time to assess complete clinical response after chemoradiotherapy in squamous cell carcinoma of the anus (ACT II): a post-hoc analysis of randomised controlled phase 3 trial.
abstract: Guidelines for anal cancer recommend assessment of response at 6-12 weeks after starting treatment. Using data from the ACT II trial, we determined the optimum timepoint to assess clinical tumour response after chemoradiotherapy.
  
  
  
  The previously reported ACT II trial was a phase 3 randomised trial of patients of any age with newly diagnosed, histologically confirmed, squamous cell carcinoma of the anus without metastatic disease from 59 centres in the UK. We randomly assigned patients (by minimisation) to receive either intravenous mitomycin (one dose of 12 mg/m2on day 1) or intravenous cisplatin (one dose of 60 mg/m2on days 1 and 29), with intravenous fluorouracil (one dose of 1000 mg/m2per day on days 1-4 and 29-32) and radiotherapy (50·4 Gy in 28 daily fractions); and also did a second randomisation after initial therapy to maintenance chemotherapy (fluorouracil and cisplatin) or no maintenance chemotherapy. The primary outcome was complete clinical response (the absence of primary and nodal tumour by clinical examination), in addition to overall survival and progression-free survival from time of randomisation. In this post-hoc analysis, we analysed complete clinical response at three timepoints: 11 weeks from the start of chemoradiotherapy (assessment 1), 18 weeks from the start of chemoradiotherapy (assessment 2), and 26 weeks from the start of chemoradiotherapy (assessment 3) as well as the overall and progression-free survival estimates of patients with complete clinical response or without complete clinical response at each assessment. We analysed both the overall trial population and a subgroup of patients who had attended each of the three assessments by modified intention-to-treat. This study is registered at controlled-trials.com, ISRCTN 26715889.
  
  
  
  We enrolled 940 patients from June 4, 2001, until Dec 16, 2008. Complete clinical response was achieved in 492 (52%) of 940 patients at assessment 1 (11 weeks), 665 (71%) of patients at assessment 2 (18 weeks), and 730 (78%) of patients at assessment 3 (26 weeks). 691 patients attended all three assessments and in this subgroup, complete clinical response was reported in 441 (64%) patients at assessment 1, 556 (80%) at assessment 2, and 590 (85%) at assessments 3. 151 (72%) of the 209 patients who had not had a complete clinical response at assessment 1 had a complete clinical response by assessment 3. In the overall trial population of 940 patients, 5 year overall survival in patients who had a clinical response at assessments 1, 2, 3 was 83% (95% CI 79-86), 84% (81-87), and 87% (84-89), respectively and was 72% (66-78), 59% (49-67), and 46% (37-55) for patients who did not have a complete clinical response at assessments 1, 2, 3, respectively. In the subgroup of 691 patients, 5 year overall survival in patients who had a clinical response at assessment 1, 2, 3 was 85% (81-88), 86% (82-88), and 87% (84-90), respectively, and was 75% (68-80), 61% (50-70), and 48% (36-58) for patients who did not have a complete clinical response at assessment 1, 2, 3, respectively. Similarly, progression-free survival in both the overall trial population and the subgroup was longer in patients who had a complete clinical response, compared with patients who did not have a complete clinical response, at all three assessments.
  
  
  
  Many patients who do not have a complete clinical response when assessed at 11 weeks after commencing chemoradiotherapy do in fact respond by 26 weeks, and the earlier assessment could lead to some patients having unnecessary surgery. Our data suggests that the optimum time for assessment of complete clinical response after chemoradiotherapy for patients with squamous cell carcinoma of the anus is 26 weeks from starting chemoradiotherapy. We suggest that guidelines should be revised to indicate that later assessment is acceptable.
  
  
  
  Cancer Research UK.
authors.affiliation: Mount Vernon Centre for Cancer Treatment, Northwood, Leeds, UK. Electronic address: rob.glynnejones@nhs.net.
authors.forename: Robert
authors.initials: R
authors.lastname: Glynne-Jones
authors.affiliation: University of Leeds, Leeds Cancer Centre, Leeds, UK.
authors.forename: David
authors.initials: D
authors.lastname: Sebag-Montefiore
authors.affiliation: Cancer Research UK and University College London Cancer Trials Centre, London, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Meadows
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Cancer Research UK and University College London Cancer Trials Centre, London, UK.
authors.forename: Rubina
authors.initials: R
authors.lastname: Begum
authors.affiliation: North Staffordshire Royal Infirmary, Stoke, UK.
authors.forename: Fawzi
authors.initials: F
authors.lastname: Adab
authors.affiliation: Cheltenham General Hospital, Cheltenham, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Benstead
authors.affiliation: Belfast City Hospital Cancer Centre, Belfast, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harte
authors.affiliation: Northampton General Hospital, Northampton, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Cancer Research UK and University College London Cancer Trials Centre, London, UK.
authors.forename: Sandy
authors.initials: S
authors.lastname: Beare
authors.affiliation: Cancer Research UK and University College London Cancer Trials Centre, London, UK.
authors.forename: Allan
authors.initials: A
authors.lastname: Hackshaw
authors.affiliation: Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK.
authors.forename: Latha
authors.initials: L
authors.lastname: Kadalayil
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001005:Anus Neoplasms / Q000473:pathology / Q000628:therapy*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D019583:Dose Fractionation, Radiation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000473:pathology / Q000628:therapy*; D009367:Neoplasm Staging; D011379:Prognosis; D012074:Remission Induction; D015996:Survival Rate; D013997:Time Factors
chemical_list: D016685:Mitomycin; D002945:Cisplatin; D005472:Fluorouracil