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demonstrated the benefit of chemoradiation over radiotherapy (RT) alone for treating epidermoid anal cancer, and it became the standard treatment. Patients in this trial have now been followed up for a median of 13 years. METHODS: A total of 577 patients were randomised to receive RT alone or combined modality therapy using 5-fluorouracil and mitomycin C. All patients were scheduled to receive 45 Gy by external beam irradiation. Patients who responded to treatment were recommended to have boost RT, with either an iridium implant or external beam irradiation. Data on relapse and deaths were obtained until October 2007. RESULTS: Twelve years after treatment, for every 100 patients treated with chemoradiation, there are an expected 25.3 fewer patients with locoregional relapse (95% confidence interval (CI): 17.5 -32.0 fewer) and 12.5 fewer anal cancer deaths (95% CI: 4.3 -19.7 fewer), compared with 100 patients given RT alone. There was a 9.1% increase in non-anal cancer deaths in the first 5 years of chemoradiation (95% CI þ 3.6 to þ 14.6), which disappeared by 10 years. CONCLUSIONS: The clear benefit of chemoradiation outweighs an early excess risk of non-anal cancer deaths, and can still be seen 12 years after treatment. Only 11 patients suffered a locoregional relapse as a first event after 5 years, which may influence the choice of end points in future studies.

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SummaryBackgroundGuidelines 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.MethodsThe 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/m2 on day 1) or intravenous cisplatin (one dose of 60 mg/m2 on days 1 and 29), with intravenous fluorouracil (one dose of 1000 mg/m2 per 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.FindingsWe 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 respo...

LBA4009 Background: Chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and mitomycin-C (MMC) is standard treatment for anal cancer. This trial addresses two questions: whether (i) replacing MMC with cisplatin (CDDP) improves the complete response (CR) rate, and (ii) two cycles of maintenance chemotherapy after CRT reduces recurrence. Methods: Between 2001 and 2008, 940 patients (pts) were recruited to a multicenter, randomized factorial trial. 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 also randomized to receive maintenance therapy (n=448) 4 weeks after CRT (two cycles of CDDP and 5-FU weeks 11 and 14) or no maintenance (n=446). Maintenance randomization was not considered appropriate in 46 pts. Statistical power was ≥80% to detect a difference in the CR rate of 5% (CDDP vs MMC), and 30% reduction in recurrence (maintenance vs no maintenance). Results: Median age 58 yrs; 62% male, 38% female; tumor 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 this did not result in 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 recurrence free survival (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. The number of pre-treatment colostomies not reversed were similar between treatments (18 MMC vs 14 CDDP, p=0.65, Maint/No maint, p=0.23) and only 9 disease-free pts had colostomies performed (5 MMC, 4 CDDP). Conclusions: ACT II is the largest trial conducted in anal cancer. High CR (95%) and RFS (75% at 3 yrs) rates were achieved with this CRT. This excellent outcome may have been influenced by the absence of a gap in the RT schedule. 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. [Table: see text]

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BACKGROUND:Only 2 prospective studies have previously reported prognostic factors for anal cancer, European Organization for Research and Treatment of Cancer trial 22861 (EORTC 22861) and Radiation Therapy Oncology Group trial . Both of those trials reported that clinically positive lymph nodes and male sex predicted poorer overall survival (OS). The EORTC 22861 trial indicated that the same factors were prognostic for locoregional control. In the current report, the authors investigated potential prognostic factors from the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I), in which patients were randomized to receive either radiotherapy alone or chemoradiation (CRT) with concurrent 5-fluorouracil/mitomycin C. METHODS: In the ACT I trial, associations between several baseline characteristics and 3 endpoints were investigated: locoregional failure (LRF), anal cancer death (ACD), and OS. The analyses were restricted to 292 patients who received CRT, which subsequently became standard treatment. A score was derived using multivariable Cox regression to identify the set of factors that, together, had the best prognostic performance. This score was then validated with a large, independent prospective trial (the ACT II trial). RESULTS: Palpable, clinically positive lymph nodes were associated with LRF (P ¼ .012), a greater risk of ACD (P ¼ .031), and decreased OS (P ¼ .006) in multivariable analyses. Men had worse outcomes than women for LRF (P ¼ .036), ACD (P ¼ .039), and OS (P ¼ .008). On average, a lower hemoglobin level had an adverse effect on ACD (P ¼ .008), and a higher white blood cell count had an adverse effect on OS (P ¼ .001). However, external validation of the score was poor for LRF (area under the curve [AUC] ¼ 54%) but was better for ACD (AUC ¼ 67%) and OS (AUC ¼ 63%). CONCLUSIONS: The results from this analysis of the ACT I trial supported evidence for palpable lymph nodes and male sex as prognostic factors for LRF and OS, and lower hemoglobin levels and a higher white blood cell count were identified as prognostic factors for ACD and OS, respectively. Cancer 2013;119:748-55. V C 2012 American Cancer Society.