A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II)

Abstract

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]

Predictors of acute toxicities during definitive chemoradiation using intensity-modulated radiotherapy for anal squamous cell carcinoma

“…Leukocytes encompass all WBCs, including lymphocytes, and lymphopenia is a known side effect of radiation of pelvic bone marrow. Significant leukopenia and neutropenia are side effects of MMC, as established by numerous trials of anal cancer patients [15,16]. Our data further corroborate the impact of MMC on the WBC count, as the number of MMC cycles was a predictor of both Grade 2 + leukopenia and neutropenia.…”

Long-Term Follow-Up of a Phase II Trial of High-Dose Radiation With Concurrent 5-Fluorouracil and Cisplatin in Patients With Anal Cancer (ECOG E4292)

“…Interestingly, the authors of the ACT II trial conclude that MMC-based therapy should remain the standard-of-care, despite the fact that both regimens had similar recurrence-free survival and overall survival. (12)…”

“…There was significantly higher hematologic toxicities with the use of MMC (25% vs. 13%; p < 0.001). (12) Unfortunately, the second randomization of two additional courses of cisplatin/5FU maintenance chemotherapy after completion of primary chemoradiation makes answering the question of primary chemoradiation using cisplatin/FU vs. MMC/FU in the primary treatment of anal cancer more difficult. Although we would agree with the authors conclusion that 5-FU/MMC without maintenance remains the standard of care for the management of anal cancer, given the more favorable side effect profile, cisplatin based chemoradiation regimens should still be considered as an alternative chemotherapy backbone on which to add biologics in clinical trials that seek to improve the local control results of patients with anal cancer.…”

“…(15) An ongoing phase II ECOG study is evaluating the efficacy of cetuximab plus cisplatin, 5-fluorouracil and radiation therapy (E3205). (16) Given the results of large randomized studies that have shown no benefit to the addition of either induction cisplatin-based chemotherapy (10) or maintenance cisplatin-based chemotherapy (12), E3205 employs cetuximab, 5-FU and radiation without the use of either induction or maintenance chemotherapy. A similar study is accruing HIV positive patients to concurrent cetuximab with cisplatin and 5-fluorouracil through the AIDS Associated Malignancies Clinical Trials Consortium (NCT00324415).…”

A Regimen of Taxol, Ifosfamide, and Platinum for Recurrent Advanced Squamous Cell Cancer of the Anal Canal

“…However, colostomy rates (cumulative rate 19 versus 10 percent; P = .02) were significantly higher in the induction cisplatin/5-FU arm [21]. The ACT II study on the other hand showed no difference between mitomycin-C or cisplatin containing regimens in any of the above parameters including colostomy rates [22]. …”