ArticlesEpidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin
Introduction
Epidermoid anal cancer has long been held to be predominantly locoregional but in surgical series over the past half century, only around 50% of cases survived for 5 years after radical or local excision.1 Assertions that radiotherapy had at least the same potential to cure as surgery while avoiding colostomy in many cases2, 3 were not followed up. Ironically, 70 years ago, the morbidity and mortality of surgery for anal carcinoma were sufficient to persuade some surgeons to favour radiotherapy. As surgery became safer, abdominoperineal excision for invading lesions and local excision for small growths became the standard for four decades, although radium implantation was advocated in 1940 for low-grade tumours.4
High-dose external-beam therapy alone gives survival rates of up to 75% at 3 years,5 and interstitial irradiation alone produces local tumour control-rates of 40–50%.3, 6 With external-beam irradiation and interstitial therapy, two-thirds of patients survived for 5 years, most maintaining adequate sphincter function.7
Norman Nigro pioneered combined chemotherapy and radiotherapy (combined modality therapy, CMT) to try to convert inoperable cases into candidates for surgical salvage.8, 9, 10 As he became more confident, he no longer pressed his patients routinely to undergo radical surgery, initially confining himself to excision of the site of the primary tumour after CMT; later he dropped even this minor surgical step.
Most other reports of CMT were encouraging, although whether similar levels of local tumour control and survival could be achieved without chemotherapy, perhaps thereby avoiding some morbidity, remained debatable.11 Papillon's group in a non-random comparison of radiation alone with CMT, reported an increase in local control from 66% to 81%.12 Cummings et al looked at patients treated by radiation therapy and another group treated more recently with CMT; local control had been maintained 6 months after treatment in 60% and 94%, respectively.13 It was accepted widely in the late 1980s that CMT should be properly assessed in a randomised trial. Accordingly, the first anal cancer trial undertaken by the UK Co-ordinating Committee on Cancer Research (UKCCCR) was set up to compare the most promising regimens of radiotherapy alone with CMT.
Section snippets
Design
The multicentre trial was launched in 1987 (figure 1). The main end-point was local failure whether due to disease or complications of treatment, as indicated by the need for major surgical intervention. 5-year survival was a secondary endpoint.
Eligible patients had epidermoid carcinoma (squamous, basaloid, or cloacogenic) of the anal canal or margin, no evidence of major hepatic or renal dysfunction, and normal blood counts. After examination under anaesthesia and biopsy, the lesion was staged
Accrual and analysis
Trial entry began in December, 1987; the original accrual target was achieved in May, 1991, when it was deemed appropriate to continue randomisation while awaiting further events. Accrual was exceptionally good (one-third of the national incidence) and continuing recruitment allowed the potential detection of a smaller difference in local failure rate.
In March, 1994, the data-monitoring committee considered data on 462 patients and concluded that a difference in local failure between treatments
Discussion
This UKCCCR trial demonstrated that the addition of 5-fluorouracil and mitomycin to radical radiotherapy substantially improved the chance of avoiding local failure of anal cancer, and hence radical surgery and colostomy. Further, there was a cancer-specific survival advantage. The local failure rate was approximately halved and the proportion of individuals requiring anorectal excision was reduced by a half. This reduction was achieved chiefly through improved duration of response (29/174
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