Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin

Summary

Background

Non-surgical management of anal cancer by radiotherapy alone or combined with chemotherapy has, in uncontrolled studies, yielded similar local tumour control and survival rates to surgery. However, whether the addition of chemotherapy improves outcome without adding to morbidity is not known. Our trial was designed to compare combined modality therapy (CMT) with radiotherapy alone in patients with epidermoid anal cancer.

Methods

From 856 patients considered for entry to our multicentre trial, 585 patients were randomised to receive initially either 45 Gy radiotherapy in twenty or twenty-five fractions over 4–5 weeks (290 patients) or the same regimen of radiotherapy combined with 5-fluorouracil (1000 mg/m² for 4 days or 750 mg/m² for 5 days) by continuous infusion during the first and the final weeks of radiotherapy and mitomycin (12 mg/m²) on day 1 of the first course (295 patients). We assessed clinical response 6 weeks after initial treatment: good responders were recommended for boost radiotherapy and poor responders for salvage surgery. The main endpoint was local-failure rate (≥6 weeks after initial treatment); secondary endpoints were overall and cause-specific survival. Analysis was by intention-to-treat.

Findings

In the radiotherapy and CMT arms, respectively, five and three were ineligible, and six and nine died 6 weeks after initial treatment. After a median follow-up of 42 months (interquartile range 28–62), 164 of 279 (59%) radiotherapy patients had a local failure compared with 101 of 283 (36%) CMT patients. This gave a 46% reduction in the risk of local failure in the patients receiving CMT (relative risk 0·54, 95% CI 0·42–0·69, p < 0·0001). The risk of death from anal cancer was also reduced in the CMT arm (0·71, 0·53–0·95, p=0·02). There was no overall survival advantage (0·86, 0·67–1·11, p=0·25). Early morbidity was significantly more frequent in the CMT arm (p=0·03), but late morbidity occurred at similar rates.

Interpretation

Our trial shows that the standard treatment for most patients with epidermoid anal cancer should be a combination of radiotherapy and infused 5-fluorouracil and mitomycin, with surgery reserved for those who fail on this regimen.

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.