Management of Anal Cancer in 2010 Part 2: Current Treatment Standards and Future Directions

The treatment of anal squamous cell cancer with definitive chemoradiation is the gold-standard therapy for localized anal cancer, primarily because of its sphincter-saving and colostomy-sparing potential. Studies have addressed different chemoradiation regimens in hopes of improving on the standard protocol of fluorouracil (5-FU), mitomycin, and radiation, but no alternative regimens have proven superior. Nevertheless, important conclusions have been derived regarding the continuity of radiation as well as the role of induction and maintenance chemotherapy in this setting. In the concluding part of this review, we consider the data on chemoradiation with 5-FU/mitomycin vs radiation alone, chemoradiation with 5-FU/mitomycin vs chemoradiation with 5-FU alone, neoadjuvant chemotherapy with cisplatin/5-FU followed by cisplatin/5-FU plus radiation vs mitomycin/5-FU plus radiation, the addition of induction or maintenance chemotherapy to chemoradiation, the effect of overall treatment time on tumor control, whether chemotherapy can be eliminated for early-stage anal cancer, and the impact of human immunodeficiency virus infection on treatment.

As noted in part 1 of this article, which appeared in the April 15th issue of ONCOLOGY (24:364-369, 2010), the treatment of anal squamous cell cancer with definitive chemoradiation is clearly the gold-standard therapy for localized anal cancer, primarily because of its sphincter-saving and colostomy-sparing potential. Studies conducted over the past 2 decades have addressed different chemoradiation regimens in hopes of improving on the standard Nigro protocol of fluorouracil (5-FU), mitomycin, and radiation. Although these studies failed to reveal any superiority of alternative regimens to the Nigro protocol, important conclusions were derived regarding the continuity of radiation as well as the role of induction (pre-chemoradiation) and maintenance chemotherapy (post-chemoradiation) in patients with anal cancer.

Part 1 of this review provided an overview of anal cancer epidemiology, risk factors, screening, prevention, and diagnosis. In part 2, we will focus on the current status of chemoradiation for anal cancer and reflect on potential areas for future treatment improvements.

Treatment

Prior to the 1980s, abdominoperineal resection of the anal canal and distal rectum, with the formation of permanent end-colostomy was the standard treatment of anal cancer and was associated with a 5-year survival of around 40% to 70%.^1-7

Subsequent work by Nigro et al showed that the administration of preoperative 5-FU and mitomycin combined with radiation therapy resulted in a reduced surgical failure rate.^8,9 Given the high rate of complete pathologic response associated with the Nigro regimen, Nigro proposed an approach of initial chemoradiation followed by abdominoperineal resection only if residual tumor remained at the time of postradiation biopsy.¹⁰ Combined-modality therapy using initial radiation therapy, 5-FU, and mitomycin followed by salvage surgery was subsequently established as the standard of care by retrospective and prospective studies, despite the lack of a randomized study comparing chemoradiation to surgery.^10-18 A randomized study comparing chemoradiation to abdominoperineal resection is generally not considered feasible, given the anticipated difficulties in patient accrual.

Chemoradiation With 5-FU/Mitomycin vs Radiation Therapy Alone

The United Kingdom Coordinating Committee on Cancer Research (UKCCCR) trial randomized 585 patients to radiation alone or radiation combined with chemotherapy (continuous 5-FU, 1,000 mg/m²/d for 4 days or 750 mg/m²/d for 5 days, during the first and final week of radiation treatment, with mitomycin, 12 mg/m² by bolus intravenous infusion on day 1 of chemoradiation).¹⁸ The radiation dose was 45 Gy in 20 to 25 fractions over 4 to 5 weeks. Tumor response was assessed at 6 weeks after completion of the first radiotherapy course. Patients with at least a 50% tumor regression received an additional boost of 15 Gy in six fractions or by 25 Gy iridium-192 implant over 2 to 3 days. Poor responders with less than 50% tumor regression underwent surgical resection.

The response rate in the assessable population was 92% on both arms; most of these patients received the intended radiation boost. Approximately 65% of the poor responders underwent abdominoperineal resection, and the rest received other therapies. Local failure was defined as persistent disease following completion of therapy, anorectal surgery, or persistent colostomy at 6 months from completion of treatment. Local failure occurred in 265 of 562 evaluable patients, defined as those who were evaluable at 6 or more weeks from treatment start.

The 3-year local relapse rate was 61% in the radiation arm vs 39% in the chemoradiation arm. The incidence of anal cancer–related death was significantly higher in the radiation arm (39%) than in the chemoradiation arm (28%). The 3-year survival-rate for the radiation arm was 58%, compared with 65% for the chemoradiation arm, which was not a statistically significant difference because of the excess non–cancer-related mortality on the chemoradiation arm.¹⁸

In the European Organisation for Research and Treatment of Cancer (EORTC) study, 103 patients with locally advanced cancers of the anal canal were entered on a trial with a similar design.¹⁶ A boost of 15 Gy for complete remission or 20 Gy for partial responders (ie, any shrinkage) was given after 6 weeks of completion of the initial 45 Gy. Chemotherapy consisted of 5-FU, 750 mg/m² daily as a continuous infusion on days 1 to 5 and 29 to 33, and mitomycin was given at 15 mg/m² on day 1 of the first course of 5-FU. Assessment of treatment effect was performed 6 weeks after completion of boost treatment. Complete response was higher in the chemoradiation arm (80%) vs the radiation arm (54%). At 5 years, Kaplan-Meier estimates showed 18% more locoregional control (P = .02) and a 32% higher colostomyfree interval (P = .002) in favor of the chemoradiation arm. Evaluation of 5-year overall survival showed a trend in favor of the chemoradiation approach (P = .17).¹⁶

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