ABSTRACT: 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(Drug information on fluorouracil) (5-FU), mitomycin(Drug information on 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(Drug information on 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.
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
The results in the chemoradiation arm of the EORTC study were somewhat better than what was seen in the UKCCCR study, despite the inclusion of patients with more advanced disease and the exclusion of T1–2, N0 patients (Table 1). The improvement in outcome in the EORTC study may be related to more stringent inclusion guidelines (no metastatic disease patients were included), more prolonged and standardized radiation (45 Gy in 25 fractions in all patients), exclusion of patients older than 75 years, and application of a boost in all patients with disease regression, irrespective of its degree (UKCCCR mandated > 50% shrinkage). Both studies clearly indicate superior locoregional control and a decrease in colostomy rates with the addition of 5-FU and mitomycin to radiation therapy.
Chemoradiation With 5-FU/Mitomycin vs 5-FU Chemoradiation
In 1991, a meta-analysis of prospective clinical trials using radiation alone, with 5-FU, and with 5-FU/ mitomycin reported a significant improvement in local control and 5-year overall survival in favor of 5-FU plus mitomycin.13 Subsequently, the Radiation Therapy Oncology Group (RTOG) 87-04/Eastern Cooperative Oncology Group (ECOG) 1289 study—a phase III randomized clinical trial—confirmed the superiority of 5-FU plus mitomycin (Nigro regimen) over 5-FU plus radiation in the definitive treatment of anal cancer.17 A total of 310 patients were randomized to radiation with 5-FU (1,000 mg/m2/d as a continuous infusion for 96 hours on days 1 and 29) or radiation with the same 5-FU schedule and the addition of mitomycin (10 mg/m2 on the first day of each 5 FU course). Radiation was given at 45 Gy in 5 weeks. Patients with palpable tumor at the end of the 45-Gy dose were given an additional 5.4 Gy. Patients with N0 disease received 45 Gy to the inguinal lymph nodes, while those with N1 disease were boosted to 50.4 Gy.
Response was documented with a mandated full-thickness tumor biopsy at 4 to 6 weeks after completion of this "induction chemoradiation." Salvage chemoradiation was administered if there was histologic confirmation of residual primary tumor. Salvage chemoradiation consisted of an additional radiation therapy boost of 9 Gy (5 fractions of 1.8 Gy) to the area of residual disease, along with concurrent 5-FU (1,000 mg/m2/d for 4 days) and a single injection of cisplatin (100 mg/ m2 on day 2 of 5-FU therapy). A total of 291 patients were assessable for disease outcome, 262 of whom underwent postinduction biopsy.
The negative biopsy rates were 86% and 92.2% in the 5-FU and 5-FU/mitomycin arms, respectively (P = .135). Colostomy rates at 4 years were lower in patients receiving 5-FU plus mitomycin (9%) vs patients receiving 5-FU (23%; P = .002). Similarly, the disease-free survival rate was significantly improved in favor of the mitomycin arm (4-year disease-free survival was 73% vs 51%; P = .0003). While these results did not translate into a survival advantage, a trend emerged in an overall survival benefit in the mitomycin group after 18 months. The assessment of the value of salvage chemoradiation was limited, as only 28 patients had positive biopsies postinduction. Of these 28 patients, 25 received salvage chemoradiation as per protocol. Twelve patients ultimately had a negative postsalvage treatment biopsy, and 4 of these 12 were disease-free 4 years later.17 These results are summarized in Table 2. The RTOG 87-04/ECOG 1289 study firmly established 5-FU/mitomycin as part of standard chemoradiation therapy for anal cancer.