Management of anal cancer has undergone major evolution and progress since last few decades. Until 1970s, the standard treatment for anal cancer was abdominoperineal resection (APR) with a resulting permanent end colostomy, thus compromising the quality of life of patients. Despite APR, the 5-year survival ranged from 40 % to 70 % with an associated mortality of approximately 3 % and significant morbidity [12, 18, 27].

In 1974, Nigro et al. [28] went a step forward and used combined modality treatment (CMT) for anal cancer. The investigators at Wayne State University administered 5-fluorouracil (5-FU) (1,000 mg/m² continuously on days 1–4 and 29–32) and mitomycin C (MMC) (10–15 mg/m² on day 1) in combination with external beam radiation therapy dose of 30 Gy in three patients. These patients had complete pathological response, thus contributing to the concept of sphincter preservation in anal cancer and APR reserved as salvage for patients with residual, recurrent or progressive disease. Since then, the treatment paradigm for anal cancer has shifted from surgical to CMT. Definitive chemoradiation (CRT) to preserve sphincter function remains the standard of care in treatment of anal cancer.

The efficacy of CMT as a definitive treatment has been confirmed in various studies. The results of United Kingdom Coordinating Committee on Cancer Research (UKCCCR) [29] and the European Organization for Research on Treatment of Cancer (EORTC) [24] both confirmed significant improvement in loco-regional control and colostomy-free survival (CFS) in patients receiving CMT without statistically significant improvement in OS. The UKCCCR trial also demonstrated better cause-specific survival, an end point not described by EORTC. The UKCCCR recently updated their results demonstrating a clear benefit of CRT which is maintained even 12 years after starting treatment [30]. CMT was associated with reduction in risk of locoregional relapse (p < 0.001), improvement of recurrence-free survival (RFS) (P < 0.001) and CFS (P = 0.004). The median survival was 7.6 years (95 % CI 5.9–9.9 years) in the CMT group and 5.4 years (95 % CI 3.6–6.8 years) in those receiving RT alone. The OS was not significantly different between two arms due to excess of deaths not from anal cancer in the CMT group in the first 5 years. Only 7 % of patients developed metastatic disease without earlier loco-regional relapse; hence the emphasis should be on loco-regional control. No significant difference was observed between the patients of the two arms in terms of late complication rate.

In a phase III randomized Intergroup study [31], patients were randomized to receive either radiotherapy and 5-FU or radiotherapy, 5-FU, and MMC. Patients in MMC arm had lower colostomy rate (p = 0.002) and higher DFS at 4 years (p = 0.0003) with no significant difference in OS. The hematologic toxicity was significantly higher in the MMC arm (23 % vs. 7 % grade 4 toxicity in MMC vs. no MMC arm; P ≤ 0.001).

Cisplatin as a substitute for MMC in the treatment of anal cancer has been evaluated in various trials. The ACT II [32] reported at the American Society of Clinical Oncology 2009 meeting is the largest trial being conducted in anal cancer. It evaluated the role and efficacy of MMC versus cisplatin in the CMT and two cycles of adjuvant or maintenance chemotherapy after CRT in anal cancer. In this trial, a total of 940 patients were recruited and randomized to receive either 5-FU plus cisplatin with radiation or 5-FU plus MMC with radiation. The patients in each arm were further randomized to receive adjuvant cisplatin plus 5-FU for two cycles (maintenance) or no maintenance therapy. High complete response (CR) (95 %) and RFS (75 % at 3 years) rates were achieved with this CRT. This excellent outcome may have been influenced by the absence of a gap in the radiotherapy schedule. There was no difference in CR rates between MMC and cisplatin or in RFS rates with or without maintenance chemotherapy. Non-hematologic toxicities were similar in both the arms while MMC pts had significantly higher incidence of acute grade 3/4 hematological toxicities (25 vs. 13 %, p < 0.001). Thus, 5-FU and MMC with radiotherapy remains the standard of care.

The US Gastrointestinal Intergroup trial RTOG 98-11 [25] randomized 682 patients between (1) 5-FU plus cisplatin induction chemotherapy (two cycles) followed by concurrent chemoradiation with 5-FU and cisplatin (experimental group) and (2) 5-FU plus MMC and concurrent radiation (control group). Role of induction chemotherapy was also assessed. Cisplatin based therapy failed to improve DFS compared with MMC based therapy, and resulted in higher cumulative rates of colostomy. In this trial, strategy of induction chemotherapy proved ineffectual compared with the standard concurrent chemoradiation with 5-FU and MMC. The results favored the 5-FU/MMC CRT arm. The long term follow-up of RTOG 98-11 trial has been published and has concluded that CRT with 5-FU and MMC has statistically significant and clinically meaningful impact on DFS (P = 0.008) and OS (P = 0.026) with trend towards significance for CFS (P = 0.05), LRF (P = 0.087), and colostomy failure (P = 0.074) as compared to cisplatin based regimen [33].

The aim of ACCORD 03 four-arm prospective randomized trial [34] was to determine the benefit of two cycles of induction chemotherapy before concomitant CRT and to test whether dose escalation can lead to improvement in CFS. Patients were randomly assigned to one of the following four treatment arms: (A) induction chemotherapy followed by conventional treatment; (B) induction chemotherapy, CRT and radiotherapy dose intensification; (C) conventional treatment alone and (D) radiotherapy dose intensification. The primary endpoint was the CFS. The 5-year CFS rates were 69.6 %, 82.4 %, 77.1 %, and 72.7 % in arms A, B, C, and D, respectively. The 5-year CFS of groups A and B versus C and D was 76.5 % versus 75 % (P = 0.37) and of group A and C versus B and D was 74 % versus 78 % (P = 0.067). The 5-year OS for groups A and B versus C and D was 74.5 % versus 71 % (P = 0.81) and for groups A and C versus B and D was 71 % versus 74 % (P = 0.43). This phase III trial with a median follow-up of 50 months, designed as a factorial 2 × 2 plan, could not demonstrate a benefit for induction chemotherapy or radiation boost in patients with locally advanced anal canal carcinoma in terms of CFS.

Anal canal cancers are mostly squamous cell cancers expressing epidermal growth factor receptors (EGFR). Role of cetuximab is still investigational. The phase II ACCORD 16 trial aimed to evaluate the objective response rate after combination of conventional CRT and cetuximab in locally advanced anal canal carcinoma [35]. Immunocompetent patients with histologically confirmed diagnosis received CRT (45 Gy/25 fractions/5 weeks, 5-FU and cisplatin during weeks 1 and 5), in combination with weekly dose of cetuximab (250 mg/m² with a loading dose of 400 mg/m² 1 week before irradiation), and a standard boost dose (20 Gy). The trial was prematurely stopped after the declaration of 15 serious adverse events in 14 out of 16 patients. CRT plus cetuximab resulted in unacceptable toxicity in these patients. In a recent update of ACCORD 16 phase II trial [36], at a median follow-up of 4.6 years in 15 evaluable patients, 4 patients had died due to disease progression resulting in a 4 year OS rate of 73 %. Nearly half (7/15) evaluable patients had relapsed which included six loco-regional and one distant failure. The 4-year CFS rate was 53 % and the 4-year cumulative colostomy rate was 43 %. The acute side-effects were higher and response rates were comparatively poorer to randomized trials of conventional CRT described in the literature. The results of others phase II trials evaluating the efficacy and safety of cetuximab with CRT are awaited.