Treatment Option Overview
Abdominoperineal resection leading to permanent colostomy was previously thought to be required for all but small anal cancers occurring below the dentate line with approximately 70% of patients surviving 5 or more years in single institutions, but such surgery is no longer the treatment of choice.[2,3]
Radiation therapy alone may lead to a 5-year survival rate in excess of 70%, but high doses (≥60 Gy) may yield necrosis or fibrosis. Chemotherapy with fluorouracil (5-FU) and cisplatin concurrent with lower-dose radiation therapy as utilized in the RTOG-8314 trial, for example, has a 5-year survival rate in excess of 70% with low levels of acute and chronic morbidity, and few patients require surgery for dermal or sphincter toxic effects.[5-10] The optimal dose of radiation with concurrent chemotherapy to optimize local control and minimize sphincter toxic effects has been studied in the RTOG-9208 trial, for example, and appears to be in the 45 Gy to 60 Gy range.[11,12]
The Anal Cancer Trial (ACT-1) from the United Kingdom Co-ordinating Committee on Cancer Research demonstrated the superiority of chemoradiation with 5-FU and mitomycin C (MMC) over radiation alone with regard to local failure and deaths from anal cancer.[Level of evidence: 1iiB] Long-term follow-up of this study has revealed 25.3 fewer patients with locoregional relapse and 12.5 fewer anal cancer deaths per 100 patients treated with chemoradiation compared with 100 patients treated with radiation alone. A 9.1% increase in nonanal cancer deaths was seen in the first 5 years following chemoradiation, which was not seen after 10 years.
The choice of chemotherapy during concurrent chemoradiation has been the subject of several trials. Analysis of an intergroup trial that compared radiation therapy plus 5-FU and MMC with radiation therapy plus 5-FU alone in patients with anal cancer demonstrated lower colostomy rates as well as higher colostomy-free and disease-free survival (DFS) with the addition of MMC.
A U.S. intergroup, randomized, phase III trial (RTOG 9811 [NCT00003596]) examined whether MMC could be replaced by cisplatin in combination with 5-FU during concurrent chemoradiation. In the cisplatin arm of this study, two cycles of induction 5-FU and cisplatin were given before concurrent chemoradiation with 5-FU and cisplatin. The MMC arm had improved local control and colostomy-free survival, but no improvement was found in DFS or overall survival (OS). Long-term follow-up of the RTOG-9811 trial has been published and demonstrated superior 5-year DFS and OS. One potential explanation for the inferiority of the cisplatin arm is delay in time to radiation, given the induction strategy employed in this study.
A strategy of maintenance chemotherapy with 5-FU and cisplatin after chemoradiation with 5-FU and MMC or 5-FU and cisplatin was evaluated in the ACT-II (NCT00025090) trial, and 3-year progression-free survival was not improved (74% with maintenance chemotherapy vs. 73% without maintenance chemotherapy). Induction chemotherapy and dose intensification were examined in the UNICANCER ACCORD-03 (NCT00003652) trial, which did not demonstrate an advantage in colostomy-free survival with induction chemotherapy with 5-FU and cisplatin or with radiation-dose intensification.
Standard salvage therapy for those patients with either gross or microscopic residual disease following chemoradiation therapy has been abdominoperineal resection. Alternately, patients may be treated with additional salvage chemoradiation therapy in the form of 5-FU, cisplatin, and a radiation boost to potentially avoid permanent colostomy.
Because of the small number of cases, information that can only come from patient participation in well-designed clinical trials is needed to improve the management of anal cancer. Patients with stages II, III, and IV disease should be considered candidates for clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
HIV and Anal Cancer
The tolerance of patients with human immunodeficiency virus and anal carcinoma to standard 5-FU and MMC chemoradiation is not well defined.[20,21] Patients with pretreatment CD4 counts of less than 200 cells/μl may have increased acute and late toxic effects;[22,23] chemoradiation doses may require modification in this subset of patients.
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- Cummings BJ: The Role of Radiation Therapy With 5-Fluorouracil in Anal Cancer. Semin Radiat Oncol 7 (4): 306-312, 1997. [PUBMED Abstract]
- Cantril ST, Green JP, Schall GL, et al.: Primary radiation therapy in the treatment of anal carcinoma. Int J Radiat Oncol Biol Phys 9 (9): 1271-8, 1983. [PUBMED Abstract]
- Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med 78 (2): 211-5, 1985. [PUBMED Abstract]
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- Fuchshuber PR, Rodriguez-Bigas M, Weber T, et al.: Anal canal and perianal epidermoid cancers. J Am Coll Surg 185 (5): 494-505, 1997. [PUBMED Abstract]
- Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiat Oncol Investig 2 (3): 152-6, 1994.
- John M, Pajak T, Flam M, et al.: Dose Escalation in Chemoradiation for Anal Cancer: Preliminary Results of RTOG 92-08 Cancer J Sci Am 2 (4): 205-11, 1996. [PUBMED Abstract]
- Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 348 (9034): 1049-54, 1996. [PUBMED Abstract]
- Northover J, Glynne-Jones R, Sebag-Montefiore D, et al.: Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer 102 (7): 1123-8, 2010. [PUBMED Abstract]
- Flam M, John M, Pajak TF, et al.: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 14 (9): 2527-39, 1996. [PUBMED Abstract]
- Ajani JA, Winter KA, Gunderson LL, et al.: Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA 299 (16): 1914-21, 2008. [PUBMED Abstract]
- Gunderson LL, Winter KA, Ajani JA, et al.: Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol 30 (35): 4344-51, 2012. [PUBMED Abstract]
- James RD, Glynne-Jones R, Meadows HM, et al.: Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol 14 (6): 516-24, 2013. [PUBMED Abstract]
- Peiffert D, Tournier-Rangeard L, Gérard JP, et al.: Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol 30 (16): 1941-8, 2012. [PUBMED Abstract]
- Holland JM, Swift PS: Tolerance of patients with human immunodeficiency virus and anal carcinoma to treatment with combined chemotherapy and radiation therapy. Radiology 193 (1): 251-4, 1994. [PUBMED Abstract]
- Peddada AV, Smith DE, Rao AR, et al.: Chemotherapy and low-dose radiotherapy in the treatment of HIV-infected patients with carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 37 (5): 1101-5, 1997. [PUBMED Abstract]
- Hoffman R, Welton ML, Klencke B, et al.: The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys 44 (1): 127-31, 1999. [PUBMED Abstract]
- Place RJ, Gregorcyk SG, Huber PJ, et al.: Outcome analysis of HIV-positive patients with anal squamous cell carcinoma. Dis Colon Rectum 44 (4): 506-12, 2001. [PUBMED Abstract]