Updated: 2 March 2005

Anal Margin

Squamous and basal cell cancers of the anal margin, including carcinoma in situ and early invasive carcinomas, should be treated with local excision, providing adequate margins can be obtained without endangering sphincter function. More extensive tumours should be considered for combined chemotherapy and localized radiotherapy.

Anal Canal

This group includes cancers of the anal canal which may be extending up into the rectum or down onto the perianal skin, and also carcinomas of the anal margin which are extending into the canal. The preferred treatment is external irradiation, combined with chemotherapy if the tumour is large or there is nodal involvement. Combined modality therapy has a high likelihood of curing the disease while maintaining sphincter function.

Radiation alone is usually sufficient for tumours less than 3 cm, and which are confined to the anal canal with no rectal involvement and no nodal involvement. For other tumours, combined modality therapy is recommended.

Randomized trials of radiation versus chemoradiation (with 5-fluorouracil and mitomycin) show better complete response rates, event free survival, colostomy-free survival, but higher early toxicity with the combined approach.^1,2 No survival difference was observed between these modalities, presumably because surgery is good salvage therapy for locally recurrent disease. A further randomized trial has shown improved disease free survival but higher toxicity with the use of both 5-fluorouracil and mitomycin combined with radiation compared with 5-fluorouracil and radiation alone³. An ongoing randomized trial is exploring the relative merits of 5-fluorouracil versus 5-fluorouracil plus cisplatin, both combined with concurrent radiation, based on promising phase II data^3-6. Other ongoing trials are also exploring the role of cisplatin in the neoadjuvant, concurrent and adjuvant settings. Until the results of these phase III trials are available, the inclusion of cisplatin in the chemotherapy regimen is not recommended.

At BC Cancer Agency centres, the usual course of radiotherapy is 5000cGy delivered as a split course of two 2500cGy courses over 2.5 weeks (12 fractions) each, separated by a three and a half week break. Chemotherapy is given for the first few days of each of the two radiation courses and consists of a 4-day continuous infusion of 5-fluorouracil, which acts as a radiation sensitizer, beginning on day 1 of each split course of radiation, and a single injection of mitomycin C also on day 1 of each radiation course. The chemotherapy is therefore given during weeks 1 and 7 of the 8.5 week course. The break reduces the incidence of acute local radiation toxicity and allows for hematologic recovery between chemotherapy cycles⁷. (GIFUART) There is non-randomized evidence, however, that intentional or unintentional breaks in the radiotherapy course reduces local control but no randomized trial has explored the issues of radiation dose and overall treatment duration. Therefore, for very fit patients, consideration may be given to a continuous 5-week course of radiation therapy (no planned break) concurrent with 2 cycles of chemotherapy given during weeks 1 and 5.

Clinically or radiographically uninvolved inguinal nodes are routinely irradiated but to a lower total dose.

Early toxicity includes diarrhea (mucositis), local skin reactions, neutropenia, mucositis, and nausea (the latter 3 predominantly from the chemotherapy). HIV patients with significant immune suppression (CD4< 200) tend to tolerate chemotherapy and radiation therapy (particularly doses > 30Gy) more poorly⁸. The most common late toxicities include frequency and urgency due to proctitis that may persist for several months after treatment, dyspareunia and other sexual problems and anal incontinence or stricture formation-particularly if the tumour had damaged the sphincter prior to treatment.

Abdominoperineal resection is reserved for patients who have persistent or recurrent disease following combined chemo-radiotherapy, or as primary therapy for patients with large tumours that have destroyed the anal sphincter. This latter group should be considered for either pre- or postoperative radiotherapy plus or minus chemotherapy to enhance local control. Salvage therapy with 5-fluorouracil plus cisplatin has also shown some promise in locally persistent disease³.

A proportion of patients will have persistence of or development of inguinal metastases following chemotherapy and radiotherapy. If this is the only site of additional disease, inguinal node dissection is usually recommended which may be combined with further radiotherapy. Surgical and radiation approaches for paravertebral nodal disease are not routinely recommended, due to anatomic location and associated technical complexity.

Palliative 5-fluorouracil based chemotherapy, with or without cisplatin, should be considered for fit patients with symptomatic distant metastases and nodal metastases not amenable to local therapies The benefit, however, is unclear.

References:

1. Bartelink H, Roelofsen F, Eschwege F et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 1997; 15: 2040-9.
2. UKCCR Anal Cancer Trial Working Party. Epidermoid anal cancer: results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fluorouracil and mitomycin. Lancet 1996; 348: 1049-54.
3. Flam M, John M, Pakak et al. Role of combination with fluorouracil and radiotherapy, and of salvage chemoradiation I the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 1996; 14: 2527-39.
4. Doci R, Zucali R, La Monica G et al. Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients. J Clin Oncol 1996; 14: 3121-5.
5. Peiffert D, Giovannini M Ducreux M et al. High-dose radiation therapy and neoadjuvant plus concomitant chemotherapy with 5-fluorouracil and cisplatin in patients with locally advanced squamous-cell anal canal cancer: final results of a phase II study. Ann Oncol, 2001; 12: 397-404.
6. Meropol N, Niedzwiecki B, Shank t, et al. Combined-Modality therapy of poor risk anal canal carcinoma: A phase II study of the Cancer and Leukemia Group B (CALGB) Proc ASCO 1999; 18: 237, a909.
7. Cummings MB, Keane TJ, O'Sullivan MB et al. Epidermoid anal canal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin c. Int J Radiation Oncology Biol Physics 1991; 21: 1115-1125.
8. Hoffman R, Welton M, 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 1999; 44: 127-31.