Squamous Cell Carcinoma of the Anal Canal

William M. Mendenhall, MD
Professor of Radiation Oncology
University of Florida College of Medicine
Gainesville, Florida, USA

The management of squamous cell carcinoma of the anal canal has changed dramatically over the last several decades. Treatment currently consists of radiation therapy alone or combined with concurrent chemotherapy (“chemoradiation”) for the majority of patients. Several questions arise pertaining to the optimal management of anal canal squamous cell carcinoma: (1) Is there a role for primary radical surgery? (2) Is chemoradiation superior to radiation therapy alone? (3) If chemoradiation is indicated, what is the best chemotherapy regimen? (4) What are the optimal radiation therapy techniques?

A review of the pertinent literature comparing the results of radical surgery and radiation therapy alone reveals no significant difference, either in local control or survival, for either modality. Because primary surgery usually entails abdominoperineal resection and a permanent colostomy, the treatment of choice is radiation therapy. Nigro et al¹ treated a small number of patients with preoperative chemoradiation followed by surgery, and stimulated considerable enthusiasm for this approach. Subsequent studies by Papillon and Montbarbon² and Cummings et al³ indicate that combined chemotherapy and radiation, using fluorouracil and mitomycin, are superior to radiation therapy alone for patients with advanced disease. Two randomized trials published recently (one from the United Kingdom Co-ordinating Committee on Cancer Research [UKCCCR]⁴ and one from the European Organization for Research and Treatment of Cancer [EORTC]⁵) have indicated that the combination of radiotherapy plus fluorouracil (5-FU) and mitomycin resulted in superior rates of local control and colostomy-free survival compared with radiation therapy alone. Acute toxicity was increased. The likelihood of late toxicity was not significantly different. The UKCCCR trial included patients with all stages of disease, as well as those with anal margin cancers. The EORTC study was confined to patients with advanced tumors. Therefore, the preponderance of the data indicates that the combination of chemotherapy and radiation therapy is indicated for patients who are medically able to tolerate the treatment, if they have moderately advanced or advanced lesions. Patients with T1 N0 tumors and early-stage T2 lesions (less than 3 cm in size with negative nodes) may not benefit from the addition of chemotherapy. In these patients, the toxicity of treatment may outweigh the potential benefit.⁶

A randomized study conducted by the Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG)⁷ compared radiation therapy plus 5-FU versus radiation therapy plus 5-FU and mitomycin. The combination of 5-FU and mitomycin was found to be superior to 5-FU alone. A retrospective study from the Princess Margaret Hospital by Cummings et al³ indicated that 5-FU plus radiotherapy was equivalent to radiation therapy alone. Therefore, if chemotherapy is indicated, the standard chemotherapy regimen at this time is 5-FU and mitomycin. Interest has been generated in substituting cisplatin for mitomycin to reduce the toxicity of the chemotherapy regimen. Limited data pertaining to this approach indicate that cisplatin and 5-FU may yield local-regional control results that are equivalent to those seen after 5-FU and mitomycin; however, the toxicity of the two-drug combinations may also be equivalent. An ongoing RTOG prospective, randomized trial currently is comparing radiation therapy plus 5-FU and mitomycin with radiation therapy plus 5-FU and cisplatin.

Controversial issues pertaining to the radiotherapeutic treatment of anal canal cancer include the arrangement and size of the radiation therapy portals, the total dose and dose per fraction, continuous-course versus split-course radiation therapy, and boost technique. It is beyond the scope of this paper to discuss these issues in detail; however, a few points will be addressed. First, because of the significant risk of regional lymph node metastases, even for early-stage lesions, the nodes should be included in the initial radiation therapy portals in all cases. Second, a total dose of 30 Gy in 15 fractions combined with chemotherapy is probably too low for advanced carcinomas. Although some authors have observed relatively good local-regional control rates after low-dose radiotherapy combined with chemotherapy for patients with T1 tumors and T2 N0 lesions, most authors use doses in the range of 50 Gy to 60 Gy. Third, the total dose should not exceed 65 Gy for two reasons: (1) the likelihood of cure at these dose levels is relatively high, and (2) doses in excess of 65 Gy are likely to result in an unacceptably high incidence of necrosis. Fourth, the daily fraction size should be in the range of 1.8 Gy to 2.0 Gy. Daily fractions greater than 2 Gy are associated with an increased risk of late complications. Finally, if a perineal field is to be used to boost the dose to the primary lesion, the use of electron beam should be avoided unless all the perianal skin in the field is involved by tumor. Otherwise, a high dose of radiation therapy will be given unnecessarily to the uninvolved perianal skin, resulting in a high risk of subcutaneous fibrosis.

The initial course of radiation therapy may be delivered with either anterior and posterior fields or a 4-field box technique. The 4-field box technique is preferred at the University of Florida in an effort to decrease the dose to the small bowel. The dose to the inguinal nodes may be supplemented with electron beam of sufficient energy to treat the deep inguinal nodes as identified on treatment-planning computed tomography scan. Alternatively, the lateral fields may be designed to include the inguinal nodes, making electron boost fields unnecessary. The disadvantage of using this technique is that more of the perineum is included in the lateral fields; the advantage is that inhomogeneities that may be encountered using electrons to irradiate the inguinal nodes may be avoided. Both techniques are preferable to a 2-field (anterior and posterior) technique where a larger volume of small bowel receives essentially the same dose as the tumor.

At the University of Florida, the radiation therapy dose to the primary lesion is boosted to a total of approximately 60 Gy; the boost technique used depends on the extent and location of the tumor. Lesions that are 6 cm or less in length and involve less than two thirds of the circumference of the anal canal are treated with an interstitial iridium implant using the technique described by Papillon and Montbarbon.² This technique entails a single-plane implant using an acrylic template with 1 cm spacing between the sources. The dose is specified at 0.5 cm from the plane of the needles at a dose rate of 1 Gy per hour. The advantage of using an implant, compared with an external beam boost, is the ability to give a high dose over a short period of time to a more limited volume of tissue. Lesions that involve more than two thirds of the circumference of the canal and are located within 3 cm to 4 cm of the anal verge are given a boost dose through a perineal field using 60Co with the patient supine, the beam angled inferiorly, and the dose calculated to the proximal margin of the tumor. Lesions unsuitable for either of these techniques receive a boost treatment with a 3-field technique (posterior field and parallel-opposed lateral fields) with the patient prone. Routine biopsy after radiation therapy alone or chemoradiation, which could result in a soft tissue necrosis, is not obtained unless there is clinical evidence of a local recurrence.

Because patients who are HIV-positive may exhibit increased toxicity secondary to treatment, the therapy may be modified depending on the patient’s extent of disease and medical condition. Patients with CD4 counts greater or equal to 200 have been reported to have excellent disease control with acceptable morbidity, whereas those with lower CD4 counts may experience increased toxicity.⁸

Local control after chemoradiation or radiation therapy alone, depending on the extent of the primary lesion, is in the range of 75% to 90%. Survival rates are approximately 60% to 70% with cause-specific survival rates being somewhat higher. If the disease is locally and regionally controlled, the likelihood of distant metastases is relatively low. The risk of late complications is in the range of approximately 5% to 10%.

Published September 2000