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Combined Radiation and Chemotherapy for Carcinoma of the Anal Canal

Combined Radiation and Chemotherapy for Carcinoma of the Anal Canal

ABSTRACT: Sphincter-preserving treatment with combined radiation and chemotherapy has replaced abdominoperineal resection as the standard of care for patients with carcinoma of the anal canal. Randomized studies have shown that the combination of radiation therapy, fluorouracil (5-FU), and mitomycin (Mutamycin) is superior to radiation alone or to radiation combined with 5-FU in these patients and that the colostomy-free survival rate is 71%. Research is underway to determine whether other combinations, such as higher doses of radiation with 5-FU and cisplatin (Platinol), will result in lower or equivalent toxicity or better locoregional control and potentially improved survival. Currently, radiation combined with 5-FU and mitomycin remains the treatment of choice in most patients with carcinoma of the anal canal. [ONCOLOGY 12(3):373-389, 1998]

Carcinoma of the anal canal occurs in approximately 2,500 people per year in the United States and represents 2% of all anorectal cancers.[1,2] In many single-institution series, this cancer shows a predilection for females, with an average age at diagnosis of 60 years.[1,3,4] However, in an urban population-based study,[5] anal cancer was most common in single males under 35 years of age and in females over age 35. Anal cancer also has been associated with anal condyloma in homosexual men.[6]

The definition of the anal canal has varied,[7] but currently it is defined as extending from the rectum to, but not including, the perianal skin.[8] The most common presenting symptoms of anal canal carcinoma are bleeding, perianal pain, and constipation or diarrhea.[4] Evaluation should include a history, physical examination, chest x-ray, complete blood count, liver function tests, and CT of the abdomen and pelvis.

As will be detailed below, the preferred treatment of carcinoma of the anal canal has evolved from being primarily surgical to combined radiation therapy and chemotherapy. Chemoradiation allows for preservation of organ function while resulting in a survival rate similar to that seen with primary surgical management.

Surgery

Before the advent of modern radiotherapy, surgery was the definitive treatment for carcinoma of the anal canal.[1,3,4,9-11] Local excision was used for carcinoma in situ or microinvasive tumors and resulted in excellent local control: In one series,[9] 4 of 4 lesions were controlled, while in another series,[1] 11 of 12 superficial, small lesions were controlled. Abdominoperineal resection of invasive tumors achieved 5-year survival rates ranging from 33% to 82%[1,9,12] and was best for small, less invasive lesions with no nodal involvement.[1]

Radiation Therapy

Radiation therapy has been used since the early 1900s for carcinoma of the anal canal. Interstitial gold or radium was used as early as 1936 by Bond,[11] who believed that curative radiation was generally equal to surgery, except that radiotherapy resulted in a higher rate of anal necrosis.

In 1961, Dalby and Pointon[13] reviewed the Manchester experience with interstitial radium therapy. They contended that radium therapy was curative, provided that an adequate dose was used. In 23% of their patients, necrosis developed, 10% of which was severe and late. Early use of “supervoltage” external-beam therapy resulted in severe necrosis in 22% of cases.[14]

More recent series provide data on local control and overall survival with the use of megavoltage radiation therapy alone (Table 1). [15-23] Local control[17,19,21,23] for T3 and T4 lesions has been inferior, and overall survival also has been worse for patients with more advanced T-stage lesions and those with clinically positive lymph nodes.[15,21] In most series using radiation alone, doses have exceeded 6,000 cGy (Table 1). The techniques used varied with respect to beam orientation and the manner in which the radiation was delivered (continuous vs split-course administration).

Combined Radiation and Chemotherapy

Early Studies

The use of chemotherapy combined with radiation for the treatment of cancer of the anal canal, with the goal of preserving anal function, was pioneered by investigators at Wayne State University[24] and the Princess Margaret Hospital,[25] among others.[1,26] Initially, the combination of fluorouracil (5-FU), mitomycin (Mutamycin), and moderate doses of radiation also was used as a preoperative regimen.[24,26] Subsequently, results with the same treatment approach from Wayne State and University other centers were published in detail (Table 2).[27-32]

The radiation technique used at Wayne State consisted of opposed anterior and posterior fields encompassing the true pelvis and medial inguinal lymph nodes. A total dose of 3,000 cGy was used, administered at a dosage of 200 cGy/d. Chemotherapy consisted of 5-FU (1,000 mg/m²/24 h) given by continuous infusion through a central venous catheter for 4 days beginning on the first day of radiation therapy. In addition, mitomycin (15 mg/m²) was given by bolus injection on day 1 of radiation. Leichman et al[27] updated the Wayne State results in 1985.

Other investigators used this approach in the mid-1980s,[4,30,33] and subsequently more single institutions reported their data.[22,23,29,30,34-37] Of particular interest is the work of Cummings et al.[25] They reported on the results of treatment with various regimens of radiation alone or combined with 5-FU, with or without mitomycin in eight different protocols. Cummings et al found that the strongest predictor for local control was the addition of mitomycin to 5-FU and radiation.

On the basis of the work of Nigro and others,[38] the Radiation Therapy Oncology Group (RTOG) conducted a phase II study (8314) of radiation combined with mitomycin and 5-FU (FUMIR) to determine whether the combination of chemotherapy and radiation therapy could be curative in a large number of patients, obviating abdominoperineal resection.[28] Radiation dosage was 170 cGy per fraction per day, to a total dose of 4,080 cGy to the whole pelvis; also, the inguinal lymph nodes received 4,080 cGy at a depth of 3 cm from the skin surface. Chemotherapy was given on day 2 and consisted of 5-FU (96-hour continuous infusion at 1,000 mg/m²/24 h) and a one-time dose of mitomycin (10mg/m²). Fluorouracil was repeated on day 28 of radiation therapy. The estimated 3-year local-regional control rate was 71% and the estimated 3-year disease-free and overall survival rates were 61% and 73%, respectively.

Intergroup Study

The encouraging results from this protocol led to the intergroup study recently reported by Flam et al[31] comparing 5-FU and radiation (FUIR) with FUMIR. In this study, the total dose of radiation was 4,500 cGy, and patients whose post-treatment biopsy was positive had the option of receiving additional chemotherapy (5-FU and cisplatin [Platinol]) and radiation (900 cGy in five fractions).

The colostomy-free survival rate at 4 years was 89% for the FUMIR group and 77% for the FUIR group (P = .002). Likewise, the 4-year disease-free survival rate was significantly improved in the FUMIR arm compared with the FUIR arm (73% vs 51%) (P = .0003). Overall survival was not statistically different in the two arms (P = .31).

Nonhematologic toxicity did not differ between the two arms. However, neutropenia and associated infection and a greater degree of thrombocytopenia occurred in the FUMIR arm. Overall, the FUIR-treated patients had a 7% incidence of grade 4 toxicity and one death (0.7%). Grade 4 toxicity occurred in 23% of the FUMIR-treated patients, and four patients (2.7%) had fatal toxicity. These differences in grades 4 and 5 toxicity were statistically significant (P

£ .001).

Randomized Trials

Two important randomized trials of radiation vs chemoradiation for cancer of the anal canal were recently reported from Europe. The first trial, conducted by the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Anal Cancer Trial Working Party,[39] compared radiation alone (4,500 cGy, with or without a boost of 1,500 to 2,000 cGy) vs radiation combined with 5-FU and mitomycin in patients with anal margin or anal canal cancer. In all, 82% of the patients received the radiation boost. Most (75%) of the patients had carcinoma of the anal canal, and there were 577 eligible, randomized patients.

The local failure rate was 59% with radiation alone and 36% with chemoradiation. There was no difference in overall survival between the two arms, but there was an increased percentage of deaths due to anal cancer in the radiation-alone arm. The rate of acute toxicity was higher in the chemoradiation arm, but the rate of late toxicity did not differ between the arms.

The European Organization for the Research and Treatment of Cancer (EORTC) Radiotherapy and Gastrointestinal Cooperative Groups[40] reported the results of a similar trial of patients with T3, T4, or tumors > 4 cm or with lymph node-positive disease, in which radiation alone was compared with FUMIR. The radiation dose, however, was similar to that used in the UKCCCR trial.[39] Initially, 4,500 cGy in 25 fractions was given. This was followed by a 6-week break, and then a 1,500- to 2,000-cGy boost was delivered in all patients. The 3-year results showed an improvement in local control and colostomy-free survival for patients in the chemoradiation group.

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