Anal Canal Carcinoma
Epidemiology, Etiology, and Risk Factors
In the United States, about 4,650 new cases of anal canal carcinoma are diagnosed each year. Overall, it is slightly more common in women than in men. More than 80% of anal canal tumors occur in individuals older than 60 years. Epidemiologic studies suggest that receptive anal intercourse and human papillomavirus (HPV) infections are strongly related to anal cancer.
The incidence rate of anal cancer for single men is reported to be six times that for married men. In persons younger than 35 years, anal carcinoma is more common in men than in women. A history of genital warts has been observed, further suggesting that HPV infection may be an etiologic factor.
Diagnosis
The diagnosis of anal canal carcinoma is usually delayed because the symptoms (bleeding, pain, and sensation of mass) are often attributed to benign anorectal disorders, such as hemorrhoids or anal fissures.
Evaluation should include a careful rectal examination, endoscopic examination with description of lesion size, and assessment of whether there is invasion of disease into adjacent organs (vagina, urethra, or bladder). Reexamination with the patient under general anesthesia may be necessary. A diagnostic incisional biopsy is required.
Pelvic CT is suggested to evaluate pelvic nodes. Although distant metastases are uncommon at diagnosis, chest radiography and liver function tests are recommended. Suspicious inguinal nodes discovered on physical examination must be assessed pathologically. The incidence of inguinal nodal metastases at diagnosis varies from 13% to 25%. The presence of perirectal, inguinal, and pelvic lymph node involvement correlates with tumor size and is unusual for tumors less than 2 cm in diameter. Formal groin dissection is not advised; needle aspiration should be performed, with limited surgical biopsy if results of aspiration are inconclusive.
Pathology
Squamous cell carcinomas
Most anal canal malignancies are squamous cell carcinomas. They have been classified as cloacogenic carcinomas, basaloid carcinomas, transitional cell carcinomas, or mucoepidermoid carcinomas. However, there is little difference in the natural history of these various types.
Unusual tumors
Unusual tumors arising in the anal canal include small-cell carcinomas, anal melanomas, and adenocarcinomas.
TNM classification of anal canal tumorsSmall-cell carcinomas of the anal canal are aggressive neoplasms similar in natural history to bronchogenic small-cell carcinomas. If such a histology is identified, the clinician should be alerted to the possibility of early distant metastases, and treatment should include chemotherapeutic regimens used in bronchogenic small-cell carcinomas.
Although advanced anal melanomas generally are associated with a dismal survival, prognosis may be related to the depth of disease penetration. Early anal melanomas less than 2 mm in depth can be cured with wide excision. More advanced disease can be treated with local excision and EBRT, with excellent local tumor control. Abdominoperineal resection is indicated only rarely in the management of anal melanoma, because lesions large enough to require radical surgery are almost always associated with distant spread of disease.
Adenocarcinomas are uncommon cancers associated with a poor prognosis. Treatment should be aggressive and based on a multimodality approach. The rarity of this tumor precludes the development of specific clinical trials.
Staging
The size of the primary tumor is the most important clinical predictor of survival for patients with anal carcinomas. Both the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) have agreed on a unified staging system (Table 11). The TNM classification distinguishes between anal canal carcinoma and anal margin tumors, because the latter exhibit biologic behavior similar to that of other skin cancers and are staged as skin cancers.
Treatment
Surgery
In select individuals with small superficial T1 tumors, local excision has achieved adequate local tumor control and survival. However, most studies of local excision have been retrospective, with small numbers of patients. Before the advent of primary radiotherapy and combined-modality treatment, abdominoperineal resection was considered to be the conventional treatment for patients with invasive anal canal cancer. Unfortunately, even with radical surgical procedures, local recurrences are frequent. Currently, radical extirpative surgery is indicated only after the failure of combined-modality treatment. Salvage abdominoperineal resection for persistent or recurrent disease has resulted in a 5-year survival of up to 60%. In one series, patients presenting with lymphadenopathy at primary diagnosis and those who received less than 55 Gy at initial chemoradiation treatment had a poorer prognosis.
Radiation therapy
Trials of primary EBRT in patients with anal canal carcinomas have used doses varying between 4,500 and 7,550 cGy. Local tumor control rates of 60% to 90%, with 5-year survival rates of 32% to 90%, are similar to the results of surgical series when the trials are controlled for tumor size.
Interstitial radiation therapy alone has been used primarily in Europe for early-stage lesions. A relatively high radiation dose is delivered to a small volume. This modality carries a high potential for radiation necrosis and fails to incorporate the treatment of the inguinal nodes.
Combined-modality treatment
Chemotherapy given concurrently with irradiation is the preferred therapy for most patients with anal canal cancer (Table 12). Investigators from Wayne State University pioneered the use of simultaneous pelvic irradiation and chemotherapy in the treatment of patients with anal canal carcinomas. They demonstrated that the majority of such patients could be treated with this combination, obviating the need for an abdominoperineal resection. The original study design used 3,000 cGy over 3 weeks with 5-FU (1,000 mg/m2/d) as a continuous infusion on days 1 to 4 and then repeated on days 29 to 32. Mitomycin, 15 mg/m2, was administered as an IV bolus on day 1. At 4 to 6 weeks after the completion of therapy, patients had a deep muscle biopsy of the anal canal scar.
Chemotherapy regimen for anal canal cancerAn updated analysis of this experience demonstrated that 38 of 45 patients (84%) were rendered disease-free after chemotherapy and irradiation. Individuals who had positive results on biopsy underwent an abdominoperineal resection.
Because of the success of this experience, other investigators have attempted to implement infusional 5-FU and mitomycin with irradiation as definitive therapy. Most studies have used similar schedules of 5-FU and mitomycin but have used higher doses of pelvic irradiation (4,500 to 5,700 cGy). Five-year survival rates greater than 70% have been reported.
A randomized trial from the Radiation Therapy Oncology Group (RTOG) showed that the use of mitomycin with irradiation and 5-FU increased complete tumor regression and improved colostomy-free survival over irradiation and 5-FU alone. At 4 years, the colostomy-free survival rate was higher in the mitomycin arm than in the 5-FU–alone arm (71% vs 59%), as was the disease-free survival rate (73% vs 51%).
Several investigators have compared the results of irradiation alone with those of irradiation plus chemotherapy. The current standard chemotherapy regimen for concurrent radiation is concurrent 5-FU and mitomycin. Intergroup RTOG 98-11 compared 5-FU plus mitomycin concurrently with radiotherapy, with 5-FU plus cisplatin induction followed by 5-FU plus cisplatin concurrently with radiotherapy. The mitomycin-containing regimen resulted in a lower colostomy rate but greater hematologic toxicity. Cummings et al found that with identical irradiation doses and techniques, the local tumor control rate for cancers larger than 2 cm rose from 49% with radiation therapy alone to 85% when 5–FU and mitomycin were combined with irradiation. Papillon and Montbarbon found an increase in the rate of local tumor control with a combined-modality approach compared with pelvic irradiation alone (81% vs 66%). Two randomized studies have shown improved local tumor control with chemoradiation therapy over irradiation.
A complete response to combined chemotherapy and radiation therapy is expected in 80% to 90% of patients with anal cancer. It is important to evaluate the response to therapy with a careful examination of the anal canal after treatment. Anal canal cancers can continue to regress for up to 3 or more months after completion of treatment. For this reason, it is recommended that a biopsy be performed no sooner than 3 months after the completion of treatment, unless there is evidence of disease progression or other evidence to suggest early recurrence. If pathologic evidence of recurrence is diagnosed, abdominoperineal resection is expected to yield long-term disease control and survival in 40% to 60% of patients.
Toxicity from combined radiotherapy and chemotherapy for anal carcinoma is significant, with high rates of dermatitis (often requiring treatment breaks) and gastrointestinal toxicity. Treatment breaks may decrease the efficacy of radiation. Intensity-modulated radiotherapy (IMRT) can help reduce the radiation dose to normal structures, such as the bowel, skin, genitalia, and femurs.
Several phase II trials, including the RTOG 0529 trial, have evaluated the use of IMRT with concurrent chemotherapy to reduce these toxicities. Some of these studies have suggested that local tumor control and survival may be improved with IMRT. Toxicity was markedly reduced with the IMRT approach. The RTOG has published contouring guidelines for radiation oncologists who use IMRT.
Chemotherapy
Reports of other chemotherapeutic agents in anal cancer have been relatively anecdotal, with limited phase II studies. Because of the activity of cisplatin in other squamous cell carcinomas, this agent has been employed as a single agent or combined with infusional 5-FU in advanced disease.
Novel chemoradiation regimens have been evaluated in the hope of providing improved tumor control rates in patients receiving combined chemotherapy and radiation. Recent studies have evaluated chemotherapy combinations including cetuximab(Drug information on cetuximab) with radiation. These early studies are promising in regard to tolerability and response rates. The combination of cetuximab, cisplatin, and 5-FU with radiation therapy is being tested by the AIDS Associated Malignancies Clinical Trials Consortium (AAMCTC) and the Eastern Cooperative Oncology Group (ECOG).
Considerations for immunocompromised patients
Immunocompromised patients are at higher risk for developing anal carcinoma. Because these patients may also have increased toxicity with combined chemotherapy and radiation, careful delivery of combined therapy should include a consideration of chemotherapy dose modification. Several series have evaluated the ability of immunocompromised patients to tolerate definitive chemoradiotherapy for anal cancer. Some series suggest that a CD4+ cell count lower than 200/μL in HIV-positive patients is associated with higher rates of toxicity. Recent studies have shown that the vast majority of immunocompromised patients can tolerate concurrent chemoradiotherapy, although dose adjustments may be required. The use of IMRT may benefit this patient subset.
