ABSTRACT: Anal cancer accounts for 1.5% of digestive system malignancies in the United States. In the past 30 years, substantial progress has been made in understanding the pathophysiology and treatment of the disease. Anal cancer was once believed to be caused by chronic local inflammation of the perianal area, and treatment was abdominoperineal resection. From epidemiologic and clinical studies, we now know that the development of anal cancer is associated with human papillomavirus infection and that the disease has a pathophysiology similar to that of cervical cancer. Less invasive treatments have also been developed, and the majority of patients with anal cancer can now be cured with preservation of the anal sphincter using concurrent external-beam radiation therapy and fluorouracil (5-FU)/mitomycin (Mutamycin) chemotherapy. Current areas under investigation include the incorporation of platinum agents into the chemotherapy regimen and the use of cytologic screening studies for high-risk populations.
Anal cancer is responsible for 1.5% of all digestive system malignancies in the United States, with 4,000 new cases anticipated in 2003.[1] The incidence of anal cancer in the general population ranges between 7 and 9 cases per million.[2] Certain groups have a higher incidence, including women,[3] human immunodeficiency virus (HIV)-positive patients,[4] patients with a history of human papillomavirus (HPV) infection, and patients who engage in anal receptive intercourse.[2] Over 90% of patients present with locoregional disease, and less than 20% of patients will present with or develop distant metastases.
In the past 30 years, much progress has been made in understanding the pathophysiology of anal cancer, and less invasive treatments have been developed.[5] Once thought to be the result of chronic perianal inflammation and treated with abdominoperineal resection, anal cancer is now known to be associated with HPV infection. The majority of patients can be cured with concurrent chemotherapy and radiation therapy alone.[6]
Anatomy and Histology
The anal canal extends from the junction of the puborectalis portion of the levator ani muscle and the external anal sphincter to the anal verge. The length of the canal varies but is approximately 4 cm. The transition from the rectal mucosa to the squamous mucosa on the hair-bearing anal margin can also vary among patients. The proximal portion of the anal canal is referred to as the transitional zone. In some patients, the distinction between the anal squamous mucosa and the rectal glandular mucosa is clear and abrupt, but others can have an intervening segment of urothelial-like pseudostratified epithelium with cuboidal or polygonal surface cells. This intervening segment was formerly referred to as junctional, basaloid, or cloacogenic mucosa. Tumors that arise from this epithelium are now called nonkeratinizing squamous cell carcinomas.
The biology and prognosis of keratinizing and nonkeratinizing squamous cell carcinomas of the anal canal are similar.[7,8] There is no easily identifiable landmark between the rectum and anus, so clinicians should rely on the pathologic classification of tumors in this area rather than the surgical or endoscopic classification. Adenocarcinomas of the anal canal are treated as rectal adenocarcinomas, as they share the same natural history.
Lymphatic drainage of anal cancers is dependent on the anatomic site of origin. Tumors located above the dentate line drain to the perirectal and paravertebral nodes, which is similar to rectal cancers. Tumors below the dentate line drain to the inguinal and femoral lymph nodes, and patients with anal cancer should undergo both physical and radiographic examination of these nodes.[9-11]
Staging
The American Joint Committee on Cancer and the International Union Against Cancer have established a tumor-node-metastasis (TNM) staging system for anal cancer (Table 1). Patients with T1 or T2 lesions have an 80% to 90% 5-year survival rate, whereas patients with T4 lesions have less than a 50% 5-year survival rate. For patients with lymph node metastases, the 5-year survival rate is approximately 50%.[12-15] At presentation, 50% to 60% of patients have a T1 or T2 lesion and 12% to 20% are nodepositive.[10,12,13,15,16] The probability of nodal spread is directly related to tumor size and location.
Epidemiology
Epidemiologic studies over the past 10 years have identified several risk factors for anal cancer, including the presence of sexually transmitted disease, the practice of anal receptive intercourse, a history of more than 10 sexual partners, and a history of cervical, vulvar, or vaginal cancers.[17-23] These risk factors are due to a link between HPV and anal cancer. Human papillomavirus can cause premalignant anal squamous intraepithelial lesions (ASIL), which can be low grade (LSIL) or high grade (HSIL). Progression of ASIL to invasive anal cancer is affected by HIV seropositivity, low CD4 count, the subtype of HPV, and high DNA levels of high-risk HPV subtypes in the anal canal.[24] Although not completely clear, there seems to be a relationship between HIV infection and anal cancer.
Patients with HIV are more likely to have HPV infection, and the risk of HPV infection evolving into HSIL and invasive anal cancer is also greater among these patients.[25] These risks appear to be inversely related to the patient's CD4 count.[24,26-28] A possible mechanism for the increased incidence of anal cancer among HIVpositive patients is immunosuppression. However, a large US study in acquired immunodeficiency syndrome (AIDS) patients found that the incidence of ASIL increases after the onset of AIDS while the risk of invasive anal cancer does not, bringing into question the relationship between immune status and the development of invasive anal cancer.[29]
Moreover, with the widespread use of highly active antiretroviral therapy (HAART), the incidence of other HIV-associated cancers such as Kaposi's sarcoma and non-Hodgkin's lymphoma have decreased while the incidence of anal cancer has not.[30] Given the high risk for ASIL among homosexual and bisexual men, investigators have conducted studies of the potential cost-effectiveness of screening these men with anal cytology every 2 to 3 years. The results of two trials that evaluated screening in both HIV-positive and HIV-negative homosexual or bisexual men suggested that such screening would be costeffective and have life expectancy benefits.[31,32]
Individuals with other causes of chronic immunosuppression including renal transplant patients and those on chronic glucocorticoid therapy also appear to be at increased risk for ASIL and anal cancer, typically associated with HPV infection.[33-38] In addition, smoking is associated with a higher risk of developing invasive anal cancer.[17,39,40]
Treatment
Before 1980, an abdominoperineal resection was the treatment of choice for tumors of the anal canal. Surgical series prior to 1980 found the overall 5-year survival rate after an abdominoperineal resection to range between 40% and 70%. Patients with large tumors and nodal metastases had poorer outcomes.[9,12,13,18,41-43] In an attempt to improve surgical outcome, Nigro and colleagues at Wayne State evaluated preoperative chemotherapy with fluorouracil (5-FU) and mitomycin (Mutamycin) combined with intermediate-dose radiation therapy (30 Gy). Unexpectedly, the investigators found that the first three patients who received treatment achieved complete responses.[44] Multiple institutional series subsequently demonstrated that chemoradiation in patients with anal cancer resulted in a colostomyfree survival of 66% to 70% as well as a 5-year survival of 58% to 92% (Table 2).[6,9,45-68]
The combination of chemotherapy and radiation therapy was also found to be generally well-tolerated and effective in patients with HIV, but patients with CD4 counts less than 200/μL and those who received greater than 30 Gy of irradiation had poorer tolerance.[69-71] In addition, trials using radiation therapy alone, given as external-beam irradiation or brachytherapy, reported good local tumor control and cure rates ranging from 70% to 90%.[15,67,72-80] However, local control and cure rates were less than 50% for patients with tumors greater than 5 cm and/or lymph node involvement.[15,81]
Chemoradiation vs Radiotherapy Alone
Attempting to evaluate the relative benefit of chemoradiation compared to radiation therapy alone, the United Kingdom Coordination Committee on Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC) each embarked on phase III studies (Table 3).[8,82] The first was conducted by the Anal Cancer Trial Working Party of the UKCCCR; 585 patients were randomized to receive either radiation therapy (45 Gy of external-beam treatment with either a 15-Gy external-beam boost or a 25-Gy brachytherapy boost) or the same radiation therapy in combination with concurrent 5-FU and mitomycin. Chemoradiation improved local control (39% vs 61%) and disease-specific survival (28% vs 30%), but the overall survival rate was not significantly different between the two groups.[82]
The EORTC randomized 110 patients to receive radiotherapy (45 Gy of external-beam administration with either a 15-Gy or 30-Gy external boost) or radiotherapy with concurrent 5-FU and mitomycin. Again, chemoradiation improved local control but did not have a significant impact on overall survival. The EORTC study also demonstrated a 32% higher colostomy-free survival among patients treated with chemoradiation. Skin ulceration and nodal involvement were poor prognostic indicators, and women had better local control and survival than men.[8]
These European trials showed that, compared to radiation therapy alone, chemoradiation offers patients a better chance of achieving local control, disease-free survival, and colostomyfree survival but does not improve overall survival, possibly because of the impact of an abdominoperineal resection as salvage therapy.
Role of Mitomycin
The Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG) then evaluated the role of mitomycin in the combined-modality regimen.[7] Mitomycin is not a known radiation sensitizer, and its renal, pulmonary, and bone marrow toxicity raised concerns about its safety.[83,84] The 310 patients entered into the trial were randomly assigned to receive radiation therapy with either concurrent 5-FU or 5-FU/mitomycin.
Patients who received mitomycin had a significantly lower 5-year rate of locoregional recurrence, lower colostomy rate, and better disease-free survival compared to patients who did not receive mitomycin. The overall survival, disease-specific survival, and posttherapy negative biopsy rate did not differ between groups. On subset analysis, the addition of mitomycin in patients with T3 or T4 tumors did not have a significant impact on outcome.
The investigators concluded that mitomycin plays a significant role in combined-modality therapy for anal cancer. The drug remains a component of the standard chemoradiation arm in the most recent RTOG trial of such therapy.
Role of Cisplatin
Platinum compounds were not available when combination regimens were originally tested, but because they have been found to be active against squamous cell carcinomas, they are now being evaluated in the treatment of anal cancers. In 1996, Doci and colleagues combined 5-FU and cisplatin with concurrent radiation therapy in 35 patients. The 3-year colostomy-free survival rate was 86%, and the complete response rate was 94%.[85] These results have been confirmed in other studies (Table 4).[85-90]
A Cancer and Leukemia Group B (CALGB) study evaluated induction 5-FU and cisplatin as well as 5-FU, cisplatin, and external-beam radiotherapy, and the preliminary results were presented at the 2000 meeting of the American Society of Clinical Oncology (ASCO); 80% of patients achieved a complete response, and the overall survival rate was 78%.[90] Currently, an ongoing multicenter, randomized Intergroup trial in the United States is comparing the same induction/concurrent regimen of 5-FU and cisplatin vs the standard mitomycin, 5-FU, and radiation therapy in patients with anal cancer; results of this study will help to define the optimal chemotherapy regimen.
Persistent or Recurrent Disease
Response to treatment is assessed approximately 6 to 8 weeks following the completion of combined chemotherapy and radiation therapy. Whether the response to treatment should be assessed by physical examination alone or in combination with a biopsy is controversial. Squamous cell carcinomas tend to regress slowly over 3 to 12 weeks after therapy.[90] In the US Intergroup study evaluating the role of mitomycin in combination with 5-FU, patients had follow-up biopsies 6 weeks after the completion of therapy. Residual disease was found in 8% of patients.
These patients were then treated with a salvage regimen of 5-FU/cisplatin and 9 Gy of external radiation; 55% achieved a complete response.[7] However, it was unclear whether this high salvage rate was due to the added therapy or the possibility that the tumors of these patients were slower to regress after primary therapy. Given the morbidity of the procedure, there is no consensus on the use and timing of biopsy in patients who have had a complete clinical response to therapy. It is reasonable to biopsy persistent abnormalities at 3 months after chemoradiation, as most tumor should be eradicated by that point.
• Persistent Disease—The therapy for persistent disease after primary chemoradiation is abdominoperineal resection. In the UKCCCR trial, 29 patients who achieved less than a 50% response to primary therapy underwent a salvage abdominoperineal resection; 83% became disease-free, but 42% went on to develop a local relapse.[82]
Salvage chemoradiation was also evaluated in this study. Patients with persistent disease were given 5-FU with cisplatin and radiation. The complete response rate in this group was 55%. Among patients who responded, one-third remained disease-free, one-third died (75% of those patients from progressive anal cancer), and one-third required resection and continue to be disease-free. All but one of the patients who did not respond to salvage therapy underwent abdominoperineal resection. At 4 years, 30% were alive without recurrent disease, and 60% developed recurrent disease and subsequently died.[7]
• Recurrent Disease—Like patients with persistent disease, those with locally recurrent disease after chemoradiation typically undergo an abdominoperineal resection. Such a salvage procedure will cure approximately 50% of patients with recurrent disease.[91-93] Although no formal trial of salvage chemotherapy and radiation therapy has been conducted, the salvage regimen for persistent disease from the RTOG/ECOG trial may also be effective in these patients.[7]
Distant recurrence occurs in 10% to 17% of patients who receive combination therapy.[8,82] The most common site of distant metastasis is the liver. No known cure exists for metastatic anal cancer, and the effectiveness of chemotherapy in these patients is unknown.[11,68,92] There are some reports of partial responses to cisplatin, 5-FU, and semustine (methyl-CCNU),[94-96] but there is little available information on the response of metastatic disease to newer agents such as taxanes, gemcitabine (Gemzar), or irinotectan (CPT-11, Camptosar).
Complications of Therapy
Complications of therapy for anal cancer depend on the treatment modality used. Late toxicity from radiation therapy includes anal ulcers, stenosis, and necrosis requiring colostomy in 6% to 12% of patients. The risk of these complications is related to the dose of radiation therapy.[15,73,92] Adding chemotherapy to radiation increases the frequency and degree of acute toxicity. Patients who receive chemoradiation are at risk for diarrhea, exfoliative dermatitis, mucositis, and myelosuppression.[7,82]
Conclusions
Remarkable progress has been made in understanding the pathophysiology and treatment of anal cancer in the past 30 years. HPV has been clearly implicated in the development of a majority of anal cancers, raising the possibility of screening programs for high-risk patients in the future. The use of sphincter-sparing chemoradiation therapy has remarkably improved quality of life and survival in patients with anal cancer. Ongoing studies are evaluating the role of cisplatin in the chemoradiation regimen.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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