ABSTRACT: Squamous cell anal cancer remains an uncommon entity; however, the incidence appears to be increasing in at-risk populations, especially those infected with human papillomavirus (HPV) and human immunodeficiency virus (HIV). Given the ability to cure this cancer using synchronous chemoradiotherapy, management practices of this disease are critical. This article considers treatment strategies for HIV-positive patients with anal cancer, including the impact on chemoradiation-induced toxicities and the role of highly active antiretroviral therapy in the treatment of this patient population. The standard treatment has been fluorouracil(Drug information on fluorouracil) (5-FU) and mitomycin(Drug information on mitomycin) (or cisplatin(Drug information on cisplatin)) as chemotherapy agents plus radiation. Consideration to modifying the standard treatment regime is based on the fact that patients with HIV tend to experience greater toxicity, especially when CD4 counts are below 200; these patients also require longer treatment breaks. Additional changes to the chemotherapy dosing, such as giving 5-FU continuously and decreasing mitomycin dose, are evaluated and considered in relation to radiation field sizes in an effort to reduce toxicity, maintain local tumor control, and limit need for colostomy. The opportunity for decreasing the radiation field size and using intensity-modulated radiation therapy (IMRT) is also considered, particularly in light of the fact that IMRT provides dose-sparing while maximizing target volume dose to involved areas. The impact of the immune system in patients with HIV and squamous cell carcinoma of the anus and the associated response to therapy remains unknown. Continued studies and phase III trials will be needed to test new treatment strategies in HIV-infected patients with squamous cell cancer of the anus to determine which treatment protocols provide the greatest benefits.
Tumors that arise from the anal canal or anal margin are de fined as anal cancer; four-fifths of all anal cancers arise from the anal canal. The anal canal extends from the cephalad to caudal border of the anal sphincter, while the anal margin consists of an approximately 4- to 5-cm area of perianal skin in reference from the anal verge. The junction between the perianal skin and the hairless nonpigmented epithelium ofthe anal canal represents the anal verge. Squamous cell cancer of the anus is normally preceded by anal intraepithelial neoplasia or dysplasia that progresses to a high-grade squamous intraepithelial lesion, the precursor to invasive cancer.
The incidence of anal cancer appears to be rising, with an estimated 4,000 cases diagnosed in 2004 according to the National Cancer Institute. This rare cancer comprises only 4% ofall lower gastrointestinal tract cancer.[ 2,3] Historically, anal cancer was a disease associated with older women. Recent epidemiologic studies indicate that human papillomavirus (HPV) causes anal intraepithelial neoplasia, and that anal cancer is frequently seen in younger patients that engage in receptive anal intercourse and in individuals with human immunodeficiency virus (HIV), as well as in people with a high number of sexual partners.
Whereas the incidence of anal cancer is uncommon in the general US population at 0.9 per 100,000 people, the incidence in men practicing receptive anal intercourse is 35 per 100,000.[3,4] However, both men and women in the United States are at increasing risk of acquiring squamous cell anal cancer, with a slight female predominance of 1.5 times.[5,6] For example, the incidence of white males with anal squamous cell carcinoma is 0.71 per 100,000, rising at approximately 2.6% per year during the period of 1993 to 1996 in the United States; in women, the incidence is increasing by 1.5% per year, resulting in an incidence of 0.78 per 100,000 from 1973 to 1976 and 0.95 per 100,000 from 1993 to 1996. Black women and men are also experiencing increases in overall incidence across the same time frame.
Anal cancer is associated with multiple risk factors. These factors include immune suppression (ie, HIV, organ transplant), multiple sexual partners, anoreceptive intercourse, smoking, chronic local inflammation (such as patients with Crohn's disease, chronic fistulas, or history of pelvic radiation therapy), and sexually transmitted diseases (particularly HPV). HIV-positive homosexual men have a much higher frequency of invasive anal cancer than individuals in the general population; they have twice the risk for anal cancer as do homosexual men without HIV. Having anal intercourse has been reported to increase the relative risk of anal cancer by 15%. Several HPV types (16, 18, 31, 33, 35) are associated with anal intraepithelial neoplasia and squamouscell cancer of the anus, with HPV type 16 having the highest associated risk. Up to 85% of people diagnosed with squamous anal cancer have been found to have HPV.[11,12] A populationbased case-control analysis by Daling and colleagues reported that 88% of anal cancer tumors were positive for HPV, 73% of which were type 16.
The relative risk of developing cancer is much higher in men with a history of anal intercourse vs women engaging in receptive anal intercourse- 33.1 and 1.8, respectively, when compared to the general population.[ 14,15] Active smokers are eight times more likely than people who do not smoke to develop squamous cell carcinoma of the anus. However, cessation of smoking will decrease risk.[2,15]
The association between AIDS and anal cancer is quite strong, with many arguing that squamous cell cancer of the anus should be considered as an AIDS-defining condition. Individuals with HIV tend to have persistent HPV and higher viral loads, which contributes to their risk of developing anal cancer.[3,16,17] Since HIV may influence the oncogenic effect of HPV, the relationship as to causality with regard to squamous cancer of the anus is confusing.
Kim and colleagues reviewed 98 HIV-negative and HIV-positive patients treated for anal neoplasms over a period from 1985 to 1998. They found that HIV-positive patients comprised a different population base as defined by age, gender, stage, or treatment. The results demonstrated that HIV-positive patients with anal cancer have a poor tolerance to combined therapy vs HIV-negative patients, as noted by increased acute toxicities (80% vs 30%). The median time to cancer-related death was 1.4 years vs 5.3 years for HIV-negative patients with anal cancer.
As in men, an association of anal cancer exists in women diagnosed with HIV or acquired immunodeficiency syndrome (AIDS). Durante et al used anal cytology and anogenital HPV to assess the incidence of anal neoplasms in 100 HIV-infected women. Using multivariate analysis, 86 women with normal baseline cytologysubsequently were found to have 22 incidences of anal cytologic abnormalities per 100 person-years. The factors associated with increased risk of squamous intraepithelial lesions of the anus were CD4 counts of < 500 cells/mm3, high-risk anal HPV infection, and smoking.
Combined-Modality Therapy in Anal Cancer
Combined-modality treatment has become the standard of care since 1974, when Nigro and colleagues reported their findings using radiation and chemotherapy to treat anal cancer.[ 20] The majority of patients (86%) will have clinical regression of their cancer after combined-modality treatment, as reported by Flam et al in a study of 30 patients treated with radiation and chemotherapy. In a more recent study by Peddada, 100% of HIVpositive patients with squamous cell anal cancer experienced a complete clinical response after combinedmodality treatment consisting of lowdose radiotherapy (30 Gy in 15 fractions) and fluorouracil (5-FU) at 1,000 mg/m2 on days 1-4 and 29-32 as a continuous infusion over 96 hours and a 10-mg/m2 bolus injection of mitomycin on day 1. Prior to Nigro's findings, the standard of care for patients with anal cancer was abdominoperineal resection. The 5-year survival results for abdominoperineal resection ranged from 40% to 70%.[22-24]
In the 1990s, multiple large trials attempted to address the toxicity effects associated with the chemotherapy treatment of squamous cancer of the anus. Common toxicities seen in patients with HIV anal cancer include severe moist desquamation in the radiation field, hematologic suppression as evidenced by decreased absolute neutrophil count < 500/mm3 and platelet count < 50,000/mm3, and intractable diarrhea leading to dehydration.These types of toxicities were observed by Hoffman et al in their study of 17 HIV-positive patients with anal cancer from 1991 to 1997. Despite the level of acute toxicity, combined- modality treatment yields excellent results (overall and diseasefree survival of 60% to 90%) while preserving the anal sphincter.[25-29]
Mitomycin, 5-FU, and Radiotherapy
Three large randomized studies have evaluated the efficacy of multimodality therapy in anal cancer. The United Kingdom Coordinating Committee on Cancer Research (UKCCCR) conducted a randomized trial of 585 patients. Patients were randomized to one of two groups: radiation alone (45 Gy with a boost of 15 Gy 6 weeks later) or concurrent chemotherapy consisting of 5-FU and mitomycin plus radiation.[5,29] Local control at 3 years was significantly better in the combined-modality group (61% vs 39%, P < .0001).
The European Organization for the Research and Treatment of Cancer (EORTC) also randomized 110 patients to radiation with or without 5-FU and mitomycin using similar dosing and scheduling to the UKCCCR study. Again the combined-modality group had better local control rates (68% vs 55% at 3 years, P = .02) and colostomy- free survival (72% vs 47% at 3 years, P = .002). Both the EORTC and the UKCCCR trials demonstrated no overall survival advantage; however, they did show that combinedmodality treatment was more effective in obtaining superior rates of local control.
In an effort to better define the role of mitomycin in multimodality therapy, the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG), as part of an Intergroup study, randomized 310 patients to two study arms: 5-FU alone and 5-FU plus mitomycin. Eachgroup received radiation and concurrent chemotherapy for the treatment of anal cancer. Higher-grade (4 and 5) toxicities were observed in the 5-FU-plus-mitomycin group vs 5-FU alone (23% vs 7%). Both colostomyfree and disease-free survival rates demonstrated a significant difference between the treatment arms: 5-FU plus mitomycin, 71% (colostomy-free) and 73% (disease-free); 5-FU alone, 59% (colostomy-free) and 51% (diseasefree).[ 28] Given the high disease-free survival rates (and despite associated toxicities), 5-FU plus mitomycin showed that combination chemotherapy resulted in positive outcomes.
These studies led to support for the combined modality of 5-FU with mitomycin in conjunction with radiation as the standard of care for patients with anal cancer. Currently, multiple studies are evaluating the use of cisplatin in lieu of mitomycin in an effort to decrease toxicity. For example, the RTOG has initiated a randomized study (RTOG 98-11) for patients with anal canal cancer comparing 5-FU/mitomycin/radiation vs 5-FU/cisplatin/radiation.