Management of Anal Cancer in the HIV-Positive Population

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 (5-FU) and mitomycin (or 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.[1] 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.

Epidemiology

The incidence of anal cancer appears to be rising, with an estimated 4,000 cases diagnosed in 2004 according to the National Cancer Institute.[2] 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.[7]

Risk Factors

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).[8] 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.[9] Having anal intercourse has been reported to increase the relative risk of anal cancer by 15%.[10] 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.[13]

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.[18]

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.[19]

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.[21] 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.[22] 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.[23] 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).[5]

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).[30] 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.[5]

HAART Therapy and Anal Cancer

Patients are now living longer and experiencing better quality of life as a result of advances in HIV treatments and highly active antiretroviral therapy (HAART). Although HAART therapy has appeared to prolong survival in AIDS patients and is associated with slowing the progression from HIV to AIDS, it does not protect against anal cancer or high-grade squamous intraepithelial lesions.[31]

In a retrospective analysis, Stadler et al looked at HIV-positive patients treated for anal cancer during the period of 1980 through 2001. Patients were divided into two groups based on whether they had received HAART or not. Of the 14 patients with squamous cancer of the anus and HIV, 8 were treated with HAART. The 24-month survival was 67% in the HAART group vs 17% in the patients receiving combined-modality treatment only (P = .0524). The authors concluded that a trend existed with respect toward higherCD4 count (255 vs 190) and improved survival with patients on HAART prior to receiving chemotherapy and radiation.[32] Thus, although HAART appears to positively impact a patient's ability to tolerate combinedmodality treatment, toxicity remains a problem for many HIV patients.

Some patients may benefit from cessation of HAART during chemoradiotherapy. Conflicting data exist as to the ability of antiviral therapy to prevent anal intraepithelial neoplasia and the subsequent development of invasive anal cancer. For example, in a study by Schuman and colleagues, HIV-positive women with CD4-positive T-cell counts less than 500 cells/mm³ were unlikely to experience regression of premalignant lesions.[33] But the risk of cervical intraepithelial neoplasia is increased in women with persistent HPV and lower CD4 counts. Likewise, current research has demonstrated that HAART can decrease anal intraepithelial neoplasia prevalence in men with persistent HPV but does not appear to affect or reduce HPV.[34] Additional research is needed to clarify whether delaying HAART in the case of lower CD4 counts will have a negative effect on anal cancer outcomes in HIV patients.

Treatment Strategies for HIV-Positive Patients With Anal Cancer

The gold standard for treating patients with anal cancer is combined chemotherapy and radiation; chemotherapy agents used are 5-FU and mitomycin, with cisplatin currently being tested as a substitute for mitomycin. The 5-FU is delivered by 96-hour infusion and mitomycin and cisplatin are administered by bolus injection during weeks 1 and 4 of radiation. The radiation schedule is 45 to 59 Gy delivered daily, with the radiation dose determined by stage of disease. Initial studies included a 2-week radiation break, but more recent studies suggest that the break may result in increased local tumor failure. Grades 3 and 4 toxicity are reported to be 40% and 23%, respectively, and the standard treatment regimen has resulted in colostomy-free survival of 70% to 80%.[35]

Toxicity

HIV-positive patients with anal tumors treated with standard chemoradiation regimens have more toxicity and require longer treatment breaks. Although there is some controversy in the literature, patients with CD4 counts less then 200/mm³ tend to have even more toxicity and inferior outcome compared to patients with CD4 counts greater than 200/mm³.[36]

Common toxicities noted in HIVpositive patients are hematologic, perineal skin desquamation, diarrhea, and small bowel injury. In a study by Holland et al in HIV-positive patients, 55% required a break of an average 16.7 days.[37]

Treatment Modifications

Should the standard chemoradiation regimen be modified in HIV-positive patients with anal canal tumors? In a study by Cleator et al, 12 HIVpositive patients were treated with standard radiation and 5-FU; 9 of 11 evaluable patients achieved complete tumor response at a median followup of 4.8 years.[38] The radiation boost was given after a 4- to 6-week treatment break. Three patients developed grade 3 hematologic toxicity and one patient developed grade 3 dermatologic toxicity. One patient died of small bowel obstruction. Mitomycin was given only during week 1.

A randomized trial conducted by the RTOG in HIV-negative patients comparing treatment with 5-FU and radiation, with and without two cycles of mitomycin, showed that mitomycin was necessary for improved colostomy- free and disease-free survival.[28] Should only one course of mitomycin be given in HIV-positive patients with a mandatory treatment break? 5-FU delivered by 96-hour infusion coupled with bolus mitomycin has resulted in significant hematologic toxicity, even in HIV-negative patients with anal canal cancer. Continuous infusion of 5-FU at doses of 200 to 300 mg/m² is associated with significantly less hematologic toxicity. Data from Hughes et al at M. D. Anderson Cancer Center support using continuous infusion 5-FU with radiation in patients who are HIVnegative with anal canal cancer. The reported local tumor control is comparableto the results seen with 96-hour infusion of 5-FU and two cycles of mitomycin.

Should HIV-positive patients be treated with low-dose infusion 5-FU and radiation with one cycle of mitomycin? The standard radiation treatment fields extend from L5/S1 to the perineum and often extend laterally to the anterior iliac crest. Thus, a fair amount of small bowel and bone marrow are included in the radiation fields. HIV-positive patients with anal canal cancer often develop grade 3 diarrhea, small bowel obstruction, and grade 4 hematologic toxicity. Data from Princess Margaret Hospital support the use of smaller radiation fields with colostomy-free and overall survival equivalent to the results reported by the RTOG. The top of the field is typically at the bottom of the sacroiliac joints, thus decreasing the volume of small bowel and bone marrow included in the radiation field design.

Should the radiation field be modified in HIV-positive patients with anal canal tumors, particularly in patients with CD4 counts less than 200/mm³? It seems reasonable that as long as the areas at risk of tumor spread and involvement are included in the field design, smaller field sizes appear to have merit. In addition, the new treatment technology of intensity-modulated radiation therapy (IMRT) allows significant sparing of the dose to critical structures while maximizing the dose to the target volume. This technology allows sparing of radiation dose to the small bowel and bone marrow. Incorporating IMRT technology into the treatment of HIV-positive patients with anal canal tumors has significant potential to reduce toxicity. The Radiation Therapy Oncology Group is developing a protocol to study this issue.

Conclusions

The current standard of care for localized anal cancer is chemotherapy and radiotherapy with 5-FU and mitomycin. For HIV patients, the optimal treatment remains unclear. Patients with well controlled HIV on HAART therapy should be treated aggressively with chemotherapy and radiation,as anal cancer is highly curable with excellent rates of organ preservation. Patients with poorly controlled HIV can also be treated with chemotherapy and radiation but must be monitored very closely, since there is a higher incidence of significant treatment- related toxicity in this population.

The aforementioned treatment strategies appear to have potential merit in addressing the problems of increased treatment toxicity in HIV-positive patients with anal canal cancer, without compromising colostomy-free and overall survival. However, such strategies must be meticulously tested and compared to the gold standard in phase III randomized trials.

Financial Disclosure: The assertions and statements made herein are not influenced by any proprietary interest. No funding or support was derived from any outside entity in order to prepare this review.

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