Anal cancer treatment less effective and more likely to cause side-effects in people with HIV

Localised chemo-radiation therapy for anal cancer has poorer outcomes and is more likely to cause side-effects in people with HIV, according to the results of a meta-analysis published in the Journal of Gastrointestinal Oncology. HIV-positive individuals were about a third more likely to experience moderate-to-severe treatment-related dermatological toxicities and also had poorer disease-free survival and overall survival. The authors hope their findings will help doctors select the most effective therapies.

Squamous cell carcinoma of the anus (SCCA), or anal cancer, is generally a rare malignancy. The main risk factor is persistent infection with high-risk strains of human papillomavirus (HPV). HIV-positive people with persistent anal HPV infection have an especially high risk of progressing to anal cancer, particularly if they have a history of immunosuppression.

Standard treatment for localised anal cancer is a combination of chemotherapy and radiotherapy (chemo-radiation). The chemotherapy agents include 5-fluorouracil (5-FU), capecitabine, mitomycin (MMC) and cisplatin. In the general population, treatment outcomes are excellent, with control rates in excess of 80%.

However, people with HIV were excluded from the randomised controlled trials that led to the formation of guidelines for the treatment of anal cancer. This means that robust evidence to guide therapeutic choices for HIV-positive individuals is lacking.

A team of investigators therefore conducted a systematic review and meta-analysis of studies examining chemo-radiation therapy for HIV-positive people with anal cancer. Clinical trials and cohort studies (prospective and randomised) were eligible for inclusion.

Outcomes were disease-free survival (the proportion living without any signs or symptoms of anal cancer) after three years, overall survival after three and five years, and moderate-to-severe toxicities, according to HIV status.

The investigators identified a total of 40 eligible studies involving 3720 people. One was a clinical trial, the others retrospective cohort studies. Twenty of the cohort studies compared HIV-positive and HIV-negative individuals, while the other 19 exclusively involved people with HIV.

Just over a third of individuals (34%) were HIV positive. Individuals with HIV were significantly younger than HIV-negative people (44 vs 62 years). Almost all the HIV-positive people (93%) were male and their median CD4 cell count was 347 cells/mm³. 

Clinical stage was reported in 24 studies and lymph node involvement did not differ according to HIV status.

Most of the studies reported on reductions in doses (usually made because of concerns about side-effects). Rates varied between 22 and 77% in the HIV-positive group and 7 and 54% in the HIV-negative group. The most common moderate/severe toxicities affected the skin, blood and gut.

People with HIV were about a third more likely to experience moderate/severe skin side-effects (mainly radiation-related dermatitis) compared to HIV-negative people (RR = 1.34; 95% CI, 1.10-1.64, p = 0.004). “A possible explanation is that protease inhibitors used in HAART can enhance radio-sensitivity,” comment the authors.

There were non-significant trends for HIV-positive people to have a higher risk of thrombocytopenia (low platelet count) and leukopenia (low white blood cell count).

Rates of gastrointestinal toxicities varied between 2 and 31% in people with HIV and between 3 and 17% in the HIV-negative people. The comparative studies showed there was no significant difference in the risk of gastrointestinal side-effects according to HIV status.

Disease-free three-year survival rates were between 33 and 94% in people with HIV and 67 and 91% in the HIV-negative group. In the non-comparative studies, the overall three-year disease free survival rate among people with HIV was 75%. Pooling the results of the comparative studies showed that HIV-positive people were significantly less likely to be disease free at the three-year evaluation point (RR = 1.32; 95% CI, 1.01-1.74, p = 0.043).

Overall three-year survival rates were between 25 and 85% among the people with HIV and between 58 and 92% in the HIV-negative group. Analysis of the comparative studies once again showed a poorer survival rate among people with HIV (RR = 1.77; 95% CI, 1.35-2.32, p < 0.001).

Five-year survival rates were between 20 and 88% among HIV-positive individuals and 65 and 84% in HIV-negative people. Comparative studies showed a significantly poorer survival rate in the HIV-positive group (RR = 1.39; 95% CI, 1.04-1.85).

Analysis according to cancer-specific survival, six-month clinical response, and colostomy-free survival, all favoured the HIV-negative group.

The poorer survival of people with HIV could not be explained by AIDS-related deaths. The authors note that cancer recurrence rates were numerically higher among HIV-positive individuals.

The authors believe their findings have implications for treatment strategies and that people with HIV should receive less toxic radiotherapy. The chemotherapy drug mitomycin should be avoided as it is more likely to cause myelosuppression (decrease in bone marrow activity, resulting in fewer red blood cells, white blood cells, and platelets) than 5 FU, capecitabine or cisplatin.

They conclude with a call for studies designed to evaluate the best treatment options for localised anal cancer in people living with HIV.