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

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

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

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.

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.