The incidence of anal carcinoma among people with HIV1 and men who have sex with men (MSM) is markedly increased.2 Moreover, anal cancer is twice as common in HIV-positive MSM as it is in HIV-negative MSM.3 US AIDS cancer registry matching calculated that the relative risk of invasive anal cancer is 37 in HIV-positive men and 6.8 in HIV-positive women.4 Highly active antiretroviral therapy (HAART) has led to a decline in the incidence of Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL),5 and the benefits on other non-AIDS-defining malignancies are emerging.4,6 The effects of HAART on the incidence of invasive anal cancer have not been addressed in cohort studies, although there is no apparent correlation between the relative risk of developing invasive anal cancer and the CD4 cell count.4 In addition, HAART can lead to regression of KS7 and cervical intraepithelial neoplasia8 but does not seem to lead to resolution of anal intraepithelial neoplasia (AIN).9,10
The incidence, demographics, and survival of patients with invasive anal cancer were measured from a prospectively collected cohort of all HIV-seropositive patients treated at the Chelsea and Westminster Hospital, which includes 8640 patients and represents 40,126 patient-years of follow-up. Twenty six patients (25 MSM and 1 heterosexual woman) had histologically confirmed cases of invasive anal cancer. The incidence was compared with that of the age- and gender-matched general population in southeast England for 1995. The data for the general population were obtained from the Thames Cancer Registry, which calculates the incidence for individual cancer types in the southeast of England (Thames Cancer Registry, personal communication). Matching was performed by only including individuals from the general population whose age fell within the 95% confidence interval (CI) of the HIV cohort (range: 18-55 years). The control group was also weighted for gender to match the HIV cohort. The overall incidence in our HIV cohort was 60/105 patient-years (95% CI: 40-89) compared with 0.52 (95% CI: 0.27-0.78) per 105 patient-years in the age- and gender-matched population. The incidence of invasive anal cancer in the HIV cohort was 35 (95% CI: 15-72) per 105 patient-years of follow-up in the pre-HAART era (1984-1995) and 92 (95% CI: 52-149) per 105 patient-years of follow-up in the post-HAART era (1996-2003) (P > 0.05). These figures are significantly higher than those for the general population (P < 0.001 for both) and give a relative risk of 67 and 176 in the pre- and post-HAARTeras, respectively, compared with the general population.
Because the risk of anal cancer in the general population increases with age, the age at entry into the pre-HAART and post-HAART era cohorts was compared. There were no statistical differences between the mean age of the pre-HAART cohort (mean = 34.6 years) and the post-HAART era cohort (mean = 34.6 years). As predicted, the mean age at diagnosis of anal cancer was significantly higher than the age of entry into either cohort (mean age = 40.6 [95% CI: 38.2-41.8]).
The patient demographics are shown in Table 1. At cancer diagnosis, 12 patients were receiving HAART, but only 5 (42%) had an undetectable HIV-1 viral load. The cancer stages at diagnosis were: T1N0M0 (n = 11 [42%]), T2N0M0 (n = 6 [23%]), T2N3M0 (n = 2 [8%]), T3N0M0 (n = 2 [8%]), T3N3M0 (n = 2 [8%]), T3NXMX (n = 1 [4%]), T4N0M0 (n = 1 [4%], and T4N3M1 (n = 1 [4%]).
Outcome and Survival
The median follow-up is 4.8 years (maximum = 14 years). Twenty-two patients were treated with combined modality chemoradiotherapy,11 2 T1N0M0 tumors confined to the anal verge were only completely excised, and 2 patients received best supportive care alone. Eleven patients have died (7 from anal cancer and 4 in remission from HIV-related illness). For all patients and all causes of death, the actuarial overall survival at 5 years is 47% (95% CI: 24%-70%). The anal cancer disease-free survival at 5 years is 66% (95% CI: 45%-87%). Five patients (23%) relapsed after chemoradiotherapy, and all died of anal cancer.
There is no difference in overall survival between the pre- and post-HAART eras (log rank, P = 0.19). In univariate analysis, overall survival was not correlated with CD4 cell count (P = 0.61), a prior AIDS-defining illness (P = 0.49), or duration of the interval between HIV diagnosis and anal cancer diagnosis (P = 0.35). Age at the time of anal cancer diagnosis correlated significantly with overall survival with younger people faring less well (P = 0.023), however.
This cohort study is the largest series of HIV-associated invasive anal cancer patients published thus far and includes 12 patients previously reported.11 The incidence is 120-fold higher than that of the age- and gender-matched general population. Although there has been no significant change in the incidence since the start of 1996 when HAART was introduced into standard care for patients in our cohort, there is a trend toward an increasing incidence.12,13 This finding is in marked contrast to the declines in KS and NHL.5,14 One explanation for this is the lack of clear correlation between anal cancer incidence and falling CD4 cell count. Moreover, HAART does not cause regression of AIN, the presumed precursor of invasive anal cancer.9,10 The duration of immune dysfunction (as measured by the interval from HIV infection to anal cancer diagnosis) is longer in patients who have developed anal cancer in the era of HAART. We speculate that the duration rather than the severity of immune suppression may determine the risk of invasive anal cancer. This would concur with the prolonged time course of progression from anal human papillomavirus (HPV) infection via dyskaryosis and AIN to invasive anal cancer. In the case of cervical cancer, the progression from infection to invasive cervical cancer takes 10 to 20 years. Certainly, the prolonged survival of people with HIV in the HAART era may account for the trend toward an increasing incidence of anal cancer, because people are now living long enough for this progression to invasive anal cancer to occur. There are no major differences between patients diagnosed in the pre- and post-HAART eras, suggesting little or no influence of HAART on the biology of the disease.
The overall survival in this series is better than that reported recently from Texan hospitals,15 although earlier published series with shorter follow-up were more promising.16-18 Most centers report that in the general immunocompetent population, 85% of tumors can be controlled locally with chemoradiotherapy and that 5-year survival rates are in the range of 65% to 85%.19 In this cohort, the overall survival at 5 years is 47% (95% CI: 24%-70%), whereas the anal cancer disease-free survival at 5 years is 66% (95% CI: 45%-87%). The 2-year survival rate is 74%, however, with no relapses of anal cancer occurring after this time, and all deaths after this time point are attributed to HIV infection. These results are particularly encouraging because they include 2 (8%) patients who received palliative care only. Moreover, 9 of the patients had locally advanced disease (T3/4 or N+), and this is associated with 5-year survival rates of less than 50% in the general population.
1. Melbye M, Cote TR, Kessler L, et al. High incidence of anal cancer among AIDS patients. The AIDS/Cancer Working Group. Lancet.
2. Frisch M, Melbye M, Moller H. Trends in incidence of anal cancer in Denmark. BMJ.
3. Palefsky JM, Holly EA, Ralston ML, et al. High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS.
4. Frisch M, Biggar R, Goedert J. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst.
5. Portsmouth S, Stebbing J, Gill J, et al. A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma. AIDS.
6. Bower M, Powles T, Nelson M, et al. HIV-related lung cancer in the era of highly active antiretroviral therapy. AIDS.
7. Stebbing J, Portsmouth S, Gazzard B. How does HAART lead to the resolution of Kaposi's sarcoma? J Antimicrob Chemother. 2003;51:1095-1098.
8. Minkoff H, Ahdieh L, Massad LS, et al. The effect of highly active anti-retroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women. AIDS.
9. Fox P, Stebbing J, Portsmouth S, et al. Lack of response of anal intraepithelial neoplasia to highly active antiretroviral therapy. AIDS.
10. Palefsky JM, Holly EA, Ralston ML, et al. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis.
11. Cleator S, Fife K, Nelson M, et al. Treatment of HIV-associated invasive anal cancer with combined chemoradiation. Eur J Cancer.
12. British HIV Association. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med.
13. British HIV Association. British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. BHIVA Guidelines Coordinating Committee. Lancet.
14. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst.
15. Place RJ, Gregorcyk SG, Huber PJ, et al. Outcome analysis of HIV-positive patients with anal squamous cell carcinoma. Dis Colon Rectum.
16. Holland JM, Swift PS. Tolerance of patients with human immunodeficiency virus and anal carcinoma to treatment with combined chemotherapy and radiation therapy. Radiology.
17. Chadha M, Rosenblatt EA, Malamud S, et al. Squamous-cell carcinoma of the anus in HIV-positive patients. Dis Colon Rectum.
18. Hoffman R, Welton ML, Klencke B, et al. The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys.
19. Cummings BJ. Anal cancer. Int J Radiat Oncol Biol Phys.