Gay men and anal cancer

HIV Australia | Vol. 11 No. 2 | July 2013

Mary Poynten and Andrew Grulich explore the connection between the human papillomavirus (HPV) and anal cancer among gay men, highlighting findings from the SPANC study.

Background – human papilloma virus, anal intraepithelial neoplasia and anal cancer

Human papillomavirus (HPV), which predominantly spreads through direct skin to skin contact, is the most common sexually transmitted infection globally.

Approximately 40 types of HPV have the propensity to infect the ano-genital area. These types are classified into high risk (HR) and low risk (LR) HPV, depending on their oncogenic potential – i.e., their capacity to induce tumour formation.¹

Oncogenic high risk HPV can be detected in 80% to 90% of anal cancers,² ³ placing anal cancer second only to cervical cancer in the strength of its association with HPV infection.

HPV16 is the most common type of HPV associated with anal cancer (85–90% of all HPV-positive cases), followed by HPV18 (less than 10%).⁴ ⁵

Anal HPV infection among gay men is substantially more common than cervical HPV infection is in women.

A recently published meta-analysis of the prevalence of anal HPV and related lesions in gay men found that detection of any high risk types was much higher in HIV-positive than HIV-negative men (74% and 37% respectively for any high risk type).

Over one third of HIV-positive men (34%), but only around one in eight HIV-negative men (13%) had anal HPV16 detected.⁶ Even among young gay men with fewer than five lifetime sexual partners, the prevalence for any HPV types in the anal canal was 42%.⁷

It is generally accepted that, similar to the natural history of HPV in the cervix, anal high risk HPV infection has the potential to progress to high grade anal intra-epithelial neoplasia (HGAIN) and eventually to invasive cancer.⁸

Some cervical lesions regress spontaneously.⁹ However, if untreated, about 1% of pre-cancerous high grade cervical lesions will eventually progress to invasive cancer per year.¹⁰ In the anus, there is less known about the natural history of HPV infection especially concerning rates of progression and regression of HGAIN.¹¹

In the meta-analysis by Machalek et al., the pooled prevalence of HGAIN was 29% in HIV-positive men and 22% in HIV-negative men.¹² There were only two longitudinal studies which allowed estimation of progression rates of anal intraepithelial neoplasia (AIN).

These identified extremely high incidence rates of HGAIN of around 10% per year in HIV-positive men.¹³ Based on a comparison of data on prevalence of HGAIN and incidence of anal cancer, a progression rate of less than one in 600 per year in HIV-positive men overall (about one in 377 in more recent years), and less than one in 4000 per year in HIV-negative men was estimated.¹⁴

Epidemiology of anal cancer

Anal cancer is a relatively rare cancer in the general population. However, its incidence among men and women has been steadily increasing.¹⁵ ¹⁶

Gay men experience rates of anal cancer of up to 20 fold higher than the general population.¹⁷ ¹⁸ For HIV-positive gay men, the risk is further elevated.

The meta-analysis by Machalek et al., reported an incidence of 22/100,000 cases per year of anal cancer among gay men with HIV in the period before 1996, increasing to 78/100,000 per year in reports published after this date.¹⁹

In a 2012 report from a cohort of HIV-positive homosexual men in North America, incidence had reached 131/100,000 per year.²⁰

These data suggest that incidence of anal cancer is increasing in HIV-positive men, despite the improved general health associated with effective HIV therapies.

A linkage study of the Australian HIV and cancer registers found that anal cancer had become the most common non AIDS-defining cancer, and the third most common cancer overall among people with HIV in Australia.²¹

Prevention of anal cancer

Prevention of anal cancer can take the form of primary prevention – as vaccination against HPV; or secondary prevention – as early detection of HGAIN and anal cancer.

The quadrivalent HPV vaccine (HPV 6,11,16 and 18) has been available in school programs for girls since 2007, and for boys since 2013. It is approved for women up to 45 years.

For men it is recommended only to the age of 26, as there are no male efficacy data at older ages.

Though trials of HPV vaccine have shown that widespread vaccination should eventually lead to a substantial reduction in anal cancer incidence,²² the vaccine is likely to be less effective in adult men already infected with HPV, who comprise the majority of gay men.²³

Thus the impact of vaccination on anal cancer morbidity and mortality is not likely to be seen for decades. Screening programs for anal cancer and its precursor lesions are potential secondary prevention measures.

These programs would be similar to those for cervical cancer, with anal cytology followed by high resolution anoscopy (HRA), which is the anal equivalent of colposcopy (pap smear diagnostic procedure).

Digital anorectal exam (DARE) is also an important cancer detection tool, identifying early small tumours, with correspondingly better prognoses.

Currently, there are no generally accepted guidelines on how anal cancer screening programs should be implemented and anal cancer screening only occurs in specialised clinics in a small number of countries.

There are very few trained and experienced high resolution anoscopists in Australia, even in capital cities such as Sydney and Melbourne.

Treatment options for high grade anal intraepithelial neoplasia (HGAIN)

There is little evidence for the effectiveness of treatment of HGAIN to prevent anal cancer. Most commonly used approaches are therapies such as cautery, infrared coagulation, laser or cryotherapy.

Other options include surgical excision, therapeutic vaccines and topical treatments such as imiquimod (an immune response modifier) and 5-flourouracil. Most of these therapies require multiple treatments and have substantial recurrence rates.

A Cochrane review of interventions for AIN published in 2012 identified only one randomised study, which compared imiquimod, with placebo. No statistically significant improvement in cure rates was seen with imiquimod.

The authors concluded that there was insufficient evidence to support efficacy of available interventions for AIN.²⁴

Since then, an open label randomised controlled trial of imiquimod, topical fluorouracil and electrocautery for the treatment of AIN (both high grade and low grade) in 156 HIV-positive gay men in the Netherlands has been published.

Only 13% of imiquimod, 17% of fluoruracil and 39% of electrocautery-treated patients had a complete response at four weeks.

Of those who responded, 67% had recurred 72 weeks after treatment.²⁵ Because of the lack of evidence on treatment outcomes and the substantial associated morbidity, some advocate watchful waiting of HGAIN lesions, with early treatment of anal cancer should it develop.

In Australia, there is currently no consensus on the preferred approach to management of HGAIN lesions.

The Study of the Prevention of Anal Cancer (SPANC) The Study of the Prevention of Anal Cancer (the SPANC study) is a community-based cohort study of the natural history of anal human papillomavirus infection and anal cancer precursors in HIV-positive and negative homosexual men aged 35 and older.

The study, based at St Vincent’s Hospital in Sydney, involves anal cancer screening visits at baseline, 6, 12, 24 and 36 months.

At the five study visits participants complete detailed behavioural questionnaires and undergo anal cytology, anal HPV genotyping (37 HPV genotypes) and high resolution anoscopy (HRA) with biopsy of any visible abnormalities.

Men complete two follow up questionnaires after each visit to collect details of any physical and psychological morbidity associated with the procedures. The study aims to determine:

Prevalence, incidence and risk factors for specific types of HPV detection
Prevalence, incidence and risk factors for histologically confirmed LGAIN and HGAIN
Type-specific rates of clearance and persistence of anal HPV infection, and HPV type association with LGAIN and HGAIN lesions
Rates and predictors of AIN progression and regression
Psychosocial/quality of life impacts and costs of anal cancer screening in homosexual men.

As of April 2013, the study has enrolled 342 men, with a median age of 49 years (range 35–79 years). Almost a third of men (98, 28.7%) are HIV-positive.

Thus far, at the baseline visit, 84% of men have had at least one biopsy. Evidence of high grade disease was present in 46% of men at baseline (50% in the HIV-positive and 44% in the HIV-negative, p=0.30).

HPV16 was detected in 30% of men at baseline (32% and 29% of the HIV-positive and negative respectively, p=0.61).

Among 129 men who did not have evidence of high grade disease at baseline and had been followed up for up to 24 months, the incidence of new high grade disease was 28/100 person-years.

Among the 100 men with high grade disease at baseline, the rate of regression (defined as having no histological or cytological evidence of high grade disease at the subsequent visit) was very high, at 42/100 person-years.

These are early data on anal lesion regression, but we believe they are essential for the development of evidencebased HGAIN treatment guidelines.

Importantly, two cases of anal cancer, one peri-anal and one superficially invasive anal canal SCC, have been detected in SPANC participants.

In 2013, a collaboration of researchers, clinicians and community advocates were awarded a $1.96 million Cancer Council NSW (CCNSW) Strategic Research Partnership Grant.

The purpose of this grant is to reduce the morbidity and mortality from anal cancer. To achieve this goal, in collaboration with CCNSW, the infrastructure available for anal cancer prevention research in Australia will be expanded; the existing SPANC study will be extended to enrol 600 participants, and a platform for related studies will be created.

This will provide the scope to address the uncertainties surrounding AIN/anal cancer natural history and the role of anal cancer screening among gay men and other high risk groups.

For further information about the SPANC study, or to participate, visit www.nchecrsurveys.unsw.edu.au/spanc/

References

1 Schiffman, M., Herrero, R., Desalle R, Hildesheim, A., Wacholder, S., Rodriguez, A., et al. (2005). The carcinogenicity of human papillomavirus types reflects viral evolution. Virology, 337(1), 76–84.

2 De Vuyst, H., Clifford G., Nascimento, M., Madeleine, M., Franceschi, S. (2009). Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. International Journal of Cancer, 124(7), 1626–36.

3 Hoots, B., Palefsky, J., Pimenta, J., Smith, J. (2009). Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. International Journal of Cancer, 124(10), 2375–83.

4 De Vuyst, H., et. al. (2009). op. cit.

5 Hoots, B., et al. (2009). op. cit.

6 Machalek, D., Poynten, M., Jin, F., Fairley, C., Farnsworth, A., Garland, S., et. al.(2012). Anal human papillomavirus infection, and associated neoplastic lesions in homosexual men: systematic review and meta-analysis. Lancet Oncology, 13(5), 487–500.

7 Goldstone, S., Palefsky, J., Giuliano, A., Moreira Jr., E., Aranda, C., Jessen, H., et al. (2011). Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men. The Journal of Infectious Diseases, 203(1), 66–74.

8 Darragh, T., Colgan, T., Cox, J., Heller, D., Henry, M., Luff, R., et al. (2012). The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis, 16(3), 205–42.

9 Woodman, C., Collins, S., Young, L. (2007). The natural history of cervical HPV infection: unresolved issues. Nature reviews, 7(1), 11–22.

10 McCredie, M., Sharples, K., Paul, C., Baranyai, J., Medley, G., Jones, R. (2008). Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncology, 9(5), 425–34.

11 Machalek, D., et al. (2012). op. cit.

12 ibid.

13 ibid.

14 ibid.

15 Robinson, D., Coupland, V., Møller, H. (2009). An analysis of temporal and generational trends in the incidence of anal and other HPV-related cancers in Southeast England. British Journal of Cancer, 100(3), 527–31.

16 Jin, F., Stein, A., Conway, E., Regan, D., Law, M., Brotherton, J., et al. (2011). Trends in anal cancer in Australia, 1982–2005. Vaccine, 29(12), 2322–7.

17 Daling, J., Weiss, N., Hislop, T., Maden, C., Coates, R., Sherman, K., et al. (1987). Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. The New England Journal of Medicine, 317(16): 973–7.

18 D’Souza, G., Wiley, D., Li, X., Chmiel, J., Margolick, J., Cranston, R., et al. (2008). Incidence and epidemiology of anal cancer in the multicenter AIDS cohort study. J of Acquir Immune Defic Syndr, 48(4), 491–9.

19 Machalek, D., et al. (2012). op. cit.

20 Silverberg, M., Lau, B., Justice, A., Engels, E., Gill, M., Goedert, J., et al. (2012). Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Clin Infect Dis, 54(7), 1026–34.

21 van Leeuwen, M., Vajdic, C., Middleton M., McDonald, A., Law, M., Kaldor, J., et al. (2009). Continuing declines in some but not all HIV-associated cancers in Australia after widespread use of antiretroviral therapy. AIDS, 23(16), 2183–90.

22 Palefsky, J., Giuliano, A., Goldstone, S., Moreira, E., Jr., Aranda, C., Jessen, H., et al. (2011). HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. The New England Journal of Medicine, 365(17), 1576–85.

23 Machalek, D., et al. (2012). op. cit.

24 Macaya, A., Munos-Santos, C., Balaguer, A., Barbera, M. (2012). Interventions for anal canal intraepithelial neoplasia. Cochrane Database of Systematic Reviews, John Wiley and Sons, Ltd.

25 Richel, O., de Vries, H., van Noesel, C., Dijkgraaf, M., Prins, J. (2013). Comparison of imiquimod, topical fluorouracil, and electrocautery for the treatment of anal intraepithelial neoplasia in HIV-positive men who have sex with men: an open label, randomised controlled trial. Lancet Oncology, 14(4), 346–53.

Dr Mary Poynten is Senior Lecturer, HIV Epidemiology and Prevention Program at The Kirby Institute and is project leader of the SPANC study.

Professor Andrew Grulich is Program Head of the HIV Epidemiology and Prevention Program at The Kirby Institute and is Principal Investigator of the SPANC study.