The prevalence and causes of oropharyngeal cancer (OPC) have altered significantly over the past 20 years. As tobacco use declines, particularly in Western countries, Human Papilloma Virus (HPV) has now become the main risk factor for OPC, accounting for more than 70% of cases in the United States [1]. In comparison, the relative rates of Australian HPV-associated OPC have risen from 0.2% in 1995 to over 63.2%, as reported by Hong et al., 2015 [2]. OPC has overtaken cervical cancer as the main cause of HPV-related malignancy [1]. In contrast to cervical cancer, HPV-associated OPC does not have an identifiable precursor stage that can be screened for and managed, which further complicates diagnosis and adds to the urgency of preventing OPC before it initiates and progresses [3].

Over 90% of HPV-associated OPCs are caused by HPV16 and after first exposure at least two years passes before cancer develops, however it can often occur significantly later, with a mean timing of 35 years [4]. OPC due to HPV usually occur in a younger and healthier demographic as opposed to non-HPV associated OPC, which tends to occur in smokers and those who consume significant quantities of alcohol [5]. The amount of oral sex partners is the major risk factor associated with OPC development [1, 2]. The proportion of HPV-positive individuals was estimated at 6.9% in an American study of individuals aged between 14 to 69 years, with more men than women being positive for HPV (10.1% versus 3.6% respectively) [4]. This correlates with the consensus that there is increased incidence of HPV-associated OPC in men [2, 6, 7].

By comparison, many nations with HPV-vaccination programmes only target women due to the more widely known, and robust link between HPV-positivity and cervical cancer [8, 9]. Cervical cancer has the pre-cancerous stage of carcinoma-in-situ (CIN), which can be detected with screening and prevented with HPV vaccination [3]. OPC, by contrast, has no identifiable pre-cancerous stage and some have postulated that oral HPV-positivity may be the oropharyngeal equivalent to CIN and thus advocate strongly for its early elimination to prevent OPC occurrence [3, 10].

HPV-vaccination has been identified as a convenient and cost-effective way of reducing incidence of HPV-related OPC, [11]. Most HPV-vaccination programmes largely target women, despite men being disproportionately affected by OPC [11].

Well-designed studies are lacking given the relatively recent implementation of HPV-vaccination and the late development of HPV-associated OPC (which occurs at a mean age of between 40-60). Studies have noted that HPV vaccines have been shown to reduce oral infection with HPV16. Oral HPV16 has been used in previous studies as a marker of OPC risk and its elimination as evidence of protection against HPV-associated OPC [12]. The FDA approved Gardasil (which targets HPV-6, 11, 16 and 18) as prophylaxis against HPV-related OPC in June 2020 [13]. Other countries, such as Australia, offer Gardasil free of charge to both boys and girls, through the National Immunisation Programme since 2013 and 2007 respectively [2].

The argument for pangender HPV vaccination has been countered in certain countries by querying cost-effectiveness and the potential ability to achieve herd-immunity through female vaccination only [14, 15]. These arguments do not take into consideration men-who-have-sex-with-men or that ‘gender-specific’ vaccination has markedly lower effectiveness than pangender vaccination against HPV [16, 17]. The case for male vaccination against HPV could be strengthened by a detailed examination of HPV-vaccination’s role in combatting OPC.

This review aims to explore whether it is beneficial to undertake pangender HPV-vaccination to prevent HPV-associated OPC, focusing specifically on men. While HPV-vaccination has been shown to prevent cervical cancer, there is still a research gap surrounding HPV-vaccination and its role in preventing HPV-associated OPC, as fewer men have been vaccinated than women [1, 4, 18].

This study aims to provide recommendations for pangender HPV-vaccination to reduce HPV-associated OPC in men. This study is significant, as showing a relationship between these two variables could lead to international practice change, resulting in pangender vaccination, to prevent HPV-associated OPC.

Accordingly, the research question of this review is: how effective is HPV vaccination (intervention, comparator: unvaccinated) in preventing oropharyngeal cancer (outcome) in men (population)?

The null hypothesis is that HPV vaccination has no effect on prevention of oropharyngeal cancer in men.

The alternative hypothesis is that HPV vaccination has an effect on the prevention of oropharyngeal cancer in men.

To ensure that various sources were captured, the Ovid Medline, ProQuest Central and the Scopus databases were searched, including studies published between January 2017-present, for articles in the English language. The Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews were included from January 2005-present, to identify grey literature or ongoing clinical trials.

The searches were carried out on 22nd October 2021. See "Appendix 2" for search strategies and key words for each database. Inclusion criteria were studies that had full text available; were written in English; were related to cancer; were related to HPV; and were published from 2017 to present.

Exclusion criteria included studies that were non-systematic reviews (e.g., review articles, case reports); had no vaccination intervention; included a qualitative analysis only; did not include men in the study; had no mention of OPC; did not show overall prevalence of HPV; had no comparator group; and had no relevant or original data.

The search strategy was separately carried out by two authors (P.M. and E.M.). These two reviewers worked independently using the screening software Covidence, to screen title and abstracts for the first screening and then full text articles for the second screening, to determine articles for inclusion in this review [19]. All disputes were resolved by another independent author (S.D.).

The Cochrane Risk of Bias tool 2 (RoB-2) was employed to evaluate the included randomised controlled trial [20]. This tool was deemed appropriate to evaluate the strengths and weaknesses of included RCTs and has been validated extensively. One reviewer P.M. conducted the risk assessment. Each item was rated as “high”, “low” or “unclear” risk of bias. The ROBINS-1 tool was used to assess risk of bias for the non-randomised controlled trial and is another extensively externally validated tool [20].

The National Institute of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies and the NIH quality assessment tool for systematic reviews evaluated the quality of the observational studies and systematic reviews respectively [21]. By examining various aspects of the study design, a value of good, fair, or poor was allocated. The results of these are described later in the "Results" section.