Human papillomavirus related head and neck cancer survival: A systematic review and meta-analysis

Summary

Human Papillomavirus (HPV) related oropharyngeal squamous cell carcinomas (OPSCCs) are reported to have improved prognosis and survival in comparison to other head and neck squamous cell cancers (HNSCCs). This systematic review and meta-analysis examines survival differences in HPV-positive HNSCC and OPSCC subtypes including tonsillar carcinoma in studies not previously investigated. Four electronic databases were searched from their inception till April 2011. A random effects meta-analysis was used to pool study estimates evaluating disease-specific (death from HNSCC), overall (all-cause mortality), progression-free and disease-free (recurrence free) survival outcomes in HPV-positive vs. HPV-negative HNSCCs. All statistical tests were two-sided. Forty-two studies were included. Patients with HPV-positive HNSCC had a 54% better overall survival compared to HPV-negative patients HR 0.46 (95% CI 0.37–0.57); the pooled HR for tonsillar cancer and OPSCC was 0.50 (95% CI 0.33–0.77) and HR 0.47 (95% CI 0.35–0.62) respectively. The pooled HR for disease specific survival was 0.28 (95% CI 0.19–0.40); similar effect sizes were found irrespective of the adjustment for confounders, HPV detection methods or study location. Both progression-free survival and disease-free survival were significantly improved in HPV-positive HNSCCs. HPV-positive HNSCCs and OPSCCs patients have a significantly lower disease specific mortality and are less likely to experience progression or recurrence of their cancer than HPV-negative patients; findings which have connotations for treatment selection in these patients.

Introduction

Head and neck cancer (HNC) is the fifth most common cancer diagnosed worldwide¹ and the eighth most common cause of cancer death.² HNC defines a heterogeneous group of malignancies including those of the lip, oral cavity, nose and paranasal sinuses, nasopharynx, oropharynx, hypopharynx and larynx³; the majority of which (85%) are of squamous cell carcinoma histology (HNSCC).⁴ Since the 1970s the incidence rates of some oropharyngeal cancers (OPSCCs), particularly those of the tongue base and tonsil, have risen steadily in the USA and Northern Europe[5], [6], [7], [8], [9], [10], [11], [12], [13], [14] especially in younger patients without recognised HNC risk factors, suggesting alternate aetiological pathways.[15], [16] This is thought to be a consequence of persistent infection with high-risk Human Papillomavirus (HPV),[6], [17] possibly in combination with other aetiological factors. In contrast the incidence rates of non-HPV related HNSCCs (such as laryngeal cancer) have remained stable or decreased among men in Europe and the USA, whilst rates among females has increased; trends which largely reflect changes in gender specific smoking rates.[18], [19]

Demographically, patients with HPV-related HNSCCs are more likely to be male, white, non-smokers, non-drinkers, younger in age and have a higher socioeconomic status.[9], [20], [21] Changes in sexual behaviour,²² including a higher number of lifetime sex partners, an increase in oral sex practices, same sex-contact and earlier age at sexual debut have all been implicated in HPV-related OPSCC.[21], [23]

HPV-related OPSCC may therefore represent a distinct tumour entity with unique clinical, pathological and biological features.²⁴ Importantly, patients with HPV-related OPSCCs are typically younger²⁵ and have improved survival and treatment response to chemotherapy and radiotherapy than those patients with HPV-negative OPSCCs or HNSCCs.[26], [27], [28] Five-year relative survival rates have been reported between 70–80% vs. 25–40% comparing HPV-positive to HPV-negative OPSCCs respectively, with these differences independent of age, gender and tumour stage.[9], [17], [20], [29], [30], [31] There is a clear need therefore to develop an understanding of the molecular characteristics of HPV-positive and negative tumours, in order that targeted therapies can be developed to better serve all patients with HNSCC.

The authors acknowledge five previous reviews of HPV in association with HNC. One systematic review³² and one meta-analysis³³ has examined the prevalence of HPV infection in various HNC sub types. A further systematic review and meta-analysis³⁴ looked at the association of HPV16 with HNC. Only two previous meta-analyses have examined survival in relation to HPV associated HNCs[35], [36]; however, neither review was adequately systematic and the findings from both were inconsistent. In the most recent analysis, Dayyani et al.³⁵ examined overall survival in HPV-positive patients with HNSCC and a subset with OPSCC finding an approximate 55% reduction in all cause mortality at each sub-site. Ragin and Taioli³⁶ found a much lower reduction (20%) in all-cause mortality across HNSCC sites. All-cause mortality was 28% lower and disease-free survival 50% greater in HPV-related OPSCC. There have been several large scale publications which have examined survival in HPV-related HNCs since these reviews were published. Given that OPSCC patients have different risk factor profiles and are typically younger than non-OPSCC patients, factors which may be influential on all-cause mortality, the aim of this systematic review and meta-analysis was to comprehensively examine disease-specific mortality, progression and recurrence of disease in HPV-related HNSCCs.