Source: BMJ 2010;340:c1439
Author: Staff

Incidence is increasing rapidly, with implications for prognosis and policy

Head and neck cancer is the sixth most common cancer, with about 640,000 new cases each year worldwide. Despite an overall marginal decline in the incidence of most head and neck cancers in recent years,1 the incidence of oropharyngeal squamous cell carcinoma has increased greatly, especially in the developed world. In the United States, the incidence of oropharyngeal squamous cell carcinoma increased by 22% from 1.53 per 100,000 to 1.87 per 100,000 between 1999 and 2006, after showing no change between 1975 and 1999. 1 The United Kingdom has seen a 51% increase in oral and oropharyngeal squamous cell carcinoma in men from seven per 100,000 to 11 per 100,000 between 1989 and 2006.

2 The increase in incidence of oropharyngeal squamous cell carcinoma seems to be accounted for by a rise in human papillomavirus (HPV) related oropharyngeal carcinoma. A recent retrospective study showed a progressive proportional increase in the detection of HPV in biopsies taken to diagnose oropharyngeal squamous cell carcinoma in the Swedish county of Stockholm over the past three decades (23.3% in 1970s, 29% in 1980s, 57% in 1990s, 68% between 2000 and 2002, 77% between 2003 and 2005, and 93% between 2006 and 2007).3 Similarly, HPV related oropharyngeal carcinoma has been reported in 60-80% of recent oropharyngeal biopsy samples in studies conducted in the US, compared with 40% in the previous decade.4 More research is needed to establish the incidence of HPV related oropharyngeal carcinoma in African, Asian, and South American countries.

HPV related oropharyngeal carcinoma seems to be a new and distinct disease entity. 5 It has a more favourable prognosis than non-HPV related oropharyngeal carcinoma, particularly in non-smokers. Two recent randomized trials have shown significantly improved two year overall survival in stage III and stage IV HPV type 16 related oropharyngeal carcinoma compared with non-HPV related cancers (87.5% and 95% compared with 67.2% and 62%). 5 6 The reason for this improved survival is not fully understood; it may be the result of an increased immunological response to HPV antigens in the host,7 or an increased sensitivity to radiotherapy because the presence of wild-type p53 causes an increase in apoptosis.8 Smoking seems to worsen outcomes for patients with HPV related oropharyngeal carcinoma—outcomes are similar to non-smokers with non-HPV related oropharyngeal carcinoma.9

Sexual transmission of HPV—primarily through orogenital intercourse might be the reason for the increase in incidence of HPV related oropharyngeal carcinoma. A pooled analysis of eight multinational observational studies that compared 5642 cases of head and neck cancer with 6069 controls found that the risk of developing oropharyngeal carcinoma was associated with a history of six or more lifetime sexual partners (odds ratio 1.25, 95% confidence interval 1.01 to 1.54), four or more lifetime oral sex partners (3.36, 1.32 to 8.53), and—for men—an earlier age at first sexual intercourse (2.36, 1.37 to 5.05).10

The rising incidence of HPV related oropharyngeal carcinoma has implications for health service providers and commissioners. Patients are typically younger and employed, and—because outcomes seem to be more favourable than for patients with non-HPV related carcinoma—they will live longer with the functional and psychological sequelae of their treatment. Consequently, they need prolonged support from health, social, and other services, and may require help in returning to work.

There are also public health implications. Female only HPV vaccination programmes may affect the incidence of HPV related oropharyngeal carcinoma. A recent modelling study of the effects of HPV vaccination in males concluded that routinely vaccinating boys for HPV could not be justified on health economic grounds.11 However, the low incidence of HPV related oropharyngeal carcinoma in that study has led to concern because the recent rapid rise in HPV related oropharyngeal carcinoma may alter the cost effectiveness of vaccinating boys before they become sexually active.12

Studies reporting treatment outcomes for head and neck cancer, particularly oropharyngeal carcinoma, must now account for HPV status, because of its association with improved prognosis. Newly diagnosed patients may wish to know their HPV status, and future stratification by HPV status will probably be necessary. Widely used methods to detect tumor associated HPV infection include detection of HPV-16 DNA using polymerase chain reaction or in situ hybridization, detection of HPV E6 or E7 mRNA using reverse transcriptase-polymerase chain reaction, and immunohistochemical analysis of p16 over expression, all of which act as markers of transcription or “activity.” However, standardized definitions and cut-off points must be agreed to identify the best test or combination of tests for clinical diagnosis, and to regulate quality assurance in clinical laboratories.

To date, we have no good evidence to support managing patients with HPV related head and neck cancer differently from those whose tumors are not HPV related, although several studies are being planned to evaluate different treatment options. Until data from such studies are available, we suggest that clinicians should not change their current treatment policies for patients with HPV related oropharyngeal squamous cell carcinoma, but should aim to offer all patients with oropharyngeal cancer the opportunity to enroll in an appropriate clinical trial.

Hisham Mehanna, director 1, Terence M Jones, reader2, Vincent Gregoire,

professor3, K Kian Ang, professor4

1 Institute of Head and Neck Studies and Education (InHANSE), University Hospital, Coventry CV2 2DX, 2 Liverpool CR-UK Cancer Centre, School of Cancer Studies, Division of Surgery and Oncology, University of Liverpool, Liverpool L69 3GA, 3 Radiation Oncology Department and Centre for Molecular Imaging and Experimental Radiotherapy, Université Catholique de Louvain, 1200 Brussels, Belgium, 4 Department of Radiation Oncology, University of Texas, MD Anderson Cancer Centre, Houston, TX 77030, USA [email protected] Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: (1) None have support from any companies for the submitted work; (2) HM is the director of an institute that does contract work for GlaxoSmithKline that has interests in head and neck cancers; (3) Their spouses, partners, and children have no financial relationships that may be relevant to the submitted work; and (4) TMJ holds a CR-UK research grant for a phase I clinical trial involving patients with HPV related oropharyngeal carcinoma and for which Advaxis will be providing a therapeutic vaccine (ADXS11-001) free of charge. Provenance and peer review: commissioned not externally peer reviewed