New Chapter in Our Understanding of Human Papillomavirus-Related Head and Neck Cancer
Authors: David G. Pfister, Matthew G. Fury
Journal: Journal of Clinical Oncology (2014)

Our knowledge about the relationship between human papillomavirus (HPV) and squamous cell upper aerodigestive track cancers has advanced considerably over the last decade. We now know the oropharynx is the head and neck subsite particularly vulnerable to the development of tumors attributed to prior HPV infection. HPV 16 is the most common viral subtype, with implications regarding potential preventive measures. The incidence of HPV-related head and neck cancer is increasing, and the epidemiology of the disease and its risk factors are better understood. Patients with HPVpositive versus -negative disease differ. The former are younger and more likely to be white, a nonsmoker, have disease that is more responsive to therapy and overall have a better prognosis. Other factors such as prior tobacco use can still adversely affect the anticipated survival outcomes of patients with HPV-related head and neck cancer. Patients at the initial presentation of their locoregional disease have been the focus of the work to date that has generated these and other insights. The role of HPV tumor status in the recurrent or metastatic setting, however, has received far less attention. In this regard, the article by Fakhry et al that accompanies this editorial represents an important contribution to a new chapter in our understanding of HPV-related head and neck tumors. Specifically, how the HPV status of a recurrent or metastatic oropharynx cancers affects anticipated prognosis, and the related implications for disease management and the evaluation of new therapies. In their article, Fakhry et al present a comprehensive retrospective analysis of 181 patients who were enrolled on either Radiation Therapy Oncology Group (RT0G) 0129 or 0522 for their primary chemoradiotherapy treatment, subsequently experienced progressive disease, and in whom immunohistochemical p16 data were available as a surrogate marker for HPV status. With a median follow-up of 4 years after progression, time to progression (8.2 v 7.3 months, P .67, for p16-positive v –negative tumors) and patterns of disease progression did not differ significantly based on p16 status. The central finding was a dramatic difference in median overall survival after disease progression: 2.6 years for p16-positive cases versus 0.8 years for p16negative cases (P .001). This impact of tumor p16 status on overall survival after progression remained robust after multivariable analysis to address potential prognostic confounders and accounted for a 52% reduction in risk of death. Of note, the application of salvage surgery was associated with a reduction in mortality of similar magnitude. The observed difference in median overall survival between the p16-positive and -negative groups is not entirely unexpected. The molecular underpinnings of the inferior prognosis for p16-negative tumors in the locoregional disease setting after primary treatment would be expected to remain relevant at least in part in the recurrent/ metastatic setting. In addition, a similar analysis by Canadian investigators who analyzed a cohort of patients with oropharynx cancer with distant spread of disease after radiation or chemoradiotherapy, found that patients with an HPV-related cancer had a better survival rate at 2 years than patients with HPV-unrelated disease (11% v 4%, P .02). Based on their data, Fakhry et al understandably conclude that tumor HPV status should be a stratification factor in clinical trials studying patients with recurrent or metastatic oropharynx cancers. It has become commonplace for a number of cancers to design trials specifically for patients with tumors harboring predefined molecular characteristics. Stratification by p16 or HPV status is already occurring and expected in trials evaluating therapies for patients with previously untreated locally or regionally advanced head and neck cancers. Indeed, studies in this untreated population for which entry is limited to patients with HPV-related oropharynx cancer are in progress, evaluating, as examples, different chemoradiotherapy programs (RTOG 1016), different radiation doses after induction chemotherapy (Eastern Cooperative Oncology Group [ECOG] 1308) and primary management with transoral robotic surgery (ECOG 3311). Considering tumor HPV status and avoiding prognostic imbalance in treatment groups so as to avoid potentially misleading comparisons would seem particularly prudent when planning studies in the recurrent and metastatic setting, given that very modest improvements in survival, even in the 1to 2-month range, have provided the basis for the approval and licensing of often expensive drugs for the treatment of advanced, refractory cancer. It should be emphasized, however, that the anticipated survival differences by tumor p16 or HPV status will depend on what starting point for the survival analysis is chosen. The estimated difference in typical clinical trials evaluating drug therapies for patients with recurrent or metastatic head and neck cancer may be far less than the 1.8 year difference in medians reported by Fakhry et al, since attempts at salvage with surgery or radiation would have likely already occurred pre-enrollment. Thus patients with a better prognosis rendered disease free by these interventions are eliminated from the denominator. Available data from the EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer) and SPECTRUM JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 30 OCTOBER 2