Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancer

Summary

Objectives

To describe the natural course of distant metastases (DMs) following radiotherapy (RT) or chemoradiotherapy (CRT) in HPV(+) oropharyngeal carcinoma (OPC).

Methods

OPC treated with RT/CRT from 1/1/2000 to 5/31/2010 were reviewed. The natural course of DM were compared between HPV(+) and HPV(−) cohorts.

Results

Median follow-up was 3.9 years. The DM rate were similar (11% vs. 15% at 3-years, p = 0.25) between the HPV(+) (n = 457) vs. the HPV(−) (n = 167) cases. While almost all (24/25) HPV(−) DM occurred within 2-years following RT (1 was at 2.1 years), 7/54 (13%) of HPV(+) DM were detected beyond 3 years (up to 5.3 years). Disseminating to >2 organs occurred in 18 (33%) HPV(+) vs. none in HPV(−). Post-DM survival rates were 11% vs. 4% at 2-years (p = 0.02) for the HPV(+) vs. HPV(−) cases respectively. 5/6 HPV(+) with lung oligo-metastasis were still alive with stable disease beyond 2-years after salvage procedures for DM (chemotherapy: 3; surgical resection: 2; radiotherapy: 1).

Conclusions

Although DM rates are similar, the natural course of HPV(+) DM differs from that of HPV(−) patients: it may occur after a longer interval, often with a “disseminating” phenotype, and a small number may have prolonged survival after salvage for DM.

Introduction

At least two types of pharyngeal mucosal cancers are related to viral infection. Epstein–Barr virus (EBV) is associated with non-keratinizing subtypes of nasopharyngeal cancer (NPC).[1], [2] Human papillomavirus (HPV) is a confirmed cancer-causing agent for a subset of oropharyngeal cancer (OPC).³ Both cancers share unique similarities. They are more likely to exhibit non-keratinizing morphology,[4], [5] to have significant cervical lymphadenopathy at presentation,[6], [7] and to be more sensitive to radiotherapy (RT), compared to conventional (non-virally related) squamous cell carcinoma at the same respective anatomical location.[6], [8]

HPV infection is currently responsible for 40–80% of OPC in North America.⁹ HPV-related [HPV(+)] OPC exhibits fundamental differences compared to HPV-unrelated [HPV(−)] OPC, which is classically related to smoking and alcohol exposure. Despite more extensive regional lymph node involvement at presentation, HPV(+) OPC patients have superior loco-regional control and survival following RT or chemoradiotherapy (CRT) compared to their HPV(−) counterparts.[3], [8], [10], [11] However, some HPV(+) patients suffer from poor outcomes, mainly related to the development of distant metastases (DM). As is the case for NPC,¹² DM seems to have become the dominant pattern of failure for OPC patients in the contemporary era.¹³

Although the reported DM rate is similar between HPV(+) and HPV(−) patients,[10], [14] some striking difference in their clinical behavior and prognosis have been observed. We previously reported preliminary data showing that HPV(+) OPC may exhibit a more “disseminating” phenotype (often involving multiple organs and unusual sites) once DM manifests¹⁵ but a low-event rate and insufficient follow-up hindered an analysis of the subsequent oncologic course. In the present report we expand the cohort and extend our evaluation to investigate the pattern of failure, time course following the development of DM, and the potential for long-term control after salvage procedures for HPV(+) DM in a larger sample size with more robust follow-up.