Journal of the National Cancer Institute Advance Access originally published online on February 12, 2008
JNCI Journal of the National Cancer Institute 2008 100(4):261-269; doi:10.1093/jnci/djn011
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Improved Survival of Patients With Human Papillomavirus–Positive Head and Neck Squamous Cell Carcinoma in a Prospective Clinical Trial
Affiliations of authors: Johns Hopkins Medical Institutions, Baltimore, MD (CF, WHW, AF, MGL); Dana-Farber Cancer Institute, Boston, MA (SL); Vanderbilt University, Nashville, TN (AC); Stanford University, Palo Alto, CA (HP); Fox Chase Cancer Center, Philadelphia, PA (JAR)
Correspondence to: Maura L. Gillison, MD, PhD, Johns Hopkins Kimmel Cancer Center, Cancer Research Bldg I, Rm 3M 54A, 1650 Orleans St, Baltimore, MD 21231 (e-mail: gillima{at}jhmi.edu).
Background: The improved prognosis for patients with human papillomavirus (HPV)–positive head and neck squamous cell carcinoma (HNSCC) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospective clinical trial.
Methods: We prospectively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group (ECOG) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and standard fractionation radiation therapy. The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction (PCR) and in situ hybridization. Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan–Meier analysis. The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age, ECOG performance status, stage, and other covariables was estimated by use of a multivariable Cox proportional hazards model. All statistical tests were two-sided.
Results: Genomic DNA of oncogenic HPV types 16, 33, or 35 was located within tumor cell nuclei of 40% (95% confidence interval [CI] = 30% to 50%) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR. Compared with patients with HPV-negative tumors, patients with HPV-positive tumors had higher response rates after induction chemotherapy (82% vs 55%, difference = 27%, 95% CI = 9.3% to 44.7%, P = .01) and after chemoradiation treatment (84% vs 57%, difference = 27%, 95% CI = 9.7% to 44.3%, P = .007). After a median follow-up of 39.1 months, patients with HPV-positive tumors had improved overall survival (2-year overall survival = 95% [95% CI = 87% to 100%] vs 62% [95% CI = 49% to 74%], difference = 33%, 95% CI = 18.6% to 47.4%, P = .005, log-rank test) and, after adjustment for age, tumor stage, and ECOG performance status, lower risks of progression (hazard ratio [HR] = 0.27, 95% CI = 0.10 to 0.75), and death from any cause (HR = 0.36, 95% CI = 0.15 to 0.85) than those with HPV-negative tumors.
Conclusion: For patients with HNSCC of the oropharynx, tumor HPV status is strongly associated with therapeutic response and survival.
| CONTEXT AND CAVEATS Prior knowledge Analyses of retrospective case series had demonstrated that patients with head and neck squamous cell carcinoma (HNSCC) whose tumors were human papillomavirus (HPV)-positive had a better prognosis than patients whose tumors were HPV-negative, but this remained to be confirmed in a study that adequately controlled for factors of known prognostic value. Study design The association of tumor HPV status with therapeutic response and survival was evaluated in patients participating in a trial of chemotherapy and radiation therapy by Kaplan–Meier analysis and a Cox proportional hazards model. Contribution The presence of HPV in tumors of patients with HNSCC was positively associated with response to treatment and overall survival after adjustment for a set of other factors known to be associated with clinical outcome. Implications The risks and benefits of current therapies may need to be assessed separately according to the HPV status of the patient's tumor. Limitations Larger samples may be needed to more thoroughly evaluate the possibility of confounding by smoking and other variables.
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Manuscript received July 6, 2007; revised November 29, 2007; accepted January 8, 2008.
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J Natl Cancer Inst 2008 100: 227.
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