Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer

University of Texas M.D. Anderson Cancer Center, Houston, USA.
New England Journal of Medicine (Impact Factor: 55.87). 07/2010; 363(1):24-35. DOI: 10.1056/NEJMoa0912217
Source: PubMed


Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown.
We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer.
The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage.
Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. ( number, NCT00047008.)

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    • "Interestingly, whereas the p16 status does not correlate with HPV positivity in HNC outside the oropharynx such as the oral tongue, it still associates with a better prognosis irrespective of the HPV status (Harris et al, 2011). It is well established that patients with HPV-positive tumours fare better than patients with HPV-negative tumours (Ang et al, 2010). This has resulted in discussion of altering therapy (deescalation ) of HPV-positive tumours by reducing the dose of radiation or trials of cetuximab rather than cisplatin in an effort to reduce the side effects of chemoradiation therapy (Masterson et al, "
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    ABSTRACT: Head and neck cancers (HNC) are aggressive tumours. Overexpression of p16 in HNC correlates with human papilloma virus (HPV)-associated HNC that carry a better prognosis than HPV-negative tumours. Angiogenesis is an important factor in tumour progression. Our aim was to dissect the impact of p16 expression on angiogenesis factors in HNC. Eighteen newly diagnosed HNC patients and controls were analysed. Eleven pro- and anti-angiogenesis factors were quantified using multiplex ELISA in HNC patients and controls. Angiogenesis factors were analysed in tumour tissue using immunohistochemistry. Circulating levels of endostatin (anti-angiogenesis factor) were higher in the HNC group compared with healthy donors. Interestingly, the pro-angiogenesis factors angiopoietin-1 and vascular endothelial growth factor (VEGF) were significantly higher in patients with p16-negative compared with p16-positive HNC. Moreover, the major source of VEGF in p16-positive HNC tissue was tumour stromal cells. In contrast, both tumour cells and stromal cells expressed VEGF in p16-negative tissue. We show that p16-negative tumours associate with increased circulating levels of pro-angiogenic VEGF and angiopoietin-1. Tissue expression of VEGF differs between p16-positive and p16-negative tumours. These findings may explain differences in the biological behaviour of p16-positive and p16-negative HNC. Better understanding of mechanisms by which the p16 status influences tumour angiogenesis may guide the development of targeted therapies.British Journal of Cancer advance online publication: 14 July 2015; doi:10.1038/bjc.2015.251
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    • "This is in clear contrast to HPV+ OPSCC patient cohorts from the United States where the relative portions of current smokers comprise less than 15% [10] [25]. Since smoking has been shown to represent an independent risk factor of reduced treatment efficacy and overall survival [10] [14], this high prevalence of smokers has to be considered in future clinical trials, especially in studies aiming at the evaluation of de-escalation strategies in HPV+ OPSCC. Our data revealing 2-year survival rates of 98% versus 74% in never/ex-smokers compared to current smokers in the HPV+ OPSCC patients underline the need for high caution in such de-escalation strategies . "
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    ABSTRACT: Increases in incidence of oropharyngeal squamous cell carcinoma (OPSCC) in countries with falling tobacco use have been attributed to a growing role of human papilloma virus (HPV) in the carcinogenesis. Trends of HPV prevalence in populations with persistently high portions of smokers are poorly characterised. Registry data from East Germany were used to determine incidence trends between 1998 and 2011. Data from patients treated at the Charité University Medicine Berlin between 2004 and 2013 (cohort 1, N=436) were used for estimation of trends in HPV prevalence, smoking and survival. HPV prevalence was prospectively confirmed in cohort 2 (N=213) comprising all primary HNSCC cases at the Charité in 2013. Between 1998 and 2011 incidence of both OPSCC and non-OPSCC increased. An increase in HPV prevalence (% of HPV+ cases in 2004-2006 versus 2012-2013: 27% versus 59%, P=0.0004) accompanied by a moderate decrease in the portion of current smokers was observed in OPSCC but not in non-OPSCC. The change in disease epidemiology in OPSCC was associated with significant improvement in overall survival. Increased HPV prevalence in OPSCC (48%) compared to non-OPSCC (11%) was confirmed in cohort 2. Despite clear differences to the United States in terms of tobacco use, the increase in OPSCC incidence in a European population was also mainly attributed to HPV, and the HPV status significantly affected prognosis. For clinical trial design it is important to consider the large group of smokers within HPV-induced OPSCC. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jan 2015 · European journal of cancer (Oxford, England: 1990)
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    • "Although the overall incidence of HNSCC has decreased in some regions of the world (e.g., US) over the last two decades, owing to a reduction in smoking prevalence, the incidence of HPV-related HNC is ever increasing , with approximately 60% of oropharyngeal cancer being HPV positive [16,17]. HPV-positive patients are now recognised as a distinct subgroup of HNC and are associated with an improved response to treatment and better prognosis compared with HPVnegative patients [16]. As such, patients with HPV-associated HNC are considered to have their own clinicopathological profile that warrants investigation in dedicated clinical trials. "
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    ABSTRACT: Despite substantial improvements in the treatment of head and neck cancer (HNC) over the last two decades, overall survival rates remain unsatisfactory. The need for improved therapeutic approaches for HNC patients is hampered by low patient recruitment rates in HNC clinical trials, particularly Phase III studies. Based on an analysis of, this article identified several potential barriers to patient recruitment in Phase I-III clinical trials of treatments for HNC. Of 694 HNC trials identified on from multiple sites worldwide, 91 (13.1%) were identified as either terminated, suspended or withdrawn; 27.5% (n=25) of these did not provide an additional reason for stopping recruitment early. Insufficient accrual was the most common reason provided for trial closure (n=23, 25.3%). Possible reasons for the insufficient accrual rates include the inappropriate designs of these studies given the change in HNC tumour biology in the last 20years, the low incidence of the disease, and the diversity of treatment standards and referral processes across countries. Given the low numbers of drugs approved for HNC, it is important that barriers to recruitment in this field are addressed to allow new therapies to be successfully validated in completed clinical trials. This review discusses how these accrual challenges may be overcome with changes to clinical trial designs, including their adaptation to specific subgroups, such as human papillomavirus-positive patients. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jan 2015 · Oral Oncology
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