Background. HPV is a positive prognostic factor in HNSCC. We studied the prevalence and prognostic impact of HPV on survival parameters and treatment toxicity in patients with locally advanced HNSCC treated with concomitant chemoradiation therapy. Methods. Data on efficacy and toxicity were available for 560 patients. HPV was detected by PCR. Analysis was performed using Kaplan-Meier survival curves, Fisher’s test for categorical data, and log-rank statistics for failure times. Results. Median follow-up was 4.7 years. DNA extraction was successful in 255 cases. HPV prevalence was 68.6%, and 53.3% for HPV 16. For HPV+ and HPV？, median LRC was 8.9 and 2.2 years ( ), median DFS was 8.9 and 2.1 years ( ), and median OS was 8.9 and 3.1 years ( ). Survival was different based on HPV genotype, stage, treatment period, and chemotherapy regimen. COX adjusted analysis for T, N, age, and treatment remained significant ( ). Conclusions. Oropharyngeal cancer is increasingly linked to HPV. This study confirms that HPV status is associated with improved prognosis among H&N cancer patients receiving CRT and should be a stratification factor for clinical trials including H&N cases. Toxicity of CRT is not modified for the HPV population. 1. Introduction Tobacco and alcohol consumption has long been known as the major risk factor for HNSCC. However, HPV has recently been recognised to play a role in the pathogenesis of a subset of clinically and molecularly distinct HNSCC, most often located in the oropharynx and associated with wild-type p53 and downregulation of cyclin D and retinoblastoma protein pRb [1–5], and in which viral oncoproteins E6 and E7 play a crucial part [6]. HPV prevalence in HNSCC has been increasing significantly in the past few decades [5, 7]; it is estimated at 25% in HNSCC [8], but reaches up to 70% or more in tonsillar SCCs [9–11]. Unlike the HPV-negative oropharyngeal cancers, the HPV-positive subset is not associated with tobacco or alcohol use, but with certain types of sexual behaviours [12, 13]. The HPV 16 subtype is present in up to 90% of HPV-related oropharyngeal cancers, while HPVs 18, 31, and 33 have been identified in the remainder [14, 15]. HPV has recently been recognised as a good prognostic factor in head and neck (H&N) cancer [5, 16–26], which has been attributed to several mechanisms, including absence of field cancerisation and increased sensitivity to chemoradiation therapy [5, 16, 20, 22–24, 26]. Most of the available data is derived from small randomised trials with different treatment options or small heterogeneous cohorts;
References
[1]
W. H. Westra, J. M. Taube, M. L. Poeta, S. Begum, D. Sidransky, and W. M. Koch, “Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck,” Clinical Cancer Research, vol. 14, no. 2, pp. 366–369, 2008.
[2]
T. Wiest, E. Schwarz, C. Enders, C. Flechtenmacher, and F. X. Bosch, “Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRB cell cycle control,” Oncogene, vol. 21, no. 10, pp. 1510–1517, 2002.
[3]
H. C. Hafkamp, J. J. Manni, A. Haesevoets et al., “Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas,” International Journal of Cancer, vol. 122, no. 12, pp. 2656–2664, 2008.
[4]
B. Kumar, K. G. Cordell, J. S. Lee et al., “EGFR, p16, HPV titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer,” Journal of Clinical Oncology, vol. 26, no. 19, pp. 3128–3137, 2008.
[5]
M. L. Gillison, W. M. Koch, R. B. Capone et al., “Evidence for a causal association between human papillomavirus and a subset of head and neck cancers,” Journal of the National Cancer Institute, vol. 92, no. 9, pp. 709–720, 2000.
[6]
C. T. Allen, J. S. Lewis Jr., S. K. El-Mofty, B. H. Haughey, and B. Nussenbaum, “Human papillomavirus and oropharynx cancer: biology, detection and clinical implications,” Laryngoscope, vol. 120, no. 9, pp. 1756–1772, 2010.
[7]
A. K. Chaturvedi, E. A. Engels, W. F. Anderson, and M. L. Gillison, “Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States,” Journal of Clinical Oncology, vol. 26, no. 4, pp. 612–619, 2008.
[8]
A. R. Kreimer, G. M. Clifford, P. Boyle, and S. Franceschi, “Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systemic review,” Cancer Epidemiology Biomarkers and Prevention, vol. 14, no. 2, pp. 467–475, 2005.
[9]
L. Hammarstedt, D. Lindquist, H. Dahlstrand et al., “Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer,” International Journal of Cancer, vol. 119, no. 11, pp. 2620–2623, 2006.
[10]
A. N？sman, P. Attner, L. Hammarstedt et al., “Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?” International Journal of Cancer, vol. 125, no. 2, pp. 362–366, 2009.
[11]
T. Ramqvist and T. Dalianis, “Oropharyngeal cancer epidemic and human papillomavirus,” Emerging Infectious Diseases, vol. 16, no. 11, pp. 1671–1677, 2010.
[12]
M. L. Gillison, G. D'Souza, W. Westra et al., “Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers,” Journal of the National Cancer Institute, vol. 100, no. 6, pp. 407–420, 2008.
[13]
G. D'Souza, A. R. Kreimer, R. Viscidi et al., “Case-control study of human papillomavirus and oropharyngeal cancer,” The New England Journal of Medicine, vol. 356, no. 19, pp. 1944–1956, 2007.
[14]
R. Chen, L. M. Aaltonen, and A. Vaheri, “Human papillomavirus type 16 in head and neck carcinogenesis,” Reviews in Medical Virology, vol. 15, no. 6, pp. 351–363, 2005.
[15]
C. C. R. Ragin and E. Taioli, “Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis,” International Journal of Cancer, vol. 121, no. 8, pp. 1813–1820, 2007.
[16]
C. Fakhry, W. H. Westra, S. Li et al., “Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial,” Journal of the National Cancer Institute, vol. 100, no. 4, pp. 261–269, 2008.
[17]
C. Fakhry and M. L. Gillison, “Clinical implications of human papillomavirus in head and neck cancers,” Journal of Clinical Oncology, vol. 24, no. 17, pp. 2606–2611, 2006.
[18]
P. M. Weinberger, Z. Yu, B. G. Haffty et al., “Molecular classification identifies a subset of human papillomavirus- associated oropharyngeal cancers with favorable prognosis,” Journal of Clinical Oncology, vol. 24, no. 5, pp. 736–747, 2006.
[19]
N. F. Schlecht, “Prognostic value of human papillomavirus in the survival of head and neck cancer patients: an overview of the evidence,” Oncology Reports, vol. 14, no. 5, pp. 1239–1247, 2005.
[20]
K. Lindel, K. T. Beer, J. Laissue, R. H. Greiner, and D. M. Aebersold, “Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma,” Cancer, vol. 92, pp. 805–813, 2001.
[21]
S. R. Schwartz, B. Yueh, J. K. McDougall, J. R. Daling, and S. M. Schwartz, “Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study,” Otolaryngology, vol. 125, no. 1, pp. 1–9, 2001.
[22]
J. M. Ritchie, E. M. Smith, K. F. Summersgill et al., “Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx,” International Journal of Cancer, vol. 104, no. 3, pp. 336–344, 2003.
[23]
L. Dahlgren, H. Dahlstrand, D. Lindquist et al., “Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients,” International Journal of Cancer, vol. 112, no. 6, pp. 1015–1019, 2004.
[24]
M. L. Gillison, “Human papillomavirus and prognosis of oropharyngeal squamous cell carcinoma: implications for clinical research in head and neck cancers,” Journal of Clinical Oncology, vol. 24, no. 36, pp. 5623–5625, 2006.
[25]
D. Rischin, R. J. Young, R. Fisher et al., “Prognostic significance of p16INK4Aand human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial,” Journal of Clinical Oncology, vol. 28, no. 27, pp. 4142–4148, 2010.
[26]
K. K. Ang, J. Harris, R. Wheeler et al., “Human papillomavirus and survival of patients with oropharyngeal cancer,” The New England Journal of Medicine, vol. 363, no. 1, pp. 24–35, 2010.
[27]
F. Coutlée, C. Hankins, and N. Lapointe, “Comparison between vaginal tampon and cervicovaginal lavage specimen collection for detection of human papillomavirus DNA by the polymerase chain reaction,” Journal of Medical Virology, vol. 51, no. 1, pp. 42–47, 1997.
[28]
F. Coutlée, D. Rouleau, P. Petignat et al., “Enhanced detection and typing of human papillomavirus (HPV) DNA in anogenital samples with PGMY primers and the linear array HPV genotyping test,” Journal of Clinical Microbiology, vol. 44, no. 6, pp. 1998–2006, 2006.
[29]
M. V. Jacobs, A. M. de Roda Husman, A. J. C. van den Brule, P. J. F. Snijders, C. J. L. M. Meijer, and J. M. M. Walboomers, “Group-specific differentiation between high- and low-risk human papillomavirus genotypes by general primer-mediated PCR and two cocktails of oligonucleotide probes,” Journal of Clinical Microbiology, vol. 33, no. 4, pp. 901–905, 1995.
[30]
N. Reimers, H. U. Kasper, S. J. Weissenborn et al., “Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer,” International Journal of Cancer, vol. 120, no. 8, pp. 1731–1738, 2007.
[31]
C. S. Kong, B. Narasimhan, H. Cao et al., “The relationship between human papillomavirus status and other molecular prognostic markers in head and neck squamous cell carcinomas,” International Journal of Radiation Oncology Biology Physics, vol. 74, no. 2, pp. 553–561, 2009.
[32]
S. J. Smeets, A. T. Hesselink, E. J. M. Speel et al., “A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen,” International Journal of Cancer, vol. 121, no. 11, pp. 2465–2472, 2007.
[33]
C. A. Fischer, I. Zlobec, E. Green et al., “Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality?” International Journal of Cancer, vol. 126, no. 5, pp. 1256–1262, 2010.
[34]
N. F. Schlecht, R. D. Burk, L. Adrien et al., “Gene expression profiles in HPV-infected head and neck cancer,” Journal of Pathology, vol. 213, no. 3, pp. 283–293, 2007.
[35]
K. Specht, T. Richter, U. Müller, A. Walch, M. Werner, and H. H？fler, “Quantitative gene expression analysis in microdissected archival formalin-fixed and paraffin-embedded tumor tissue,” The American Journal of Pathology, vol. 158, no. 2, pp. 419–429, 2001.
[36]
R. L. Cantley, E. Gabrielli, F. Montebelli, D. Cimbaluk, P. Gattuso, and G. Petruzzelli, “Ancillary studies in determining human papillomavirus status of squamous cell carcinoma of the oropharynx: a review,” Pathology Research International, vol. 2011, Article ID 138469, 7 pages, 2011.
[37]
W. Shi, H. Kato, B. Perez-Ordonez et al., “Comparative prognostic value of HPV16 E6 mRNA compared with in situ hybridization for human oropharyngeal squamous carcinoma,” Journal of Clinical Oncology, vol. 27, no. 36, pp. 6213–6221, 2009.
[38]
J. H. Maxwell, B. Kumar, F. Y. Feng et al., “Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence,” Clinical Cancer Research, vol. 16, no. 4, pp. 1226–1235, 2010.
[39]
M. L. Gillison, Q. Zhang, R. Jordan et al., “Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer,” Journal of Clinical Oncology, vol. 30, no. 17, pp. 2102–2111, 2012.
[40]
D. J. Adelstein, Y. Li, G. L. Adams et al., “An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer,” Journal of Clinical Oncology, vol. 21, no. 1, pp. 92–98, 2003.
[41]
J. P. Pignon, A. L. Ma？tre, E. Maillard, and J. Bourhis, “Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients,” Radiotherapy and Oncology, vol. 92, no. 1, pp. 4–14, 2009.
[42]
A. A. Forastiere, H. Goepfert, and M. Maor, “Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer,” The New England Journal of Medicine, vol. 349, pp. 2091–2098, 2003.
