The Epidemic of HPV-Associated Oropharyngeal Cancer Is Here: Is It Time to Change Our Treatment Paradigms?

Although relatively uncommon, oropharyngeal cancers are increasing in incidence despite declining prevalence of smoking and in direct opposition to a decreasing incidence of all other head and neck cancers. An epidemic of human papillomavirus (HPV)–associated oropharyngeal cancers seems to account for these incidence trends. Important demographic, behavioral, and prognostic characteristics define this unique population. Changes in prevention, diagnosis, evaluation, staging, and treatment are needed. This article summarizes the epidemiology and clinical behavior of HPV-associated oropharyngeal cancer and discusses evolving/potential paradigms of treatment. However, data are currently insufficient to change treatment paradigms for HPV-associated oropharyngeal cancer outside of a closely monitored clinical trial.

Abstract

Although relatively uncommon, oropharyngeal cancers are increasing in incidence despite declining prevalence of smoking and in direct opposition to a decreasing incidence of all other head and neck cancers. An epidemic of human papillomavirus (HPV)–associated oropharyngeal cancers seems to account for these incidence trends. Important demographic, behavioral, and prognostic characteristics define this unique population. Changes in prevention, diagnosis, evaluation, staging, and treatment are needed. This article summarizes the epidemiology and clinical behavior of HPV-associated oropharyngeal cancer and discusses evolving/potential paradigms of treatment. However, data are currently insufficient to change treatment paradigms for HPV-associated oropharyngeal cancer outside of a closely monitored clinical trial.

The Epidemic of HPV-Associated Oropharyngeal Cancer

Significant site admixture occurs in the annual United States “Cancer Statistics” overview in which all subsites of pharyngeal cancer are listed as the single site “pharynx” (including not only oropharyngeal cancers but also hypopharyngeal and nasopharyngeal cancers), and base of tongue (lingual tonsil or oropharyngeal tongue) cancers are often listed collectively with oral (mobile or oral cavity) tongue cancers as the generic site “tongue.”1,2 Regardless of these site admixtures and without consideration of a growing and aging United States population, the number of both pharyngeal and tongue cancers is increasing (approximately 13,000 and 11,000, respectively, in 2010).1,3 As early as 2005, a conflict in the trends in age-adjusted incidence rates was noted, with increasing or stagnate rates for tongue and oropharyngeal cancer but significantly decreasing rates for laryngeal, hypopharyngeal, and oral cavity cancer2,4 (Figure 1). More careful site stratification has made it apparent that age-adjusted incidence of oropharyngeal cancer is rising dramatically (estimated at 5% annual increase) in the United States, whereas oral cavity cancer incidence is falling (approximately –2% annually).5 Furthermore, the increase in oropharyngeal cancer incidence seems to be seen primarily in middle-aged (40–59 years) white men.5 Notably, these trends among white men have completely eliminated the dramatic racial disparity that existed in oral cavity/pharyngeal cancer incidence.2

As a result of the Surgeon General's warning and the mounting evidence showing the association between tobacco and cancer, per capita tobacco consumption and cigarette smoking prevalence rates declined consistently since the mid-1960s3,6 (Figure 2). In 1965, more than half of men and one-third of women in the United States were actively smoking, and currently fewer than a quarter of men and fewer than one-fifth of women smoke.6 As might be expected for diseases with a long initiation associated with chronic tobacco exposure, the primary public health goal of reducing lung cancer (and laryngeal, oral cavity, and hypopharyngeal cancer) incidence did not begin until the late 1980s.2,3 However, during this same period, oropharyngeal cancer incidence initially plateaued and subsequently rose dramatically25 (Figure 1). These complex trends in oropharyngeal cancer incidence are consistent with the decline of one carcinogenic exposure (smoking) but, during the same period, the emergence of a second unrelated etiologic exposure.

Several lines of evidence have established the carcinogenic potential of human papillomavirus (HPV), and since the early 1990s HPV DNA has been consistently identified in many head and neck cancers.712 A systematic review and meta-analysis have confirmed that the oropharynx is the principal site of head and neck cancers and that HPV type 16 accounts for more than 90% of positive cases.13,14 Cohorts consisting of patients chiefly from the 1990s had reported HPV prevalence rates of approximately 50%, whereas more recent reports ranged from 70% to 80%.10,1319

Numerous case series have also established that HPV-positive oropharyngeal cancers have unique demographic, behavioral, and clinical characteristics. Patients with HPV-positive oropharyngeal cancer are often middle-aged white men, of higher socioeconomic status, and nonsmokers and non-drinkers.11,16,2023 However, sexual behaviors do seem to be associated with this disease, and patients with HPV-positive oropharyngeal cancer as a group have a higher number of sexual partners, particularly oral sexual partners.10,11,20,23,24 HPV-positive oropharyngeal cancers tend to occur in either the tonsils or base of tongue rather than other oropharyngeal subsites, and they often have nonkeratinizing histologies, including basaloid, lymphoepithelial, or poorly differentiated carcinomas.25 Finally, these patients usually present for medical care because of nodal metastases and, after initial evaluation, are found to have small primaries with multiple positive nodes.25

HPV-associated oropharyngeal cancers chiefly from single-institution case series have distinctive demographic, behavioral, and clinical characteristics. Population level trends in oropharyngeal cancer mirror these characteristics and support HPV as the cause of the national increase in oropharyngeal cancer incidence. First, the increasing incidence appears greatest among the middle-aged white male population.5 Although many behavioral researchers have suggested that oral sex prevalence has risen over the past 3 decades, reliable data on these national trends are lacking. However, smoking prevalence has clearly dropped over this period and, as expected, tobacco-associated malignancies have subsequently declined in incidence, with a notable exception being oropharyngeal cancer.2,3,5,2628 More specifically, the increasing incidence seems to be restricted to the oropharyngeal subsites that tend to be HPV-positive (tonsils and base of tongue).29

Figure 1
Figure 1

Age-adjusted SEER incidence rates for laryngeal cancers, floor of mouth/gingival/other mouth cancer, tongue cancers, and oropharyngeal cancers in the United States.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 6; 10.6004/jnccn.2011.0055

Figure 2
Figure 2

Trends in per capita consumption of various tobacco products in the United States, 1880–2004.

Reprinted from American Journal of Preventive Medicine, Volume 33, Giovino GA, The tobacco epidemic in the United States, pg. 320, Copyright 2007, with permission from Elsevier.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 6; 10.6004/jnccn.2011.0055

National trends also show a rising proportion of higher-grade tumors for cancers of the tongue and tonsil but not of other sites.29 Additionally, in recent years a greater proportion of patients with oropharyngeal cancer have been presenting with regional rather than localized disease.4 Most importantly, several groups have shown a dramatic increase in HPV-positive oropharyngeal cancer over time among archived tumor specimens within population-based registries.15,17,19,30 Taken together, the findings within case series and these national epidemiologic trends support the assertion that the United States is experiencing an epidemic of HPV-associated oropharyngeal cancers, in direct opposition to a declining incidence of tobacco-associated cancers. Unfortunately, although HPV-preventive vaccines are now available and likely would prevent oropharyngeal HPV infection and subsequent oropharyngeal cancers, these vaccines have not received Centers for Disease Control and Prevention recommendation for routine use in boys.31 Additionally, no clinically applicable equivalent to the routine cervical Pap test is available for detecting oropharyngeal premalignancy or in early cancer screening.

Clinical Behavior of HPV-Associated Oropharyngeal Cancer

National trends also show a dramatic improvement in 5-year relative survival rates for patients with tonsil and tongue cancer, in direct contrast to the relatively stagnate survival for those with laryngeal and oral cavity cancer.2,4 Some oncologists believe that the greater use of multimodality chemoradiation in the treatment of oropharyngeal cancer can account for the observed dramatically improved survival; however, treatment of laryngeal cancer has undergone a similar evolution without improvements in survival rates.32,33 More likely, the dramatic changes in oropharyngeal cancer survival are from the shift in disease origin and a corresponding responsiveness to treatment. Interestingly, disparities in survival for African Americans, not explained by disparities in classic prognostic confounders, may be ascribed to a difference in oropharyngeal cancer origin (chiefly tobacco-related among African Americans and HPV-associated among white Americans).22,34

Although early series exploring the prevalence of HPV-positivity among head and neck cancers suffered from site admixture (oropharynx mixed with nonoropharyngeal sites), stage/treatment heterogeneity, and other retrospective confounding factors, these studies were relatively consistent in finding an improved survival for HPV-positive patients.35 In 2008, Fakhry et al.36 reported the first multicenter clinical trial in which tumors were prospectively tested for HPV (ECOG 2399 phase II trial), which showed that 61% of 62 oropharyngeal cancers were HPV-positive, and immunohistochemistry for p16 overexpression was used to confirm the association. Patients with HPV-positive oropharyngeal cancers had significantly better overall and progression-free survival in univariate analyses, but only a borderline effect remained after multivariate analyses. Recently, the results of a Radiation Therapy Oncology Group phase III trial (RTOG 0129) were reported for the subgroup of patients with oropharyngeal cancer (N = 433), among whom HPV and p16 status could be determined retrospectively in 323 patients.37 Of these patients, 64% were HPV-positive, 66% were p16 positive, and these 2 markers were highly correlated. Patients with HPV-positive tumors had significantly better overall and progression-free survival than those with HPV-negative tumors, and these results remained highly significant after multivariable adjustment. The difference in outcome was more striking when analyzed using p16 status.

Most recently, the results of a Trans-Tasman Radiation Oncology Group phase III trial (TROG 02.02) were reported for the subgroup of patients with oropharyngeal cancer (N = 465), among whom HPV and p16 status could be determined retrospectively in 206 patients.38 Of these patients, 57% were p16-positive, and 86% of p16-positive tumors were HPV-positive. Patients with p16-positive tumors had significantly better overall and failure-free survival than those with p16-negative tumors, and these results remained significant after multivariable adjustment. Two additional phase III head and neck cancer trials have presented data stratified by HPV-status, with both supporting the findings of improved survival for patients with HPV-positive cancers; however, only limited subgroup analyses restricted to patients with oropharyngeal cancer were reported.22,39

Now that HPV is accepted as an important prognostic factor in oropharyngeal cancer, a clear algorithm of what constitutes an HPV-positive tumor is needed. Although research studies have used numerous methods to define HPV-positivity, clinical pathology laboratories will need an accepted common methodology for clinical application, a process currently in evolution but likely to include more than a single assay.25,40 Because the overexpression of p16 is highly correlated with HPV-positivity, many laboratories find that testing for p16 using immunohistochemistry is a simple and cost-effective first step to exclude the HPV-negative cases from further testing.38,40 Subsequent HPV in situ hybridization testing will confirm HPV-positivity in most p16-positive cases.40 However, a relatively small subset of p16-positive but HPV in situ–negative tumors remains a group with unclear status, for which more intensive testing will ultimately require standardization.38,40,41

Among patients with head and neck cancer, smokers have a much worse prognosis than neversmokers.42,43 Although many HPV-positive tumors have an HPV-driven phenotype with excellent prognosis, emerging data suggest that other molecular alterations (derived chiefly from tobacco exposures) contribute to cancer phenotype and prognosis even among HPV-positive tumors. Smokers tend to have oropharyngeal cancers with mutated p53 and epidermal growth factor receptor (EGFR) overexpression, and lower HPV titer and p16 expression.44 Although patients with HPV-negative oropharyngeal cancer consistently have the worst prognosis, patients with HPV-positive oropharyngeal cancer who have the highest HPV16 titer or p16 expression and those who have wild-type p53 or low EGFR expression have a better prognosis than those with low HPV16 titer or p16 expression or with mutant p53 or high EGFR expression.4346 These retrospective data suggest that identification of other complementary markers can further refine prognostic classification and hopefully predict tumor response to various therapy modalities.

An HPV-driven phenotype would seem more likely to occur in nonsmokers, and wild-type p53, low EGFR, high p16, and high HPV titer in oropharyngeal cancers may be associated with a lack of smoking exposure.44 An attempt to further stratify oropharyngeal cancer prognosis beyond HPV status was conducted using recursive partitioning analysis of phase III trial data.37 Although molecular data such as p53 mutation status and EGFR expression were not available, prospectively obtained smoking data were recorded. Prognostic factors were identified and incorporated into a prognostic model to stratify patient outcomes into low-, intermediate-, and high-risk groups (Figure 3). As expected, the high-risk group consisted principally of smokers with HPV-negative tumors (only 11% were nonsmokers with large primaries). However, this analysis was able to identify a low-risk group with a 3-year overall survival rate of more than 90%, consisting of HPV-positive patients with no or limited smoking history (only 23% were smokers with limited nodal stage: N0, N1, and N2a). Contemporary studies have found very limited stratification of HPV-associated oropharyngeal cancer outcomes attributable to the TNM staging system, partly because very few HPV-positive cancers present without adenopathy.25,37,38,4346 However, the studies outlined earlier suggest the existence of a HPV-driven oropharyngeal cancer group with extremely good prognosis independent of stage and within the larger sample of HPV-positive cancers.37,4346 This prognostic stratification seems to be consistent and powerful, and thus may lead to modification of the current TNM staging system through the incorporation of HPV status, and possibly smoking status.

Figure 3
Figure 3Figure 3

Classification of patients with oropharyngeal cancer from RTOG 0129 into risk-of-death categories through recursive partitioning analysis and Kaplan-Meier estimates of overall survival according to those categories.

From Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:33; with permission.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 6; 10.6004/jnccn.2011.0055

Current Standards, Future Opportunities

Although the head and neck cancer specialty is rethinking and debating the paradigm of oropharyngeal cancer management, the goals are clear: individualize care, reduce toxicity, and maximize survival. To advance these goals, customizing care is critical and will require stratification of patients beyond the current TNM staging system and a more sophisticated understanding of the predictive effect of HPV status. To reiterate, HPV-positive oropharyngeal tumors occurring in nonsmokers seem to have a cancer phenotype that is driven by the HPV oncoproteins E6 and E7 and their effects on tumor suppressor/apoptosis/cell cycle pathways, whereas HPV-positive oropharyngeal cancers occurring in smokers often also have the classic tobacco-associated somatic alterations and a cancer phenotype of mixed origin. It is postulated that HPV-positive cancers in nonsmokers have intact apoptotic mechanisms and thus in theory are more responsive to cytotoxic therapies, whereas HPV-negative and HPV-positive cancers occurring in smokers have somatic alterations in these mechanisms that are associated with resistance to cytotoxic treatments and thus recurrence.

Current standards of care include radiation alone or surgery alone for stage I/II oropharyngeal cancer (and selected patients with low-volume stage III). Available options established through prospective trials for more locally advanced cancers are radiation with concurrent cisplatin47 or cetuximab,48 induction chemotherapy followed by radiation with or without concurrent systemic therapy,49,50 and surgery with postoperative radiation with or without concurrent cisplatin.51,52 However, these treatment options induce severe acute toxicities, swallowing dysfunctions, and long-term morbidities, which have not been fully documented and are particularly concerning in younger patients with highly curable HPV-associated oropharyngeal cancers.

Based on emerging data, head and neck oncologists are beginning to address whether and to what extent therapy for HPV-associated oropharyngeal carcinoma can be deintensified. Because of the risk of compromising tumor control, treatment deintensification should be conducted in closely monitored clinical trials. Achieving reduced toxicity will either require reducing the extent and impact of current therapies or adopting novel therapies with inherently less toxicity. Because cancer cure remains paramount, it is the group with the best prognosis in whom less aggressive therapy with equivalent cure rates might best be feasible.

The development and introduction of high-precision intensity-modulated radiation therapy (IMRT) allows delivery of tumoricidal doses while limiting normal tissue toxicity. Whether intensity-modulated proton therapy can further improve functional outcomes of radiotherapy must be addressed. In a retrospective series of 299 consecutive patients with oropharyngeal cancer treated with radiation alone at a single-institution, the 5-year estimated locoregional control rate was 85%.53 This result was confirmed by a recent phase II multi-institutional prospective trial (RTOG 0022), which showed that radiation alone yielded an estimated locoregional control rate of 91% in 69 patients with T1–2, N0–1 (including some radiologically N2B) oropharyngeal carcinoma.54 Despite requiring bilateral irradiation, the use of IMRT was associated with low long-term toxicity. These results with radiation alone seem to warrant evaluation of whether some patients with HPV-associated oropharyngeal carcinoma traditionally treated with concurrent chemoradiotherapy (low-volume stage III) can be well managed with radiation alone and thus be spared the added acute and late toxicity of chemotherapy. Similarly, surgery alone may be an option for patients with stage I, II, and low-volume stage III disease in whom final pathologic assessment/staging may not yield adverse features requiring adjuvant postoperative radiotherapy or concurrent chemotherapy.

Two additional strategies to deintensify therapy are combining standard radiation dose with less-toxic targeted agents and combining an effective systemic therapy or promising new combinations with lower radiation dose. For example, both cisplatin and cetuximab are now considered acceptable concurrent agents to radiotherapy for locally advanced oropharyngeal cancer. Available efficacy data are more extensive for cisplatin and radiation, but these same studies suggest that concurrent cetuximab overall seems to be less toxic than cisplatin. In a secondary analysis of a phase III trial of radiation alone versus radiation with concurrent cetuximab, the latter was associated with improved survival principally in subgroups likely to have HPV-positive tumors.55 Further refinements in radiation field and dose, broadening the role of radiation alone, administering less-toxic concurrent agents, or using novel combinations with lower-dose radiation are all intriguing options to deintensify treatment of HPV-associated oropharyngeal cancer. However, ad hoc application of these treatment approaches is strongly discouraged, and clinical trials with these designs will have to proceed in an incremental and measured way, because reasonable salvage options after radiation are limited.56

Advances in transoral surgery and the development of robotic systems are also being advocated as treatment deintensification. Although these approaches are certainly less morbid than traditional transcervical resections, most patients with oropharyngeal cancer have nodal metastases, and therefore most patients who undergo surgery will still require postoperative radiotherapy.57 Although definitive transoral resection seems to be a reasonable option for patients presenting with small primaries without nodal metastases, and has a lower long-term toxicity profile than definitive radiotherapy, these patients (stage I and II) are rare, particularly for HPV-positive oropharyngeal cancer. Only a well-organized, multi-institutional clinical trial with a stringent quality assurance program and long-term collection of functional outcomes can properly determine the role of transoral resection in the treatment of HPV-associated oropharyngeal carcinoma. Although the dose is lower than with definitive radiotherapy for patients requiring postoperative radiotherapy, the long-term toxicity profile and acute complications associated with transoral resection and postoperative radiotherapy have not been formally compared with radiotherapy. Other issues for study will be the added costs and longer treatment times for patients treated with surgery and postoperative radiotherapy, and the potential cost savings and lower toxicity for surgical patients avoiding chemotherapy or radiotherapy. Although the advantages of a clinical trial comparing transoral surgery in combination with postoperative radiotherapy with definitive radiotherapy alone are clear, patient acceptance of this type of randomization and the complexity of a trial such as this likely preclude a phase III design.

Ideally, scientific questions to be addressed will vary among the different risk categories of patients with head and neck cancer. The HPV-associated oropharyngeal carcinoma is a prime example of such a dilemma. Ideally, scientific questions to be addressed differ among the 3 risk categories of oropharyngeal carcinomas presented previously. However, the power limitations of dividing an already relatively rare disease into several groups with distinct features make the feasibility of launching multiple clinical trials, even in the intergroup setting, questionable. Other challenges include lack of funding, particularly to support functional assessment and translational studies, and physician and patient biases preventing enrollment into randomized comparative trials. Consequently, the field will partly rely on prospective data with inferred comparative survival, toxicity, and costs from parallel phase II and other designs, such as prospective registries.

Clinical trials have been proposed and some are ongoing to address potential modifications of treatment for HPV-positive oropharyngeal cancer. The ECOG is conducting an active phase II trial (E1308) for HPV-associated oropharyngeal carcinoma. This trial was designed to study the use of induction paclitaxel, cisplatin, and cetuximab followed by 54 Gy of radiation in 27 fractions, with concurrent cetuximab for patients who had a clinical and radiographic complete response at the primary, and 69.3 Gy of radiation in 33 fractions of radiotherapy with concurrent cetuximab for those who had a less than complete response at the primary. The sample size is 75 patients and may ultimately support a more definitive trial of induction chemotherapy with lower-dose radiotherapy. The Radiation Therapy Oncology Group is currently developing a phase III clinical trial (RTOG 1016) to formally compare 70 Gy of radiation in 35 fractions over 6 weeks with concurrent cisplatin, with the same radiation regimen with concurrent cetuximab. The study is designed to accrue 706 patients with p16-positive oropharyngeal cancer and is intended to show that cetuximab concurrent with radiation is not inferior to treatment with cisplatin concurrent with radiation in this patient population, but that the overall side effect profile of cetuximab may be more favorable. Additionally, this trial will prospectively collect smoking data to confirm the strong stratification of HPV-associated oropharyngeal cancer outcomes that smoking provides. At the University of Maryland, the response to and safety of the MAGE-A3/HPV16 vaccine for recurrent, progressive, or metastatic oropharyngeal cancer is being explored. In the United Kingdom, a phase I trial of recombinant listeria HPV16 vaccine (REALISTIC trial) as an adjuvant to standard definitive therapy is being conducted at 3 centers (Liverpool, Royal Marsden, and Cardiff).

Conclusions

The increasing incidence of oropharyngeal cancer in the United States represents the emergence of a distinct entity of HPV-associated cancers. These cancers tend to occur in middle-aged white men of medium to high socioeconomic status, are associated with oral sexual behaviors, and are very responsive to currently available, yet rather toxic, therapies. Several problems exist, including a need for prevention efforts to be expanded beyond tobacco/alcohol control, a need for oropharyngeal premalignancy and early cancer screening, a consistent approach to HPV testing, and a revision in the current oropharyngeal cancer staging system. Most importantly, because the prognosis of a subset of these HPV-positive oropharyngeal cancers is excellent, many of these patients are probably overtreated with the current aggressive multidisciplinary approach. Consequently, a careful, measured, and scientific approach is needed to modify the current treatment paradigms. Current trials will begin to address the choice of agents concurrent to radiotherapy, the concepts of induction chemotherapy combined with reduced radiation dose, the potential of therapeutic vaccines, and the role of transoral/robotic surgery. No justification exists to modify treatment of HPV-associated oropharyngeal cancer outside of a closely monitored protocol study setting.

References

  • 1

    JemalASiegelRXuJWardE. Cancer Statistics, 2010. CA Cancer J Clin2010;60:277300.

  • 2

    Cancer Statistics Section - Fast Stats. Surveilane Epidemiology and End Results Web site. Available at: www.seer.cancer.gov/faststats. Accessed January 15 2011.

    • Search Google Scholar
    • Export Citation
  • 3

    SturgisEMCinciripiniPM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of HPV associated cancers?Cancer2007;110:14291435.

    • Search Google Scholar
    • Export Citation
  • 4

    CarvalhoALNishimotoINCalifanoJAKowalskiLP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer2005;114:806816.

    • Search Google Scholar
    • Export Citation
  • 5

    ChaturvediAKEngelsEAAndersonWFGillisonML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the united states. J Clin Oncol2008;26:612619.

    • Search Google Scholar
    • Export Citation
  • 6

    GiovinoGA. The tobacco epidemic in the United States. Am J Prev Med2007;33:318326.

  • 7

    SchwartzSMDalingJRDoodyDR. Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst1998;90:16261636.

    • Search Google Scholar
    • Export Citation
  • 8

    GillisonMLKochWMCaponeRB. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst2000;92:709720.

    • Search Google Scholar
    • Export Citation
  • 9

    MorkJLieAKGlattreE. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med2001;344:11251131.

    • Search Google Scholar
    • Export Citation
  • 10

    D’SouzaGKreimerARViscidiR. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med2007;356:19441956.

  • 11

    GillisonMLD’SouzaGWestraW. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst2008;100:407420.

    • Search Google Scholar
    • Export Citation
  • 12

    SmithEMRitchieJMSummersgillKF. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst2004;96:449455.

    • Search Google Scholar
    • Export Citation
  • 13

    KreimerARCliffordGMBoylePFranceschiS. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev2005;14:467475.

    • Search Google Scholar
    • Export Citation
  • 14

    HobbsCGSterneJABaileyM. Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. Clin Otolaryngol2006;31:259266.

    • Search Google Scholar
    • Export Citation
  • 15

    ErnsterJASciottoCGO’BrienMM. Rising incidence of oropharyngeal cancer and the role of oncogenic human papilloma virus. Laryngoscope2007;117:21152128.

    • Search Google Scholar
    • Export Citation
  • 16

    JiXNeumannASSturgisEM. p53 codon 72 polymorphism associated with risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never-smokers. Carcinogenesis2008;29:875879.

    • Search Google Scholar
    • Export Citation
  • 17

    NäsmanAAttnerPHammarstedtL. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?Int J Cancer2009;125:362366.

    • Search Google Scholar
    • Export Citation
  • 18

    AttnerPDuJNäsmanA. Human papillomavirus and survival in patients with base of tongue cancer. Int J Cancer2011;128:28922897.

  • 19

    HongAMGrulichAEJonesD. Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets. Vaccine2010;28:32693272.

    • Search Google Scholar
    • Export Citation
  • 20

    D’SouzaGZhangHHD’SouzaWD. Moderate predictive value of demographic and behavioral characteristics for a diagnosis of HPV16-positive and HPV16-negative head and neck cancer. Oral Oncol2010;46:100104.

    • Search Google Scholar
    • Export Citation
  • 21

    GuanXSturgisEMLeiD. Association of TGF-beta1 genetic variants with HPV16-positive oropharyngeal cancer. Clin Cancer Res2010;16:14161422.

    • Search Google Scholar
    • Export Citation
  • 22

    SettleKPosnerMRSchumakerLM. Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. Cancer Prev Res (Phila)2009;2:776781.

    • Search Google Scholar
    • Export Citation
  • 23

    DahlstromKRLiGTortolero-LunaG. Differences in history of sexual behavior between patients with oropharyngeal squamous cell carcinoma and patients with squamous cell carcinoma at other head and neck sites. Head Neckin press.

    • Search Google Scholar
    • Export Citation
  • 24

    HeckJEBerthillerJVaccarellaS. Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol2010;39:166181.

    • Search Google Scholar
    • Export Citation
  • 25

    MarurSD’SouzaGWestraWHForastiereAA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol2010;11:781789.

    • Search Google Scholar
    • Export Citation
  • 26

    LicitraLZigonGGattaG. Human papillomavirus in HNSCC: a European epidemiologic perspective. Hematol Oncol Clin North Am2008;22:11431153

    • Search Google Scholar
    • Export Citation
  • 27

    MorkJMøllerBDahlTBrayF. Time trends in pharyngeal cancer incidence in Norway 1981-2005: a subsite analysis based on a reabstraction and recoding of registered cases. Cancer Causes Control2010;21:13971405.

    • Search Google Scholar
    • Export Citation
  • 28

    AuluckAHislopGBajdikC. Trends in oropharyngeal and oral cavity cancer incidence of human papillomavirus (HPV)-related and HPV-unrelated sites in a multicultural population: the British Columbia experience. Cancer2010;116:26352644.

    • Search Google Scholar
    • Export Citation
  • 29

    MehtaVYuGPSchantzSP. Population-based analysis of oral and oropharyngeal carcinoma: changing trends of histopathologic differentiation, survival and patient demographics. Laryngoscope2010;120:22032212.

    • Search Google Scholar
    • Export Citation
  • 30

    AttnerPDuJNäsmanA. The role of human papillomavirus in the increased incidence of base of tongue cancer. Int J Cancer2010;126:28792884.

    • Search Google Scholar
    • Export Citation
  • 31

    Centers for Disease Control and Prevention (CDC). FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep2010;59:630632.

    • Search Google Scholar
    • Export Citation
  • 32

    ChenAYSchragNHaoY. Changes in treatment of advanced oropharyngeal cancer, 1985-2001. Laryngoscope2007;117:1621.

  • 33

    ChenAYSchragNHaoY. Changes in treatment of advanced laryngeal cancer 1985-2001. Otolaryngol Head Neck Surg2006;135:831837.

  • 34

    ChenLMLiGReitzelLR. Matched-pair analysis of race or ethnicity in outcomes of head and neck cancer patients receiving similar multidisciplinary care. Cancer Prev Res (Phila)2009;2:782791.

    • Search Google Scholar
    • Export Citation
  • 35

    RaginCCTaioliE. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer2007;121:18131820.

    • Search Google Scholar
    • Export Citation
  • 36

    FakhryCWestraWHLiS. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst2008;100:261269.

    • Search Google Scholar
    • Export Citation
  • 37

    AngKKHarrisJWheelerR. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med2010;363:2435.

  • 38

    RischinDYoungRJFisherR. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol2010;28:41424148.

    • Search Google Scholar
    • Export Citation
  • 39

    LassenPEriksenJGHamilton-DutoitS. HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer. Radiother Oncol2010;94:3035.

    • Search Google Scholar
    • Export Citation
  • 40

    SinghiADWestraWH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer2010;116:21662173.

    • Search Google Scholar
    • Export Citation
  • 41

    BraakhuisBJBrakenhoffRHMeijerCJ. Human papilloma virus in head and neck cancer: the need for a standardised assay to assess the full clinical importance. Eur J Cancer2009;45:29352939.

    • Search Google Scholar
    • Export Citation
  • 42

    PytyniaKBGrantJREtzelCJ. Matched-pair analysis of survival of never smokers and ever smokers with squamous cell carcinoma of the head and neck. J Clin Oncol2004;22:39813988.

    • Search Google Scholar
    • Export Citation
  • 43

    WordenFPKumarBLeeJS. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol2008;26:31383146.

    • Search Google Scholar
    • Export Citation
  • 44

    KumarBCordellKGLeeJS. EGFR, p16, HPV titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol2008;26:31283137.

    • Search Google Scholar
    • Export Citation
  • 45

    WeinbergerPMYuZHafftyBG. Molecular classification identifies a subset of human papillomavirus—associated oropharyngeal cancers with favorable prognosis. J Clin Oncol2006;24:736747.

    • Search Google Scholar
    • Export Citation
  • 46

    LicitraLPerroneFBossiP. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol2006;24:56305636.

    • Search Google Scholar
    • Export Citation
  • 47

    PignonJPMaître AlMaillardEBourhisJ. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol2009;92:414.

    • Search Google Scholar
    • Export Citation
  • 48

    BonnerJAHarariPMGiraltJ. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med2006;354:567578.

  • 49

    PosnerMRHershockDMBlajmanCR. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med2007;357:17051715.

    • Search Google Scholar
    • Export Citation
  • 50

    VermorkenJBRemenarEvan HerpenC. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med2007;357:16951704.

    • Search Google Scholar
    • Export Citation
  • 51

    CooperJSPajakTFForastiereAA. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. New Engl J Med2004;350:19371944.

    • Search Google Scholar
    • Export Citation
  • 52

    BernierJDomengeCOzsahinM. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. New Engl J Med2004;350:19451952.

    • Search Google Scholar
    • Export Citation
  • 53

    GardenASAsperJAMorrisonWH. Is concurrent chemoradiation the treatment of choice for all patients with stage III or IV head and neck carcinoma?Cancer2004;100:11711178.

    • Search Google Scholar
    • Export Citation
  • 54

    EisbruchAHarrisJGardenAS. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Biol Phys2010;76:13331338.

    • Search Google Scholar
    • Export Citation
  • 55

    BonnerJAHarariPMGiraltJ. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol2010;11:2128.

    • Search Google Scholar
    • Export Citation
  • 56

    ZafereoMEHanasonoMMRosenthalDI. The role of salvage surgery in recurrent oropharyngeal squamous cell carcinoma. Cancer2009;115:57235733.

    • Search Google Scholar
    • Export Citation
  • 57

    CohenMAWeinsteinGSO’MalleyBWJr. Transoral robotic surgery and human papillomavirus status: oncologic results. Head Neck2011;33:573580.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.

Correspondence: Erich M. Sturgis, MD, MPH, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Unit 1445, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: esturgis@mdanderson.org

Article Sections

Figures

  • View in gallery

    Age-adjusted SEER incidence rates for laryngeal cancers, floor of mouth/gingival/other mouth cancer, tongue cancers, and oropharyngeal cancers in the United States.

  • View in gallery

    Trends in per capita consumption of various tobacco products in the United States, 1880–2004.

    Reprinted from American Journal of Preventive Medicine, Volume 33, Giovino GA, The tobacco epidemic in the United States, pg. 320, Copyright 2007, with permission from Elsevier.

  • View in gallery View in gallery

    Classification of patients with oropharyngeal cancer from RTOG 0129 into risk-of-death categories through recursive partitioning analysis and Kaplan-Meier estimates of overall survival according to those categories.

    From Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:33; with permission.

References

  • 1

    JemalASiegelRXuJWardE. Cancer Statistics, 2010. CA Cancer J Clin2010;60:277300.

  • 2

    Cancer Statistics Section - Fast Stats. Surveilane Epidemiology and End Results Web site. Available at: www.seer.cancer.gov/faststats. Accessed January 15 2011.

    • Search Google Scholar
    • Export Citation
  • 3

    SturgisEMCinciripiniPM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of HPV associated cancers?Cancer2007;110:14291435.

    • Search Google Scholar
    • Export Citation
  • 4

    CarvalhoALNishimotoINCalifanoJAKowalskiLP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer2005;114:806816.

    • Search Google Scholar
    • Export Citation
  • 5

    ChaturvediAKEngelsEAAndersonWFGillisonML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the united states. J Clin Oncol2008;26:612619.

    • Search Google Scholar
    • Export Citation
  • 6

    GiovinoGA. The tobacco epidemic in the United States. Am J Prev Med2007;33:318326.

  • 7

    SchwartzSMDalingJRDoodyDR. Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst1998;90:16261636.

    • Search Google Scholar
    • Export Citation
  • 8

    GillisonMLKochWMCaponeRB. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst2000;92:709720.

    • Search Google Scholar
    • Export Citation
  • 9

    MorkJLieAKGlattreE. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med2001;344:11251131.

    • Search Google Scholar
    • Export Citation
  • 10

    D’SouzaGKreimerARViscidiR. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med2007;356:19441956.

  • 11

    GillisonMLD’SouzaGWestraW. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst2008;100:407420.

    • Search Google Scholar
    • Export Citation
  • 12

    SmithEMRitchieJMSummersgillKF. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst2004;96:449455.

    • Search Google Scholar
    • Export Citation
  • 13

    KreimerARCliffordGMBoylePFranceschiS. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev2005;14:467475.

    • Search Google Scholar
    • Export Citation
  • 14

    HobbsCGSterneJABaileyM. Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. Clin Otolaryngol2006;31:259266.

    • Search Google Scholar
    • Export Citation
  • 15

    ErnsterJASciottoCGO’BrienMM. Rising incidence of oropharyngeal cancer and the role of oncogenic human papilloma virus. Laryngoscope2007;117:21152128.

    • Search Google Scholar
    • Export Citation
  • 16

    JiXNeumannASSturgisEM. p53 codon 72 polymorphism associated with risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never-smokers. Carcinogenesis2008;29:875879.

    • Search Google Scholar
    • Export Citation
  • 17

    NäsmanAAttnerPHammarstedtL. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?Int J Cancer2009;125:362366.

    • Search Google Scholar
    • Export Citation
  • 18

    AttnerPDuJNäsmanA. Human papillomavirus and survival in patients with base of tongue cancer. Int J Cancer2011;128:28922897.

  • 19

    HongAMGrulichAEJonesD. Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets. Vaccine2010;28:32693272.

    • Search Google Scholar
    • Export Citation
  • 20

    D’SouzaGZhangHHD’SouzaWD. Moderate predictive value of demographic and behavioral characteristics for a diagnosis of HPV16-positive and HPV16-negative head and neck cancer. Oral Oncol2010;46:100104.

    • Search Google Scholar
    • Export Citation
  • 21

    GuanXSturgisEMLeiD. Association of TGF-beta1 genetic variants with HPV16-positive oropharyngeal cancer. Clin Cancer Res2010;16:14161422.

    • Search Google Scholar
    • Export Citation
  • 22

    SettleKPosnerMRSchumakerLM. Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. Cancer Prev Res (Phila)2009;2:776781.

    • Search Google Scholar
    • Export Citation
  • 23

    DahlstromKRLiGTortolero-LunaG. Differences in history of sexual behavior between patients with oropharyngeal squamous cell carcinoma and patients with squamous cell carcinoma at other head and neck sites. Head Neckin press.

    • Search Google Scholar
    • Export Citation
  • 24

    HeckJEBerthillerJVaccarellaS. Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol2010;39:166181.

    • Search Google Scholar
    • Export Citation
  • 25

    MarurSD’SouzaGWestraWHForastiereAA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol2010;11:781789.

    • Search Google Scholar
    • Export Citation
  • 26

    LicitraLZigonGGattaG. Human papillomavirus in HNSCC: a European epidemiologic perspective. Hematol Oncol Clin North Am2008;22:11431153

    • Search Google Scholar
    • Export Citation
  • 27

    MorkJMøllerBDahlTBrayF. Time trends in pharyngeal cancer incidence in Norway 1981-2005: a subsite analysis based on a reabstraction and recoding of registered cases. Cancer Causes Control2010;21:13971405.

    • Search Google Scholar
    • Export Citation
  • 28

    AuluckAHislopGBajdikC. Trends in oropharyngeal and oral cavity cancer incidence of human papillomavirus (HPV)-related and HPV-unrelated sites in a multicultural population: the British Columbia experience. Cancer2010;116:26352644.

    • Search Google Scholar
    • Export Citation
  • 29

    MehtaVYuGPSchantzSP. Population-based analysis of oral and oropharyngeal carcinoma: changing trends of histopathologic differentiation, survival and patient demographics. Laryngoscope2010;120:22032212.

    • Search Google Scholar
    • Export Citation
  • 30

    AttnerPDuJNäsmanA. The role of human papillomavirus in the increased incidence of base of tongue cancer. Int J Cancer2010;126:28792884.

    • Search Google Scholar
    • Export Citation
  • 31

    Centers for Disease Control and Prevention (CDC). FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep2010;59:630632.

    • Search Google Scholar
    • Export Citation
  • 32

    ChenAYSchragNHaoY. Changes in treatment of advanced oropharyngeal cancer, 1985-2001. Laryngoscope2007;117:1621.

  • 33

    ChenAYSchragNHaoY. Changes in treatment of advanced laryngeal cancer 1985-2001. Otolaryngol Head Neck Surg2006;135:831837.

  • 34

    ChenLMLiGReitzelLR. Matched-pair analysis of race or ethnicity in outcomes of head and neck cancer patients receiving similar multidisciplinary care. Cancer Prev Res (Phila)2009;2:782791.

    • Search Google Scholar
    • Export Citation
  • 35

    RaginCCTaioliE. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer2007;121:18131820.

    • Search Google Scholar
    • Export Citation
  • 36

    FakhryCWestraWHLiS. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst2008;100:261269.

    • Search Google Scholar
    • Export Citation
  • 37

    AngKKHarrisJWheelerR. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med2010;363:2435.

  • 38

    RischinDYoungRJFisherR. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol2010;28:41424148.

    • Search Google Scholar
    • Export Citation
  • 39

    LassenPEriksenJGHamilton-DutoitS. HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer. Radiother Oncol2010;94:3035.

    • Search Google Scholar
    • Export Citation
  • 40

    SinghiADWestraWH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer2010;116:21662173.

    • Search Google Scholar
    • Export Citation
  • 41

    BraakhuisBJBrakenhoffRHMeijerCJ. Human papilloma virus in head and neck cancer: the need for a standardised assay to assess the full clinical importance. Eur J Cancer2009;45:29352939.

    • Search Google Scholar
    • Export Citation
  • 42

    PytyniaKBGrantJREtzelCJ. Matched-pair analysis of survival of never smokers and ever smokers with squamous cell carcinoma of the head and neck. J Clin Oncol2004;22:39813988.

    • Search Google Scholar
    • Export Citation
  • 43

    WordenFPKumarBLeeJS. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol2008;26:31383146.

    • Search Google Scholar
    • Export Citation
  • 44

    KumarBCordellKGLeeJS. EGFR, p16, HPV titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol2008;26:31283137.

    • Search Google Scholar
    • Export Citation
  • 45

    WeinbergerPMYuZHafftyBG. Molecular classification identifies a subset of human papillomavirus—associated oropharyngeal cancers with favorable prognosis. J Clin Oncol2006;24:736747.

    • Search Google Scholar
    • Export Citation
  • 46

    LicitraLPerroneFBossiP. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol2006;24:56305636.

    • Search Google Scholar
    • Export Citation
  • 47

    PignonJPMaître AlMaillardEBourhisJ. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol2009;92:414.

    • Search Google Scholar
    • Export Citation
  • 48

    BonnerJAHarariPMGiraltJ. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med2006;354:567578.

  • 49

    PosnerMRHershockDMBlajmanCR. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med2007;357:17051715.

    • Search Google Scholar
    • Export Citation
  • 50

    VermorkenJBRemenarEvan HerpenC. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med2007;357:16951704.

    • Search Google Scholar
    • Export Citation
  • 51

    CooperJSPajakTFForastiereAA. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. New Engl J Med2004;350:19371944.

    • Search Google Scholar
    • Export Citation
  • 52

    BernierJDomengeCOzsahinM. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. New Engl J Med2004;350:19451952.

    • Search Google Scholar
    • Export Citation
  • 53

    GardenASAsperJAMorrisonWH. Is concurrent chemoradiation the treatment of choice for all patients with stage III or IV head and neck carcinoma?Cancer2004;100:11711178.

    • Search Google Scholar
    • Export Citation
  • 54

    EisbruchAHarrisJGardenAS. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Biol Phys2010;76:13331338.

    • Search Google Scholar
    • Export Citation
  • 55

    BonnerJAHarariPMGiraltJ. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol2010;11:2128.

    • Search Google Scholar
    • Export Citation
  • 56

    ZafereoMEHanasonoMMRosenthalDI. The role of salvage surgery in recurrent oropharyngeal squamous cell carcinoma. Cancer2009;115:57235733.

    • Search Google Scholar
    • Export Citation
  • 57

    CohenMAWeinsteinGSO’MalleyBWJr. Transoral robotic surgery and human papillomavirus status: oncologic results. Head Neck2011;33:573580.

    • Search Google Scholar
    • Export Citation

Article Information

Cited By

PubMed

Google Scholar

Related Articles

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 345 345 44
PDF Downloads 70 70 18
EPUB Downloads 0 0 0