Incidence of Oropharyngeal Cancer Among Elderly Patients in the United States

Research

JAMA Oncology | Original Investigation Incidence of Oropharyngeal Cancer Among Elderly Patients in the United States

Zachary S. Zumsteg, MD; Galen Cook-Wiens, MS; Emi Yoshida, MD; Stephen L. Shiao, MD, PhD; Nancy Y. Lee, MD; Alain Mita, MD; Christie Jeon, PhD; Marc T. Goodman, PhD; Allen S. Ho, MD

Supplemental content IMPORTANCE An escalating incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has been reported predominantly among middle-aged adults. However, HPV infection is believed to occur many years before cancer develops, and tissue studies suggest that HPV DNA is found in the majority of OPSCC diagnosed in patients 65 years or older.

OBJECTIVE To update the trends in OPSCC incidence using US cancer registry data, with an emphasis on age-specific trends.

DESIGN, SETTING, AND PARTICIPANTS Data from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2012) were queried to compare changes in incidence and survival trends in OPSCC with selected tobacco-related cancers (larynx, oral cavity, hypopharynx, lung) and an HPV-related cancer (anus). A total of 40 264 patients who received a diagnosis of OPSCC from 2000 to 2012 were included. Elderly patients were defined as those 65 years or older.

MAIN OUTCOMES AND MEASURES The annual percentage change in OPSCC incidence from 2000 to 2012, stratified according to age group.

RESULTS Among the 40 264 patients who received a diagnosis of OPSCC from 2000 to 2012, 13 313 (33.1%) were aged 65 years or older and 80.3% were male. Significant increases in the age-adjusted incidence of OPSCC were observed during the study period for both younger adults aged 45 to 64 years (annual percentage change [APC], 2.31; 95% CI, 1.76-2.86; P < .001) and patients 65 years or older (APC, 2.92; 95% CI, 2.32-3.51; P < .001). These changes were driven predominantly by base-of-tongue and tonsil cancers in men. Concomitantly, the incidence of tobacco-associated head and neck cancers decreased for elderly patients (larynx: APC, −1.54; 95% CI, −2.00 to −1.08; P < .001; oral cavity: APC, −1.23; 95% CI, −1.84 to −0.62; P = .001; hypopharynx: APC, −2.44; 95% CI, −3.01 to −1.86; P < .001), whereas the incidence of anal cancer significantly increased (APC, 4.42; 95% CI, 3.28 to 5.57; Author Affiliations: Department of P < .001). Furthermore, improved overall and cause-specific survival over time were observed Radiation Oncology, Cedars-Sinai for both younger and elderly patients with OPSCC. Nevertheless, absolute cause-specific Medical Center, Los Angeles, California (Zumsteg, Yoshida, Shiao); survival remained worse for elderly patients (3-year CSS, 60.8%; 95% CI, 59.6%-61.9%) in Samuel Oschin Comprehensive comparison with those aged 45 to 64 years (75.7%; 95% CI, 75.1%-76.4%; P < .001). Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California CONCLUSIONS AND RELEVANCE The incidence of OPSCC is increasing among elderly patients (Zumsteg, Cook-Wiens, Yoshida, Shiao, Mita, Jeon, Goodman, Ho); in the United States, likely driven by HPV-associated cancers. Given the unique challenges Department of Biostatistics and related to treating elderly patients with OPSCC, their limited enrollment in clinical trials, and Bioinformatics, Cedars-Sinai Medical the aging US population, clinical studies investigating improved therapeutic strategies for Center, Los Angeles, California (Cook-Wiens); Department of elderly patients with HPV-positive OPSCC should be performed. Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (Lee, Ho); Cancer Prevention and Control Program, Cedars-Sinai Medical Center, Los Angeles, California (Jeon, Goodman). Corresponding Author: Zachary S. Zumsteg, MD, Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, JAMA Oncol. 2016;2(12):1617-1623. doi:10.1001/jamaoncol.2016.1804 Los Angeles, CA 90048 (zachary Published online July 14, 2016. [email protected]).

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ver the past several decades, the epidemiologic and clinical landscape of head and neck cancer has radi- Key Points cally transformed in the United States and other eco- O Question Is the increasing incidence of oropharyngeal cancer, 1-7 nomically developed countries. This transformation has been initially observed primarily in middle-aged patients, also occurring driven by substantial shifts in the prevalence of the 2 major in elderly patients in recent years? risk factors underlying head and neck carcinogenesis, with Findings This study of SEER data found that the incidence of markedly declining tobacco use8 and increasing prevalence of oropharyngeal cancer increased between 2000 and 2012 in human papillomavirus (HPV) in oropharyngeal squamous cell patients 65 years and older, whereas smoking-associated head and carcinomas (OPSCCs) from these regions.9 These altered risk neck cancers decreased in this population. This was mostly driven profiles have led to significant decreases in incidence of can- by cancers in white men. cers arising in tobacco-associated head and neck cancer sites, Meaning Given the rapidly increasing prevalence of such as the oral cavity and larynx, but increased incidence of oropharyngeal cancer in elderly patients, the poor representation HPV-associated OPSCCs.1-3 In fact, a recent meta-analysis found of this group in clinical trials, and the challenges treating these that the prevalence of HPV detected in OPSCCs in the United patients with multimodality therapy, prospective clinical trials States increased from approximately 20% prior to 1990 to 65% specifically focusing on this group should be performed. in 2000.10 As a result of these trends, OPSCC is projected to represent more than half of all head and neck cancers in the United States by 2030.2 casesintheUnitedStates(http://seer.cancer.gov). Race Studies to date have suggested that HPV-associated OPSCCs information was extracted from the SEER-18 database and are more commonly diagnosed in younger patients1,3,11-14 and analyzed given that previous publications have observed an that the increasing incidence of OPSCC is found almost exclu- increasing incidence of OPSCC only in white patients.1 This sively among middle-aged individuals.1,3 These reports have led study was deemed to be exempt from full institutional review to the widespread belief that HPV-associated OPSCC affects pre- board review by Cedars-Sinai Medical Center due to the dominantly younger, otherwise healthy patients.15 However, retrospective nature of the study. these studies describe incidence trends that were established more than a decade ago and do not account for more recent Classification of Anatomic Sites changes in patterns of HPV infection and associated cancers in Cases of OPSCC were identified on the basis of their International the United States. In fact, an analysis of 2009 through 2010 Na- Classification of Diseases for Oncology, Third Edition (ICD-O-3), tional Health and Nutrition Examination Survey (NHANES) data primary site codes as arising in the tonsil (C090-C091, C098- shows the highest prevalence of oral HPV infection in 55- to C099), base of tongue (C019, C024), Waldeyer ring (C142), val- 60-year-olds,16 and a recent study observed high-risk HPV DNA lecula (C100), soft palate (C051), uvula (C052), oropharyngeal wall in 65% of OPSCC specimens from patients aged 70 years and (C102-103), or other oropharynx site (C108-C109). Anatomic older.17 Thus, HPV-associated cancers in elderly patients may codes considered ambiguous for oropharynx origin, including be more common in contemporary clinical practice than sug- C028, C029, C101, and C140, were excluded. Given that tobacco gested by earlier reports. and alcohol are the other main etiologic risk factors for OPSCC The elderly represent a unique subset of patients with head other than oral HPV infection, we also analyzed changes in and neck cancer given that they do not generally benefit from the incidence of other head and neck sites, such as the larynx intensification strategies such as concomitant chemoradiation (C320-329), hypopharynx (C129-139), and oral cavity, that are therapy,18 concomitant cetuximab-based bioradiation therapy,19 driven primarily by these factors. Oral cavity cancers were tumors or altered fractionation20 in comparison with radiotherapy arising in the lip (C000-009), oral tongue (C020-023), gums alone. Furthermore, elderly patients have historically been un- (C030-031, C039), floor of mouth (C040-049), hard palate (C050), derrepresented in head and neck cancer clinical trials.18 Thus, cheek (C060), vestibule of mouth (C061), or retromolar area demographic shifts in HPV-associated head and neck cancer (C062). Lung (C340-349) and anal (C210-219) cancers were also would have important implications for future clinical investi- analyzed to determine changes in incidence trends in cancers gations. In this analysis, we explore trends in OPSCC incidence driven primary by tobacco use and HPV,respectively,arising out- and survival in the United States from 2000 to 2012 using the side the head and neck. Surveillance, Epidemiology, and End results (SEER) database, Only patients with invasive squamous cell histologic subtype with a specific focus on the epidemiologic patterns among pa- based on ICD-O-3 were included for all head and neck cancer sites tients 65 years and older. (ICD-O-3 histology codes 8051-8052, 8070-8078, 8083, or 8084). For lung cancer, both squamous and small-cell histologic subtypes (8041-8045) were included, given that these histologic 21 Methods subtypes are most strongly associated with tobacco use. Data Sources Statistical Analysis All data regarding demographic characteristics and cancer in- All analyses were performed using SEER*Stat, version 8.2.1, cidence were obtained from the SEER-18 database spanning Joinpoint Regression Program, version 4.2.0.2, or R, version 2000 through 2012, derived from 18 cancer registries across 3.2.2. Elderly patients were defined as those 65 years and older the United States, covering approximately 28% of incident at the time of diagnosis. Younger patients were dichotomized

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Figure 1. Age-Adjusted Incidence of Oropharyngeal Squamous Cell Carcinoma (OPSCC) From 2000 to 2012, Stratified by Age at Diagnosis

A All patients B Stratified by sex

16 Age 28 Men <45 y 26 <45 y 45-64 y 45-64 y 14 ≥65 y 24 ≥65 y

22 Women 12 <45 y P 20 APC = 2.92, < .001 APC = 3.64, P < .001 45-64 y 18 ≥65 y 10 000 Person-years 000 Person-years

8 14 APC = 2.31, P < .001 APC = 2.50, P < .001 12 6 10

8 4 6 APC = –0.02, P = .95

Age-Adjusted Incidence/100 Age-Adjusted Incidence/100 Age-Adjusted 4 2 APC = 1.25, P = .001 APC = 0.77, P = .31 2 APC = 0.83, P = .27 Annual percentage change (APC) was 0 0 APC = 0.75, P = .61 calculated using log-linear regression. 2000 2004 2008 2012 2000 2004 2008 2012 P < .05 denotes a statistically Year of Diagnosis Year of Diagnosis significant change in the incidence of OPSCC.

into ages 45 to 64 and younger than 45 years, given the low or older at diagnosis were less likely to be treated with surgery incidence of OPSCC in the latter group. For more granular analy- and more likely to receive no treatment to the primary site com- sis, patients were also classified by 5-year age groups, except pared with younger patients (eFigure 1 in the Supplement). for subgroups containing patients younger than 40 years and From 2000 to 2012, the age-adjusted incidence of OPSCC 80 years or older, respectively. significantly increased for patients aged 65 years or older (APC, Baseline characteristics were compared between elderly and 2.92; 95% CI, 2.32-3.51; P < .001) at a similar rate (parallelism nonelderly patients using the χ2 or Fisher exact test. Age- P = .24) to what was observed in those aged 45 to 64 years (APC, adjusted incidence rates, expressed per 100 000 persons, were 2.31; 95% CI, 1.76-2.86; P < .001) (Figure 1A). In both sub- calculated as the weighted average of crude cancer rates stan- groups, these changes were driven by significant increases in dardized to the US Census 2000 population. Annual percent- tonsil and base-of-tongue primaries, whereas other orophar- age change (APC) was calculated with log-linear regression, and ynx subsites were stable or decreased (eFigure 2 in the Supple- comparison of the parallelism of incidence trends was per- ment). When stratifying patients into subgroups by 5-year formed with the Joinpoint Regression Program.22 Given the rela- increments, the incidence of OPSCC significantly increased for tively short study period, the maximum number of joinpoints all subgroups between the ages of 50 and 79 years (Table). Al- was set to zero to avoid overfitting the data. Trends in male to though there was no overall increase in total OPSCC for pa- female incidence ratios were analyzed with linear regression. tients aged 80 years or older (APC, 1.47; 95% CI, −0.24 to 3.21; Graphs were created in GraphPad Prism and Tableau. P = .09), there was a significant increase in the incidence of Estimated overall survival and cause-specific survival (CSS) tonsil and base-of-tongue primaries in these patients (APC, was calculated according to the Kaplan-Meier method. For rela- 2.01; 95% CI, 0.31-3.74; P = .02). tive survival, the ratio of the observed survival to the ex- Stratifying by sex, similar to the overall cohort, men aged pected survival, calculated according to the Ederer II method, 65 years and older experienced an increased incidence of is reported.23 Time trends in 3-year survival, based on year of OPSCC from 2000 to 2012 (APC, 3.64; 95% CI, 2.94-4.34; diagnosis, were assessed with linear regression. Treatment of P < .001) (Figure 1B and Table). Notably, this included a signifi- the primary site (surgery, radiation, or none) was determined cant increase in the incidence of OPSCC among men 80 years on the basis of the initial local treatment delivered. Two- or older (APC, 2.03; 95% CI, 0.11-3.99; P = .04). Additionally, the sided P values <.05 were considered significant. APC for elderly men was significantly higher (parallelism P = .01) than that observed in men aged 45 to 64 years (APC, 2.50; 95% CI, 1.86-3.15; P < .001). By contrast, although there was a mod- Results est increase in the incidence of OPSCC among women aged 45 to 64 years (APC, 1.25; 95% CI, 0.61-1.88; P = .001), no increase Among the 40 264 patients who received a diagnosis of OPSCC in OPSCCs was observed for any other age group, including from 2000 to 2012, 13 313 (33.1%) were aged 65 years or older and women 65 years and older. As a result of these trends, in- 80.3% were male (eTable 1 in the Supplement). Patients 65 years creases in the male to female incidence ratios for OPSCC were

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Table. Mean Age-Adjusted Incidence (AAI) and Annual Percentage Change (APC) of Oropharyngeal Squamous Cell Carcinoma Diagnosed From 2000 to 2012, Stratified by Age at Diagnosis and Sex

All Patients Men Women Age, y Mean AAI APC (95% CI) P Value Mean AAI APC (95% CI) P Value Mean AAI APC (95% CI) P Value 0-39 0.12 1.60 (−1.13 to 4.40) .23 0.17 1.65 (−1.06 to 4.43) .21 0.07 1.55 (−3.98 to 7.40) .56 40-44 2.04 0.49 (−1.27 to 2.27) .56 3.33 0.55 (−1.26 to 2.39) .52 0.75 −0.14 (−4.07 to 3.95) .94 45-49 5.10 0.23 (−1.10 to 1.57) .72 8.61 0.07 (−1.20 to 1.35) .91 1.66 0.78 (−1.62 to 3.25) .49 50-54 8.90 1.89 (1.13 to 2.65) <.001 15.30 1.94 (1.06 to 2.83) .001 2.73 1.34 (0.06 to 2.64) .04 55-59 11.94 3.07 (2.21 to 3.93) <.001 20.72 3.30 (2.38 to 4.24) <.001 3.68 1.75 (−0.41 to 3.96) .10 60-64 13.92 3.38 (2.33 to 4.44) <.001 24.12 3.87 (2.67 to 5.08) <.001 4.57 0.86 (−0.69 to 2.42) .25 65-69 13.56 3.48 (2.52 to 4.44) <.001 23.13 4.04 (3.04 to 5.06) <.001 5.19 0.81 (−0.93 to 2.59) .33 70-74 12.20 3.25 (2.37 to 4.13) <.001 20.30 4.04 (2.80 to 5.30) <.001 5.59 0.20 (−1.59 to 2.02) .81 75-79 9.92 2.65 (1.32 to 4.00) .001 16.67 3.72 (2.10 to 5.37) <.001 4.95 −0.92 (−2.74 to 0.93) .29 ≥80 6.50 1.47 (−0.24 to 3.21) .09 11.36 2.03 (0.11 to 3.99) .04 3.67 −0.64 (−2.34 to 1.10) .43

observed in both elderly and younger patients (45 to 64 years) not collect data on p16 immunohistochemical analysis or other over time (eFigure 3 in the Supplement). When further strati- HPV-specific testing, multiple lines of evidence suggest that fying based on race, both within the entire cohort and among the increased incidence of OPSCCs among elderly patients is elderly patients, increases in the incidence of OPSCC were ob- a direct consequence of increased rates of oral HPV infec- served primarily in white men (eFigure 4 in the Supplement). tions and consequent HPV-driven cancers in this population. In contrast to trends observed for OPSCC, there were For example, the increase in OPSCC in the elderly was primar- significant decreases in the incidence of tobacco- and alcohol- ily driven by cancers in white men and tumors arising from the related head and neck cancers from 2000 to 2012 among almost tonsil and base of tongue, consistent with what would be ex- all subgroups of patients, including elderly patients (Figure 2 pected from HPV-associated cancers. Moreover, during the and eTable 2 in the Supplement). Similarly,significant decreases study period, near-universal decreases in the incidence of to- in the incidence of tobacco-related lung cancer histologic sub- bacco- and alcohol-related head and neck cancers such as la- types, such as squamous cell carcinoma and small-cell carci- ryngeal cancer, oral cavity cancer, and hypopharyngeal can- noma, were nearly universally observed, except for squamous cer were observed across virtually all age subgroups with cell carcinoma in elderly patients (eFigure 5 and eTable 3 in the increasing OPSCC incidence, including patients aged 65 years Supplement). By contrast, the incidence of anal cancer signifi- or older. Similar negative trends were observed in tobacco- cantly increased for all age groups 45 years and older. associated lung cancer histologic subtypes, such as squa- We found that for both younger and elderly patients with mous cell and small-cell carcinoma. By contrast, the inci- OPSCC, the probability of 3-year overall survival and CSS sig- dence of anal cancer, a disease associated with HPV in more nificantly increased from 2000 to 2009 (Figure 3 and eFigure than 90% of cases,24 markedly increased across most age 6A and eTable 4 in the Supplement). Similar trends were ob- groups from 2000 to 2012, including in the elderly popula- served when analyzing survival in patients with OPSCC relative tion. Furthermore, given that HPV-related OPSCC has been as- to the expected survival of an aged-matched population (eFig- sociated with improved survival in comparison with HPV- ure6BintheSupplement). Despite relative increases in survival negative OPSCCs,12-14,25,26 we performed survival analysis across age groups, CSS remained significantly worse for patients among elderly patients with OPSCC and observed signifi- 65 years and older (3-year CSS, 60.8%; 95% CI, 59.6%-61.9%) cantly improved overall, cause-specific, and relative survival in comparison with those aged 45 to 64 years (75.7%; 95% CI, during the interval of this study at a similar rate to what was 75.1%-76.4%; P < .001) (Figure 4). Of note, overall, cause- observed for younger patients. By contrast, survival out- specific, and relative survival were stable during this period for comes were stable for elderly patients with head and neck can- elderly patients with head and neck cancers arising in tobacco- cers arising in tobacco- and alcohol-associated primary sites, and alcohol-related primary sites (eFigure 7 in the Supplement). suggesting that these survival improvements for OPSCC in the elderly may be due to changes in the etiology of this disease rather than improvements in treatment of head and neck can- Discussion cers. Taken together, these data provide strong circumstantial support for HPV as the primary driver of the changes in In this study, we show that contrary to the conventional incidence and outcomes for OPSCC among elderly patients. belief that the epidemic of HPV-driven OPSCC affects predomi- Several other data sets support the high prevalence of HPV- nantly middle-aged individuals, the incidence of OPSCC in the associated OPSCC among the elderly in the modern era. For ex- United States has increased dramatically across a broad spec- ample, in a recent analysis of the 2009 to 2010 NHANES data trum of patient age groups since 2000, including patients aged set comprising more than 9000 patients aged 14 to 69 years, the 65 years or older. In fact, the APC of OPSCC for elderly pa- highest incidence of active oral HPV infection, as detected by tients closely mirrored that of younger patients aged 45 to 64 polymerase chain reaction, was observed in the subgroup aged years in the SEER data set. Although the SEER database does 55 to 60 years.16 Given that the typical latency of development

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Figure 2. Age-Adjusted Incidences of Laryngeal Squamous Cell Carcinoma (SCC), Oral Cavity SCC, Hypopharyngeal SCC, and Anal SCC From 2000 to 2012, Stratified by Age at Diagnosis

A Laryngeal SCC B Oral cavity SCC

20 Age 20 <45 y 45-64 y 18 18 ≥65 y

16 16 APC = –1.23, P = .001

14 14 APC = –1.54, P < .001 12 12 000 Person-years 000 Person-years

10 10

8 8 APC = –2.87, P < .001 APC = –1.43, P = .002 6 6

4 4 Age-Adjusted Incidence/100 Age-Adjusted Incidence/100 Age-Adjusted 2 2 APC = –3.90, P = .001 APC = –2.40, P = .007 0 0

2000 2004 2008 2012 2000 2004 2008 2012 Year of Diagnosis Year of Diagnosis

C Hypopharyngeal SCC D Anal SCC

5 5

4 4

APC = –2.44, P < .001 APC = 4.42, P < .001

3 3 000 Person-years 000 Person-years

2 2 APC = 4.82, P < .001 APC = –2.26, P < .001

1 1 Age-Adjusted Incidence/100 Age-Adjusted Incidence/100 Age-Adjusted APC = –1.47, P = .16 APC = –10.54, P < .001 0 0 Annual percentage change (APC) was calculated using log-linear regression. 2000 2004 2008 2012 2000 2004 2008 2012 P values are based on the APC of each Year of Diagnosis Year of Diagnosis age subgroup within a given cancer site.

of an HPV-driven head and neck cancer is estimated to be 10 to Our data diverge significantly from what has been reported 30 years, almost all cancers due to these infections would be previously.For example, in one of the seminal reports in the epi- expected to occur in patients aged 65 years or older. Addition- demiology of OPSCC, also using the SEER database, there was ally,a recent US Centers for Disease Control and Prevention study no significant increase in the incidence of OPSCC among the of 557 OPSCCs diagnosed between 1995 and 2005 reported that population 60 years and older in the United States from 1973 to oncogenic HPV DNA was detected in 65% of OPSCCs from pa- 2004.1 Similarly, an international study using the Cancer Inci- tients 70 years or older.17 This was identical to the proportion dence in Five Continents database found that in 7 of 9 countries of HPV-positive tumors found in patients aged 60 to 69 years, with an increasing incidence of OPSCC, significantly stronger and only approximately 10% lower than the rate detected in pa- trends were observed in patients younger than 60 years in com- tients 59 years or younger. In combination with our results, these parison with older patients from 1983 to 2002.3 These differences data provide an emerging picture of the relatively high, and in- in age-specific trends in OPSCC in data sets that are little more creasing, burden of HPV oral infection and HPV-associated than a decade older than that used for this analysis highlight the OPSCC among elderly patients since 2000. rapidly changing epidemiology of OPSCC in the United States.

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Figure 3. Trends in the 3-Year Kaplan-Meier Estimates for Cause-Specific Figure 4. Kaplan-Meier Estimated Cause-Specific Survival for Patients Survival for Patients With Oropharyngeal Cancer as a Function of Year of With Oropharyngeal Squamous Cell Carcinoma, Stratified by Age at Diagnosis From 2000 to 2009, Stratified by Age Diagnosis

100 100

90 80 P = .03 80 60 70 P < .001 40 60 Age P = .003 <45 y 50 Survival, % Cause-Specific 20 45-64 y ≥65 y P < .001 40 0 0 2 4 6 8 10 12 30 Time, y 3-Year Cause-Specific Survival, Cause-Specific % 3-Year No. at risk 20 Age <45 y 2206 1520 1122 791 510 276 67 <45 y 45-64 y 21 797 13 264 8761 5724 3465 1686 461 45-64 y ≥65 y 9499 4287 2469 1411 742 291 75 10 ≥65 y

0 modality therapy better than the lifelong tobacco and alcohol 2000 2004 2008 2012 users who accounted for the majority of patients in historical Year of Diagnosis head and neck cancer trials. Given the excellent locoregional outcomes observed for P values represent the comparison of the linear regression line and a line with 12,13,26 slope equal to zero for each age group. HPV-positive OPSCCs, deintensification strategies are cur- rently being investigated in this disease and may help de- crease toxicity while maintaining acceptable oncologic The ramifications of these changes in the incidence of outcomes.31 Although these approaches appear particularly ap- OPSCC among elderly patients will be amplified by concomi- pealing for elderly patients, they should be implemented with tant changes in the demographic characteristics of the US popu- caution in this population given that our study found CSS to be lation over the next several decades. Specifically, the number worse for elderly patients in comparison with younger of adults 65 years and older is projected to increase from 35 patients with OPSCC. Although these worse outcomes could million in 2000 to 72 million by 2030.27 A multiplicative ef- be due to treatment-related morbidity, hesitance to adminis- fect on the absolute number of elderly patients with OPSCC ter aggressive multimodality therapy, differences in utiliza- would thus be expected to result from the combination of a tion of definitive treatments, or persistent absolute differ- growing number of elderly Americans and an increased pro- ences in the proportion of HPV-positive OPSCCs in elderly vs portion harboring oral HPV infections. Moreover, older men younger patients, they underscore the need for more robust seem to have lower clearance rates of oral HPV than younger therapeutic paradigms in this population. Thus, trials that op- men,28,29 which may result in a higher rate of malignant pro- timize management specifically for this unique population are gression among elderly patients. Collectively, these data sup- imperative. port that HPV-associated OPSCC in the elderly will become an Aside from the absence of information on p16 immuno- increasingly common medical condition facing patients and histochemistry or other markers that distinguish between HPV- clinicians in the United States. positive and -negative OPSCCs, a further caveat of our analy- Importantly, these results also have implications for fu- sis is that we cannot entirely rule out the possibility that ture clinical investigations in elderly patients, a group that is changes in OPSCC survival could be influenced by treatment- historically underrepresented in head and neck cancer clini- related improvements involving radiation therapy tech- cal trials.18 It is widely recognized that the treatment of el- niques, systemic therapy, or supportive care. However, none derly patients with head and neck cancer is challenging.30 In- of these strategies has demonstrated the ability to improve sur- tensification strategies, including the addition of concomitant vival in elderly patients in clinical trials. Furthermore, no chemotherapy, concomitant cetuximab, and altered fraction- change in CSS was seen among elderly patients for other to- ation, have demonstrated improvements in both locore- bacco- and alcohol-related head and neck treatment sites gional control and overall survival in patients with head and during the period studied. neck cancer but have failed to show a survival benefit among the elderly subgroup compared with radiotherapy alone.18-20 This is likely due, at least in part, to the poor tolerance of these Conclusions intense treatment regimens in a relatively frail population. Nev- ertheless, the elderly population is heterogeneous, and el- We report that the incidence of OPSCC from 2000 to 2012 in- derly patients with HPV-positive OPSCCs may tolerate multi- creased over a broad population of patient age groups, includ-

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ing the elderly, with no evidence of plateau in this subgroup. coming decades, HPV-associated OPSCCs in older patients will Based on multiple lines of circumstantial evidence, the likely represent an exponentially growing problem in the com- increased incidence of OPSCC in elderly patients is likely attrib- ing decades. Given the unique challenges of treating elderly pa- utable to increased HPV-associated carcinogenesis. Thus, HPV- tients with head and neck cancer and their historical under- associated OPSCC should no longer be considered a disease representation in clinical trials, future clinical investigations primarily afflicting younger patients. In combination with pro- are needed to identify optimal therapeutic strategies for this jected increases in the size of the US elderly population in the population.

ARTICLE INFORMATION 7. Jemal A, Simard EP, Dorell C, et al. Annual report data from a phase 3 randomised trial, and relation Accepted for Publication: April 19, 2016. to the nation on the status of cancer, 1975-2009, between cetuximab-induced rash and survival. featuring the burden and trends in human Lancet Oncol. 2010;11(1):21-28. Published Online: July 14, 2016. papillomavirus (HPV)-associated cancers and HPV doi:10.1001/jamaoncol.2016.1804 20. Bourhis J, Overgaard J, Audry H, et al; vaccination coverage levels. J Natl Cancer Inst. Meta-Analysis of Radiotherapy in Carcinomas of Author Contributions: Dr Zumsteg had full access 2013;105(3):175-201. Head and Neck (MARCH) Collaborative Group. to all of the data in the study and takes 8. Ng M, Freeman MK, Fleming TD, et al. Smoking Hyperfractionated or accelerated radiotherapy in responsibility for the integrity of the data and the prevalence and cigarette consumption in 187 head and neck cancer: a meta-analysis. Lancet. accuracy of the data analysis. countries, 1980-2012. JAMA. 2014;311(2):183-192. 2006;368(9538):843-854. Study concept and design: Zumsteg, Lee, Jeon, Goodman, Ho. 9. Louie KS, Mehanna H, Sasieni P. Trends in head 21. Khuder SA. Effect of cigarette smoking on major Acquisition, analysis, or interpretation of data: and neck cancers in England from 1995 to 2011 and histological types of lung cancer: a meta-analysis. Zumsteg, Cook-Wiens, Yoshida, Shiao, Lee, Mita, projections up to 2025. Oral Oncol. 2015;51(4): Lung Cancer. 2001;31(2-3):139-148. Jeon, Goodman. 341-348. 22. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Drafting of the manuscript: Zumsteg, Cook-Wiens, 10. Stein AP, Saha S, Yu M, Kimple RJ, Lambert PF. Permutation tests for joinpoint regression with Yoshida, Goodman, Ho. Prevalence of human papillomavirus in applications to cancer rates. Stat Med. 2000;19(3): Critical revision of the manuscript for important oropharyngeal squamous cell carcinoma in the 335-351. intellectual content: Zumsteg, Shiao, Lee, Mita, United States across time. Chem Res Toxicol. 2014; 23. Hakulinen T, Seppä K, Lambert PC. Choosing Jeon, Goodman, Ho. 27(4):462-469. the relative survival method for cancer survival Statistical analysis: Zumsteg, Cook-Wiens, Shiao, 11. Gillison ML, D’Souza G, Westra W, et al. Distinct estimation. Eur J Cancer. 2011;47(14):2202-2210. Jeon, Goodman, Ho. risk factor profiles for human papillomavirus type Administrative, technical, or material support: 24. Saraiya M, Unger ER, Thompson TD, et al; HPV 16-positive and human papillomavirus type Typing of Cancers Workgroup. US assessment of Yoshida, Shiao, Ho. 16-negative head and neck cancers. J Natl Cancer Inst. Study supervision: Zumsteg, Lee, Ho. HPV types in cancers: implications for current and 2008;100(6):407-420. 9-valent HPV vaccines. J Natl Cancer Inst. 2015;107 Conflict of Interest Disclosures: Dr Zumsteg is on 12. O’Sullivan B, Huang SH, Siu LL, et al. (6):djv086. the external advisory board for the Scripps Proton Deintensification candidate subgroups in human 25. Fakhry C, Westra WH, Li S, et al. Improved Therapy Center. Dr Lee is on the external advisory papillomavirus-related oropharyngeal cancer board for Merck, Vertex Pharmaceuticals, and survival of patients with human papillomavirus- according to minimal risk of distant metastasis. positive head and neck squamous cell carcinoma in Pfizer. Dr Goodman is a consultant for Johnson and J Clin Oncol. 2013;31(5):543-550. Johnson. No other disclosures are reported. a prospective clinical trial. J Natl Cancer Inst. 13. Ang KK, Harris J, Wheeler R, et al. Human 2008;100(4):261-269. REFERENCES papillomavirus and survival of patients with 26. Rischin D, Young RJ, Fisher R, et al. Prognostic oropharyngeal cancer. 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