Abstract
Background
The socioeconomic factors affecting outcomes of human papillomavirus (HPV)-associated squamous cell carcinoma of the head and neck (SCCHN) are poorly characterized.
Methods
A custom Surveillance, Epidemiology, and End Results (SEER) database identified adult patients with primary non-metastatic SCCHN and known HPV status diagnosed between 2013–14. Multivariable logistic regression defined associations between patient characteristics and HPV status, with adjusted odds ratios (AORs) and 95% confidence intervals (CIs) reported. Fine-Gray competing risks regression estimated adjusted hazard ratios (AHRs) and 95% CIs for cancer-specific mortality (CSM), including a disease subsite*HPV status*race interaction term.
Results
4735 patients with non-metastatic SCCHN and known HPV status were identified. HPV-associated SCCHN was positively associated with oropharyngeal primary, male sex and higher education and negatively associated with uninsured status, single marital status, and non-white race (p≤0.001 for all). For HPV-positive oropharyngeal SCCHN, white race was associated with lower CSM (AHR 0.55, 95%CI 0.34–0.88, p=0.01) and uninsured status was associated with higher CSM (AHR 3.12, 95%CI 1.19–8.13, p=0.02). These associations were not observed in HPV-negative or non-oropharynx SCCHN. Accordingly, there was a statistically significant disease subsite*HPV status*race interaction (pint<0.001).
Conclusions
Non-white race and uninsured status were associated with worse CSM in HPV-positive oropharyngeal SCCHN, while no such associations were observed in HPV-negative or non-oropharyngeal SCCHN. These results suggest that, despite having clinically favorable disease, non-white patients with HPV-positive oropharyngeal SCCHN have worse outcomes than their white peers. Further work is needed to understand and reduce socioeconomic disparities in SCCHN.
Keywords: head and neck, oropharynx, radiation therapy, human papillomavirus, race, socioeconomic status
1. Background
Squamous cell carcinomas of the head and neck (SCCHN) are increasing in incidence worldwide.1,2 Contemporary reports have identified human papillomavirus (HPV) infection as a leading risk factor for the development of SCCHN, particularly in oropharyngeal carcinoma.3,4 While the incidence of HPV-negative oropharyngeal carcinoma in the United States has been declining due to decreased smoking, HPV-positive disease is on the rise.5
Social determinants of health for HPV-positive and HPV-negative SCCHN are poorly characterized—available data are limited to case reports or retrospective analyses of prospective trials.5,6,15,7–14 It has been suggested that HPV-negative SCCHN is more common amongst non-white, urban, and poorly insured individuals due to higher smoking rates in these populations.7,14 Furthermore, the inferior outcomes observed in patients of lower socioeconomic status with SCCHN have largely been attributed to a predominance of HPV-negative disease.7,14 These hypotheses however have not been tested in the prospective setting, as clinical trials tend to include a disproportionate number of patients who are white and of higher socioeconomic status.16 Furthermore, there have been no large population-based studies examining the burden of HPV-associated disease and cancer-related survival as affected by socioeconomic factors.
As such, we sought to characterize the interplay between HPV status, race, socioeconomic factors, and outcomes in SCCHN.
2. Methods
2.1. Study Cohort
We used a custom Surveillance, Epidemiology, and End Results (SEER) Head and Neck with HPV Status Database to identify 4,735 adult patients (age > 18) with primary non-metastatic (M0) SCCHN with known HPV status diagnosed from 2013–2014.17 This data is not yet public; we obtained access via a proposal to the SEER custom data group, where the a priori analyses described were determined to be appropriate use of the data. The study inclusion period of 2013–2014 represents the years in which HPV status has been collected and reviewed for quality assurance.
SEER cancer registries code primary cancer site and histology per the International Classification of Diseases for Oncology, third edition (ICD-O-3). Squamous cell carcinoma histology of the head and neck was identified by the following ICD-O-3 histologic type codes: 8050, 8051, 8054, 8070–8076, 8083, 8094. Tumor node metastasis (TNM) staging was determined using the American Joint Committee on Cancer (AJCC) 7th edition, as provided by SEER (8th edition staging is not yet reported by the database). Race was classified as non-Hispanic white versus non-white/Hispanic. Small area estimates for percent ever smoker was linked to SEER via estimates developed from the Behavioral Risk Factor Surveillance System (BRFSS) and the National Health Interview Survey (NHIS).
2.2. Statistical Analyses
Comparison of baseline patient characteristics by HPV status
The Wilcoxon rank-sum and Mantel-Haenszel χ2 tests compared distributions of continuous and categorical covariates, stratified by HPV status among patients with non-metastatic (M0) disease (N=4,735). Multivariable logistic regression defined adjusted odds ratios (AORs) and 95% confidence intervals (CIs) between patient characteristics and HPV status.
Adjusted odds ratios for presentation with advanced disease
In Table 1, baseline patient characteristics are presented. Additionally, we performed multivariable logistic regressions to calculate the adjusted odds ratios of presenting with HPV-positive disease. The following variables pertaining to socioeconomic status (SES) were included in the model: race (non-white [referent] or white), insurance status (private or other insurance [referent], uninsured, Medicaid, unknown insurance), and marital status (married [referent], single, divorced/widowed/separated, unknown). Demographic and clinical variables included in the model were age at diagnosis (continuous), sex (female [referent], male), tumor stage (T1 [referent], T2, T3, T4, unknown T), nodal stage (N0 [referent], N2a, N2b, N2c, N2 NOS, N3 and unknown N), oropharynx vs. non-oropharynx (Non-oropharynx included nasopharynx, hypopharynx, and other pharyngeal SCCHN) smoking propensity, income (continuous county variable), education (continuous county variable) and treatment (none [referent], surgery, radiation therapy, chemotherapy). In the SEER database, smoking propensity, education, and household income are population-level variables abstracted from county data. In Table 2, multivariable logistic regressions defined AORs and associated 95% CIs for the odds of presenting with advanced disease (defined as T3-T4 or N2-N3). Given that advanced stage was the outcome of interest in this analysis, T and N characteristics were not included in the model separately.
Table 1.
Distribution of baseline patient characteristics by HPV status with associated multivariable odds ratios for odds of HPV-positive HNSCC among U.S. patients age 18 and older with M0 disease (N= 4,735).
| Characteristic a | HPV-Positive HNSCC (N=3,262) | HPV-Negative HNSCC (N=1,473) | Odds of HPV-Positive HNSCC | ||
|---|---|---|---|---|---|
| AOR (95% CI) | P | ||||
| HNSCC Subsite, N (Percent) | |||||
| Non-Oropharynx | 199 (6.1) | 400 (27.2) | 1.0 (Referent) | ||
| Oropharynx | 3063 (93.9) | 1073 (72.8) | 1.90 (1.62–2.24) | <0.001 | |
| Tumor Stage, N (Percent) | |||||
| T1 | 806 (24.7) | 298 (20.2) | 1.0 (Referent) | ||
| T2 | 1183 (36.3) | 397 (27.0) | 1.14 (0.94–1.37) | 0.18 | |
| T3 | 507 (15.5) | 294 (20.0) | 0.80 (0.64–0.99) | 0.04 | |
| T4 | 403 (12.4) | 305 (20.7) | 0.68 (0.54–0.85) | 0.001 | |
| Unknown T | 345 (10.6) | 176 (11.9) | 0.91 (0.69–1.20) | 0.502 | |
| Nodal Stage, N (Percent) | |||||
| N0 | 407 (12.5) | 306 (20.8) | 1.0 (Referent) | ||
| N1 | 595 (18.2) | 300 (20.4) | 1.39 (1.11–1.73) | 0.004 | |
| N2a | 374 (11.5) | 93 (6.3) | 2.16 (1.61–2.88) | <0.001 | |
| N2b | 1139 (34.9) | 369 (25.1) | 1.82 (1.48–2.23) | <0.001 | |
| N2c | 450 (13.8) | 178 (12.1) | 1.70 (1.32–2.18) | <0.001 | |
| N2 NOS | 54 (1.7) | 71 (4.8) | 1.29 (0.83–2.01) | 0.254 | |
| N3 | 163 (5.0) | 82 (5.6) | 1.62 (1.16–2.27) | 0.004 | |
| Unknown N | 80 (2.5) | 74 (5.0) | 2.10 (1.32–3.34) | 0.002 | |
| Initial Definitive Treatment, N (Percent) | |||||
| None | 124 (3.8) | 116 (7.9) | N / A (not patient level characteristic) | ||
| Surgery | 969 (29.7) | 299 (20.3) | |||
| Radiation Therapy | 2959 (90.7) | 1248 (84.7) | |||
| Chemotherapy | 2375 (72.8) | 1009 (68.5) | |||
| Age at Diagnosis, Median (IQR) | N/A | 0.92 (0.98–0.99) | <0.001 | ||
| Race, N (Percent) | |||||
| White | 2774 (85.0) | 990 (67.2) | 1.0 (Referent) | ||
| Non-White | 518 (15.9) | 483 (32.8) | 0.40 (0.31–0.52) | <0.001 | |
| Sex, N (Percent) | |||||
| Female | 428 (13.1) | 338 (22.9) | 1.0 (Referent) | ||
| Male | 2834 (86.9) | 1135 (77.1) | 1.59 (1.33–1.89) | <0.001 | |
| Insurance Status, N (Percent) | |||||
| Private or Other Insurance | 2835 (86.9) | 1091 (74.1) | 1.0 (Referent) | ||
| Uninsured | 79 (2.4) | 70 (4.8) | 0.53 (0.37–0.77) | 0.001 | |
| Medicaid | 302 (9.3) | 286 (19.4) | 0.58 (0.47–0.71) | <0.001 | |
| Unknown | 46 (1.4) | 26 (1.8) | 0.74 (0.43–1.28) | 0.28 | |
| Smoking Propensity,b Median (IQR) | N/A | 1.00 (0.99–1.00) | 0.72 | ||
| Percent High School Education,c Median (IQR) | N/A | 1.02 (1.00–1.03) | 0.01 | ||
| Household Income,c Median (IQR) | N/A | 1.00 (1.00–1.00) | 0.22 | ||
| Marital Status, N (Percent) | |||||
| Married | 2013 | 723 | 1.0 (Referent) | ||
| Single | 532 | 354 | 0.67 (0.56–0.80) | <0.001 | |
| Divorced/Widowed/Separated | 571 | 312 | 0.83 (0.69–0.99) | 0.04 | |
| Unknown | 146 | 84 | 0.78 (0.57–1.07) | 0.13 | |
Abbreviations: AOR, Adjusted Odds Ratio; CI, confidence interval; HNSCC, Head and Neck Squamous Cell Carcinoma; HPV, Human Papillomavirus; N/A, not applicable
Percent may not add up to 100 due to rounding (Percent for Initial Definitive Treatment does not add up to 100 due to receipt of multiple treatments).
Percent ever smoker determined by small area estimates, linked to SEER via estimates developed from the Behavioral Risk Factor Surveillance System (BRFSS) and the National Health Interview Survey (NHIS).
County attribute data, linked to SEER population data by state-county FIPS codes.
When age at diagnosis was treated as a categorical variable (Age 60–64 versus all other ages 15 and older [referent]), age 60–64 was associated with an increased odds of HPV-positive HNSCC (AOR 1.22, 1.02–1.45, P=0.33).
Table 2:
Multivariable adjusted odds ratios of presenting with advanced disease (T3-T4 or N2-N3) among N=4,735 patients with M0 HNSCC
| Characteristic | Early Stage (N=1,246) | Advanced Stage (N=3,489) | Odds of Advanced Stage | ||
|---|---|---|---|---|---|
| AOR (95% CI) | P | ||||
| HNSCC Subsite, N (Percent) | |||||
| Non-Oropharynx | 248 (19.9) | 351 (10.1) | 1.0 (Referent) | ||
| Oropharynx | 998 (80.1) | 3138 (89.9) | 2.31 (1.91–2.80) | <0.001 | |
| HPV Status | |||||
| HPV-negative | 452 (36.3) | 1021 (29.3) | 1.0 (Referent) | ||
| HPV-positive | 794 (63.7) | 2468 (70.7) | 1.22 (1.05–1.42) | 0.10 | |
| Race, N (Percent) | |||||
| White | 1091 (87.6) | 2947 (84.5) | 1.0 (Referent) | ||
| Non-White | 155 (12.4) | 542 (15.5) | 0.68 (0.57–0.81) | <0.001 | |
| Age at Diagnosis, Median (IQR) | |||||
| Sex, N (Percent) | |||||
| Female | 258 (20.7) | 508 (14.6) | 1.0 (Referent) | ||
| Male | 988 (79.3) | 2981 (85.4) | 1.50 (1.26–1.78) | <0.001 | |
| Insurance Status, N (Percent) | |||||
| Private or Other Insurance | 1055 (84.7) | 2871 (82.3) | 1.0 (Referent) | ||
| Uninsured | 33 (2.6) | 116 (3.3) | 1.18 (0.79–1.78) | 0.42 | |
| Medicaid | 127 (10.2) | 461 (13.2) | 1.33 (1.06–1.66) | 0.01 | |
| Unknown | 31 (2.5) | 41 (1.2) | 0.44 (0.26–0.72) | 0.001 | |
| Smoking Propensity,b Median (IQR) | 40.4 (33.5–44.9) | 40 (33.3–44.6) | 0.99 (0.98–1.00) | 0.19 | |
| Percent High School Education,c Median (IQR) | 87.0 (82.3–89.7) | 87.0 (83.1–89.8) | 1.01 (1.00–1.06) | 0.18 | |
| Household Income,c Median (IQR) | 56,600 (48,700–71,380) | 59,740 (50,310–71,020) | 1.00 (1.00–1.00) | 0.94 | |
| Marital Status, N (Percent) | |||||
| Married | 770 (61.8) | 1966 (56.3) | 1.0 (Referent) | ||
| Single | 201 (16.1) | 685 (19.6) | 1.28 (1.06–1.54) | 0.01 | |
| Divorced/Widowed/Separated | 210 (16.9) | 673 (19.3) | 1.38 (1.15–1.66) | 0.001 | |
| Unknown | 65 (5.2) | 165 (4.7) | 1.16 (0.84–1.60) | 0.36 | |
CSM estimates by HPV status, tumor and SES characteristics
Stata/SE 14.2 (StataCorp, College Station, TX, USA) was used for survival analyses of patients with M0 disease with at least 1 month of follow-up (N=4,476), where the primary endpoint was cancer-specific mortality (CSM). Patients were stratified into the following four subgroups: HPV-positive oropharynx, HPV-negative oropharynx, HPV-positive non-oropharynx and HPV-negative non-oropharynx. For each of these subgroups, multivariable Fine-Gray competing-risks regression was used to estimate hazard ratios for the socioeconomic and clinical factors described above.
To ascertain whether there was a differential prognosis of race by HPV status and disease site, a Fine-Gray competing-risks regression model for CSM included a race (non-white vs. white) * disease site (non-oropharynx versus oropharynx) * HPV status (positive versus negative) interaction term. Once it was established that this interaction was statistically significantly, we performed further multivariable analyses of the individual subgroups—HPV positive oropharynx, HPV negative oropharynx, HPV positive non-oropharynx, HPV negative non-oropharynx—which included the original factors including in the model, excluding the interaction term, HPV status, and disease site.
Using the aforementioned models, cumulative incidence plots for CSM were generated for the purposes of illustration along with estimation of 20-month CSM for each subgroup. Adjusted hazard ratios (AHR) with associated 95% CIs and P-values were calculated for all covariates. Statistical testing was two-sided with level of significance set at P=0.05. The Dana-Farber/Harvard Cancer Center IRB granted permission for the performance of this study.
3. Results
Comparison of baseline patient characteristics by HPV status
As shown in Table 1, there were significant clinical and socioeconomic differences between HPV-positive and HPV-negative subgroups of SCCHN. Patients with an oropharyngeal primary (AOR 1.90, 95%CI 1.62–2.24, p<0.001), nodal involvement (AOR 1.62, 95%CI 1.16–2.27, p=0.004 for N3 vs. N0), male sex (AOR 1.59, 95%CI 1.33–1.89, p<0.001), and higher education (AOR 1.02, 95%CI 1.00–1.03), p=0.001) had greater odds of having HPV-positive SCCHN. In contrast, those with bulky primary tumors (AOR 0.68, 95%CI 0.54–0.85, p=0.001 for T4 vs T1), older age at diagnosis (AOR 0.92, 95%CI 0.98–0.99, p<0.001), no health insurance (AOR 0.53, 95%CI 0.37–0.77, p=0.001 for uninsured vs. private or other insurance), single marital status (AOR 0.67, 95%CI 0.56–0.80, p<0.001) or non-white race (AOR 0.40, 95%CI 0.31–0.52, p<0.001) had higher odds of having HPV-negative SCCHN.
Adjusted odds ratios for presentation with advanced disease
Associations between patient characteristics and advanced stage at presentation are shown in Table 2. On multivariable analysis, advanced stage at presentation was positively associated with oropharyngeal subsite (AOR 2.31, 95%CI 1.91–2.80, p<0.001), HPV positive disease (AOR 1.22, 95% CI 1.05–1.42, p=0.01), male sex (AOR 1.50, 95%CI 1.26–1.78, p<0.01), Medicaid insurance (AOR 1.33, 95%CI 1.06–1.66, p=0.01), single marital status (AOR 1.28, 95%CI 1.06–1.54, p=0.01) or divorced/widowed/separated marital status (AOR 1.38, 95%CI 1.15–1.66, p=0.001), and negatively associated with white race (AOR 0.68, 95%CI 0.57–0.81, p<0.001).
CSM estimates by HPV status, tumor and SES characteristics
After a median follow up of 10 months, there were 339 cancer-related deaths and 109 competing deaths. White patients with HPV-positive oropharyngeal SCCHN had a significantly lower risk of CSM as compared to their non-white peers (AHR 0.55, 95%CI 0.34–0.88, p=0.01, 20-month CSM 5.6 vs. 11.2%, p=0.01) (Figure 1)). Among those with HPV-negative oropharyngeal SCCHN, there was no statistically significant difference in CSM between whites and non-whites (AHR 1.11, 95%CI 0.74–1.67, 20-month CSM 22.9 vs. 20.9%, p=0.53). Similarly, there were no significant differences in CSM between white and non-white groups for non-oropharyngeal SCCHN, regardless of HPV status (Table 3, Figure 1). Accordingly, that there was a significant interaction between race, primary site, and HPV status (Pint<0.001, Table 3).
Figure 1.
Kaplan-Meier cancer-specific survival curves comparing white (dashed line) and non-white (solid line) patient with A) HPV-positive oropharyngeal cancer, B) HPV-negative oropharyngeal cancer, C) HPV-positive non-oropharyngeal cancer, and D) HPV-negative non-oropharyngeal cancer.
Table 3.
Multivariable adjusted hazard ratios for cancer-specific mortality among patients with M0 HNSCC and at least 1 month of follow-up (N=4,476)
| Characteristic | No. patients / No. Cancer-Deaths / No. Competing Deaths | Cancer-Specific Mortality | ||
|---|---|---|---|---|
| AHR (95% CI) | P | |||
| Race * HPV Status * Disease Sitea | 4,476/323/98 | 0.33 (0.24–0.45) | <0.001 | |
| HPV Positive Disease, Oropharynxb | 2,903/110/49 | |||
| White | 2,471/83/43 | 1.0 (ref) | ||
| Non-White | 432/27/6 | 1.82 (1.14–2.94) | 0.01 | |
| Private or other insurance | 2,541/81/42 | 1.0 (ref) | ||
| Uninsured | 73/7/2 | 3.12 (1.19–8.13) | 0.02 | |
| Medicaid | 255/15/5 | 1.73 (0.91–3.27) | 0.09 | |
| Unknown insurance | 34/7/0 | 3.62 (1.56–8.42) | 0.003 | |
| HPV Negative Disease, Oropharynxc | 1,014/148/34 | |||
| White | 745/110/22 | 1.0 (ref) | ||
| Non-White | 269/38/12 | 1.11 (0.74–1.67) | 0.60 | |
| Private or other insurance | 771/104/21 | 1.0 (ref) | ||
| Uninsured | 46/7/5 | 0.85 (0.36–2.05) | 0.72 | |
| Medicaid | 178/33/4 | 1.13 (0.73–1.75) | 0.59 | |
| Unknown insurance | 19/4/4 | 1.00 (0.22–4.73) | 0.99 | |
| HPV Positive Disease, Non-Oropharynxd | 180/19/3 | |||
| White | 135/15/3 | 1.0 (ref) | ||
| Non-White | 45/4/0 | 1.26 (0.18–8.75) | 0.82 | |
| Private or other insurance | 146/12/3 | 1.0 (ref) | ||
| Uninsured | 3/2/0 | 87.48 (5.02–1524.14 | 0.002 | |
| Medicaid | 29/4/0 | 1.51 (0.15–15.52) | 0.73 | |
| Unknown insurance | 2/1/0 | 139.5 (5.53–3520.18 | 0.003 | |
| HPV Negative Disease, Non-Oropharynxe | 379/46/12 | |||
| White | 191/27/4 | 1.0 (ref) | ||
| Non-White | 188/19/8 | 1.39 (0.73–2.62) | 0.31 | |
| Private or other insurance | 269/28/9 | 1.0 (ref) | ||
| Uninsured | 20/3/0 | 1.81 (0.50–6.51) | 0.37 | |
| Medicaid | 86/15/3 | 1.30 (0.60–2.81) | 0.50 | |
| Unknown insurance | 4/0/0 | |||
| Age at Diagnosis (per year increase) | 4,476/323/98 | 1.04 (1.03–1.05) | <0.001 | |
| Sex | ||||
| Female | 727/76/13 | 1.0 (ref) | ||
| Male | 3,749/247/85 | 0.67 (0.51–0.87) | 0.003 | |
| Smoking Propensity (per 10% increase) | 4,476/323/98 | 1.01 (0.99–1.03) | 0.38 | |
| High School Education (per 10% increase) | 4,476/323/98 | 1.02 (1.00–1.05) | 0.13 | |
| Median Household Income (per 10K increase) | 4,476/323/98 | 1.00 (1.00–1.00) | 0.03 | |
| Tumor Stage | ||||
| T1 | 1,041/32/11 | 1.0 (ref) | ||
| T2 | 1,512/60/24 | 1.37 (0.88–2.12) | 0.16 | |
| T3 | 764/71/21 | 3.10 (1.99–4.84) | <0.001 | |
| T4 | 654/125/30 | 5.30 (3.47–8.10) | <0.001 | |
| Unknown T | 486/35/12 | 1.81 (1.06–3.11) | 0.03 | |
| Nodal Stage | ||||
| N0 | 675/54/14 | 1.0 (ref) | ||
| N1 | 838/61/11 | 1.17 (0.79–1.73) | 0.44 | |
| N2a | 444/11/7 | 0.69 (0.36–1.31) | 0.27 | |
| N2b | 1,439/84/36 | 1.18 (0.80–1.72) | 0.41 | |
| N2c | 589/64/15 | 1.23 (0.80–1.89) | 0.35 | |
| N2 NOS | 116/11/4 | 1.64 (0.84–3.17) | 0.15 | |
| N3 | 233/25/5 | 1.81 (1.10–2.97) | 0.02 | |
| Unknown N | 142/13/7 | 0.93 (0.44–1.99) | 0.86 | |
| Definitive Treatment | ||||
| None | 204/67/10 | 1.0 (ref) | ||
| Surgery | 1,215/35/12 | 0.40 (0.27–0.60) | <0.001 | |
| Radiation Therapy | 4,001/221/80 | 0.22 (0.18–0.30) | <0.001 | |
| Chemotherapy | 3,223/197/62 | 0.80 (0.59–1.08) | 0.14 | |
Abbreviations: AHR, Adjusted Hazard Ratio; CI, confidence interval; HNSCC, Head and Neck Squamous Cell Carcinoma; HPV, Human Papillomavirus; N/A, not applicable
Interaction term was tested in multivariable analysis with HPV status, disease site, race, smoking propensity, high school education, median household income, tumor stage, nodal stage and definitive treatment. Following the identification of a statistically significant interaction amongst these variables, subgroups b-e were examined in separate models, excluding the aforementioned interaction term, to examine the effect of race on CSS in each subgroup.
In addition to race, patients with HPV-positive oropharyngeal SCCHN who were uninsured had a higher risk of CSM compared to their privately insured peers (AHR 3.12, 95%CI 1.19–8.13, p=0.02); notably, such differences were not seen in other HPV-negative or non-oropharyngeal subgroups. Marital status did not have a significant effect on CSM in patients with HPV-positive oropharyngeal SCCHN, but amongst HPV-negative oropharyngeal cancer patients, those who were single had worse CSM (AHR 1.66, 95%CI 1.04–2.65, p=0.04).
4. Discussion
This report is, to our knowledge, the largest population-based analysis of the socioeconomic factors affecting outcomes in HPV-associated SCCHN. We found that non-white patients with HPV-positive oropharyngeal SCCHN were at higher risk of CSM than white patients, while both white and non-white patients with HPV-negative or non-oropharyngeal HPV-positive SCCHN had similarly poor outcomes (pINT<0.001). In addition, uninsured patients with HPV-associated oropharyngeal SCCHN had an increased risk of CSM as compared to their privately insured peers.
Our findings are significant in that they contradict prior reports and hypotheses suggesting that the worse CSM seen in non-white populations with SCCHN is driven by a higher likelihood of HPV-negative disease among this subgroup,6 or that non-white patients with HPV-negative disease and lower SES have disproportionately worse outcomes.18,19 The differences in CSM between white and non-white populations with HPV-associated oropharyngeal cancer persisted even after adjusting for relevant potential socioeconomic confounders such as insurance status, age, gender, smoking status, education and household income. As such, our results raise the concern that non-white patients may not be achieving the full potential for improved outcomes seen in HPV-associated SCCHN in the modern era. Similar concerns exist regarding those without insurance coverage.
A plausible explanation for these findings is that non-white and uninsured patients may have inferior access to care, such as supportive therapies during intensive treatment for SCCHN. Others have hypothesized that worse outcomes in SCCHN may be due in part to insufficient access to screening programs allowing detection of cancer at earlier and more treatable stages.20,21 Indeed, prior work has demonstrated that African-Americans are less likely to receive definitive treatment, with a consequent increased risk of CSM.20 Finally, there may be undescribed genomic differences that result in worse outcomes in non-white patients with HPV-associated SCCHN. On the other hand, known HPV status may itself be an indicator of access to appropriate cancer care and good health care delivery.
Interestingly, despite the known association between sexual activity and HPV-infection, married patients in our study were more likely single patients to present with HPV-positive SCCHN. We hypothesize that these differences may be due to HPV-coinfection amongst couples or alternatively, due to uncaptured risk factors such as smoking and alcohol that may increase the likelihood of HPV-negative disease in singles. We also found that single patients with HPV-negative SCCHN had a higher risk of CSM than married patients with HPV-negative SCCHN, which is consistent with prior studies.21–23
Due to the retrospective nature of SEER, with incompletely captured data on smoking habits and the use of county-level indices to estimate economic and educational factors, caution should be taken when interpreting our results. Particularly, given the well-established effect of smoking status on outcome amongst patients with oropharyngeal cancers, the lack of individual-level patient data on smoking in the SEER database poses an ongoing challenge. Nonetheless, this study represents the first large report describing the effect of socioeconomic factors on HPV-associated SCCHN and cancer-specific mortality for those patients. Prior studies have relied on small case series of patients from academic centers and retrospective reviews of prospective studies, which are not representative of the general population.16,24 By contrast, SEER registries capture a wider cross-section of the population, including a more representative racial and economic balance from both academic and community medical centers in urban and rural areas.17
In conclusion, our study highlights the socioeconomic differences between HPV-positive and HPV-negative SCCHN and identifies striking racial disparities amongst individuals with HPV-positive oropharyngeal SCCHN. This work suggests a potentially missed opportunity for cure amongst non-white and uninsured populations with HPV-positive OPC and an unmet need for access to high quality cancer care. Further work is urgently needed to reduce socioeconomic disparities in SCCHN.
Footnotes
Conflicts of interest: Luke Pike receives compensation from Third Rock Ventures for unrelated consulting work. The other authors have no conflicts to disclose.
5. References
- 1.Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide Trends in Incidence Rates for Oral Cavity and Oropharyngeal Cancers. J Clin Oncol. 2013;31(36):4550–4559. doi: 10.1200/JCO.2013.50.3870 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Jemal A, Simard EP, Dorell C, et al. Annual Report to the Nation on the Status of Cancer, 1975–2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)–Associated Cancers and HPV Vaccination Coverage Levels. JNCI J Natl Cancer Inst. 2013;105(3):175–201. doi: 10.1093/jnci/djs491 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Gillison ML, Zhang Q, Jordan R, et al. Tobacco Smoking and Increased Risk of Death and Progression for Patients With p16-Positive and p16-Negative Oropharyngeal Cancer. J Clin Oncol. 2012;30(17):2102–2111. doi: 10.1200/JCO.2011.38.4099 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wilting SM, Steenbergen RDM. Molecular events leading to HPV-induced high grade neoplasia. Papillomavirus Res. 2016;2:85–88. doi: 10.1016/J.PVR.2016.04.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Schache AG, Powell NG, Cuschieri KS, et al. HPV-Related Oropharynx Cancer in the United Kingdom: An Evolution in the Understanding of Disease Etiology. Cancer Res. 2016;76(22):6598–6606. doi: 10.1158/0008-5472.CAN-16-0633 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Settle K, Posner MR, Schumaker LM, et al. 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(9):776–781. doi: 10.1158/1940-6207.CAPR-09-0149 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Fakhry C, Westra WH, Wang SJ, et al. The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer. 2017;123(9):1566–1575. doi: 10.1002/cncr.30353 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612–619. doi: 10.1200/JCO.2007.14.1713 [DOI] [PubMed] [Google Scholar]
- 9.D’Souza G, Kreimer AR, Viscidi R, et al. Case–Control Study of Human Papillomavirus and Oropharyngeal Cancer. N Engl J Med. 2007;356(19):1944–1956. doi: 10.1056/NEJMoa065497 [DOI] [PubMed] [Google Scholar]
- 10.Gillison ML, D’Souza G, Westra W, et al. Distinct Risk Factor Profiles for Human Papillomavirus Type 16–Positive and Human Papillomavirus Type 16–Negative Head and Neck Cancers. JNCI J Natl Cancer Inst. 2008;100(6):407–420. doi: 10.1093/jnci/djn025 [DOI] [PubMed] [Google Scholar]
- 11.Sinha P, Logan HL, Mendenhall WM. Human papillomavirus, smoking, and head and neck cancer. Am J Otolaryngol. 2012;33(1):130–136. doi: 10.1016/j.amjoto.2011.02.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Frisch M, Goodman MT. Human papillomavirus-associated carcinomas in Hawaii and the mainland U.S. Cancer. 2000;88(6):1464–1469. http://www.ncbi.nlm.nih.gov/pubmed/10717631. Accessed March 28, 2018. [DOI] [PubMed] [Google Scholar]
- 13.Stenmark MH, Shumway D, Guo C, et al. Influence of human papillomavirus on the clinical presentation of oropharyngeal carcinoma in the United States. Laryngoscope. 2017;127(10):2270–2278. doi: 10.1002/lary.26566 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Worsham MJ, Stephen JK, Chen KM, et al. Improved Survival with HPV among African Americans with Oropharyngeal Cancer. Clin Cancer Res. 2013;19(9):2486–2492. doi: 10.1158/1078-0432.CCR-12-3003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Rubin SJ, Kirke DN, Ezzat WH, Truong MT, Salama AR, Jalisi S. Marital status as a predictor of survival in patients with human papilloma virus-positive oropharyngeal cancer. Am J Otolaryngol. 2017;38(6):654–659. doi: 10.1016/j.amjoto.2017.09.003 [DOI] [PubMed] [Google Scholar]
- 16.Murthy VH, Krumholz HM, Gross CP. Participation in Cancer Clinical Trials. JAMA. 2004;291(22):2720. doi: 10.1001/jama.291.22.2720 [DOI] [PubMed] [Google Scholar]
- 17.Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/. Accessed February 3, 2018.
- 18.Chu KP, Habbous S, Kuang Q, et al. Socioeconomic status, human papillomavirus, and overall survival in head and neck squamous cell carcinomas in Toronto, Canada. Cancer Epidemiol. 2016;40:102–112. doi: 10.1016/j.canep.2015.11.010 [DOI] [PubMed] [Google Scholar]
- 19.Worsham MJ, Stephen JK, Chen KM, et al. Improved survival with HPV among African Americans with oropharyngeal cancer. Clin Cancer Res. 2013;19(9):2486–2492. doi: 10.1158/1078-0432.CCR-12-3003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Mahal BA, Inverso G, Aizer AA, Bruce Donoff R, Chuang S-K. Impact of African–American race on presentation, treatment, and survival of head and neck cancer. Oral Oncol. 2014;50(12):1177–1181. doi: 10.1016/J.ORALONCOLOGY.2014.09.004 [DOI] [PubMed] [Google Scholar]
- 21.Inverso G, Mahal BA, Aizer AA, Donoff RB, Chau NG, Haddad RI. Marital status and head and neck cancer outcomes. Cancer. 2015;121(8):1273–1278. doi: 10.1002/cncr.29171 [DOI] [PubMed] [Google Scholar]
- 22.Aizer AA, Chen M-H, McCarthy EP, et al. Marital Status and Survival in Patients With Cancer. J Clin Oncol. 2013;31(31):3869–3876. doi: 10.1200/JCO.2013.49.6489 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Schaefer EW, Wilson MZ, Goldenberg D, Mackley H, Koch W, Hollenbeak CS. Effect of marriage on outcomes for elderly patients with head and neck cancer. Head Neck. 2015;37(5):735–742. doi: 10.1002/hed.23657 [DOI] [PubMed] [Google Scholar]
- 24.Posner MR, Lorch JH, Goloubeva O, et al. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol. 2011;22(5):1071–1077. doi: 10.1093/annonc/mdr006 [DOI] [PMC free article] [PubMed] [Google Scholar]