Abstract
Purpose
Treatment for oropharyngeal cancer (OPC) has changed over the past two decades under multiple influences. We provide a population-based description of the application of radiotherapy, surgery, and chemotherapy to OPC in 1997, 2004 and 2009.
Methods
The National Cancer Institute’s Patterns of Care study for OPC included multiple variables not available in the public-use dataset. We identified factors correlating with selection of primary surgery versus radiotherapy with or without chemotherapy (RTC) and analyzed predictors of all-cause mortality. We estimated the frequency of human papillomavirus (HPV) testing.
Results
RTC was more common in 2009 than in 1997, and was more commonly applied to Stage IV cases. However, RTC was not an independent risk factor for mortality compared with surgery. HPV status was known in 14% of patients in 2009.
Conclusions
RTC is the most common treatment for OPC, but it may not provide the best outcomes. HPV testing was uncommon in 2009.
Keywords: oropharyngeal neoplasm, radiotherapy, chemoradiotherapy, surgery, human papillomavirus
Introduction
Oropharyngeal cancer (OPC) has changed dramatically over recent years. While alcohol [1] and tobacco [2] remain risk factors of OPC, there has been a significant increase in disease incidence which has been associated with human papillomavirus (HPV) [3, 4]. The increase of HPV-related OPC potentially has significant implications for treatment and selection survival outcomes.
Both surgery, with or without adjuvant radiotherapy (RT), and nonsurgical treatment, RT with or without chemotherapy, have been utilized and advocated [5–7], though to date there are no high-quality studies providing a direct comparison of these treatment approaches. Previous studies have demonstrated that RT alone [8] and RT plus chemotherapy [9] confer effective locoregional tumor control and survival. For example, Denis et al. reported that RT plus chemotherapy may be more effective than RT alone in the setting of advanced stage tumors. However, both RT alone and RT plus chemotherapy have been associated with long-term complications such as dysphagia and pharyngeal strictures [10, 11]. The more recent introduction of transoral surgical strategies has been temporally associated with an upswing in the proportion of patients receiving primary surgery [12].
These recent countercurrents have not been measured with population-based data. The details of treatment selection are not described with population basis for patients at all ages The purpose of this study was to examine trends in OPC treatment selection for surgery vs. RT with or without chemotherapy (RTC), and differences by treatment setting across the US population using Surveillance, Epidemiology, and End Results (SEER) Patterns of Care (POC) data. We also describe patients with known HPV status in order to determine which characteristics are associated with receipt of HPV testing.
Methods
This study is based on the National Cancer Institute’s SEER POC data for head and neck cancer. Those data were collected for cases incident in 1997, 2004 and 2009. SEER is a population-based cancer registry program which collects demographic, tumor and some treatment information and is generally representative of the U.S. cancer patient population [13]. SEER POC studies entail the collection of additional information not contained in public-use SEER records on a sample of patients with select cancers from participating SEER registries such as systemic therapy regimens, co-morbidities, physician residency training status and information about the facility where patient received treatment. Non-Hispanic blacks, Hispanics, Asian/Pacific Islanders and American Indians/Native Alaskans are over-sampled to provide more stable estimates for analyses examining race/ethnicity. American Joint Committee on Cancer (AJCC) 6th Ed. [14] staging data were available for the 2004 and 2009 cohorts. For the 1997 cohort, SEER extent-of-disease variables describing tumor size, extension, and nodal status were used to derive AJCC 6th Ed. [14] stage by an algorithm composed with consultation from SEER and AJCC cancer registrars (B. Matt and D. Gress, personal communications). Extent of disease coding rules in use during 1988–2003 by cancer registries, including SEER, classified supraclavicular nodes as sites of distant metastasis rather than as regional nodal disease as they would be considered by AJCC 6th Ed. [14] rules. Our algorithm was consistent with the latter. Cases were followed actively by the SEER program until death, loss to follow up, or December 31, 2011.
Treatment variables included receipt of surgical treatment, RT, and chemotherapy. Those who received surgery alone or surgery and RT (with or without chemotherapy) were classified as having “primary surgery,” whereas patients who had RT only (with or without chemotherapy) were classified as having “RTC.”
OPC cases were identified using the International Classification of Diseases of Oncology, Third Edition (ICD-O-3) primary site codes 19, 24, 51-52, 90-91, 98-103, 108-109, 140, 142 and 148 and malignant squamous neoplasms with histology codes between 8050 and 8089. A total of 872 OPC patients were retrieved from SEER POC data. Patients whose treatment status was unknown (n=37) were excluded from the analysis. Furthermore, patients who received either no cancer-directed therapy or chemotherapy only (n =48) were excluded from the bivariate analysis and multivariable models because these approaches are primarily used in the palliative setting for oropharyngeal cancer, and the focus in this study was on selection of curative treatments.
Statistical analyses were performed using SAS statistical software (version 9.4). Sample weights were used to account for oversampling in all the analyses using PROC SURVEY. The sample weights were derived from the inverse of the sampling proportion in each sample strata; sample strata were characterized by age, race, cancer stage and SEER registry. Bivariate analyses were done to determine the association between demographic, tumor and hospital characteristics with treatment selection. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression to predict receiving primary surgery versus RTC. Multivariable Cox proportional hazards regression was used to determine factors associated with all cause survival. In both multivariable models, purposeful selection by backward elimination was used to select variables to include in the model with a p-value of 0.2 or less required to stay in the model[15]; the base model for logistic regression included age, race, gender, marital status and Charlson comorbidity index (a broad measure of multisystem comorbidity which has been validated as a predictor of survival outcome, including for head and neck cancer[16, 17]) while the base model for the Cox proportional model included age, race, gender and hospital size (measured by number of inpatient beds). Given current treatment controversies related to primary treatment of advanced stage OPC, we also analyzed the subset of patients with T4 stage OPC to examine the specific patterns of care and survival in that select population.
Results
We identified 872 patients in the cohort, of whom 37 were excluded due to unknown treatment status (Figure 1). There were 125 patients in 1997, 375 in 2004, and 335 in 2009 (Table 1). There were no statistically significant differences in age at diagnosis, sex, marital status, or insurance status between the three cohorts; there were fewer non-white patients in 1997 (12% vs 14% in 2004 and 2009; Rao-Scott chi-square p<.0001). Treatment selection varied significantly with time for all cases and for T4 stage only OPC cases. The percentage of cases receiving primary surgery decreased from 46% in 1997 to 35% in 2004 and 28% in 2009. Conversely, there was an increase in the proportion of cases receiving RTC from 47% in 1997 to 61% in 2004 and 65% in 2009. The same trends were present within the subset of patients with T4 class. Patients receiving no cancer-directed therapy or chemotherapy only consisted of 8%, 4% and 7% in 1997, 2004 and 2009, respectively. The most commonly used chemotherapy agents were cisplatin/carboplatin, followed by methotrexate, 5-fluorouracil, and taxanes.
Figure 1.
Flow chart of study inclusion and exclusion criteria in analyses.
Table 1.
Treatment approaches for OPC patients for all stages and T4 stage only cases by year of diagnosis, weighted column %).
| All Stages (n=835) | T4 Stage Only (n=194) | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| Treatment | 1997 (n=125) |
2004 (n=375) |
2009 (n=335) |
1997 (n=33) |
2004 (n=79) |
2009 (n=82) |
| No cancer-directed therapy† | 8% | 4% | 7% | 6% | 5% | 7% |
|
| ||||||
| Primary surgery | ||||||
| Surgery only‡ | 6% | 6% | 5% | 6% | 1% | 4% |
| Surgery and RT§ | 40% | 29% | 23% | 30% | 23% | 10% |
|
| ||||||
| RTC | ||||||
| RT only | 21% | 15% | 9% | 27% | 16% | 15% |
| RT & Chemotherapy | 26% | 46% | 56% | 30% | 54% | 65% |
|
| ||||||
| P-value‖ | < 0.0001* | < 0.0001* | ||||
OPC=oropharyngeal cancer; RTC= radiotherapy with or without chemotherapy; RT=radiotherapy
Significant at α = 0.05
Includes patients who received chemotherapy only
Includes patients who received both surgery and chemotherapy (chemotherapy received after surgery).
Includes patients who received both Surgery and RT with or without chemotherapy.
Pearson Chi-Square P-value. P-value compares patients who had primary surgery versus those who had RTC. This excludes patients who did not receive cancer-directed therapy or chemotherapy only.
There were 284 and 503 OPC cases that received primary surgery and RTC, respectively (Table 2). The mean age was 56 years for primary surgery patients and 58 years for RTC patients (p < 0.0001). While treatment selection was not distributed differently by sex, race, marital status, insurance status, or Charlson score, there was an association with tumor stage: patients with stages I/II/III OPC cancer had similar proportions of patients receiving surgery or RTC, but a significantly greater proportion of those with IVA/IVB/IVC received RTC. When specifically examining T class, a significantly greater proportion of those with T1 tumors received surgery, whereas RTC became more prevalent as T class increased (p < 0.0001). Similar patterns were observed when examining N class among all cases but did not reach statistical significance (p = 0.06). Treatment did not differ significantly by metastasis status. Hospital residency training status and bed size were not significantly associated with treatment selection among all cases.
Table 2.
†. Demographic, tumor and hospital characteristics by treatment and stage, (weighted row %).
| All Stages, (n=787) | T4 Stage Only, (n=182) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| Characteristics | Surgery (n=284) |
RTC (n=503) |
Row total, n | P value‖ | Surgery (n=42) |
RTC (n=140) |
Row total, n | P value‖ | |
| Year | 1997 | 59% | 41% | 115 | 43% | 57% | 31 | ||
| 2004 | 38% | 62% | 359 | 18% | 82% | 75 | |||
| 2009 | 28% | 72% | 313 | 0.0006* | 15% | 85% | 76 | 0.0442* | |
|
| |||||||||
| Age | 20–49 | 44% | 56% | 162 | 20% | 80% | 39 | ||
| 50–64 | 35% | 65% | 421 | 17% | 83% | 98 | |||
| 65+ | 34% | 66% | 204 | 0.40 | 28% | 72% | 45 | 0.51 | |
|
| |||||||||
| Sex | Female | 45% | 55% | 249 | 23% | 67% | 61 | ||
| Male | 35% | 65% | 538 | 0.08 | 20% | 80% | 121 | 0.76 | |
|
| |||||||||
| Race | Non-white | 31% | 69% | 339 | 21% | 79% | 100 | ||
| White | 37% | 63% | 448 | 0.13 | 21% | 79% | 82 | 0.97 | |
|
| |||||||||
| Marital status | Married | 39% | 61% | 385 | 28% | 72% | 72 | ||
| Unmarried | 33% | 67% | 402 | 0.40 | 17% | 83% | 110 | 0.23 | |
|
| |||||||||
| Health | Yes | 36% | 63% | 718 | 20% | 80% | 162 | ||
| Insurance | No/Unknown | 37% | 63% | 69 | 0.93 | 29% | 61% | 20 | 0.47 |
|
| |||||||||
| Charlson | 0 | 38% | 62% | 581 | 22% | 78% | 135 | ||
| Score | ≥ 1 | 32% | 68% | 206 | 0.42 | 18% | 82% | 47 | 0.70 |
|
| |||||||||
| Stage Group | I, II & III | 53% | 47% | 197 | – | – | |||
| (AJCC 6th Ed.) | IVA & IVB | 29% | 71% | 374 | 21% | 79% | 161 | ||
| IVC | 29% | 71% | 49 | 7% | 93% | 12 | |||
| Unknown | 30% | 70% | 167 | 0.0012* | 16% | 84% | 9 | 0.18 | |
|
| |||||||||
| T Class | T1 | 64% | 36% | 139 | – | – | – | ||
| (2 missing) | T2 | 39% | 61% | 192 | – | – | – | ||
| T3 | 16% | 84% | 83 | – | – | – | |||
| T4 | 21% | 79% | 182 | 21% | 79% | 182 | |||
| Unknown | 25% | 75% | 189 | <0.0001* | – | – | – | <0.0001* | |
|
| |||||||||
| N Class | N0 | 51% | 49% | 167 | 45% | 55% | 29 | ||
| N1 | 34% | 66% | 171 | 4% | 96% | 32 | |||
| N2 | 30% | 70% | 338 | 22% | 78% | 90 | |||
| N3 | 23% | 77% | 32 | 9% | 91% | 16 | |||
| Unknown | 43% | 57% | 79 | 0.06 | 26% | 74% | 15 | 0.0045* | |
|
| |||||||||
| M Class | M0 | 38% | 62% | 686 | 21% | 79% | 161 | ||
| M1 | 29% | 71% | 49 | 7% | 93% | 12 | |||
| Unknown | 25% | 75% | 52 | 0.17 | 16% | 84% | 9 | 0.18 | |
|
| |||||||||
| Residency | Yes | 36% | 64% | 494 | 24% | 76% | 123 | ||
| Program | No/ Unknown | 38% | 62% | 293 | 0.75 | 13% | 87% | 59 | 0.12 |
|
| |||||||||
| Hospital Beds | 1–299/Unknown | 37% | 63% | 318 | 12% | 88% | 69 | ||
| ≥ 300 | 35% | 65% | 469 | 0.76 | 26% | 74% | 113 | 0.0055* | |
RTC= radiotherapy with or without chemotherapy
Excluded patients who either received chemotherapy or no cancer directed therapy
Weighted Rao-Scott Chi-Square P-value
Significant at α = 0.05
In a subgroup analysis of the T4 class cases, the use of primary surgery changed over time – from 36% in 1997 to 24% in 2004 and 14% in 2009. In 1997, 2004 and 2009, 6%, 5% and 7%, respectively, of T4 stage only OPC cases received no cancer-directed therapy or chemotherapy only (Table 1). After excluding patients with either no cancer-directed therapy or chemotherapy only, age distribution was similar between primary surgery and RTC groups (p = 0.51). N class (p = 0.0045) and hospital size (p = 0.0055) were significantly associated with receipt of primary surgery among T4 cases (Table 2).
Multivariate models involving all OPC cases demonstrated that earlier year of diagnosis and earlier stage independently predicted receipt of primary surgery versus RTC after adjusting for age at diagnosis, race, sex, marital status at diagnosis, Charlson score, AJCC stage and hospital size (Table 3). The adjusted odds ratio for receiving primary surgery versus RTC was 0.29 (95% CI; 0.15, 0.55) in 2004 and 0.17 (95% CI; 0.09, 0.33) in 2009, with 1997 as the reference group. The adjusted odds of receiving primary surgery versus RTC were higher for early stage versus late stage with I/II/III as the reference [0.36 (95% CI; 0.18, 0.70) for stage IVA and IVB cases and 0.28 (95% CI; 0.08, 0.97) for IVC cases].
Table 3.
Multivariate logistic model predicting primary surgery versus RTC for all stages and T4 stage only patients diagnosed in 1997, 2004 and 2009 using SEER POC (weighted data).
| Surgery versus RTC Odds Ratio (95% CI) |
|||
|---|---|---|---|
|
| |||
| Characteristics | All Stages n= (787) |
T4 Stage Only n= (182) |
|
| Year of diagnosis | 1997 | 1.00 (Referent) | 1.00 (Referent) |
| 2004 | 0.29 (0.15, 0.55)* | 0.19 (0.07, 0.52)* | |
| 2009 | 0.17 (0.09, 0.33)* | 0.15 (0.04, 0.51)* | |
|
| |||
| Age continuous) | 0.98 (0.95, 1.01) | 1.04 (0.99, 1.10) | |
|
| |||
| Race | Non-white | 1.00 (Referent) | 1.00 (Referent) |
| White | 0.80 (0.59, 1.37) | 1.23 (0.52, 2.93) | |
|
| |||
| Sex | Female | 1.00 (Referent) | 1.00 (Referent) |
| Male | 1.47 (0.88, 2.47) | 1.08 (0.40, 2.89) | |
|
| |||
| Marital status | Married | 1.00 (Referent) | 1.00 (Referent) |
| Unmarried | 1.26 (0.74, 2.17) | 1.46 (0.58, 3.70) | |
|
| |||
| Charlson Score | 0 | 1.00 (Referent) | 1.00 (Referent) |
| ≥ 1 | 0.95 (0.50, 1.78) | 0.57 (0.16, 2.08) | |
|
| |||
| Stage Group | I, II & III | 1.00 (Referent) | – |
| (AJCC 6th Ed.) | IVA & IVB | 0.36 (0.18, 0.70)* | 1.00 (Referent) |
| IVC | 0.28 (0.08, 0.97)* | 0.35 (0.04, 3.22) | |
| Unknown | 0.25 (0.12, 0.52)* | 0.36 (0.13, 0.95)* | |
|
| |||
| Hospital Beds | 1–299/Unknown | 1.00 (Referent) | 1.00 (Referent) |
| ≥ 300 | 0.95 (0.55, 1.65) | 3.33 (1.67, 6.66)* | |
OPC=oropharyngeal cancer; RTC= radiotherapy with or without chemotherapy
Significant at α = 0.05
Similar to the analysis of all OPC patients, T4 cases diagnosed with OPC in earlier years had higher odds of receiving primary surgery versus RTC (Table 3) on multivariate analysis. Unlike with the all-stages cohort, the odds of receiving surgery increased with increasing bed size in T4 cases; the odds ratio was 3.33 (95% CI; 1.67, 6.66) for patients treated at hospitals with bed size greater than or equal to 300 with bed size less than 300 as the reference group.
Each additional year of age at diagnosis (HR= 1.03: 95% CI; 1.02, 1.05), being unmarried (HR= 2.10: 95% CI; 1.51, 2.91), and having a Charlson score of at least one or more (HR= 1.77: 95% CI; 1.20, 2.62) were also significantly associated with increased hazard of death (Table 4). Diagnosis in 2009 (versus 1997) (HR= 0.51: 95% CI; 0.33, 0.78) was significantly related to lower risk of death. Compared to stages I-III cases, stage IVC patients had a significantly greater hazard of death (HR 2.22: 95% CI; 1.16, 4.26). RTC versus primary surgery was not significantly associated with increased hazard of death from all causes (HR= 1.42: 95% CI; 0.93, 2.17). Neither hospital size (Table 4) nor residency training status (results not shown) was significantly associated with risk of death when included in multivariable models. Among T4 cases, only stage remained significant in multivariate models (Table 4). Those with Stage IVC disease had a hazard 5.64 (95% CI; 3.00, 10.58) times higher than stage IVA/ IVB patients.
Table 4.
Hazard ratios and 95% CI for all stages and T4 stage only OPC patients diagnosed in 1997, 2004 and 2009 using SEER POC (weighted data).
| Hazard Ratio 95 CI) | |||
|---|---|---|---|
|
| |||
| Characteristics | All Stages n= (787) |
T4 Stage Only n= (182) |
|
| Year of diagnosis | 1997 | 1.00 (Referent) | 1.00 (Referent) |
| 2004 | 0.69 (0.47, 1.01) | 0.87 (0.50, 1.52) | |
| 2009 | 0.51 (0.33, 0.78)* | 1.00 (0.55, 1.83) | |
|
| |||
| Age continuous) | 1.03 (1.02, 1.05)* | 1.02 (0.99, 1.04) | |
|
| |||
| Race | Non-white | 1.00 (Referent) | 1.00 (Referent) |
| White | 0.74 (0.54, 1.00) | 1.04 (0.72, 1.49) | |
|
| |||
| Sex | Female | 1.00 (Referent) | 1.00 (Referent) |
| Male | 0.94 (0.64, 1.38) | 0.82 (0.57, 1.18) | |
|
| |||
| Marital status | Married | 1.00 (Referent) | 1.00 (Referent) |
| Unmarried | 2.10 (1.51, 2.91)* | 1.85 (0.96, 3.55) | |
|
| |||
| Charlson Score | 0 | 1.00 (Referent) | 1.00 (Referent) |
| ≥ 1 | 1.77 (1.20, 2.62)* | 1.61 (0.88, 2.96) | |
|
| |||
| Stage Group | I, II & III | 1.00 (Referent) | – |
| (AJCC 6th Ed.) | IVA & IVB | 1.37 (0.83, 2.26) | 1.00 (Referent) |
| IVC | 2.22 (1.16, 4.26)* | 5.64 (3.00, 10.58)* | |
| Unknown | 1.25 (0.72, 2.17) | 0.19 (0.13, 1.06) | |
|
| |||
| Type of Therapy | Surgery | 1.00 (Referent) | 1.00 (Referent) |
| RTC | 1.42 (0.93, 2.17) | 0.71 (0.37, 1.38) | |
|
| |||
| Hospital Beds | 1–299 /Unknown | 1.00 (Referent) | 1.00 (Referent) |
| ≥ 300 | 1.24 (0.90, 1.71) | 1.38 (0.77, 2.48) | |
Significant at α = 0.05
OPC=oropharyngeal cancer
HPV status was only collected for OPC cases diagnosed in 2009. HPV status was known in 14% of 2009 cases (Figure 2). The rate of HPV testing was greatest among cases with OPC located on the tongue base (16%) and on the tonsils (12%); other oropharynx sites combined had a testing rate of 11%. For the OPC cases with known HPV status, 43% of tongue base cancers and 52% of tonsil cancers were HPV-positive. HPV status was not significantly associated with the type of therapy received, p=0.79. (Table 5).
Figure 2. Weighted percentages of HPV Status for OPC Patients Diagnosed in 2009.
HPV=human papillomavirus; OPC=oropharyngeal cancer
Table 5.
Treatment selection by HPV status, all patients diagnosed in 2009.
| Treatment | ||
|---|---|---|
| HPV status | Surgery (n=94) |
RTC (n=219) |
| Positive | 8% | 5% |
| Negative | 6% | 9% |
| Unknown | 86% | 86% |
Chi-square p=0.79.
Discussion
Evaluating population-level data, our results show a clear trend away from primary surgery for management of OPC from over half of patients diagnosed in 1997 to fewer than one quarter of those diagnosed in 2009. Although no high-quality studies directly compared surgery to RTC, previous research describing the addition of chemotherapy to radiotherapy for locally advanced oropharyngeal cancer [9, 18, 19] provided evidence that there was an alternative to surgery, with its evident detriments related to tumor exposure and reconstruction. There were additional studies of patients with unresectable cancer [20, 21] that provided a basis for RTC in the setting of Stage IVB disease as well. Forastiere and Trotti stated in 1999 [22] that RTC should be considered standard of care on the basis of studies published at that time, and our results suggest that there was general agreement with their perspective.
Our data show a similar trend to that reported by Goldenberg et al, [23] who found that about 60% of patients received RTC and that chemoradiation or radiation alone were the most common treatment selections based on 2,192 Medicare recipients between 1997 and 2005. Our findings in a representative sample of younger and older adults in the U.S. population were concordant, which is noteworthy because that study included only patients age 66 and older, a group representing 23% of the population. Chen et al. [24] also reported similar trends in a 1985-2001 National Cancer Data Base cohort derived mainly from patients treated at larger hospitals. Our data in fact indicate that at larger hospitals, patients with T4 cancers were more likely to undergo primary surgery, probably related to availability of subspecialist multidisciplinary treatment teams at larger hospitals, including oncologic and reconstructive surgeons. Our study includes populations not covered by prior studies.
Survival analysis identified year of diagnosis as a predictor of mortality. Patients diagnosed in 2009 had a lower hazard of death than those in 1997. The prevalence of HPV may explain a large portion of that variation. The proportion of OPCs associated with HPV has risen steadily over the past 20 years, and with the improved prognosis of HPV-associated OPC [3], substantial differences would be expected over the years we studied. Unfortunately, information on HPV was available only in 2009 for our cohort, so we could not account for its confounding effect. As shown in prior studies [25–27], age, unmarried status, and Charlson score ≥ 1 were independent predictors of mortality. However, RTC was not associated with greater hazard of all-cause mortality for either the entire cohort or the T4 subgroup.
The management of OPC has changed substantially over the past decade, with two major reasons being the identification of HPV as an etiologic factor in a large subgroup of patients and the introduction of transoral surgical techniques that obviate many difficulties with tumor exposure and reconstruction. The latter is not well-represented in our data. Transoral laser techniques have been adapted to the oropharynx over the past decade [28], and although a small number of centers have described good results over a large number of cases, [29] these techniques have not been widely applied across the population. Robotic surgery has become more common recently [30], but was much less common until FDA approval in 2010. Analysis of those trends would require more recent data than was available to us.
This study reports the frequency of HPV testing in patients with oropharyngeal cancer across the population. The clinical importance of HPV was first recognized about 10 years ago.[31] In 2009, 14% of OPC cases in our dataset had known HPV status. Of the cases with known status, 35% were HPV-positive. The only other population-based estimate for the frequency of HPV testing was reported by Polednak and Phillips,[32] who reported known HPV status in 46% of Connecticut registry patients in 2010 rising to 66% in 2012. As understanding of the prognostic value of HPV becomes more widespread, we would expect more cases to be tested. Our calculated proportion, measured relatively early in the HPV era, should serve as a comparison for future studies.
Despite adjustment for a number of sociodemographic and clinical factors, including Charlson score, a limitation of this study is the unavailability of factors that may be key to the clinical decision-making process, such as functional status, treatment options offered to patients, and patient preferences, potentially leading to residual confounding. However, a strength of the study is that the use of SEER POC data represents diverse geographical regions of the US population. Furthermore, detailed information about cancer treatment and other variables that would otherwise not be available allows for increased classification of treatment and the control of potential confounders. Another advantage of this study is the use of AJCC staging, which is more clinically relevant than SEER-coded stage and provides the ability to delineate between stage IVA, IVB and IVC.
Given the absence of high level evidence to inform decisions about initial treatment of OPC cancer, this analysis provides useful information about how decisions are made across the population. Future research should analyze the impact of treatment on cancer outcomes such as quality of life and incorporate newer treatment modalities as they are developed and incorporated into clinical practice.
Acknowledgments
Bobbi J. Matt, RHIT-CTR and Donna M. Gress, RHIT-CTR, for assistance with data analysis.
Support: This work was supported in part under NIH/NCI contract number HHSN261201300020I/HHSN26100006 with University of Iowa (MEC, JAS, CC). This work was also supported by the University of Iowa Holden Comprehensive Cancer Center, which is funded in part by NIH/NCI P30 CA086862.
References
- 1.Bagnardi V, Blangiardo M, La Vecchia C, Corrao G. Alcohol consumption and the risk of cancer: a meta-analysis. Alcohol Res Health. 2001;25:263–270. [PMC free article] [PubMed] [Google Scholar]
- 2.Lewin F, Norell SE, Johansson H, Gustavsson P, Wennerberg J, Biorklund A, Rutqvist LE. Smoking tobacco, oral snuff, and alcohol in the etiology of squamous cell carcinoma of the head and neck: a population-based case-referent study in Sweden. Cancer. 1998;82:1367–1375. doi: 10.1002/(sici)1097-0142(19980401)82:7<1367::aid-cncr21>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
- 3.Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, Jiang B, Goodman MT, Sibug-Saber M, Cozen W, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294–4301. doi: 10.1200/JCO.2011.36.4596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ryerson AB, Peters ES, Coughlin SS, Chen VW, Gillison ML, Reichman ME, Wu X, Chaturvedi AK, Kawaoka K. Burden of potentially human papillomavirus-associated cancers of the oropharynx and oral cavity in the US, 1998-2003. Cancer. 2008;113:2901–2909. doi: 10.1002/cncr.23745. [DOI] [PubMed] [Google Scholar]
- 5.Weber RS, Gidley P, Morrison WH, Peters LJ, Hankins P, Wolf P, Guillamondegui O. Treatment selection for carcinoma of the base of the tongue. Am J Surg. 1990;160:415–419. doi: 10.1016/s0002-9610(05)80556-2. [DOI] [PubMed] [Google Scholar]
- 6.Allal AS, Nicoucar K, Mach N, Dulguerov P. Quality of life in patients with oropharynx carcinomas: Assessment after accelerated radiotherapy with or without chemotherapy versus radical surgery and postoperative radiotherapy. Head and Neck-Journal for the Sciences and Specialties of the Head and Neck. 2003;25:833–839. doi: 10.1002/hed.10302. [DOI] [PubMed] [Google Scholar]
- 7.Zhen WN, Karnell LH, Hoffman HT, Funk GF, Buatti JM, Menck HR. The national cancer data base report on squamous cell carcinoma of the base of tongue. Head and Neck-Journal for the Sciences and Specialties of the Head and Neck. 2004;26:660–674. doi: 10.1002/hed.20064. [DOI] [PubMed] [Google Scholar]
- 8.Chera BS, Amdur RJ, Hinerman RW, Morris CG, Villaret DB, Werning JW, Mendenhall WM. Definitive radiation therapy for squamous cell carcinoma of the soft palate. Head and Neck-Journal for the Sciences and Specialties of the Head and Neck. 2008;30:1114–1119. doi: 10.1002/hed.20848. [DOI] [PubMed] [Google Scholar]
- 9.Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, Bergerot P, Rhein B, Tortochaux J, Calais G. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. Journal of Clinical Oncology. 2004;22:69–76. doi: 10.1200/JCO.2004.08.021. [DOI] [PubMed] [Google Scholar]
- 10.Pederson AW, Haraf DJ, Witt ME, Stenson KM, Vokes EE, Blair EA, Salama JK. Chemoradiotherapy for locoregionally advanced squamous cell carcinoma of the base of tongue. Head Neck. 2010;32:1519–1527. doi: 10.1002/hed.21360. [DOI] [PubMed] [Google Scholar]
- 11.Eisbruch A, Harris J, Garden AS, Chao CK, Straube W, Harari PM, Sanguineti G, Jones CU, Bosch WR, Ang KK. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22) Int J Radiat Oncol Biol Phys. 2010;76:1333–1338. doi: 10.1016/j.ijrobp.2009.04.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Liederbach E, Lewis CM, Yao K, Brockstein BE, Wang CH, Lutfi W, Bhayani MK. A Contemporary Analysis of Surgical Trends in the Treatment of Squamous Cell Carcinoma of the Oropharynx from 1998 to 2012: A Report from the National Cancer Database. Ann Surg Oncol. 2015;22:4422–4431. doi: 10.1245/s10434-015-4560-x. [DOI] [PubMed] [Google Scholar]
- 13.Warren JL, Klabunde CN, Schrag D, Bach PB, Riley GF. Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population. Med Care. 2002;40:IV, 3–18. doi: 10.1097/01.MLR.0000020942.47004.03. [DOI] [PubMed] [Google Scholar]
- 14.Greene FL, American Joint Committee on Cancer., American Cancer Society . AJCC cancer staging manual. 6th. New York: Springer-Verlag; 2002. [Google Scholar]
- 15.Bursac Z, Gauss CH, Williams DK, Hosmer DW. Purposeful selection of variables in logistic regression. Source Code Biol Med. 2008;3:17. doi: 10.1186/1751-0473-3-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–383. doi: 10.1016/0021-9681(87)90171-8. [DOI] [PubMed] [Google Scholar]
- 17.Singh B, Bhaya M, Stern J, Roland JT, Zimbler M, Rosenfeld RM, Har-El G, Lucente FE. Validation of the Charlson comorbidity index in patients with head and neck cancer: a multi-institutional study. Laryngoscope. 1997;107:1469–1475. doi: 10.1097/00005537-199711000-00009. [DOI] [PubMed] [Google Scholar]
- 18.Brizel DM, Albers ME, Fisher SR, Scher RL, Richtsmeier WJ, Hars V, George SL, Huang AT, Prosnitz LR. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. New England Journal of Medicine. 1998;338:1798–1804. doi: 10.1056/NEJM199806183382503. [DOI] [PubMed] [Google Scholar]
- 19.Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, Rhein B, Tortochaux J, Oudinot P, Bertrand P. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. Journal of the National Cancer Institute. 1999;91:2081–2086. doi: 10.1093/jnci/91.24.2081. [DOI] [PubMed] [Google Scholar]
- 20.Wendt TG, Grabenbauer GG, Rodel CM, Thiel HJ, Aydin H, Rohloff R, Wustrow TPU, Iro H, Popella C, Schalhorn A. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter study. Journal of Clinical Oncology. 1998;16:1318–1324. doi: 10.1200/JCO.1998.16.4.1318. [DOI] [PubMed] [Google Scholar]
- 21.Adelstein DJ, Li Y, Adams GL, Wagner H, Jr, Kish JA, Ensley JF, Schuller DE, Forastiere AA. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21:92–98. doi: 10.1200/JCO.2003.01.008. [DOI] [PubMed] [Google Scholar]
- 22.Forastiere AA, Trotti A. Radiotherapy and concurrent chemotherapy: a strategy that improves locoregional control and survival in oropharyngeal cancer. Journal of the National Cancer Institute. 1999;91:2065–2066. doi: 10.1093/jnci/91.24.2065. [DOI] [PubMed] [Google Scholar]
- 23.Goldenberg D, Mackley H, Koch W, Bann DV, Schaefer EW, Hollenbeak CS. Age and stage as determinants of treatment for oral cavity and oropharyngeal cancers in the elderly. Oral Oncology. 2014;50:976–982. doi: 10.1016/j.oraloncology.2014.07.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Chen AY, Schrag N, Hao YP, Stewart A, Ward E. Changes in treatment of advanced oropharyngeal cancer, 1985-2001. Laryngoscope. 2007;117:16–21. doi: 10.1097/01.mlg.0000240182.61922.31. [DOI] [PubMed] [Google Scholar]
- 25.VanderWalde NA, Meyer AM, Liu H, Tyree SD, Zullig LL, Carpenter WR, Shores CD, Weissler MC, Hayes DN, Fleming M, Chera BS. Patterns of care in older patients with squamous cell carcinoma of the head and neck: a surveillance, epidemiology, and end results-medicare analysis. J Geriatr Oncol. 2013;4:262–270. doi: 10.1016/j.jgo.2013.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Borggreven PA, Kuik DJ, Langendijk JA, Doornaert P, de Bree R, Leemans CR. Severe comorbidity negatively influences prognosis in patients with oral and oropharyngeal cancer after surgical treatment with microvascular reconstruction. Oral Oncol. 2005;41:358–364. doi: 10.1016/j.oraloncology.2004.08.012. [DOI] [PubMed] [Google Scholar]
- 27.de Cassia Braga Ribeiro K, Kowalski LP, Latorre Mdo R. Perioperative complications, comorbidities, and survival in oral or oropharyngeal cancer. Arch Otolaryngol Head Neck Surg. 2003;129:219–228. doi: 10.1001/archotol.129.2.219. [DOI] [PubMed] [Google Scholar]
- 28.Steiner W, Fierek O, Ambrosch P, Hommerich CP, Kron M. Transoral laser microsurgery for squamous cell carcinoma of the base of the tongue. Arch Otolaryngol Head Neck Surg. 2003;129:36–43. doi: 10.1001/archotol.129.1.36. [DOI] [PubMed] [Google Scholar]
- 29.Zenga J, Wilson M, Adkins DR, Gay HA, Haughey BH, Kallogjeri D, Michel LS, Paniello RC, Rich JT, Thorstad WL, Nussenbaum B. Treatment Outcomes for T4 Oropharyngeal Squamous Cell Carcinoma. Jama Otolaryngology-Head & Neck Surgery. 2015;141:1118–1127. doi: 10.1001/jamaoto.2015.0764. [DOI] [PubMed] [Google Scholar]
- 30.Zevallos JP, Mitra N, Swisher-McClure S. Patterns of care and perioperative outcomes in transoral endoscopic surgery for oropharyngeal squamous cell carcinoma. Head and Neck-Journal for the Sciences and Specialties of the Head and Neck. 2016;38:402–409. doi: 10.1002/hed.23909. [DOI] [PubMed] [Google Scholar]
- 31.D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, Westra WH, Gillison ML. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944–1956. doi: 10.1056/NEJMoa065497. [DOI] [PubMed] [Google Scholar]
- 32.Polednak AP, Phillips C. Surveillance of the frequency and results of testing of incident oropharyngeal cancers for human papillomavirus: the potential role of population-based cancer registries. J Registry Manag. 2014;41:113–119. [PubMed] [Google Scholar]