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Abstract

Importance

The necessity of adjuvant radiotherapy in patients with pT1-2N1-2b oropharyngeal squamous cell carcinoma (OPSCC) remains unclear.

Objective

To examine the prognostic role of adjuvant radiotherapy in patients with either p16-positive or p16-negative pT1-2N1-2b OPSCC.

Design

Retrospective study.

Setting

Surveillance, Epidemiology, and End Results database.

Participants

Patients diagnosed between 2010 and 2015 with either p16-positive or p16-negative T1-2N1-2bM0 OPSCC who received primary surgery with neck dissection with or without adjuvant radiotherapy were screened for inclusion.

Intervention

Primary surgery with neck dissection with or without adjuvant radiotherapy.

Main Outcomes and Measures

Overall survival (OS) and disease-specific survival (DSS) were main outcomes. The overlap propensity score weighting method was applied to account for known confounding. Cox regression analysis and weighted cox regression analysis were used to calculate the hazard ratio (HR) and 95% confidence interval (CI).

Results

A total of 247 patients with p16-negative OPSCC (median follow-up duration: 39 months; 3-year OS: 84.9%; 3-year DSS: 89.5%) and 1175 patients with p16-positive OPSCC (median follow-up duration: 35 months; 3-year OS: 95.3%; 3-year DSS: 96.7%) were included. Adjuvant radiotherapy was associated with improved OS [weighted HR (95% CI): 0.37 (0.17-0.79)] and DSS [weighted HR (95% CI): 0.34 (0.13-0.88)] in pT1-2N1-2b p16-negative OPSCC. No prognostic role of adjuvant radiotherapy was observed in pN1 subgroup of p16-negative OPSCC [weighted HR (95% CI) for OS: 0.89 (0.20-4.06); weighted HR (95% CI) for DSS: 1.12 (0.19-6.71)]. Adjuvant radiotherapy was associated with improved OS [weighted HR (95% CI): 0.34 (0.18-0.62)] and DSS [weighted HR (95% CI): 0.30 (0.14-0.64)] in pT1-2N1-2b p16-positive OPSCC. Subgroup analyses of p16-positive OPSCC, including pN1, pN2a-2b, and positive lymph nodes ≤4 subgroups, supported that adjuvant radiotherapy had positive prognostic role.

Conclusions and Relevance

Consistent with the National Comprehensive Cancer Network guidelines, patients with pT1-2N2a-2b OPSCC should receive adjuvant radiotherapy (regardless of p16 status), while patients with pT1-2N1 p16-negative OPSCC could consider omitting adjuvant radiotherapy. Patients with pT1-2N1 p16-positive OPSCC may benefit from adjuvant radiotherapy.

Graphical Abstract

Keywords

oropharyngeal squamous cell carcinoma adjuvant radiotherapy p16 overall survival disease-specific survival propensity score weighting

Key Messages

Adjuvant RT improves survival in pT1-2N2a-2b (AJCC 7th edition) OPSCC.

Adjuvant RT improves survival in pT1-2N1 (AJCC 7th edition) p16-positive OPSCC.

Adjuvant RT fails to improve survival in pT1-2N1 (AJCC 7th edition) p16-negative OPSCC.

Introduction

The incidence of human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma (OPSCC) has been constantly increasing during recent decades.¹ Compared with HPV-unrelated OSPCC, HPV-mediated OPSCC has a much better prognosis irrespective of treatment modality.^2,3 Overexpression of the protein p16 is an excellent surrogate biomarker for HPV causation in OPSCC.⁴ Due to the relative ease of application, p16 immunohistochemistry was chosen as the preferred assay for the 8th edition of the American Joint Committee on Cancer (AJCC) staging. The AJCC 8th edition staging system took into account the prognostic differences between p16-positive and p16-negative OPSCC, and separate staging criteria were published.⁵ Although the AJCC 8th edition N classification for p16-positive OPSCC has changed significantly from the 7th edition, the treatment recommendations for p16-positive OPSCC are very similar to those for p16-negative OPSCC in the National Comprehensive Cancer Network (NCCN) guidelines version 4.2025, because the treatment algorithms for OPSCC in the NCCN guidelines are still largely based on data from trials that included OPSCC staged according to the AJCC 7th edition staging system.⁶ Validation of clinical decision-making for p16-positive OPSCC based on the AJCC 8th edition staging system is necessary.

Risk-adapted adjuvant radiotherapy (RT) based on adverse pathological features is an important component of treatment for patients with OPSCC who undergo upfront surgery.⁷ However, the indications for adjuvant RT are still being debated, particularly in the context of p16-positive OPSCC.⁶ According to the NCCN guidelines, patients with p16-positive T1-2 OPSCC and a single ipsilateral positive regional lymph node ≤3 cm without other adverse pathological features could omit adjuvant RT, while patients with p16-negative T1-2 OPSCC and a single ipsilateral positive regional lymph node ≤3 cm without other adverse pathological features should consider adjuvant RT.⁶ However, the evidence in support of the above recommendations is weak.⁶ Here in this study, we aimed to evaluate the prognostic values of adjuvant RT in patients with pT1-2N1-2b (AJCC 7th edition) OPSCC.

Materials and Methods

Patients

Patients included in this study were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (SEER*Stat, version 8.3.9). OPSCC cases were identified using the International Classification of Disease of Oncology, 3rd edition (ICD-O-3) primary site codes, including C01.9, C02.4, C05.1, C05.2, C09.0, C09.1, C09.8, C09.9, C10.0, C10.2, C10.3, C10.4, C10.8, and C10.9, and the ICD-O-3 histology codes ranging from 8050 to 8089, which define squamous cell neoplasms. Patients diagnosed between 2010 and 2015 with T1-2N1-2bM0 disease (according to the AJCC 7th edition staging system) were included in our study. The exclusion criteria were as follows: (1) patients with prior cancer history; (2) patients with unknown p16 status; (3) patients without primary surgery; (4) patients without neck dissection; (5) radiation was not adjuvant; (6) patients with unknown cause of death. This study was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-sen University (No. 2023-068).

Covariates and Outcomes

Demographic and clinicopathological data, including sex, age, race, year of diagnosis, insurance status, marital status, tumor subsite, pathology grade, p16 status, and tumor, node, metastasis (TNM) stage (AJCC 7th edition), were extracted from the SEER database. The outcomes of this study were overall survival (OS) and disease-specific survival (DSS). A survival time of 0 months was recorded as 0.5 months to include patients who died within 1 month of diagnosis.

Statistical Analyses

All the analyses were conducted in the p16-negative cohort and the p16-positive cohort separately. Demographic and clinicopathological characteristics were compared between the 2 treatment groups using Pearson’s χ² or Fisher’s exact tests. To account for the potential confounding, a propensity score (PS) for receiving adjuvant RT was estimated from a multivariable logistic regression model including patient age, sex, race, year of diagnosis, insurance status, marital status, and tumor subsite, pathology grade, T classification, and N classification. The overlap propensity score weighting method was then applied, in which each patient’s weight is the probability of that patient being assigned to the opposite treatment group.⁸ Specifically, patients who received adjuvant RT were assigned with a weight of 1–PS, and patients who did not receive adjuvant RT were assigned with a weight of PS. Overlap weighting is a propensity score method that attempts to mimic important attributes of randomized clinical trials.⁹ Overlap weighting can reduce bias, improve estimation efficiency, and handle cases with extreme propensity scores better than some other propensity score methods like inverse probability of treatment weighting.⁸ The covariate balance was checked using the absolute standardized difference (ASD), and an ASD ≤ 0.1 indicates good balance.¹⁰ Actuarial survival rates were estimated using the Kaplan-Meier method. Cox regression analysis and weighted cox regression analysis were used to calculate the hazard ratio (HR) and 95% confidence interval (CI). Subgroup analyses were conducted in patients with pN1 disease and those with pN2a-2b disease. For the p16-positive cohort, subgroup analyses were further performed in patients with ≤4 positive lymph nodes and those with >4 positive lymph nodes. Statistical analyses were conducted using Stata 16 (StataCorp LLC, College Station, TX) and R version 4.3.1 (R Core Team) with the package PSweight. A 2-sided P-value ≤ .05 was considered statistically significant.

Results

Characteristics of Patients

A total of 1422 patients were included (Figure 1). The p16-negative cohort comprised 247 patients, with a median age of 58 years (interquartile range, 52-65) and a proportion of 78.5% male patients. In this cohort, 206 (83.4%) patients received adjuvant RT and 41 (16.6%) patients did not. The p16-positive cohort comprised 1175 patients, with a median age of 57 years (interquartile range, 52-63) and a proportion of 86.4% male patients. In this cohort, 1002 (85.3%) patients received adjuvant RT and 173 (14.7%) patients did not. Tonsil was the most common subsite of OPSCC in both cohorts. The N classification significantly influenced the decision to receive adjuvant RT in both cohorts (Table 1).

Figure 1.

Flow diagram of selection of included patients. HPV, Human papillomavirus; OPSCC, Oropharyngeal squamous cell carcinoma; RT, Radiotherapy.

Table 1.

Characteristics of OPSCC Patients.

Characteristics	p16-negative cohort			p16-positive cohort
Characteristics	No RT	RT	P-value	No RT	RT	P-value
Total	41 (16.6)	206 (83.4)		173 (14.7)	1002 (85.3)
Age, year			.692			.074
≤50	8 (19.5)	37 (18.0)		34 (19.7)	211 (21.1)
<65	20 (48.8)	115 (55.8)		95 (54.9)	610 (60.9)
≥ 65	13 (31.7)	54 (26.2)		44 (25.4)	181 (18.1)
Sex			.080			.894
Male	28 (68.3)	166 (80.6)		150 (86.7)	865 (86.3)
Female	13 (31.7)	40 (19.4)		23 (13.3)	137 (13.7)
Race			.413			.436
White	25 (85.4)	185 (89.8)		159 (91.9)	937 (93.5)
Others/Unknown	6 (14.6)	21 (10.2)		14 (8.1)	65 (6.5)
Year of diagnosis			.509			.604
2010-2012	19 (46.3)	84 (40.8)		53 (30.6)	327 (32.6)
2013-2015	22 (53.7)	122 (59.2)		120 (69.4)	675 (67.4)
Insurance status			.171			.520
Insured	32 (78.0)	178 (86.4)		155 (89.6)	913 (91.1)
Others/Unknown	9 (22.0)	28 (13.6)		18 (10.4)	89 (8.9)
Marital status			.658			.066
Married	26 (63.4)	123 (59.7)		106 (61.3)	685 (68.4)
Unmarried/ Unknown	15 (36.6)	83 (40.3)		67 (38.7)	317 (31.6)
Tumor subsite			.513			.402
Tonsil	24 (58.5)	135 (65.5)		119 (68.8)	717 (71.6)
Base of tongue	12 (29.3)	56 (27.2)		50 (28.9)	249 (24.9)
Others	5 (12.2)	15 (7.3)		4 (2.3)	36 (3.6)
Pathology grade			.416			.720
1-2	17 (41.5)	84 (40.8)		58 (33.5)	337 (33.6)
3-4	22 (53.7)	98 (47.6)		83 (53.8)	558 (55.7)
Unknown	2 (4.9)	24 (11.7)		22 (12.7)	107 (10.7)
T classification			.089			.061
T1	28 (68.3)	111 (53.9)		107 (61.8)	543 (54.2)
T2	13 (31.7)	95 (46.1)		66 (38.2)	459 (45.8)
N classification			.043			<.001
N1	20 (48.8)	62 (30.1)		83 (48.0)	218 (21.8)
N2a	9 (22.0)	45 (21.8)		45 (26.0)	298 (29.7)
N2b	12 (29.3)	99 (48.1)		45 (26.0)	486 (48.5)

Data are presented as number (%).

P-values are calculated by Pearson’s χ² test or Fisher’s exact test as appropriate.

Abbreviations: OPSCC, Oropharyngeal squamous cell carcinoma; RT, Radiotherapy.

Survival Outcomes in the p16-Negative Cohort

The median follow-up duration was 39 months (interquartile range, 24-59). There were 38 deaths from any cause, 24 of which were due to OPSCC. The 3-year OS was 84.9%, and the 3-year DSS was 89.5%. In the original cohort, adjuvant RT was associated with improved OS (HR, 0.36; 95% CI, 0.18-0.71) and DSS (HR, 0.33; 95% CI, 0.14-0.76) (Figure 2A-B). After propensity score weighting, the covariates were well balanced between the 2 groups (Supplemental Figure S1), and adjuvant RT continued to be a positive prognostic factor for both OS (weighted HR, 0.37; 95% CI, 0.17-0.79) and DSS (weighted HR, 0.34; 95% CI, 0.13-0.88) (Figure 2C-D). In the pN1 subgroup, adjuvant RT was not a significant prognostic factor (Figure 3). In the pN2a-2b subgroup, adjuvant RT was associated with improved OS (weighted HR, 0.25; 95% CI, 0.11-0.60) and DSS (weighted HR, 0.17; 95% CI, 0.06-0.52) (Figure 3).

Figure 2.

Survival curves for the p16-negative cohort. (A) overall survival for original cohort; (B) disease-specific survival for original cohort; (C) overall survival for weighted cohort; (D) disease-specific survival for weighted cohort.

Figure 3.

Forest plots showing prognostic values of adjuvant radiotherapy in the p16-negative subgroups. CI, Confidence interval; DSS, Disease-specific survival; HR, Hazard ratio; OS, Overall survival; RT, Radiotherapy.

Survival Outcomes in the p16-Positive Cohort

The median follow-up duration was 35 months (interquartile range, 21-52). There were 57 deaths from any cause, 37 of which were due to cancer. The 3-year OS was 95.3%, and the 3-year DSS was 96.7%. In the original cohort, adjuvant RT was associated with improved OS (HR, 0.34; 95% CI, 0.19-0.59) and DSS (HR, 0.32; 95% CI, 0.16-0.64) (Figure 4A-B). After propensity score weighting, the covariates were well balanced between the 2 groups (Supplemental Figure S2), and adjuvant RT continued to be a positive prognostic factor for both OS (weighted HR, 0.34; 95% CI, 0.18-0.62) and DSS (weighted HR, 0.30; 95% CI, 0.14-0.64) (Figure 4C-D). In the pN1 subgroup, adjuvant RT was associated with improved OS (weighted HR, 0.36; 95% CI, 0.13-0.97) and DSS (weighted HR, 0.21; 95% CI, 0.06-0.77) (Figure 5). In the pN2a-2b subgroup, adjuvant RT was associated with improved OS (weighted HR, 0.34; 95% CI, 0.16-0.72) and DSS (weighted HR, 0.39; 95% CI, 0.14-1.03), although the statistical significance was not achieved for the DSS (Figure 5). According to the AJCC 8th edition staging system, pN1 is defined as positive lymph nodes ≤ 4. In the subgroup of positive lymph nodes ≤ 4, adjuvant RT was associated with improved OS (weighted HR, 0.32; 95% CI, 0.17-0.62) and DSS (weighted HR, 0.28; 95% CI, 0.12-0.66) (Figure 5). The analysis for subgroup of positive lymph nodes >4 was not conducted due to the limited sample size (9 patients did not receive adjuvant RT and no events).

Figure 4.

Survival curves for the p16-positive cohort. (A) overall survival for original cohort; (B) disease-specific survival for original cohort; (C) overall survival for weighted cohort; (D) disease-specific survival for weighted cohort.

Figure 5.

Forest plots showing prognostic values of adjuvant radiotherapy in the p16-positive subgroups. CI, Confidence interval; DSS, Disease-specific survival; HR, Hazard ratio; OS, Overall survival; RT, Radiotherapy.

Discussion

In patients with locally-advanced head and neck cancer, adjuvant radiotherapy with or without concomitant chemotherapy is usually adopted to reduce the risk of locoregional relapse.^11
-15 According to the NCCN guidelines, the indications for adjuvant RT for OPSCC patients are based on the presence of adverse pathological features that are associated with locoregional relapse, including extranodal extension, positive or close margins, pT3 or pT4 primary, positive nodal disease, nodal disease in level IV or V, perineural invasion, vascular invasion, and lymphatic invasion.⁶ Among these adverse features, pN1 (single lymph node ≤ 3 cm) is still an unclear indication for adjuvant RT, even when it comes to other head and neck cancers.¹⁶ Two retrospective studies reported that adjuvant RT did not improve survival of patients with pN1 head and neck cancer.^17,18 Another prospective multicentric cohort study found that adjuvant RT in patients with early squamous cell carcinoma of the oral cavity and oropharynx (pT1-2N1, AJCC 7th edition) did not influence OS, but it improved progression-free survival.¹⁹ In our study, we also found that adjuvant RT did not improve the OS or DSS of patients with pT1-2N1 p16-negative OPSCC. However, the adjuvant RT did improve the OS and DSS of patients with pT1-2N2a-2b p16-negative OPSCC. The above findings are consistent with the recommendations of the NCCN guidelines, although evidence from prospective clinical trials is needed. With regard to p16-positive OPSCC, our findings partially contradict the NCCN guidelines. We found that patients with a single ipsilateral positive regional lymph node ≤ 3 cm (pN1 according to the AJCC 7th edition) could benefit from adjuvant RT in terms of OS and DSS, although the NCCN guidelines do not define pN1 (AJCC 7th edition) as an indication for adjuvant RT in p16-positive OPSCC. In addition, for patients with N1-2b disease (equals to cN1 according to the AJCC 8th edition) and patients with positive lymph nodes ≤ 4 (equals to pN1 according to the AJCC 8th edition), the adjuvant RT was also associated with improved OS and DSS.

Considering the good prognosis of p16-positive OPSCC, treatment de-escalation is now an active research area, which aims to preserve superior oncologic outcomes while minimizing toxicity.^20
-22 There are a number of studies investigating the role of definitive surgery with de-escalation of adjuvant RT in p16-positive OPSCC. The MC1273 trial (a single-arm phase II trial) explored an aggressive course of de-escalated adjuvant RT (dose de-escalation from 60 to 66 Gy to 30 to 36 Gy) after curative-intent surgery for p16-positive OPSCC patients with either a pathologic high-risk factor (extranodal extension) or 1 or more intermediate-risk factors (lymphovascular invasion, perineural invasion, involvement of ≥ 2 regional lymph nodes, any lymph node >3 cm in size, or ≥ T3 primary tumor).²³ A total of 80 patients were recruited in MC1273 trial, with a 2-year locoregional tumor control rate of 96.2%, which was comparable to historical control. The AVOID trial (a single-arm phase II trial) explored the feasibility of omission of adjuvant RT to the primary tumor bed after transoral robotic surgery for pT1-2N2a-3 (AJCC 7th edition) p16-positive OPSCC without adverse features on primary tumor pathology.²⁴ Of the 60 patients recruited in the AVOID trial, 1 patient developed a local tumor recurrence at the base of tongue 20 months after the completion of RT, yielding a 2-year local control rate of 98.3%. The E3311 trial defined pN1 (AJCC 7th edition) as a low-risk factor, and patients with T1-2 disease with negative margins >3 mm and N0-1 without extranodal extension were given no adjuvant RT in the E3311 trial, resulting in a 2-year progression-free survival rate of 96.9%.²⁵ Until now, no randomized clinical trial has investigated the role of adjuvant RT in low-risk (pT1-2N1 without other adverse pathological features) p16-positive OPSCC patients. Although lacking solid evidence, there seems to be a consensus that patients with low-risk p16-positive OPSCC could omit adjuvant RT, given that these patients have a much better prognosis.²⁵ Compared with p16-negative OPSCC, p16-positive OPSCC is more prone to respond to RT.²⁶ This may explain discrepancy in our results regarding the role of adjuvant RT in pN1 p16-negative and p16-positive OPSCC. For p16-positive OPSCC, radiosensitivity does not necessarily imply that the disease is more indolent. We found that patients with p16-positive OPSCC could still benefit from adjuvant RT, even though the 3-year OS rate for these patients was more than 90%. The favorable prognosis of p16-positive OPSCC can be partially attributed to the good responses to treatment. Without treatment of an appropriate intensity, the favorable prognosis conferred by HPV may be compromised. However, patients with pT1-2N1 p16-negative OPSCC could not benefit from adjuvant RT, although these patients had a worse prognosis. Our findings indicated that the use of p16 status to guide the treatment tailoring should be cautious. Without solid evidences from randomized clinical trials, the de-escalation treatment for p16-positive OPSCC should be critically used in clinical practice.

When interpreting the results of this study, some unmeasured covariates should be noted. The consumption of tobacco and alcohol, the performance status of the patient, and the presence of comorbidities are significant prognostic factors that also inform clinicians’ decisions regarding the administration of adjuvant RT. Although the pathological grade was included in the propensity score calculation, other adverse pathological features including surgical margin, extranodal extension, perineural invasion, and lymphovascular invasion were not included. Patients with heavy smoking history or more adverse pathological features were more likely to receive adjuvant RT, which may negatively influence the OS and DSS of these patients. This kind of confounding may explain the results of the pN1 subgroup analyses in p16-negative OPSCC. With regard to the results of the analyses in p16-positive OPSCC and the pN2a-2b subgroup analyses in p16-negative OPSCC, the benefit of adjuvant RT should still be tenable even after accounting for the confounding effects. Another non-negligible confounding was caused by the fact that patients in poorer health were less likely to receive adjuvant RT, which may contribute to the poorer survival of patients who did not receive adjuvant RT. However, the DSS, which is less likely to be influenced by patients’ health status, was improved as was the OS, suggesting that adjuvant RT could reduce the risk of death from cancer.

The study was limited by its retrospective nature with unavoidable selection bias and confounding, such as the unmeasured surgical margin status, smoking history, and comorbidities. Furthermore, the occurrence of coding errors in SEER databases is inevitable, which may introduce bias into the results. In the future, prospective randomized clinical trials should be conducted to validate our findings.

Conclusions

Adjuvant RT was associated with improved OS and DSS in patients with pT1-2N1-2b (AJCC 7th edition) p16-positive OPSCC and pT1-2N2a-2b (AJCC 7th edition) p16-negative OPSCC without other adverse pathological features, suggesting that omitting adjuvant RT should not be adopted in clinical practice for these patients. Patients with pT1-2N1 (AJCC 7th edition) p16-negative OPSCC without other adverse pathological features may not benefit from adjuvant RT, suggesting that omitting adjuvant RT should be considered in clinical practice for these patients. In the future, carefully-designed prospective clinical trials are needed to confirm our findings.

Supplemental Material

sj-tif-1-ohn-10.1177_19160216251406522 – Supplemental material for Prognostic Role of Adjuvant Radiotherapy in Patients With pT1-2N1-2b Oropharyngeal Squamous Cell Carcinoma

Supplemental material, sj-tif-1-ohn-10.1177_19160216251406522 for Prognostic Role of Adjuvant Radiotherapy in Patients With pT1-2N1-2b Oropharyngeal Squamous Cell Carcinoma by Liang Peng, Lin Chen, Zhang-Feng Wang, Xiao-Lin Zhu, Wei Sun, Wei-Ping Wen and Wen-Bin Lei in Journal of Otolaryngology - Head & Neck Surgery

Supplemental Material

sj-tif-2-ohn-10.1177_19160216251406522 – Supplemental material for Prognostic Role of Adjuvant Radiotherapy in Patients With pT1-2N1-2b Oropharyngeal Squamous Cell Carcinoma

Supplemental material, sj-tif-2-ohn-10.1177_19160216251406522 for Prognostic Role of Adjuvant Radiotherapy in Patients With pT1-2N1-2b Oropharyngeal Squamous Cell Carcinoma by Liang Peng, Lin Chen, Zhang-Feng Wang, Xiao-Lin Zhu, Wei Sun, Wei-Ping Wen and Wen-Bin Lei in Journal of Otolaryngology - Head & Neck Surgery

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National Natural Science Foundation of China (NSFC) grants no. 82303323, no. 82273053, and no. 81972528, Guangzhou Science and Technology Project of China grant no. 2024A04J4568, Basic and Applied Research Foundation of Guangdong Province grant no. 2022B1515130009, 5010 Clinical Research Program of Sun Yat-sen University grant no. 2017004.

Ethical Approval and Informed Consent Statements

This study was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-sen University. As this was a retrospective analysis of publicly-available data, written consent was not required.

ORCID iD

Liang Peng

Data Availability Statement

The raw data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (SEER*Stat, version 8.3.9).

Supplemental Material

Supplemental material for this article is available online.

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