Relation Between the Level of Lymph Node Metastasis and Survival in Locally Advanced Head and Neck Squamous Cell Carcinoma

Transcription

1 Original Article Relation Between the Level of Lymph Node Metastasis and Survival in Locally Advanced Head and Neck Squamous Cell Carcinoma Yan Xing, MD, PhD 1 ; Jianjun Zhang, MD, PhD 2,3 ; Heather Lin, PhD 4 ; Kathryn A. Gold, MD 2 ; Erich M. Sturgis, MD 5 ; Adam S. Garden, MD 6 ; J. Jack Lee, PhD, MS, DDS 4 ; and William N. William Jr, MD 2 BACKGROUND: The current head and neck squamous cell carcinoma (HNSCC) staging system may not capture the full prognostic implications of regional lymph node involvement. This study investigated the impact of the level of lymph node metastasis (LNM) on survival. METHODS: The Surveillance, Epidemiology, and End Results registry was queried for oral cavity (OC), oropharynx (OP), larynx (LAR), and hypopharynx (HP) HNSCC. A multivariate Cox proportional hazards model was used to evaluate whether the level of LNM was an independent prognostic factor. Site-specific recursive-partitioning analysis was performed to classify patients into different risk groups. RESULTS: In all, 14,499 patients, including OC (n ), OP (n ), LAR (n ), and HP patients (n ), were analyzed. Both the American Joint Committee on Cancer (AJCC) N classification and the level of LNM showed significant effects on overall survival (OS) in patients with OC, OP, or LAR HNSCC but not in patients with HP HNSCC. In patients with N2 disease, the AJCC subclassification (N2a, N2b, or N2c) was significantly associated with the OS of patients with OP and LAR HNSCC but not with the OS of patients with OC or HP HNSCC, whereas the level of LNM (primary, secondary, or tertiary) was significantly associated with the OS of patients with OC, OP, and LAR HNSCC but not HP HNSCC. With recursive-partitioning analysis, a simple, primary site specific prognostic tool integrating the AJCC T and N classifications and the level of LNM was designed, and it could be easily used by health care providers in clinic. CONCLUSIONS: The level of LNM is an independent prognostic factor for patients with locally advanced HNSCC and could add to the prognostic value of AJCC T and N classifications in patients with locally advanced HNSCC. Cancer 2016;122: VC 2015 American Cancer Society. KEYWORDS: head and neck neoplasms, lymph nodes, metastasis, squamous cell cancer, survival, Surveillance, Epidemiology, and End Results (SEER), TNM. INTRODUCTION More than 50% of head and neck squamous cell carcinoma (HNSCC) patients present with regional lymph node involvement at the time of diagnosis. 1,2 Lymph node metastasis (LNM) is associated with poor survival 2-5 and is one of the most important factors for the determination of the appropriate treatment. 6 Previous studies have shown that patterns of lymph node drainage differ among HNSCC subsites. 7-9 Although many studies have confirmed that the extent of LNM is an important prognostic factor for locally advanced HNSCC, as reflected in the American Joint Committee on Cancer (AJCC) staging system, 10,11 little is known about the impact of the level of LNM on survival for patients with HNSCC. We hypothesized that the level of LNM is an independent prognostic factor in patients with locally advanced HNSCC. To evaluate our hypothesis, we examined the impact of the level of LNM on overall survival (OS) in patients with HNSCC of the oral cavity (OC), oropharynx (OP), larynx (LAR), or hypopharynx (HP) with the Surveillance, Epidemiology, and End Results (SEER) registry. Corresponding author: William N. William, Jr, MD, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0432, Houston, TX 77030; Fax: (713) ; wnwillia@mdanderson.org 1 Department of Medicine, Harvard Medical School/Mount Auburn Hospital, Cambridge, Massachusetts; 2 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 3 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; 4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas; 5 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas; 6 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The first 3 authors contributed equally to this article. Some of the results were presented as a poster at the 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. DOI: /cncr.29780, Received: April 27, 2015; Revised: October 13, 2015; Accepted: October 14, 2015, Published online November 10, 2015 in Wiley Online Library (wileyonlinelibrary.com) 534 Cancer February 15, 2016

2 HNSCC Lymph Node Level and Survival/Xing et al MATERIALS AND METHODS The SEER registry was queried for HNSCC cases diagnosed from 2004 to HNSCC cases from 4 subsites (OC, OP, LAR, and HP) were characterized with respect to age, race, T classification (AJCC), N classification (AJCC), level of LNM, and treatment (surgery and/or radiation therapy). Within our study period, there were 58,734 patients who had a pathologically confirmed diagnosis of HNSCC at these 4 subsites: OC, OP, LAR, and HP. Cases were eligible for further detailed analysis if they fulfilled all of the following criteria: 1) lymph node positive diseases (N1); 2) squamous cell carcinoma histology (histology codes and 8078 from International Classification of Diseases for Oncology, 3rd edition), 3) absence of LNM at levels VI and VII and in facial, parotid, and suboccipital areas; and 4) absence of distant metastases. Cases were excluded if there were missing or unknown data (code 999 or 988) for any of the variables captured by SEER that would not allow the level of LNM to be clearly defined. Data checks were conducted to exclude patients with inconsistent information between the N classification (as captured by SEER with the variable AJCC_N_ stage) and the level of LNM (as captured by SEER with the variables CS_SSF3, CS_SSF4, CS_SSF5, and CS_SSF6). The resultant final study cohort comprised 14,499 cases of locally advanced HNSCC at stages III, IVA, and IVB (AJCC staging, 7th edition), with full characterization of LNM confined to levels I to V. 10 Definition of the for Each Subsite Patterns of lymph node drainage differ among HNSCC subsites. Regional lymphadenopathy was classified as primary, secondary, or tertiary LNM on the basis of the frequencies of nodal involvement within each subsite of HNSCC. In brief, we analyzed previously published independent data sets 8,12,13 and classified LNM as primary, secondary, or tertiary according to the frequencies of lymph node involvement (highest to lowest) at each subsite. We then confirmed that the pattern of nodal spread previously reported held true in our SEER data set (Table 1), and we used these predefined criteria for all subsequent analyses. The consistency of the SEER findings with the previously reported data increased our confidence in the accuracy of the data collected in the SEER registry. As such, level 5 was considered a tertiary level of LNM for all subsites (OC, OP, LAR, and HP). Level 4 was considered a secondary level of LNM for all subsites. Levels 2 and 3 were considered primary levels of LNM for all subsites. Level 1 was considered a primary level of LNM for OC TABLE 1. Level of Lymph Node Metastasis Based on the Frequency of Involvement Drainage Oral Cavity Oropharynx Larynx Hypopharynx Primary 1, 2, 3 (84%) 2, 3 (60%) 2, 3 (57%) 2, 3 (57%) Secondary 4 (10%) 1, 4 (30%) 1, 4 (32%) 1, 4 (30%) Tertiary 5 (6%) 5 (10%) 5 (11%) 5 (13%) and a secondary level of LNM for OP, LAR, and HP. It should be noted that the terms primary, secondary, and tertiary may be an oversimplification of the biology that determines LNM and might be best interpreted as preferential levels of cancer spread rather than a (suboptimal) reflection of anatomic relations. Statistical Analysis The distribution of OS, defined as the time from diagnosis to death or the time of last contact, was estimated with the Kaplan-Meier method. 14 A log-rank test was performed to test the difference in survival between groups. 15 Regression analyses of survival data based on the Cox proportional hazards model were conducted for OS. 16 The proportional hazards assumption for the Cox proportional hazards model was evaluated. No major violations were detected. Regression diagnostics (eg, generalized residuals, Martingale residuals, and Shoenfeld residuals) were examined to ensure that the models were appropriate. All the analyses included only complete cases for all of the variables. The Wald test was used to estimate the 95% confidence intervals (CIs) of hazard ratios. Recursive-partitioning analysis (for censored survival data) was performed with STREE software ( for all 4 subsites separately with the T classification, N classification, and level of LNM. Patients were classified as having a low, (intermediate-low), intermediate, (intermediate-high), or high risk of death accordingly. 17 RESULTS The distribution of eligible cases (n 5 14,499) according to the primary tumor site was as follows: 2463 OC cases, 8567 OP cases, 2332 LAR cases, and 1137 HP cases. The median follow-up times for living patients were 1.75 years for OC cases, 2.17 years for OP cases, 1.92 years for LAR cases, and 1.67 years for HP cases. Survival Impact of the Versus the The effect of the AJCC N classification on survival is illustrated by the Kaplan-Meier curves in Figure 1(A,C,E,G). A separation of the curves between the N1, N2, and N3 subgroups is clearly evident for the LAR subsite (Fig. 1E). Cancer February 15,

3 Original Article OC OC OP A B C D OP 1 ( E / N = 526 / 1125 ) 2 ( E / N = 696 / 1267 ) 3 ( E / N = 40 / 71 ) Primary ( E / N = 1036 / 2057 ) Secondary ( E / N = 140 / 257 ) Tertiary ( E / N = 86 / 149 ) 1 ( E / N = 721 / 2812 ) 2 ( E / N = 1305 / 5289 ) 3 ( E / N = 157 / 466 ) Primary ( E / N = 1160 / 5150 ) Secondary ( E / N = 761 / 2605 ) Tertiary ( E / N = 262 / 812 ) P-value =.001 LAR LAR HP E F G H HP 1 ( E / N = 394 / 909 ) 2 ( E / N = 635 / 1311 ) 3 ( E / N = 60 / 112 ) Primary ( E / N = 564 / 1325 ) Secondary ( E / N = 392 / 748 ) Tertiary ( E / N = 133 / 259 ) 1 ( E / N = 217 / 425 ) 2 ( E / N = 323 / 642 ) 3 ( E / N = 39 / 70 ) Primary ( E / N = 310 / 642 ) Secondary ( E / N = 184 / 344 ) Tertiary ( E / N = 85 / 151 ) P-value=.235 P-value=.17 Figure 1. Kaplan-Meier survival plots and multivariate Cox proportional hazards model for patients with locally advanced HNSCC. Survival plots show overall survival according to (A,C,E,G) the N classification (AJCC staging, 7th edition) or (B,D,F,H) the level of LNM. Hazard ratios, 95% confidence intervals, and P values were computed with a multivariate Cox model. AJCC indicates American Joint Committee on Cancer; E/N, number of events/total number of patients; HP, hypopharynx; LAR, larynx; LNM, lymph node metastasis; OC, oral cavity; OP, oropharynx. However, overlaps between the N2 and N3 curves can be observed for OC (especially after 18 months of follow-up; Fig 1A), and overlaps between the N1 and N2 curves are evident for OP (Fig. 1C) and HP (Fig. 1G). These results indicate that although there is some prognostic effect of the AJCC N classification, this variable alone suboptimally predicts OS for a large portion of HNSCC patients. We then evaluated the effects of the level of LNM on OS for each of the subsites (Fig. 1B,D,F,H). The results demonstrated a clear separation of the curves according to the primary, secondary, and tertiary levels of LNM status at all subsites except HP, and this raises the hypothesis that the level of LNM may be a more accurate predictor of survival than the AJCC N classification and/ or may add to the prognostic value of the already established AJCC N classification. To evaluate whether the level of LNM and the AJCC N classification are independent prognostic factors for our patient population, we performed a multivariate analysis including the aforementioned 2 variables in addition to other known/putative factors that could affect survival (eg, age, sex, race, AJCC T classification, and treatment) for each of the 4 subsites (Table 2). The results demonstrated that both the AJCC N classification and the level of LNM were independent prognostic factors for OC (P and P , respectively), LAR (P <.0001 and P , respectively), and OP HNSCC (P and P <.0001, respectively). Neither the AJCC N classification nor the level of LNM was an independent prognostic factor for HP HNSCC in our multivariate model (P , and P , respectively). The AJCC T classification was associated with survival at all 4 subsites. Because the level of LNM may be more accurately captured for patients who undergo surgical resection as part of their treatment, we performed the same multivariate analysis with only the subset of surgically resected patients. Similarly to the data 536 Cancer February 15, 2016

4 HNSCC Lymph Node Level and Survival/Xing et al TABLE 2. Multivariate Cox Proportional Hazards Model of Overall Survival for Patients With Head and Neck Squamous Cell Carcinoma All Patients Site Demographic Parameter HR 95% CI P OC Age 7 (80 y) vs < 30 y < (70-79 y) vs < 30 y (60-69 y) vs < 30 y (50-59 y) vs < 30 y (40-49 y) vs < 30 y (30-39 y) vs < 30 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T <.0001 T3 vs T T2 vs T AJCC N classification N3 vs N N2 vs N Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no Surgery Yes vs no OP Age 7 (80 y) vs < 40 y < (70-79 y) vs < 40 y (60-69 y) vs < 40 y (50-59 y) vs < 40 y (40-49 y) vs < 40 y Race Asian/Pacific Islander vs Caucasian <.0001 Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T <.0001 T3 vs T T2 vs T AJCC N classification N3 vs N N2 vs N Tertiary vs primary <.0001 Secondary vs primary Radiotherapy Yes vs no Surgery Yes vs no LAR Age 7 (80 y) vs < 40 y < (70-79 y) vs < 40 y (60-69 y) vs < 40 y (50-59 y) vs < 40 y (40-49 y) vs < 40 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T <.0001 T3 vs T T2 vs T AJCC N classification N3 vs N <.0001 N2 vs N Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no Surgery Yes vs no HP Age 7 (80 y) vs < 50 y < (70-79 y) vs < 50 y (60-69 y) vs < 50 y (50-59 y) vs < 50 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T <.0001 T3 vs T T2 vs T Cancer February 15,

5 Original Article TABLE 2. Continued All Patients Site Demographic Parameter HR 95% CI P AJCC N classification N3 vs N N2 vs N1 Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no Surgery Yes vs no Abbreviations: AJCC, American Joint Committee on Cancer; CI, confidence interval; HP, hypopharynx; HR, hazard ratio; LAR, larynx; LNM, lymph node metastasis; OC, oral cavity; OP, oropharynx. for the general population, the level of LNM was an independent prognostic factor for survival for OC (P ), LAR (P ), and OP HNSCC (P <.0001) but not HP HNSCC (P ; Table 3). Survival Impact of the AJCC N Subclassification Versus the in Patients With N2 Disease HNSCC with N2 lymph node involvement represents one of the most diverse groups of patients. In the AJCC staging system, N2 is divided into N2a, N2b, and N2c subclasses on the basis of the number, size, and laterality of the lymph nodes involved. 10 To investigate whether the level of LNM could provide additional prognostic information for this specific group of patients, we contrasted the effects of the AJCC N2 subclassification and the level of LNM on survival within the N2 subgroup only. As illustrated by the Kaplan-Meier curves in Figure 2, a separation of the curves between AJCC N2a, N2b, and N2c subgroups is clearly evident for the OP subsite (Fig. 2C). However, overlaps between the N2a and N2b curves can be observed for the OC (Fig. 2A) and HP subsites (Fig. 2G), and N2b and N2c curves seem to overlap for LAR (Fig. 2E). These results indicate that the AJCC N subclassification does not optimally predict OS for OC, LAR, and HP patients with N2 disease. On the other hand, a separation of the curves between the primary, secondary, and tertiary levels of LNM status was observed for all subsites except HP (Fig. 2B,D,F,H), and this suggests that the level of LNM may be a more accurate predictor of survival than the AJCC N subclassification for HNSCC patients with N2 disease (especially for LAR and OC). In a multivariate analysis for the N2 subgroup (Table 4), the AJCC N2 subclassification was associated with survival for OP (P <.0001) and LAR patients (P 5.012) but not for OC (P 5.48) or HP patients (P 5.07). On the other hand, the association of the level of LNM with OS was statistically significant for OP (P ), OC (P ), and LAR patients (P 5.02) but not for HP patients (P 5.24). These data again suggest that the level of LNM may improve prognostication within the N2 subgroup of patients with HNSCC. Recursive-Partitioning Analysis Site-specific recursive-partitioning analysis was performed to identify prognostic factors with the most significance in a proportional hazards model of OS. The analysis allowed us to classify patients according to risk-of-death categories (low [low-intermediate], intermediate [intermediatehigh], and high) on the basis of the AJCC T classification, AJCC N classification, and level of LNM. This approach provides a guide for integrating these 3 complex variables in a prognostic tool that can be easily used by health care providers. For all 4 sites, T classification was the most important determinant of OS, and it was followed by the level of LNM for the OC (within the T2 subgroup; Fig. 3A), and HP subsites (within the T2/3 subgroup; Fig. 3G). Patients with OC were classified into 3 categories with respect to the risk of death: low risk, with a 3-year OS rate of 55%; intermediate risk, with a 3-year rate of 48.2% (hazard ratio for the comparison with low risk, 1.41; 95% CI, , P 5.001); and high risk, with a 3-year rate of 28.3% (hazard ratio for the comparison with low risk, 2.43; 95% CI, ; P <.001; Fig. 3B). OP cases were classified with the following 5 categories: low risk, with a 3-year OS rate of 84.8%; low-intermediate risk, with a 3-year rate of 76.4% (hazard ratio for the comparison with low risk, 1.51; 95% CI, ; P <.001); intermediate risk, with a 3-year rate of 67.3% (hazard ratio for the comparison with low risk, 2.11; 95% CI, ; P <.001); intermediate-high risk, with a 3-year rate 538 Cancer February 15, 2016

6 TABLE 3. Multivariate Cox Proportional Hazards Model of Overall Survival for Patients With Head and Neck Squamous Cell Carcinoma Treated With Surgery All Patients Site Demographic Parameters HR 95% CI P OC (n ) Age 7 (80 y) vs < 30 y < (70-79 y) vs < 30 y (60-69 y) vs < 30 y (50-59 y) vs < 30 y (40-49 y) vs < 30 y (30-39 y) vs < 30 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T <.0001 T3 vs T T2 vs T AJCC N classification N3 vs N N2 vs N Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no OP (n ) Age 7 (80 y) vs < 40 y < (70-79 y) vs < 40 y (60-69 y) vs < 40 y (50-59 y) vs < 40 y (40-49 y) vs < 40 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T <.0001 T3 vs T T2 vs T AJCC N classification N3 vs N N2 vs N Tertiary vs primary <.0001 Secondary vs primary Radiotherapy Yes vs no LAR (n 5 654) Age 7 (80 y) vs < 40 y (70-79 y) vs < 40 y (60-69 y) vs < 40 y (50-59 y) vs < 40 y (40-49 y) vs < 40 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T T3 vs T T2 vs T AJCC N classification N3 vs N N2 vs N Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no HP (n 5 143) Age 7 (80 y) vs < 50 y (70-79 y) vs < 50 y (60-69 y) vs < 50 y (50-59 y) vs < 50 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T T3 vs T T2 vs T AJCC N classification N3 vs N N2 vs N Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no Abbreviations: AJCC, American Joint Committee on Cancer; CI, confidence interval; HP, hypopharynx; HR, hazard ratio; LAR, larynx; LNM, lymph node metastasis; OC, oral cavity; OP, oropharynx.

7 Original Article A OC-N2 B OC-N2 C OP-N2 D OP-N2 N2a ( E / N = 71 / 129 ) N2b ( E / N = 439 / 845 ) N2c ( E / N = 186 / 293 ) Primary ( E / N = 520 / 960 ) Secondary ( E / N = 109 / 191 ) Tertiary ( E / N = 67 / 116 ) N2a ( E / N = 201 / 1214 ) N2b ( E / N = 608 / 2705 ) N2c ( E / N = 496 / 1370 ) Primary ( E / N = 668 / 3098 ) Secondary ( E / N = 455 / 1600 ) Tertiary ( E / N = 182 / 591 ) P-value =.001 P-value =.029 E F G H LAR-N2 LAR-N2 HP-N2 HP-N2 N2a ( E / N = 72 / 119 ) N2b ( E / N = 248 / 586 ) N2c ( E / N = 315 / 606 ) Primary ( E / N = 308 / 706 ) Secondary ( E / N = 229 / 418 ) Tertiary ( E / N = 98 / 187 ) N2a ( E / N = 60 / 117 ) N2b ( E / N = 166 / 347 ) N2c ( E / N = 97 / 178 ) Primary ( E / N = 157 / 337 ) Secondary ( E / N = 113 / 209 ) Tertiary ( E / N = 53 / 96 ) P-value =.002 P-value =.001 P-value =.052 P-value =.269 Figure 2. Kaplan-Meier survival plots and multivariate Cox proportional hazards model for patients with locally advanced N2 HNSCC. Survival plots show overall survival according to (A,C,E,G) the N classification (AJCC staging, 7th edition) or (B,D,F,H) the level of LNM. Hazard ratios, 95% confidence intervals, and P values were computed with a multivariate Cox model. AJCC indicates American Joint Committee on Cancer; E/N, number of events/total number of patients; HP, hypopharynx; LAR, larynx; LNM, lymph node metastasis; OC, oral cavity; OP, oropharynx. of 58.4% (hazard ratio for the comparison with low risk, 2.82; 95% CI, ; P <.001); and high risk, with a 3-year rate of 47.2% (hazard ratio for the comparison with low risk, 4.1; 95% CI, , P <.001; Fig. 3D). LAR cases were classified into 3 risk groups: low risk, with a 3-year OS rate of 60.7%; intermediate risk, with a 3-year rate of 49.3% (hazard ratio for the comparison with low risk, 1.49; 95% CI, ; P 5.004); and high risk, with a 3-year rate of 36.9% (hazard ratio for the comparison with low risk, 2.43; 95% CI, ; P <.001; Fig. 3F). For HP, the 3-year OS was 59.3% for the low-risk group, 42.8% for the intermediate-risk group (hazard ratio for the comparison with low risk, 1.84; 95% CI, ; P 5.003), and 29.8% for the high-risk group (hazard ratio for the comparison with low risk, 3.09; 95% CI, ; P <.001; Fig. 3H). Notably, the AJCC N classification was not a determinant of OS for HP patients. DISCUSSION In this SEER registry based study, we have demonstrated that the level of LNM is an independent prognostic factor for survival for patients with locally advanced HNSCC (especially for patients with OC, OP, and LAR cancers) and for the subgroup of patients with N2 disease; this suggests that the level of LNM may add to the prognostic value of already established AJCC factors. Using recursive-partitioning analysis, we were able to design a primary site specific prognostic tool integrating the AJCC T classification, the AJCC N classification, and the level of LNM that can be easily used by health care providers. The current AJCC N classification system is mainly based on the number, size, and laterality of involved cervical lymph nodes. However, HNSCC prognostication based on this system may not always capture the full implications of regional lymph node spread for OS. 540 Cancer February 15, 2016

8 HNSCC Lymph Node Level and Survival/Xing et al TABLE 4. Multivariate Cox Proportional Hazards Model of Overall Survival for Patients With N2 Head and Neck Squamous Cell Carcinoma N2-Only Disease Site Demographic Parameters HR 95% CI P OC Age 7 (80 y) vs < 30 y < (70-79 y) vs < 30 y (60-69 y) vs < 30 y (50-59 y) vs < 30 y (40-49 y) vs < 30 y (30-39 y) vs < 30 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T <.0001 T3 vs T T2 vs T AJCC N classification N2c vs N2a N2b vs N2a Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no Surgery Yes vs no OP Age 7 (80 y) vs < 40 y < (70-79 y) vs < 40 y (60-69 y) vs < 40 y (50-59 y) vs < 40 y (40-49 y) vs < 40 y Race Asian/Pacific Islander vs Caucasian <.0001 Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T <.0001 T3 vs T T2 vs T AJCC N classification N2c vs N2a <.0001 N2b vs N2a Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no Surgery Yes vs no LAR Age 7 (80 y) vs < 40 y < (70-79 y) vs < 40 y (60-69 y) vs < 40 y (50-59 y) vs < 40 y (40-49 y) vs < 40 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T <.0001 T3 vs T T2 vs T AJCC N classification N2c vs N2a N2b vs N2a Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no Surgery Yes vs no HP Age 7 (80 y) vs < 50 y < (70-79 y) vs < 50 y (60-69 y) vs < 50 y (50-59 y) vs < 50 y Race Asian/Pacific Islander vs Caucasian Hispanic vs Caucasian African American vs Caucasian AJCC T classification T4 vs T T3 vs T T2 vs T Cancer February 15,

9 Original Article TABLE 4. Continued N2-Only Disease Site Demographic Parameters HR 95% CI P AJCC N classification N2c vs N2a N2b vs N2a Tertiary vs primary Secondary vs primary Radiotherapy Yes vs no Surgery Yes vs no Abbreviations: AJCC, American Joint Committee on Cancer; CI, confidence interval; HP, hypopharynx; HR, hazard ratio; LAR, larynx; LNM, lymph node metastasis; OC, oral cavity; OP, oropharynx. Indeed, in our analysis, survival curves for AJCC N1, N2, and/or N3 groups overlapped, to some extent, for patients with OC, OP, and HP primary sites. The HP cohort had the smallest number of patients (n ), and the limited sample size could explain the lack of statistical significance for the differences in survival according to the AJCC N classification. However, the cohort included 2463 patients with OC HNSCC and 8567 patients with OP HNSCC, and this should have provided a reasonable power for detecting major differences in survival between the groups defined by the AJCC N classification. As such, the data indicate that optimization of the categorization of lymph node involvement is needed to improve prognostication. The limitations of the current staging system in determining survival for patients with OP cancers have been documented by several groups, 18,19 largely because of the favorable prognostic effects of human papillomavirus (HPV) related cancers at this subsite. The incidence of HPV-related OP cancers has been increasing in the United States, and past HPV infections are now estimated to account for approximately 70% of all newly diagnosed OP cancer cases HPV-related cancers typically present with advanced nodal involvement and small primary tumors. Not surprisingly, recent series of survival analyses of OP cancers notstratifiedbythehpvstatushaveshownworseoutcomes for N0 patients (and more frequently HPV-negative tumors) than patients with lymph node involvement (and more frequently HPV-positive tumors). 18,19 A more accurate way of determining the survival impact of lymph node involvement, if any, on OP (and largely HPV-positive) cancers is, therefore,clearlyneeded.asaresult,anewprognosticmodelhas been proposed for HPV-related OP cancer that takes into account TNM as well as the smoking status and age. 23 Unfortunately, the SEER database does not capture the HPV status of HNSCC or the smoking history. Nonetheless, patients included in our analysis were diagnosed between 2004 and 2009, an era during which the frequency of HPV-related cancers was already high. Moreover, our analysis focuses only on node-positive cancers. As such, it is very likely that our study population of OP cancers may largely represent HPV-related malignancies. Nonetheless, our OP findings need to be confirmed in other cohorts with a known HPV status. Previous studies have evaluated the effects of the level of LNM on outcomes. Our single-institution data (n patients) demonstrated shorter survival for patients with OP cancers with lower level cervical lymph node involvement treated with intensity-modulated radiation therapy. 24 Li et al 25 demonstrated that the number of cervical levels with lymph node involvement was associated with a higher risk of distant metastases (n 5 391). On the basis of these single-institution experiences, we designed the current population-based study to investigate the impact level of LNM on survival, and we took advantage of the more detailed collection of this information by the SEER database since 2004 on a large scale. SEER currently collects and publishes cancer incidence and survival data from population-based cancer registries covering approximately 28% of the US population. In addition, SEER provides information on patients from across the country in many different treatment settings, both community and academic practices, and this makes our analysis more representative of the general US patient population. Because we included surgically and nonsurgically treated patients, it is likely that the data obtained are broadly applicable for most clinical scenarios. Our results show that the level of LNM is an independent prognostic factor for patients with locally advanced OC, OP, or LAR HNSCC even after adjustments for the AJCC N classification. We have also demonstrated the limited prognostic value of the AJCC N2a, N2b, and N2c subclassification for OC and LAR cancers. In contrast, the level of LNM within N2 disease can 542 Cancer February 15, 2016

10 HNSCC Lymph Node Level and Survival/Xing et al Figure 3. Site-specific risk classification for HNSCC and associated Kaplan-Meier survival. (A,C,E,G) Flow charts of resulting classifications. The number of cases in each risk group and its proportion of the total number of cases are shown under each risk group. (B,D,F,H) OS for the classified patients with OC, OP, LAR, and HP head and neck squamous cell carcinoma, respectively. HP indicates hypopharynx; LAR, larynx; LNM, lymph node metastasis; OC, oral cavity; OP, oropharynx; OS, overall survival; P, primary; S, secondary; T, tertiary. Cancer February 15,

11 Original Article predict survival for the OP, OC, and LAR subsites. The lack of an association of nodal involvement at the HP subsite with survival (whether assessed by the AJCC N classification or the LNM level classification proposed herein) can possibly be explained by a different biology of this tumor, which reflects distinct molecular signatures 26 and leads to aggressive clinical behavior less dependent on patterns of nodal spread. The strengths of our analysis include the following: 1) the use of a large sample representative of the United States and encompassing patients with multiple treatment modalities; 2) the evaluation of the 4 major HNSCC primary sites individually, which thus takes into account differences in natural history, treatment patterns, and outcomes between these groups; and 3) the construction of an easy-to-use prediction tool that can integrate the complex variables of the AJCC T classification, the AJCC N classification, and the level of LNM. This tool is able to clearly separate risk groups for each of the 4 subsites and can be readily applied to patients in clinical practice. An example of how the use of such tool could improve prognostication is illustrated by the following scenario. A patient with a T2N2c LAR cancer would be classified as stage IVA according to the 7th edition of the AJCC staging manual. According to our tool, this patient could be classified within the intermediate- or high-risk group according to the involvement of primary or secondary/tertiary levels of LNM, respectively. The 3-year survival rates for these 2 groups are estimated to be 49% and 37%, respectively, and they represent clinically meaningful differences. The limitations of our analysis include the following: 1) the relatively short median follow-up time for the cohort; 2) the lack of HPV data in SEER, particularly for OP cancers; 3) the lack of information on patterns of failure (ie, locoregional recurrence, distant metastases, and development of second primary tumors); and 4) the lack of details on treatment and pathology such as margins, perineural invasion, and extracapsular invasion. Recent studies have demonstrated that although patients with HPV-related OP cancers have improved survival in comparison with patients with non HPV-related OP cancers, there are clearly subgroups with HPV-related HNSCC that are at increased risk of recurrence and death after definitive treatment. A history of smoking, for example, has been consistently associated with a worse prognosis for HPV-related OP cancers O Sullivan et al 27 demonstrated that the presence of T4 tumors and N3 disease were also associated with an increased risk of distant metastases and death in 505 patients with HPV-related OP cancers. These data illustrate that refinement of prognostication with clinical and molecular criteria could assist with the development of treatment strategies tailored to each patient s individual risk. Moreover, the ability to predict the risk of locoregional recurrence and distant recurrence with clinical, demographic, or molecular criteria could lead to the study of treatment approaches to intensify local or systemic therapies in patients specifically at risk for locoregional or distant relapse, respectively. We speculate that in the near future, novel molecular markers may be integrated with known prognostic factors to better assess each patient s individual risk of recurrence and death. For example, preliminary data from our group demonstrate that genomic intratumor heterogeneity may be associated with a higher risk of recurrence in early-stage non small cell lung cancer. 28 Intratumoral genetic heterogeneity in HNSCC has also been associated with worse survival in a small cohort of patients. 29 As these and other novel prognostic markers evolve, prediction tools that can integrate detailed molecular, clinical, and treatment outcome data are likely to become part of the standard evaluation of patients in clinic. Another limitation of our study is the lack of quality control of the data captured by SEER: there is potential for the misclassification of the level of LNM, such as an inaccurate assessment by the radiologist (or false-positive findings resulting from reactive nodes in nonsurgically treated patients), incomplete nodal dissection, and inaccurate processing and/or labeling of surgical specimens by surgeons and/or pathologists. Nonetheless, a recent analysis demonstrated high concordance rates between lung cancer histology data captured by SEER and independent pathology review of the same data, and this provides further evidence for the reasonable accuracy of 1 complex data aspect captured by SEER. 30 We caution, however, that results from any SEER analysis (including the findings presented herein) would be more robust if confirmed in independent, carefully curated data sets, and we strongly recommend the validation of our findings by other groups before routine use in the clinic. As an example of such a framework, the SEER database was used as a validation tool for the revised TNM classification of non small cell lung cancers originally proposed on the basis of an independent international database, and it was ultimately incorporated into the 7th edition of the AJCC staging manual. This approach illustrates the significant potential for using the SEER registry as a powerful tool for identifying and/or validating novel prognostic factors Cancer February 15, 2016

12 HNSCC Lymph Node Level and Survival/Xing et al In conclusion, we have demonstrated that the level of LNM can add to the prognostic value of the AJCC T and N classification for patients with locally advanced HNSCC. As we approach discussions regarding the TNM classification of HNSCC for the 8th edition of the AJCC staging manual, considerations should be given to refining the currently suboptimal N classification within both HPV-related and HPV-unrelated HNSCC. Comprehensive data collection and analysis regarding novel clinical and molecular prognostic factors, as increasingly supported by SEER, 32 will assist clinicians in improving risk assessment and developing user-friendly tools (such as the one presented here) that can inform clinical decision making. FUNDING SUPPORT This work was supported in part by the National Institutes of Health (grant P30 CA ). CONFLICT OF INTEREST DISCLOSURES Kathryn A. 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