IDENTIFICATION OF A HIGH-RISK GROUP AMONG PATIENTS WITH ORAL CAVITY SQUAMOUS CELL CARCINOMA AND pt1 2N0 DISEASE

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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 1, pp , 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved /$ - see front matter CLINICAL INVESTIGATION Head and Neck Cancer IDENTIFICATION OF A HIGH-RISK GROUP AMONG PATIENTS WITH ORAL CAVITY SQUAMOUS CELL CARCINOMA AND pt1 2N0 DISEASE CHUN-TA LIAO, M.D.,* y CHIEN-YU LIN, M.D., yz KANG-HSING FAN, M.D.,* z HUNG-MING WANG, M.D.,* x SHU-HANG NG, M.D.,* k LI-YU LEE, M.D., y{ CHUEN HSUEH, M.D., y{ I-HOW CHEN, M.D.,* y SHIANG-FU HUANG, M.D.,* y CHUNG-JAN KANG, M.D.,* y AND TZU-CHEN YEN, M.D, PH.D. y# *Department of Otorhinolaryngology, Head and Neck Surgery, y Department of Head and Neck Oncology Group, x Department of Hema-Oncology, k Department of Diagnostic Radiology, { Department of Pathology, and # Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; and z Department of Radiation Oncology, Chang Gung Memorial Hospital and Graduate Institute of Clinical Medical Sciences of Chang Gung University, Taoyuan, Taiwan Purpose: In the American Joint Committee on Cancer 2010 classification system, pt1 2N0 oral cavity squamous cell carcinoma (OSCC) is considered an early-stage cancer treatable with surgery alone (National Comprehensive Cancer Network 2010 guidelines). Our aim was to evaluate the feasibility of surgery alone for pt1 2N0 OSCC patients. Methods and Materials: Among 1279 previously untreated OSCC patients referred to our hospital between January 1996 and May 2008, we identified 457 consecutive patients with pt1 2N0 disease. All had radical tumor excision with neck dissection. A total of 387 patients showing pathologic margins greater than 4 mm and treated by surgery alone were included in the final analysis. All were followed up for at least 24 months after surgery or until death. The 5-year rates of control, distant metastasis, and survival were the main outcome measures. Results: The 5-year rates in the entire group of pt1 2N0 patients were as follows: local control, 91%; neck control, 92%; distant metastases, 1%; disease-free survival, 85%; disease-specific survival, 93%; and overall survival, 84%. Multivariate analysis identified poor differentiation and pathologic tumor depth of 4 mm or greater as independent risk factors for neck control, disease-free survival, and disease-specific survival. A scoring system using poor differentiation and tumor depth was formulated to define distinct prognostic groups. The presence of both poorly differentiated tumors and a tumor depth of 4 mm or greater resulted in significantly poorer 5-year neck control (p < ), disease-free (p < ), disease-specific (p < ), and overall survival (p = ) rates. Conclusion: The combination of poor differentiation and pathologic tumor depth of 4 mm or greater identified a subset of pt1 2N0 OSCC patients with poor outcome, who may have clinical benefit from postoperative adjuvant radiotherapy. Ó 2012 Elsevier Inc. Adjuvant radiotherapy, Oral cavity, Squamous cell carcinoma, Survival, Outcome. INTRODUCTION In the American Joint Committee on Cancer 2010 classification system, pt1 2N0 oral cavity squamous cell carcinoma (OSCC) is considered to be an early-stage cancer (p Stage I II) (1). Numerous reports, including the NCCN 2010, do not recommend the use of postoperative adjuvant radiotherapy (RT) in OSCC patients with pt1 2N0 disease (2). We have previously shown that specific pathologic characteristics are important independent adverse prognostic factors in patients with OSCC (3 8). However, the prognostic significance of these factors has not been specifically tested in patients with pt1 2N0 disease. This report expands on previous research by focusing on this patient group. The aim of this study was twofold. The first was to identify potential prognostic factors affecting the outcomes of pt1 2N0 OSCC patients. The second was to determine whether a subgroup of high-risk patients may benefit from more aggressive adjuvant therapies (radiation alone or chemoradiation). We sought to address these issues in 387 consecutive patients with pt1 2N0 disease showing pathologic margins greater than 4 mm and treated by surgery alone between January 1996 and May METHODS AND MATERIALS Patients All work was performed in accordance with the Declaration of Helsinki, and approval was granted by the Institutional Review Reprint requests to: Tzu-Chen Yen, M.D., Ph.D., Department of Nuclear Medicine, Chang Gung Memorial Hospital at Linko, No. 5, Fu-Hsing St., Kwei-Shan, Taoyuan, Taiwan, Republic of China. Tel: , ext. 2673; Fax: ; yen1110@adm.cgmh.org.tw 284 This study was supported by grants CMRPG and CMRPG from Chang Gung Memorial Hospital. Conflict of interest: none. Received June 1, 2010, and in revised form Aug 2, Accepted for publication Sept 8, 2010.

2 High-risk patients and pt1-2n0 OSCC d C.-T. LIAO et al. 285 Board of Chang Gung Memorial Hospital, Taoyuan, Taiwan. The inclusion criteria were as follows: presence of a previously untreated tumor scheduled for radical surgery with neck dissection (ND), histologic diagnosis of OSCC, and presence of pt1 2N0 (pt1 2 tumor status and pn0 status) disease. Because all patients were required to have pn0 disease, cn0 patients who were pn+ were excluded. In contrast, cn+ patients who had pn0 disease were eligible to participate. Additional inclusion criteria were the patient s willingness to undergo computed tomography guided biopsy or surgical exploration if necessary and the absence of other suspected distant metastatic lesions detected by imaging. Exclusion criteria were refusal or inability to receive definitive treatment. Patients with close or positive margins were also excluded. In addition, no patient had received any previous adjuvant therapy. All participants underwent an extensive presurgical evaluation. This included a medical history and complete physical examination, flexible fiberoptic pharyngoscopy, complete blood count and routine blood biochemistry, computed tomography or magnetic resonance imaging scans of the head and neck, chest radiographs, bone scan, and liver ultrasonography. Patient staging was performed according to the 2010 American Joint Committee on Cancer 7th edition staging criteria (1). Surgery The primary tumors were excised with surgical margins of 1 cm or greater (both peripheral and deep margins). Classic radical or modified NDs (Level I V) were performed in patients with clinically positive lymph nodes, whereas supraomohyoid NDs (Level I III) were used in clinically node-negative patients. Patients were treated with bilateral NDs if the primary tumor reached or crossed the midline sagittal plane of the oral cavity. The tumor margins were sent for frozen section. If a margin was positive, additional tissue was excised and sent for frozen section to ensure that the margin was free of tumor. The surgical defects were repaired with primary closure or reconstructed immediately by plastic surgeons using free or local flaps. Determination of optimal cutoff values for pathologic tumor depth The optimal cutoff values for tumor depth were calculated as previously described (7). In brief, different values of tumor depth (from 1 to 15 mm) were tested by use of the Kaplan-Meier method based on the 5-year local control, neck control, distant metastases, disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) rates. A cutoff point of 4 mm yielded the highest significance in terms of control and survival rates. Statistical methods Follow-up was continued until May All patients received follow-up examinations for at least 24 months after surgery or until death. Descriptive statistics are summarized as frequencies, percentages, means, medians, ranges, and standard deviations. The survival time and the time intervals to recurrence or distant metastases were calculated from the operation date. The Kaplan-Meier method was applied for outcome analysis of the 5-year local control, neck control, distant metastases, DFS, DSS, and OS rates. Statistical significance was tested by log-rank test. Univariate and multivariate analyses were used to identify the independent predictors of outcome. Multivariate analysis was performed via Cox regression through a forward selection procedure. Two-sided p values < 0.05 were considered statistically significant. RESULTS Patients Among 1279 previously untreated OSCC patients referred to our hospital between January 1996 and May 2008, we identified 548 consecutive patients with pt1 2 disease. Of the 548 pt1 2 patients, 91 were excluded because they did not undergo ND. Of the 457 pt1 2N0 patients, 70 were excluded because of previous adjuvant RT (n = 60) or the presence of close margins (#4 mm) (n = 22). A total of 12 patients had both a history of previous adjuvant RT and close margins. Therefore the final study population included 387 patients (359 men and 28 women; mean age, years; age range, years). In total, 357 patients (92%) received ipsilateral ND whereas the remaining 30 (8%) had bilateral ND. The median follow-up was 66 months (mean, months; range, months). At the time of analyses, 315 patients (81%) were alive and 72 (19%) were dead (27 from primary cancer, 23 from other forms of cancers, and 22 from non-neoplastic causes). In an event-based analysis, 38 patients (10%) had local recurrences, 31 (8%) had neck recurrences, 6 (2%) had distant metastases, and 77 (20%) had second primary tumors. A total of 59 patients (15%) showed local and/or neck recurrences, and salvage therapy was carried out in 53 individuals (90%). Of this patient group, 30 (57%) subjects were alive and 23 (43%) were dead. The 5-year rates were as follows: local control, 91%; neck control, 92%; distant metastases, 1%; DFS, 85%; DSS, 93%; and OS, 84%. The demographic and clinicopathologic characteristics of the study participants are presented in Table 1. Prognostic factors In univariate analyses, poor differentiation was an adverse predictor of 5-year neck control, DFS, and DSS; tumor depth of 4 mm or greater was a significant prognostic factor for neck control, DFS, and OS; perineural invasion was a significant prognostic factor for neck control; and lymphatic invasion was an adverse predictor for OS. Multivariate analysis of 5-year control and survival rates is depicted in Table 2. Poor differentiation of tumor was an independent risk factor for 5-year neck control, DFS, and DSS; tumor depth of 4 mm or greater was an independent adverse prognostic factor for 5-year neck control, DFS, and DSS rates; and lymphatic invasion was an independent adverse predictor for OS. However, only 2 patients showed lymphatic invasion. Table 3 depicts the clinical course of pt1 2N0 patients with poorly differentiated tumors (n = 19). Prognostic scoring system using differentiation and tumor depth A scoring system using poor differentiation and tumor depth was formulated to define distinct prognostic groups: Group 1 (reference category), well/moderate differentiation and tumor depth less than 4 mm (n = 121); Group 2, well/ moderate differentiation and tumor depth of 4 mm or greater

3 Characteristics Table 1. Five-year control and survival rates in pt1 2N0 OSCC patients (n = 387) Local control Neck control Distant metastases Disease-free survival Disease-specific survival Overall survival 5-y %, n event p 5-y %, n event p 5-y %, n event p 5-y %, n event p 5-y %, n event p 5-y %, n event p Age #40 y (89) 95 (7) 93 (7) 4 (3) 89 (12) 94 (7) 86 (14) >40 y (298) 89 (31) 92 (24) 1 (3) 84 (48) 93 (20) 84 (58) Gender Male (359) 90 (37) 92 (30) 1 (6) 85 (58) 93 (25) 85 (65) Female (28) 96 (1) 96 (1) 0 (0) 93 (2) 92 (2) 81 (7) Tumor subsites Tongue (189) 93 (14) 90 (19) 1 (2) 84 (30) 93 (12) 86 (33) Mouth floor (16) 100 (0) 94 (1) 0 (0) 94 (1) 100 (0) 54 (6) Lip (18) 82 (2) 94 (1) 0 (0) 77 (3) 94 (1) 82 (3) Buccal (106) 93 (11) 95 (5) 1 (2) 91 (13) 95 (8) 88 (19) Alveolar ridge (37) 79 (8) 91 (3) 3 (1) 77 (9) 88 (4) 82 (6) Hard palate (4) 50 (1) 75 (1) 0 (0) 38 (2) 75 (1) 75 (1) Retromolar (17) 88 (2) 94 (1) 6 (1) 87 (2) 94 (1) 81 (4) Differentiation Well/moderate (368) 91 (36) 93 (26) 1 (5) 86 (56) 94 (22) 85 (67) Poor (19) 88 (2) 74 (5) 5 (1) 68 (4) 73 (5) 73 (5) pt status pt1 (134) 90 (12) 95 (6) 1 (2) 87 (15) 95 (7) 88 (17) pt2 (253) 91 (26) 90 (25) 2 (4) 84 (45) 93 (20) 82 (55) Tumor depth* <4 mm (128) 90 (10) 97 (4) 1 (1) 89 (11) 96 (4) 88 (17) $4 mm (259) 91 (28) 90 (27) 2 (5) 83 (49) 92 (23) 82 (55) Perineural invasion y No (339) 91 (34) 93 (23) 1 (5) 86 (49) 94 (22) 86 (61) Yes (47) 90 (4) 83 (8) 2 (1) 76 (11) 89 (5) 75 (11) Vascular invasion y No (384) 91 (38) 92 (31) 1 (6) 85 (60) 93 (27) 84 (72) Yes (2) 100 (0) 100 (0) 0 (0) 100 (0) 100 (0) 100 (0) Lymphatic invasion y < No (384) 91 (38) 92 (31) 1 (6) 85 (60) 93 (27) 85 (70) Yes (2) 100 (0) 100 (0) 0 (0) 100 (0) 100 (0) 0 (2) 286 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 Abbreviation: OSCC = oral cavity squamous cell carcinoma. * Best cutoff value of tumor depth. Tumor depth was defined as the measured thickness from the surface of the normal mucosa to the deepest portion of the tumor. y Unavailable data: perineural (n = 1), vascular (n = 1), and lymphatic (n = 1).

4 High-risk patients and pt1-2n0 OSCC d C.-T. LIAO et al. 287 Table 2. Multivariate analysis of 5-year control and survival rates (n = 387) Characteristics Local control Neck control Distant metastasis Disease-free survival Disease-specific survival Overall survival Poor differentiation p NS NS < NS HR (95% CI) ( ) ( ) ( ) Tumor depth $4 mm p NS NS NS HR (95% CI) ( ) ( ) ( ) Lymphatic invasion p NS NS NS NS NS < HR (95% CI) ( ) Abbreviations: NS = not significant; HR = hazard ratio; CI = confidence interval. (n = 247); Group 3, poor differentiation and tumor depth less than 4 mm (n = 7); and Group 4, poor differentiation and tumor depth of 4 mm or greater (n = 12). The local control, neck control, DFS, DSS, and OS rates at 5 years did not differ significantly between Groups 1, 2, and 3. Patients in Group 4 showed significantly poorer 5-year neck control, DFS, DSS, and OS rates compared with other risk categories. Of note, there was a marginally significant difference between Groups 3 and 4 in terms of DSS and OS rates (Fig. 1). DISCUSSION The NCCN 2010 guidelines do not support the use of postoperative adjuvant RT in OSCC patients with pt1 2N0 disease. A subset of these patients, however, may eventually have locoregional or distant recurrence. We hypothesized, on the basis of our clinical observations that subgroups of OSCC patients exist within pt1 2N0 disease whose clinical behavior differs. A survival benefit for postoperative RT would most readily be seen in patients with higher rates of locoregional or distant recurrence. Besides the lymph node status, numerous other pathologic characteristics (tumor depth, close/positive margins, perineural invasion, lymphovascular permeation, tumor differentiation) also act as risk factors (3 10). To our knowledge, no study has specifically addressed whether these clinicopathologic features may predict prognosis in OSCC patients with pt1 2N0 disease (11). Previous research has suggested that poor tumor differentiation is an independent risk factor for neck lymph node Table 3. Clinicopathologic characteristics of pt1 2N0 OSCC patients with poor differentiation (n = 19) Interval between primary surgery and event (mo) No. Age (y) Site Tumor depth (mm) Tumor recurrence Neck recurrence DM Tumor salvage Neck salvage DOD AND 1 45 Tongue Retromolar Tongue Tongue Tongue Tongue Tongue Buccal Tongue Gum 5 8* Buccal Tongue Tongue Lip Tongue Buccal Buccal Tongue Tongue 15 14* + 24 Abbreviations: OSCC = oral cavity squamous cell carcinoma; DM = distant metastasis; DOD = died of disease; AND = alive without disease. * In-field failure at neck region.

5 288 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 Fig. 1. Subgroup analysis of 5-year local control rates (a), neck control rates (b), distant metastasis rates (c), disease-free survival rates (d), disease-specific survival rates (e), and overall survival rates (f) according to presence of poor differentiation and tumor depth of 4 mm or greater. metastasis and clinical outcomes in OSCC patients (12 20). However, disease status varied widely among participants enrolled in previous studies. The prognostic importance of depth of tumor invasion has been similarly suggested, but its significance in OSCC patients with pt1 2N0 disease remains poorly understood. In this study we found that poor differentiation and depth of 4 mm or greater were univariate predictors of 5-year neck control, DFS, and DSS rates in OSCC patients with pt1 2N0 disease treated by surgery alone. After allowance for potential confounders, poor differentiation and tumor depth of 4 mm or greater retained their independent prognostic significance. Although several cutoff values for tumor depth have been reported (3 10), the optimal cutoff for predicting prognosis remains unclear. It is feasible that the best cutoff value for tumor depth may depend on different criteria used to select patients (e.g., T1 2 vs. T3 4). We have previously reported an optimal cutoff value of 10 mm

6 High-risk patients and pt1-2n0 OSCC d C.-T. LIAO et al. 289 for the entire group of OSCC patients (5 7), 35 mm for those with pt4n0 disease (4), and 12 mm for those with pn+ or extracapsular spread (9). A tumor depth of 5 mm or greater appeared to be the most appropriate cutoff for ND in buccal cancer patients with pt1 disease (3). Therefore treatment policies may vary according to the surgical oncologist s experience and preference. The combination of poor differentiation and tumor depth of 4 mm or greater led to the identification of four different prognostic groups. Although poor differentiation seems to be the most important negative predictor for 5-year neck control and survival rates, patients with both poor differentiation and tumor depth of less than 4 mm showed the best results in terms of outcomes, with 100% rates of control and survival at 5 years. Although this surprising result may be because of the small number of patients (n = 7) in this group, subjects in Group 4 (n = 12, poor differentiation and tumor depth $4 mm) showed the poorest outcome in terms of 5- year neck control, DFS, DSS, and OS rates. Patients in Group 4 account for only 3% of all pt1 2N0 patients in our study. It is worth noting that the number of patients in Groups 3 (n = 7) and 4 (n = 12) was so small that it is difficult to draw definite conclusions, especially on the potential role of postoperative RT. In Group 4, neck failure represents the major failure pattern, with an incidence of 42% within 2 years. In this patient group, postoperative RT may improve locoregional control. The results of the Radiation Therapy Oncology Group 9501 and European Organization for Research and Treatment of Cancer trials showed the usefulness of adjuvant concurrent chemoradiotherapy for improving locoregional control in advanced-stage highrisk patients (21, 22). Of note, the European Organization for Research and Treatment of Cancer trial enrolled T1 2N0 1 patients bearing pathologic risk factors. However, a comparative analysis of the two trials has shown that only patients with positive margins and/or positive lymph nodes with extracapsular spread would benefit from adjuvant concurrent chemoradiotherapy (23). We are currently investigating the potential usefulness of a therapeutic regimen consisting of two steps. Step 1 includes adjuvant RT alone. The second step consists of subsequent chemoradiotherapy or bioradiotherapy. Controls and survivals obtained in these therapeutic regimens will be compared with those of similar patients in our historical cohort. Several caveats of this study merit consideration. First, our data are limited to a survey of OSCC patients with pt1 2N0 selected from an endemic betel quid chewing area. Second, only a few high-risk patients (12 of 387 [3%]) were identified using tumor differentiation and tumor depth as the classification parameters. Finally, although univariate and multivariate analyses showed that poor differentiation was an independent risk factor for neck control and survival rates, patients in Group 3 (poor differentiation and depth <4 mm) showed the best survival and event-free rates. This unexpected result may be because of the small number of patients in this group (n = 7). Replication studies should be of sufficient sample size to address this issue. There are also several strengths of this report that distinguish it from previous studies. First, our investigation comprises the largest pt1 2N0 OSCC population described to date who received both wide excision of the tumor and ND. Second, all patients were uniformly assessed and treated according to our standardized protocol. 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