Journal of Surgical Oncology 2013;108:509–515

Prognostic Value of Total Tumor Volume in Advanced-Stage Laryngeal and Hypopharyngeal Carcinoma CHAN-JOO YANG, MD,1 DAE-YOON KIM, MD,2 JEONG HYUN LEE, MD,2 JONG-LYEL ROH, SEUNG-HO CHOI, MD,1 SOON YUHL NAM, MD,1 AND SANG YOON KIM, MD1,3 1

1 MD, *

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea 2 Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea 3 Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea

Background: To evaluate the prognostic value of total tumor volume (TTV) in patients with laryngeal and hypopharyngeal carcinomas. Methods: This study involved 182 patients with previously untreated advanced‐stage squamous cell carcinoma of the larynx or hypopharynx. TTV were calculated from pretreatment contrast‐enhanced computed tomography images. Univariate and multivariate analyses were used to identify factors associated with overall (OS), disease‐specific (DSS), and disease‐free survival (DFS). Results: At a median follow‐up of 63 months (range, 24–139 months), the 5 year OS, DSS, and DFS rates were 60.2%, 73.1%, and 69.4%, respectively. Multivariate analyses showed that tumor site was an independent predictor of DSS (P ¼ 0.03); Charlson comorbidity index for OS (P ¼ 0.001); second primary cancer for OS (P ¼ 0.008) and DFS (P ¼ 0.001); and vocal fold paralysis for DSS (P ¼ 0.014) and DFS (P ¼ 0.033). Extension to the tongue base was an independent predictor of OS (P ¼ 0.007), DSS (P < 0.001), and DFS (P ¼ 0.017), and TTV 8.38 ml was an independent predictor of all three survivals (P < 0.001 each). Conclusion: Radiologically determined TTV is prognostic of survival in patients with advanced‐stage laryngeal and hypopharyngeal carcinoma.

J. Surg. Oncol. 2013;108:509–515. ß 2013 Wiley Periodicals, Inc.

KEY WORDS: squamous cell carcinoma; larynx, hypopharynx; total tumor volume; survival

INTRODUCTION Tumor‐node‐metastasis (TNM) staging [1] is a universally accepted, widely used prognostic system for head and neck cancer. This staging system includes the maximal diameter and anatomical extent of the primary tumor, the size, and number of involved regional lymph nodes, and the presence or absence of distant metastasis. Clinical, pathologic, imaging, and molecular parameters found to have prognostic significance in head and neck cancer have not yet been incorporated into current staging systems. TNM staging uses one‐dimensional parameters and anatomical extensions, which are not accurate measurements of actual tumor load. Advanced tumors categorized as T3 or T4 may vary widely in volume. Increased tumor volume may have a greater impact on patient survival and locoregional control than classical tumor and nodal staging [2,3]. Tumor volume can easily be measured by analyzing the digital images obtained by pretreatment computed tomography (CT) [2,3]. Tumor volume has shown prognostic significance on treatment outcome in patients with head and neck squamous cell carcinoma (HNSCC) [4–9]. Greater pretreatment volume of laryngeal or pharyngeal cancer was related to a significantly higher chance of recurrence following radiotherapy [4,7,10,11]. Tumor measuring systems and cutoff values for local tumor response vary widely. Most studies have assessed the prognostic significance of primary tumor volume (PTV) [3–8,10,11], whereas a recent systematic review emphasized the prognostic importance of metastatic nodal volume (MNV) as well as of PTV [12]. Studies addressing the prognostic importance of TTV and/or MNV have measured the volumes of macroscopically visible tumors and lymph nodes with a short axis diameter of >1.0 cm or with an inhomogeneous aspect [12]. To our knowledge, few studies to date have investigated the prognostic role of TTV in patients with cancer of the larynx [13], suggesting the need for additional studies of large cohorts of patients

ß 2013 Wiley Periodicals, Inc.

with laryngeal and pharyngeal cancers. We hypothesized that TTV may be prognostic of survival in patients with advanced‐stage head and neck cancer. We therefore evaluated the prognostic role of TTV, measured on pretreatment CT images, in patients with stage III–IV laryngeal and hypopharyngeal carcinoma. Our goal was to determine whether this imaging parameter could stratify subsets of patients with a poorer prognosis who may require more intensive treatment.

MATERIALS AND METHODS Study Population The records of 665 patients with laryngeal or hypopharyngeal cancer, who had been treated at Asan Medical Center from January 2000 to December 2010, were reviewed. Of these patients, 331 had newly diagnosed, advanced‐stage laryngeal or hypopharyngeal cancer. Patients were included if they had histologically proven squamous

Grant sponsor: This work was supported by grants from the Asan Institute for Life Science (no. 2013‐417) and the Basic Science Research Program through the National Research Foundation (NRF) of Korea, funded by the Ministry of Education, Science and Technology (no. 2012R1A1A2002039), Seoul, Korea (J.‐L. Roh). Chan‐Joo Yang and Dae‐Yoon Kim contributed equally to this paper. Conflict of interest statements: There are no conflicts of interest. *Correspondence to: Jong‐Lyel Roh, MD, Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic‐ ro 43‐gil, Songpa‐gu, Seoul 138‐736, Republic of Korea. Fax: þ80‐2‐489‐2773. E‐mail: [email protected] Received 20 June 2013; Accepted 27 August 2013 DOI 10.1002/jso.23444 Published online 24 September 2013 in Wiley Online Library (wileyonlinelibrary.com).

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cell carcinomas of the larynx or hypopharynx, of clinical stage III or IV, without distant metastasis. Of the 331 patients, 149 were excluded because of different pathology, the presence of distant metastasis, incomplete clinical data or follow‐up, or inability to calculate tumor volume from CT scans. The remaining 182 patients were eligible for this study. This study was reviewed and approved by the Institutional Review Board of our institution, which waived the requirement for patient informed consent due to the retrospective nature of this study. Initial staging workup included physical and endoscopic examinations, contrast‐enhanced head and neck CT, and 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) or PET/CT. Primary tumors were biopsied and metastatic lymph nodes (LN) were confirmed by needle biopsy with/without ultrasonographic guidance during the routine staging workup. Clinical stage was determined according to the American Joint Committee on Cancer (AJCC) TNM staging system [14].

CT Protocol and Measurement of Tumor Volume The contrast‐enhanced CT of the head and neck was performed using a Somatom Sensation 16 (Siemens Medical Solution, Forchheim, Germany) or a LightSpeed QX/i scanner (GE Medical Systems, Milwaukee, WI) with a reconstructed slice thickness of 3 mm or less. For contrast enhancement, 90 ml of an iodinated contrast agent (Ultravist 300, Schering, Berlin, Germany) was injected intravenously at 3 ml/sec with an automated injector. The contrast‐enhanced CT images were interpreted by an experienced radiologist who was blinded to clinical outcomes. This radiologist assessed thyroid cartilage invasion, extralaryngeal extension, tumor spread into neighboring structures, and nodal involvement. The greatest diameter of each primary tumor and metastatic lymph node was measured on the axial, coronal, and sagittal CT images of each patient and used to calculate gross PTV and MNV. LNs were considered metastatic if central necrosis or inhomogeneous enhancement was present, if the shortest axial diameter was >1 cm, or if there was a cluster of three or more lymph nodes of borderline size [15,16]. The radiologist manually traced the tumor contour on CT scans, and the volumes of all metastatic neck LNs were measured separately and calculated by the summation‐of‐area technique [12]. Tumor volumes were calculated by multiplying the sum of the traced areas (surface) by the image reconstruction interval (thickness) using in‐ house software (Peta Vision 2.0; Asan Medical Center PACS, Seoul, Korea). TTV for each patient was defined as the sum of PTV and MNV.

Treatments and Follow‐Up The treatment of choice for each patient was discussed at a multidisciplinary team meeting involving surgical, medical, and radiation oncologists, pathologists, and radiologists. All patients were treated with curative intent. The patients were classified by primary treatment into a surgery and a non‐surgery group. Patients in the surgery group underwent curative resection of the primary tumor, along with neck dissection. Postoperative radiotherapy (RT) or chemoradiotherapy (CRT) was indicated for patients with adverse pathologic features. Patients treated with induction chemotherapy followed by definitive surgery were included in the surgery group. Patients in the non‐surgery group received radiotherapy (RT; median total dose 70 Gy; range 54– 78 Gy) to the primary site and neck region with/without concurrent cisplatin‐based chemotherapy. Patients who underwent salvage surgery for persistent tumors after RT or CRT were included in the non‐surgery group. After initial treatments, all patients received physical and endoscopic examinations at every clinic visit. The patients were followed‐up every 1–2 months during the first year, every 2–4 months during the second and third years, every 6 months during the fourth and fifth years, and annually thereafter. Imaging workups including head and neck CT and/ or MRI and whole body FDG PET or PET/CT. Patients with biopsy‐ Journal of Surgical Oncology

confirmed tumor recurrence or second primary tumors were scheduled for salvage or palliative treatment.

Variables All patients were evaluated for age, sex, site of the primary tumor, tumor‐node‐metastasis (TNM) stage, underlying comorbidities, smoking status, alcohol consumption, CT findings, tumor volume derived from pretreatment CT, treatment modalities, and histologic grade. Co‐existing morbidity was categorized according to the Charlson comorbidity index [17]. One drink was defined as 15.6 ml of pure ethanol [18].

Statistical Analysis Continuous variables were expressed as median and range, and categorical variables as number and percentage. Receiver operating characteristic (ROC) analysis was applied to determine the area under the curve (AUC) of PTV, MNV, and TTV. The optimal cutoff values of these volumetric parameters were obtained by calculating the sensitivity and specificity of each value and plotting sensitivity against 1‐ specificity. Disease‐free survival (DFS) was defined as the time interval from the last day of treatment until the first evidence of recurrence. Overall survival (OS) was defined as the time between the first day of treatment and the date of death from any cause or the last known date the patient was alive. Disease‐specific survival (DSS) was defined as the time between the first day of treatment and the date of death from disease or the last known date the patient was alive. Survival curves were calculated using the Kaplan–Meier method. The log‐rank test was used to assess the correlation of survival end points with variables. Variables with P < 0.1 in univariate analyses were selected for multivariate analysis using a Cox proportional hazards model. The estimated hazard ratios (HR) and 95% confidence intervals (CI) were calculated. A two‐sided P‐value of