MAXIMUM STANDARDIZED UPTAKE VALUE CUTOFF POINT OF THE LYMPH NODES METASTASES IN NSCLC DETECTED BY FDG-PET/CT A PROGNOSTIC VALUE

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2 MAXIMUM STANDARDIZED UPTAKE VALUE CUTOFF POINT OF THE LYMPH NODES METASTASES IN NSCLC DETECTED BY FDG-PET/CT A PROGNOSTIC VALUE Nina Georgieva 1, Zhivka Dancheva 2, Pavel Bochev 2, Borislav Chaushev 2, Aneliya Klisarova 2, Katya Peeva 3 1 Department of Physics, Biophysics, Roentgenology and Radiology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria 2 Department of Nuclear Medicine and Radiotherapy St. Marina University Hospital, Varna, Bulgaria 3 Department of Social Medicine and Health Management, Medical Faculty, Trakia University, Abstract: Stara Zagora, Bulgaria Aim: To determine the prognostic diagnostic value of the increased lymph nodes SUVmax in NSCLC patients and its relation to their survival. Materials and Methods: We studied 73 pretreatment patients with NSCLC using 18 FDG-РЕТ/СТ. There were 53 men (72,6%) and 20 women (27,4%), in the range of years old. Increased pathologic SUVmax was detected in 184 lymph nodes. Patients were staged according to TNM and final diagnosis registered in Bulgarian National Cancer Registry (BNCR). Disease beginning in the BNCR was considered either the date of registration or the operation date. Patients who presented with NSCLC between July 2009 and July 2012 were included in 18 FDG-РЕТ/СТ pre-treatment examination and survival was followed-up until April The distribution in BNCR according to N was as follows: 18 patients had N0 (24,7%), 10 had N1 (13,7%), 21 had N2 (28,8%), 11 had N3 (15,1%) and 13 patients had Nx (17,8%). The correlations between the primary tumor s SUVmax and the lymph nodes SUVmax were evaluated by Spearman correlation coefficient. A cutoff point was defined through the logrank test and the Wilcoxon test. Survival analysis was performed by use of the Kaplan-Meier method. The test for comparing the equality of the survival distributions between the study groups was done by use of the Mantel-Cox Log Rank, with an inclusion criterion of a P value less than 0,05. Results: Between the primary tumor SUVmax and the lymph nodes SUVmax there was statistically significant (Р<0,05) positive weak correlation (r=0,297). Between the lymph nodes SUVmax and the survival there was statistically significant (Р=0,0001) moderate inverse correlation (r=-0,311). At cutoff point equal to 4,5 for the lymph nodes SUVmax, the following NSCLC patients survival rate was estimated in months: for SUVmax<4,5, Mean=23,1, Median=16,8; for SUVmax 4,5, Mean=10,5, Median=7,1. The studied factor lymph nodes SUVmax was considered as a dichotomous variable. It influenced statistically significant the survival of the NSCLC patients (Р=0,0001). Statistically significant correlation was not established between the survival, the presence of lymph nodes with increased SUVmax and the histology of the primary tumor. Conclusion: The survival of the NSCLC patients is significantly dependent on the regional lymph nodes SUVmax before treatment. Regional lymph nodes SUVmax before treatment over 4,5 is a cutoff point which defines risk for worse survival and in operable patients it implies additional treatment options after the surgical intervention. Page 2 from 8

3 Introduction Lymph nodes SUVmax is a possible prognostic factor in NSCLC, discussed by different authors. The aim of the current paper is to determine the prognostic diagnostic value of the increase of SUVmax in lymph nodes in NSCLC patients and its relation to their survival. Subjects and Methods We studied 73 pre-treatment patients with NSCLC using 18 FDG-РЕТ/СТ. There were 53 men (72,6%) and 20 women (27,4%), in the range of years. The examinations were performed by use of the Phillips Gemini TF apparatus, manufactured in 2009, combining 16 slice CT and PET in 3D regimen with an ability for Time-of-Flight registrations. 18 F-Fluorodesoxyglucosae (FDG) was injected i.v. through a previously applied peripheral venous catheter with activity of 5,18 MBq/kg. The patients were examined after a minimum of 6 hours without any food intake meanwhile or intake of alkaloid or sweet beverages, and without cigarette smoking or chewing-gum use in the same period. The patients signed an informed consent. The blood glucose was tested on site. After the injection, the patients were left for min in a dimmed quiet room and after that they were positioned at the apparatus for scanning. Body PET/CT includes a low dose of CT and PET from the vertex to the middle of the hip, as well as an interactive reconstruction following the standard manufacturer s reconstruction algorithm for whole body scans and with the ability for fusion of the CT images from the examination. Increased pathologic SUVmax was detected in 184 lymph nodes. Patients were staged according to TNM and final diagnosis registered in Bulgarian National Cancer Registry (BNCR). Disease beginning in the BNCR was considered either the date of registration or the operation date. Patients who presented with NSCLC between July 2009 and July 2012 were included in 18 FDG-РЕТ/СТ pre-treatment examination and survival was followed-up until April The distribution in BNCR according to N was as follows: 18 patients had N0 (24,7%), 10 had N1 (13,7%), 21 had N2 (28,8%), 11 had N3 (15,1%) and 13 patients had Nx (17,8%). The correlations between the primary tumor SUVmax and the lymph nodes SUVmax were evaluated by Spearman s correlation coefficient. A cutoff point was defined through the log-rank test and the Wilcoxon test. Survival analysis was performed by use of the Kaplan-Meier method. The test for comparing the equality of the survival distributions between the study groups was done by use of the Mantel-Cox Log Rank, with an inclusion criterion of a P value less than 0,05. All statistical analysis was performed with the IBM SPSS Statistics 19 software. Results Reactive lymph nodes were defined as those having increased size and not increased SUVmax; or increased SUVmax, independent of the size, but histopathologically without tumor cell findings (with anthracosis, sinus histiocytosis, chronic lymphadenitis). We identified 21 lymph nodes as reactive lymph nodes with SUVmax from 1,6 to 4,5. The reactive lymph nodes SUVmax has Mean=2,8, SD=0,9 SE=0,2, and 95% CI (2,4; 3,2). We found in 17 nodes one dimension increased from 8 mm to 14,5mm Mean = 11,7 mm, SE= 0,5, 95%CI (10,7; 12,8); in 7 nodes we found two dimensions increased from 5 mm to13 mm Mean = 9,6 mm, SE = 1,1, 95%CI (7; 12,2). PET/CT before treatment of a 71-year-old patient with a final diagnosis: left superior lobe pulmonary carcinoma, T2N1M0 IIB stage is presented on Fig.1. Histologic result: differentiated Page 3 from 8

4 squamous cell carcinoma G2. PET/CT detected a lesion in segment III of the left lung with dimensions of 37,2mm/21,2mm and SUVmax 3,6, hilar lymph nodes, sub-carinal lymph nodes, prevascular lymph nodes with SUVmax of 3,8-4,1, engagement of cervical-jugular lymph nodes, submandibular lymph nodes, axillar lymph nodes, para-aortal iliac lymph nodes, inguinal lymph nodes with increased uptake primary carcinoma of the lungs with increased metabolic activity in all lymph chains. Intra-operatively a tumor formation in the upper lobe of segment III was found with dimensions 0,8cm/3cm. An upper left lobectomy with systemic mediastinal lymph dissection was performed. Histologic result: moderately differentiated squamous cell carcinoma with extensive necrosis, chronic unspecific lymphadenitis of the hilar and mediastinal lymph nodes. Fig. 1. PET/CT fusion and PET before treatment of a male patient, 71 year old. Metastatic lymph nodes were defined based on their increased SUVmax value, independent of the size; or with histologically verified metastases. In the defined as metastatic lymph nodes size 1 is from 5 mm to 62 mm, Mean = 16,6 mm, SE = 0,98 95%CI (14,7; 18,6), size 2 is from 7,3 mm to 52 mm, Mean = 19,8 mm, SE = 2,9, 95%CI (13,7; 25,9). The SUVmax of the metastatic lymph nodes is Mean=6, SD=2,9, SE=0,2, and 95% CI (5,5; 6,5). РЕТ/СТ before treatment of a 48 years old female patient is presented on Fig. 2. The final diagnosis was right pulmonary carcinoma T2N2M0, IIIA stage. State after lobectomy and chemotherapy. Histologic result: Squamous cell non-keratinocyte carcinoma. A soft-tissue lesion was detected by PET/CT in segment VI of the right lung with dimensions 25,6 mm/22 mm, SUVmax 20,2 and a single lower para-tracheal lymph node with diameter 11,8 mm, SUVmax 13,4 primary carcinoma of the right lung with metastatic lymph node. Page 4 from 8

5 Fig.2. РЕТ/СТ- fusion in transversal projection of a 48 year old woman with lung carcinoma in IIIA stage before treatment. The relation between primary tumor SUVmax and lymph nodes SUVmax we have evaluated by the correlation coefficient of Spearman (in testing the normality of distribution of the variables survival of the patients in months and lymph nodes SUVmax is found that they do not have normal distribution, but the variable primary tumor SUVmax has normal distribution, which is the reason we use the correlation coefficient of Spearman). Between the primary tumor SUVmax and the lymph nodes SUVmax there was statistically significant (Р<0,05) positive weak correlation (r=0,297). Between the lymph nodes SUVmax and the survival there was statistically significant (Р<0,0001) moderate inverse correlation (r=-0,311). We use SUVmax as binary variable with borderline (Cutoff) point, defined through log-rank test and Wilcoxon test. At cutoff point equal to 4,5 for the lymph nodes SUVmax, the following NSCLC patients survival rate was estimated in months: for SUVmax<4,5, Mean=23,1, Median=16,8; for SUVmax 4,5, Mean=10,5, Median=7,1. The studied lymph nodes SUVmax factor was considered as a dichotomous variable. It had statistically significant influence on the survival of the NSCLC patients (Р<0,0001). On Fig. 2 is shown the graph for survival in relation to SUVmax of the lymph nodes. Fig. 2. Survival of the patients with NSCLC of the lung before treatment, with SUVmax of the lymph nodes below and over 4,5. Page 5 from 8

6 Statistically significant correlation was not established between the survival, the presence of lymph nodes with increased SUVmax and the histology of the primary tumor. Discussion Lymph nodes SUVmax is discussed as prognostic factor from different authors. Lymph nodes SUVmax less than 8 is a single prognostic factor for a progression free survival, free of distant metastases and overall survival of patients in III stage of NSCLC(1). The ratio between pretherapeutic lymph nodes SUVmax and tumor SUVmax over 0,9 together with performance state identifies the group with increased risk for death after radiotherapy (2). At ratio between pretherapeutic lymph nodes SUVmax and tumor SUVmax 0,56 and more there is 94% probability for malignant lymph node (3). А tumor/lymph node SUVmax ratio lower than 5 predicts the metastasis to lymph nodes with a high sensitivity (4). The value of SUVmax in malignant N2 lymph nodes is cited 4,4 (5), or 5,3 (6, 7). Lymph nodes metastasis are not detected in lung cancer when tumor SUVmax is less than 2,5, while in lung cancer with a tumor SUVmax more than 12 there is a 70% probability of lymph nodes metastasis. The likelihood of lymph nodes metastasis increases together with the primary tumor SUVmax increase (8). SUVmax is not a discriminant between minimal and extensive lymph nodes involvement in the malignant process (9). The patients without FDG uptake in the N2 lymph nodes after operation have better survival than the patients with FDG uptake in N2 lymph nodes (10). FDG uptake by the primary tumor may be an independent predictor of regional lymph node metastasis in patients with NSCLC (11, 12, 13, 14, 15). Another author does not find correlation between FDG uptake by the primary tumor and the metastases in the lymph nodes (16). PET is superior to CT in staging for lung cancer, yet it cannot detect metastatic focuses in the lymph nodes less than 4mm (17). Falsely positive lymph nodes are found to be due to granulomatous infection and silicosis (18) or due to reactive lymphadenitis (17). In lymph nodes defined as reactive in current study and among the falsely positive lymph nodes the histologic findings were of sinus histiocytosis, anthracosis, follicular hyperplasia and chronic lymphadenitis. The results from the current study find relation between the primary tumor SUVmax and the lymph nodes SUVmax; and between lymph nodes SUVmax and the patient survival. These relations are statistically significant (P<0,05). SUVmax over 4,5 defines the group of patients with increased risk for worse survival. Conclusion The survival of the NSCLC patients is significantly dependent on the regional lymph nodes SUVmax before treatment. Regional lymph nodes SUVmax before treatment over 4,5 is a cutoff point which defines a risk for worse survival and in operable patients it requires additional treatment procedures after the surgical intervention. Page 6 from 8

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