Total Lesion Glycolysis Determined per RECIST 1.1 Criteria Predicts Survival in EGFR Mutation-Negative Patients With Advanced Lung Adenocarcinoma Tsung-Ying Ho, MD,* Pai-Chien Chou, MD, PhD,† Cheng-Ta Yang, MD,† Ngan-Ming Tsang, MD, PhD,‡ and Tzu-Chen Yen, MD, PhD* Objective: The aim of this retrospective study was to investigate the clinical im- pact of 18 F-FDG PET in patients with advanced lung adenocarcinoma stratified according to the epidermal growth factor receptor (EGFR) mutation status. Patients and Methods: A total of 56 patients with advanced lung adenocarci- noma were included in the study. Thirty-one patients (55%) were EGFR mutation-positive, whereas the remaining 25 (45%) participants tested negative for EGFR mutations. All of the patients underwent 18 F-FDG PET/CT for pre- treatment planning. The main outcome measure was overall survival (OS) at 24 months. The following 18 F-FDG PET/CT-derived variables were tested for their associations with OS: main tumor SUV max , main tumor total lesion glycol- ysis, and target lesions TLG determined per RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria (TLG RECIST ). We also investigated the clinical characteristics in relation to OS and EGFR mutation status. Results: In EGFR mutation-positive patients, neither the clinical characteristics nor 18 F-FDG PET/CT-derived parameters were significantly associated with OS. In contrast, univariate analysis identified male sex, a positive history of smoking, and TLG RECIST greater than or equal to 412 g as adverse prognostic factors for OS in EGFR mutation-negative patients. After adjustment for poten- tial confounders in multivariate analysis, TLG RECIST was the sole independent predictor of OS in this subgroup. Conclusions: TLG determined per RECIST 1.1 criteria is an independent predic- tor of OS in EGFR mutation-negative patients with advanced lung adenocarci- noma. Further studies are needed to investigate whether this parameter may be a promising tool for stratifying such patients for risk-adapted therapies. Key Words: lung cancer, adenocarcinoma, epidermal growth factor receptor mutations, 18 F-FDG PET, total lesion glycolysis, RECIST 1.1 (Clin Nucl Med 2015;40: e295–e299) L ung cancer remains a leading cause of cancer-related mortality worldwide. It is not only the most commonly diagnosed but also ranked first in terms of cause of cancer deaths globally. 1 In addition, the majority of lung cancer patients are diagnosed at ad- vanced stage. 2 The main prognostic factors in lung cancer include clinical variables and the presence of epidermal growth factor receptor (EGFR) mutations. 3 Importantly, the prevalence of EGFR mutations is ethnicity dependent, with a higher proportion in Asian (51.4%) than in whites (13.7%). 4,5 To date, little is known about the prognostic significance of 18 F-FDG PET/CT-derived variables in relation to EGFR muta- tions among patients with lung cancer. We therefore designed this retrospective study to investigate the clinical impact of 18 F-FDG PET- derived parameters in patients with advanced (≥ stage IIIB) lung adeno- carcinoma stratified according to the EGFR mutation status. PATIENTS AND METHODS Patients A total of 56 patients with histology-proven lung adenocarci- noma in advanced stage (≥ stage IIIB) were included in the study. Thirty-one patients (55%) were EGFR mutation-positive, whereas the remaining 25 (45%) participants tested negative for EGFR mutations. All of the participants were followed up for at least 24 months or cen- sored at the date of the last follow-up. Staging was performed using the Seventh Edition of the American Joint Committee on Cancer Stag- ing System published in 2010. Each patient's stage was determined by the consensus reached in our tumor board conference. The study proto- col was approved by the institutional review board of the Chang Gung Memorial Hospital (IRB: 102-2413B). 18 F-FDG PET/CT Imaging All 18 F-FDG PET/CT scans were performed on either Discovery ST 16 PET/CT scanner (GE Healthcare, Milwaukee, Wis) or Siemens Biograph mCT PET/CT scanner (Siemens Healthcare Molecular Im- aging, Hoffman Estates, Ill). After 6 hours of fasting, patients were injected intravenously with 370 to 444 MBq (10–12 mCi) 18 F-FDG. Pa- tients were scanned at 50 minutes from the mid thigh to the skull vertex. CT data were used for both attenuation correction and fusion with attenuation-corrected PET images. Images were reconstructed using or- dered subsets expectation maximization (4 iterations and 10 subsets). All PET, CT, and PET/CT images were displayed in axial, coronal, and sagittal views. PET data were also displayed in a rotating MIP. Two nuclear medicine physicians independently reviewed all PET imaging results. Abnormal 18 F-FDG uptake was defined as focal increased activity higher than the background activity. Regions of in- terest were measured over lesions visible on PET images. The SUV was calculated according to the following formula: SUV = radioactivity concentration in tissue [becquerel/gram]/(injected dose [becquerel]/ patient weight [gram]). EGFR Mutation Analysis Exons 18 to 21 of the EGFR gene were amplified and subjected to direct sequencing as previously described. 6 Lesion Analysis per RECIST 1.1 Criteria The following lesions were selected using the RECIST (Re- sponse Evaluation Criteria In Solid Tumors) 1.1 criteria: pulmonary main tumor with longest diameter greater than or equal to 10 mm, lymph nodes with longest diameter greater than or equal to 15 mm in short axis, and solid metastatic lesions with longest diameter greater than or equal to 10 mm. All measurable lesions up to a maxi- mum of 5 lesions per patient and 2 lesions per organ were included in the analysis. 7 Received for publication June 12, 2014; revision accepted January 26, 2015. From the Departments of *Nuclear Medicine and Molecular Imaging Center, †Thoracic Medicine and ‡Radiation Oncology, Chang Gung Memorial Hos- pital at Linkou, Taoyuan, Taiwan, Republic of China. Drs Tsung-Ying Ho and Pai-Chien Chou contributed equally to this work. Conflicts of interest and sources of funding: none declared. Reprints: Tzu-Chen Yen, MD, PhD, Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital at Linkou, No 5, Fu-Hsing St, Kwei-Shan, Taoyuan, Taiwan, Republic of China. E-mail: yentc1110@gmail.com. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0363-9762/15/4006–e295 ORIGINAL ARTICLE Clinical Nuclear Medicine • Volume 40, Number 6, June 2015 www.nuclearmed.com e295 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.