Post-chemoradiotherapy FDG PET with qualitative interpretation criteria for outcome stratification in esophageal squamous cell carcinoma

RESEARCH ARTICLE Post-chemoradiotherapy FDG PET with qualitative interpretation criteria for outcome stratification in esophageal squamous cell carcinoma Yung-Cheng Huang ID1, Shau-Hsuan Li2, Hung-I Lu3, Chien-Chin Hsu1, Yu-Ming Wang4, Wei-Che Lin5, Chao-Jung Chen6,7, Kuo-Wei Ho8, Nan-Tsing Chiu9* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, 2 Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, 3 Department of Thoracic and Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, 4 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, 5 Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, 6 Department of Nuclear Medicine, Yuan’s General Hospital, Kaohsiung, Taiwan, 7 Department of Health Business Administration, Meiho University, Pingtung, Taiwan, 8 Department of Nuclear Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan, 9 Department of Nuclear Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan OPEN ACCESS Citation: Huang Y-C, Li S-H, Lu H-I, Hsu C-C, Wang Y-M, Lin W-C, et al. (2019) Postchemoradiotherapy FDG PET with qualitative interpretation criteria for outcome stratification in esophageal squamous cell carcinoma. PLoS ONE 14(1): e0210055. https://doi.org/10.1371/journal. pone.0210055 Editor: Thomas Pyka, Technische Universitat Munchen, GERMANY Received: November 15, 2017 Accepted: December 17, 2018 Published: January 7, 2019 Copyright: © 2019 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This study was supported by research grant [CMRPG8F0681] from the Chang Gung Memorial Hospital in Kaohsiung. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. * Abstract Objectives Post-chemoradiotherapy (CRT) FDG PET is a useful prognosticator of esophageal cancer. However, debate on the diverse criteria of previous publications preclude worldwide multicenter comparisons, and even a universal practice guide. We aimed to validate a simple qualitative interpretation criterion of post-CRT FDG PET for outcome stratification and compare it with other criteria. Methods The post-CRT FDG PET of 114 patients with esophageal squamous cell carcinoma (ESCC) were independently interpreted using a qualitative 4-point scale (Qual4PS) that identified focal esophageal FDG uptake greater than liver uptake as residual tumor. Cohen’s κ coefficient (κ) was used to measure interobserver agreement of Qual4PS. The Kaplan-Meier method and Cox proportional hazards regression analyses were used for survival analysis. Other criteria included a different qualitative approach (QualBK), maximal standardized uptake values (SUVmax3.4, SUVmax2.5), relative change of SUVmax between pre- and postCRT FDG PET (ΔSUVmax), mean standardized uptake values (SUVmean), metabolic volume (MV) and total lesion glycolysis (TLG). PLOS ONE | https://doi.org/10.1371/journal.pone.0210055 January 7, 2019 1 / 14 PET with qualitative criteria for ESCC outcome stratification Competing interests: The authors have declared that no competing interests exist. Results Overall interobserver agreement on the Qual4PS criterion was excellent (κ: 0.95). Except the QualBK, SUVmax2.5, and TLG, all the other criteria were significant predictors for overall survival (OS). Multivariable analysis showed only Qual4PS (HR: 15.41; P = 0.005) and AJCC stage (HR: 2.47; P = 0.007) were significant independent variables. The 2-year OS rates of Qual4PS(–) patients undergoing CRT alone (68.4%) and patients undergoing trimodality therapy (62.5%) were not significant different, but the 2-year OS rates of Qual4PS(+) patients undergoing CRT alone (10.0%) were significantly lower than in patients undergoing trimodality therapy (42.1%). Conclusions The Qual4PS criterion is reproducible for assessing the response of ESCC to CRT, and valuable for predicting survival. It may add value to response-adapted treatment for ESCC patients, and help to decide whether surgery is warranted after CRT. Introduction Esophageal cancer is the sixth leading cause of cancer-related mortality worldwide, and the 5-year survival rate rarely exceeds 40% [1]. Most patients with esophageal cancer have advanced disease at the initial diagnosis, and are treated with neoadjuvant chemoradiotherapy (CRT) as the standard therapy [2]. A robust stratification of patient responses to CRT based on non-invasive tools has not yet been well developed. After neoadjuvant treatment, neither clinical parameters nor endoscopic ultrasonography or CT scans can reliably predict outcome. The post-CRT FDG PET, however, has emerged as a promising predictor of long-term survival, and it can be used to tailor individualized treatment for poor responders after neoadjuvant treatment [3]. Patients whose FDG PET results were a complete response might not benefit from added resection given their excellent outcomes without resection [4]. One study [5] reported that the pooled hazard ratio (HR) for a complete metabolic response (CMR) versus no response for OS was 0.51 (95% confidence interval [CI], 0.40–0.64) and for disease-free survival was 0.47 (95% CI, 0.38–0.57), respectively. Despite its utility for predicting outcomes, the lack of uniform and reliable criteria for post-CRT FDG PET interpretation appears to be the major drawback to using the reported criteria universally. Methods to improve the predictive value of PET include a qualitative approach, e.g., comparing the tumors with healthy surrounding tissue [6]; and quantitative approaches, e.g., comparing standardized uptake values (SUVs) with reported optimum SUV cut-off values, which vary from 2.5 to 4.5 [4, 7, 8], or comparing the relative reduction in SUV between pre- and post-CRT FDG PET (ΔSUV) with reported optimum cut-off values, which vary from 35% to 70% [9–11]. Wide ranges of sensitivities and specificities have been reported. The variations appear to depend upon the different sets of criteria—which are a matter of ongoing debate—used for FDG PET interpretation. Using a qualitative interpretative criterion for response assessment of FDG PET is well established and internationally recognized as the standar (...truncated)