Comparison of therapeutic evaluation criteria in FDG-PET/CT in patients with diffuse large-cell B-cell lymphoma: Prognostic impact of tumor/liver ratio

RESEARCH ARTICLE Comparison of therapeutic evaluation criteria in FDG-PET/CT in patients with diffuse largecell B-cell lymphoma: Prognostic impact of tumor/liver ratio Mathieu N. Toledano1,2, Pierre Vera1,2, Hervé Tilly3,4, Fabrice Jardin3,4, Stéphanie Becker ID1,2* 1 Nuclear Medicine Department, Henri Becquerel Cancer Center, Rouen, France, 2 QuantIF–LITIS (EA 4108-FR CNRS 3638), Faculty of Medicine, University of Rouen, Rouen, France, 3 INSERM U1245, Centre Henri Becquerel, Rouen, France, 4 Hematology department, Centre Henri Becquerel, Rouen, France a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 * Abstract Purpose OPEN ACCESS Citation: Toledano MN, Vera P, Tilly H, Jardin F, Becker S (2019) Comparison of therapeutic evaluation criteria in FDG-PET/CT in patients with diffuse large-cell B-cell lymphoma: Prognostic impact of tumor/liver ratio. PLoS ONE 14(2): e0211649. https://doi.org/10.1371/journal. pone.0211649 Editor: Giorgio Treglia, Ente Ospedaliero Cantonale, SWITZERLAND Received: October 23, 2018 Accepted: January 17, 2019 Published: February 7, 2019 Copyright: © 2019 Toledano 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 manuscript and its Supporting Information files. Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. The study objective was to compare the prognostic value of interim and end-of-treatment FDG PET/CT using five therapeutic evaluation criteria in patients with diffuse large B cell lymphoma (DLBCL). Methods 181 patients were retrospectively analysed. All patients underwent FDG-PET at baseline and after four cycles (iPET4) of first-line chemotherapy and 165 at the end-of-treatment (PET-eot). Ratio Deauville score (rDS) (SUVmax-target residual lesion/SUVmax-liver) was measured in iPET4 and PET-eot, and its optimal threshold was determined using receiver operating characteristic (ROC) curve analysis. Deauville score (DS) (iPET4 and PET-eot), ΔSUVmax, ΔSUVmax determined according to Menton 2011 criteria (ΔSUVmax+DS) and ΔSUVmax+rDS were also evaluated (iPET4 only). Median follow-up was 44 months. Results ROC analysis revealed the optimal cut-off value was 1.4-fold of SUVmax-liver on iPET4 and PET-eot. On iPET4, positive predictive value (PPV) of rDS was significantly better than DS: 81.58% vs. 67.79%. In univariate analysis, the five interpretation methods were statistically significant (p<0.0001 for progression-free survival [PFS] and overall survival [OS]). In multivariate analysis, only rDS was an independent prognostic factor (p = 0.0002 and p<0.0001 for PFS and OS, respectively). On PET-eot, similarly, the two therapeutic evaluation criteria analysed (rDS and DS) were statistically significant at the univariate level (p<0.0001). rDS was the only significant prognostic factor in multivariate analysis (p<0.0001). PPV and accuracy of rDS were also better than DS. PLOS ONE | https://doi.org/10.1371/journal.pone.0211649 February 7, 2019 1 / 16 PET evaluation criteria in DLBCL Conclusions rDS with a tumor/liver ratio of 1.4 is a robust prognostic factor in patients with DLBCL on iPET4 and PET-eot. Introduction Despite the improvement made by immunochemotherapy, 30% to 40% of patients diagnosed with large-B-cell lymphoma (DLBCL) will relapse [1], with a majority of patients dying of the disease [2]. It is therefore crucial to identify these nonresponder patients to offer them new treatments. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been widely validated as a prognostic tool in DLBCL and Hodgkin lymphoma (HL) for both interim and end-of-treatment [3–7]. Interpretation criteria have evolved to decrease false positives, and the current recommendations are to use Deauville criteria (5-point scale-Deauville Score [DS]) with a positive PET defined by tumor residual uptake moderately higher than liver (score 4) or two to three times the liver SUVmax (score 5). These criteria are applicable for both interim and end-of-treatment PET [3]. However, at present, changing treatment solely based on interim PET (iPET) is not recommended outside clinical trials [3]. Indeed, a negative iPET is truly negative (e.g., high negative predictive value [NPV]) in most cases, whereas positive iPET may be truly or falsely positive, with a high percentage of patients with abnormal uptake presenting a good outcome [8]. Studies using Deauville criteria analysis with a cut-off >3 for iPET in DLBCL reported good NPV with 2-year PFS rates between 84% and 85%, whereas the PPV ranges from 25% to 55% [9–11]. To improve iPET’s PPV, a quantitative approach was proposed after 2 and 4 courses of chemotherapy with a ΔSUVmax based on the reduction of tumor SUVmax from baseline. The ΔSUVmax method has shown to be more reproducible between readers and more robust than Deauville criteria by decreasing the number of false positives [4–7]. The PETAL study, including 600 patients with DLBCL, demonstrated that the ΔSUVmax approach with a cut-off of 66% of reduction (iPET2) was highly predictive of outcome [12]. However, it does not appear effective for lowrisk (International Prognostic Index [IPI] �1) patients, for whom the DS is accurate [13]. In addition, the determination of ΔSUVmax has been modified according to Menton 2011 criteria [14], and these modified criteria were never validated (ΔSUVmax if eligible patient and DS if SUVmax initial tumor <10 and or if SUVmax residual tumor >5). Several authors suggested a quantitative adaptation of the DS to better separate a score 3 and 4 in HL [15, 16], DLBCL [17–19] and follicular lymphoma (FL) [20], using a ratio between the residual uptake and the liver. The aim of this study was to compare the prognostic value of these different therapeutic evaluation criteria after four courses of immunochemotherapy (iPET4) and at the end-oftreatment PET (PET-eot) in patients with DLBCL: ratio Deauville score (rDS), visual DS, ΔSUVmax, ΔSUVmax determined according to Menton 2011 criteria and ΔSUVmax + rDs. Methods Study population This monocentric study was approved by the Henri Becquerel centre review board (n˚1804B). Patients were informed about the use of anonymized data for research and their right to oppose this use. The study enrolled 181 patients between July 2005 and September 2014, who were retrospectively evaluated. The inclusion criteria were as follows: DLBCL confirmed in all PLOS ONE | https://doi.org/10.1371/journal.pone.0211649 February 7, 2019 2 / 16 PET evaluation criteria in DLBCL patients by a histopathologic review of a baseline biopsy, treatment using an anthracyclinecontaining regimen with rituximab; R-CHOP chemother (...truncated)