Clinical Application ¹⁸F-FDG PET/CT In The Prognostic Prediction Of Diffuse Large B-cell Lymphoma

Part Ⅰ Clinical Application of Interim Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Prognostic Prediction of Diffuse Large B-cell Lymphoma:a New Prognostic ScoreBackground:Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), which hugely threatened human health. Increased morbidity and mortality rates have been reported in recent years. First-line treatment response of patients with DLBCL was affected by many factors such as pathophysiological, biological and pharmaceutical mechanisms. Therefore, the ability to accurately categorize patients into distinct prognostic groups (with significant outcome differences) is becoming an urgent necessity for clinicians. This retrospective study aimed to evaluate the predictive significance of clinical prognostic factors and interim 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging, and to find a new prognostic predictor significantly associated with DLBCL patients outcome.Methods:A total of 105 adult patients with DLBCL were reviewed (basic information such as age, sex, stage and so on, blood test, histopathological subtypes, and imaging examinations). Each patient underwent an interim 18F-FDG PET/CT scan after the second chemotherapy cycle. PET/CT image acquisition parameters were as follows: first, CT parameters, peak voltage,120 kV; tube current,80 mA/s; matrix,512x512; field of view,50cm; and slice thickness,3.75mm. Then PET scans were performed with a 128x128 matrix, a 15.7cm axial field of view, and in 6-8 bed positions (150 s acquisition time per bed position). The CT data were used for attenuation correction. The visual method based on the Deauville five-point scale was used to evaluate the interim-PET/CT scans. The Deauville five-point scale on interim PET analysis was listed as follows:1, no FDG uptake; 2, FDG uptake< mediastinum; 3, FDG uptake> mediastinum but< liver; 4, FDG uptake moderately increased compared to the liver at any site; 5, FDG uptake markedly increased compared to the liver at any site and new sites and/or new sites of disease. All statistical analyses were performed using the SPSS 19.0 statistical software package. Progression-free survival rate (PFS) and overall survival rate (OS) were depicted using Kaplan-Meier plots. The relationships among the prognostic factors, the 3-year PFS and OS were analyzed with log-rank test. The predictive value of the newly constructed prognostic score was analyzed with multivariate analysis (Cox proportional hazard regression model). PFS was defined as the interval between the date of diagnosis and the date of lymphoma progression, first relapse, death from any cause or the last follow-up date. OS was deemed to be the time from the date of diagnosis until death from any cause or the last follow-up date.Results:The median age was 56 years (range 19-82 years) with a slight male predominance (54.3%).40.0% of patients had over 60 years old. Forty six patients (43.8%) were presented in advanced stage (III/IV). According to immunohistochemical technique,64 patients were subclassified as germinal center B-cell-like (GCB) DLBCL and 41 patients were non-GCB DLBCL. Among the 105 patients,19 (18.1%) had a positive interim-PET/CT after the second cycle of chemotherapy, while the other 86 patients (81.9%) had a negative interim-PET/CT. The 3-year PFS and OS rates in patients with positive and negative interim-PET/CT were 21.1% and 90.7%, and 42.1% and 96.5%, respectively. The visual analysis showed statistically significant differences in both PFS and OS between the patients with a negative interim-PET/CT and those with a positive interim-PET/CT (P<0.001). Univariate analysis of PFS and OS in DLBCL patients showed age, ECOG, extranodal involvement, stage, bulky disease, histopathological subtype and interim-PET/CT were significantly associated with outcome. Multivariate analysis demonstrated that only age, stage, histopathological subtype and interim-PET/CT left could predict outcome (relapse or death). A new prognostic score that composed of the above four factors was obtained. New prognostic score stratified patients into four risk groups with 3-year PFS of 98.5%,73.9%,11.1% and 0%, and 3-year OS of 100%, 91.3%,55.6% and 0%(P<0.001 for PFS and OS). Multivariate analysis showed that the new prognostic score had the greatest ability to predict relapse [hazard ratio (HR) 8.444 (4.193-17.007), P<0.001] and death [HR 8.582 (4.220-17.452), P<0.001].Conclusions:In DLBCL patients, interim 18F-FDG PET/CT can provide significant independent prognostic information. This work illustrates that the new prognostic score has the strongest potential for accurately prognostication, for stratification in clinical trials, and for design of novel strategies for DLBCL patients in the high-risk group.Part Ⅱ Clinical Application of Pre-ASCT18F-FDG PET/CT in the Prognostic Prediction of Relapsed Diffuse Large B-cell LymphomaBackground:Diffuse large B-cell lymphoma (DLBCL) is one of the few malignant tumor can completely cure through chemotherapy. About 60% of DLBCL patients can completely cure according to first-line therapy, however, approximately 40% of patients eventually relapse after complete remission or be a refractory lymphoma, and the prognosis of patients with this type are generally poor. How to improve the quality of patients life and prolong patients survival are the concern for clinicians. The most common treatment method for patients with relapse/refractory DLBCL was second-line chemotherapy (salvage chemotherapy). However, patients response to salvage chemotherapy are varied and influenced by various factors. Generally, patients who are complete or partial remission after second-line chemotherapy, high-dose chemotherapy followed by autologous stem-cell transplantation (HDT/ASCT) is recommended. This therapy strategy has been considered as the standard of care for relapsed DLBCL patients with chemoresponsive disease. Therefore, there is significant to identify patients who may benefit from salvage chemotherapy. This retrospective study aimed to evaluate the prognostic significance of performing Fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) before HDT/ASCT in patients with chemosensitive relapsed DLBCL, and to compare the clinical usefulness of two PET interpretations (semi-quantitative and visual analysis).Methods:Totally 93 eligible patients with relapsed DLBCL were retrospectively reviewed. Patients were histological-proven DLBCL with first recurrence.18F-FDG PET scans were performed and the images were evaluated according to the visual method (based on Deauville five-point scale) and semi-quantitative analysis (based on maximal standardized uptake value reduction, ΔSUVmax). All statistical analyses were performed using the SPSS 19.0 statistical software package. The association among qualitative variables was assessed using the chi-squared test or Fisher’s exact test. The ROC curve was used to determine the optimal cut-off value of ΔSUVmax for predicting PFS and OS. The relationship between PET results and the 3-year progression-free survival (PFS), and the 3-year overall survival (OS) was analyzed with Kaplan-Meier plots and a log-rank test for categorical variables and multivariate analysis (Cox proportional hazard regression model) for continuous variables. PFS was defined as the interval from ASCT to the date of objective evidence of lymphoma recurrence/progression, or death for any reason. OS was calculated from ASCT until death from any cause.Results:The median age was 45 years (range 19-67 years) with a slight male predominance (54.8%).25.8% of patients had over 55 years old. Fifty-nine patients (63.4%) were presented in advanced stage (Ⅲ/Ⅳ). According to immunohistochemical technique,39 patients were subclassified as germinal center B-cell-like (GCB) DLBCL and 54 patients were non-GCB DLBCL. Visual method showed that the 3-year PFS and OS were 76.2% and 92.1% for relapsed patients with Deauville score<3, and 50.0% and 63.3% for those with Deauville score>3 (P<0.001). ROC curve proved the optimal cut-off value of ΔSUVmax was 73.6%. Semi-quantitative analysis showed that the 3-year PFS and OS were 82.1% and 95.5% in patients with ΔSUVmax>73.6% in contrast to 30.8% and 50.0% in patients with ΔSUVmax<73.6%(P<0.001). Univariate analysis of PFS in relapsed DLBCL patients showed extranodal sites at relapse, symptomatic relapse, sAA-IPI and PET/CT results had the ability to predict posttransplantation recurrence. Clinical factors prior to salvage treatment including age, sex, histological types, stage, LDH, Karnofsky performance status and bulky disease lacked prognostic significance. Univariate analysis of OS showed symptomatic relapse, sAA-IPI and PET/CT results had the ability to predict overall survival, but such factors as age, sex, histological types, stage, LDH, Karnofsky performance status, extranodal sites and bulky disease showed no significant differences in predicting OS. Multivariate analysis demonstrated ΔSUVmax had the greatest ability to predict posttransplantation recurrence [hazard ratio (HR) 6.824 (3.296-14.129), P<0.001] and outcome [HR 12.427 (5.060-30.520), P<0.001].Conclusions:Pre-ASCT F-FDG PET/CT is the most important independent prognostic predictor in relapsed DLBCL patients undergoing HDT followed by ASCT. Semi-quantitative analysis has superior predicted value than visual analysis in relapsed DLBCL patients.