The Value Of Interim ¹⁸F-FDG PET/CT Imaging In Prognostic Evaluation For Diffuse Large B-cell Lymphoma With Chemotherapy

Objective:To study the role of interim PET/CT assessment in the prognosis of diffuse large B-cell lymphoma,to explore the influence of clinical and interim PET/CT assessment parameters on prognosis,to identify patients at high risk of lymphoma early and to assist clinical development of individualized treatment plan,and to improve the survival of patients.Methods:1.The data of 120 patients（loss to follow up of 8）with diffuse large B-cell lymphoma（DLBCL）who has complete clinical and imaging data were collected in the Fourth Hospital of Hebei Medical University from January2011 to January 2020.All patients were statistically analyzed for gender,age,pathological subtype,ECOG score,lactate dehydrogenase（LDH）,clinical stage,in outside the junction involvement,international prognosis index（IPI）,National Comprehensive Cancer Network IPI（NCCN-IPI）,interim PET/CT results,progress-free survival（PFS）,and overall survival（OS）.All these patients underwent interim ¹⁸F-FDG PET/CT imaging after 3～4 cycles of chemotherapy,and no other tumors were found during the follow-up period,and no other treatment methods（such as surgical therapy or radiotherapy）.2.LIFEx 4.0 software is used to analyze the original PET/CT images.To maximize the standardized values(SUV_max)taken the 40%threshold,the metabolism of the top sketch in lesions interested area（region of interest,ROI）,the lesion biggest standardization to perturbation values(SUV_max),metabolic tumor volume（MTV）and the total lesion glycolysis（TLG）,and record the whole body all lesions（TMTV,TTLG）total metabolic parameters,measuring up to 6 target lesion on CT image of the maximum transverse diameter and perpendicular to the maximum transverse diameter of the sum of product of short diameter（SPD）.Receiver operating characteristic curve（ROC）was used to calculate the optimal bounds of interim PET/CT parameters(SUV_max,MTV,TMTV,TLG,TTLG,SPD,LD_max),and patients were divided into high and low group according to the optimal bounds.According to Deauville Score（DS）,patients were divided into two groups:the DS score 1～3 was divided into negative group,and the DS score 4～5 was divided into positive group.Progress Free Survival（PFS）and Overall Survival（OS）were used as endpoints,respectively.We used Kaplan-Meier survival function and Log-rank test to analyze the relationship between clinical characteristics（including gender,age,level of lactate dehydrogenase,ECOG score,stage,whether there is more than 1 knot outside involvement,cell origin of molecular subtypes,IPI and NCCN-IPI score,chemotherapy）,PET/CT parameters(SUV_max,MTV,TMTV,TLG,TTLG,SPD,LD_max),DS score and prognosis of patients with DLBCL.Cox proportional risk model was used for multivariate analysis,and P<0.05 was considered statistically significant.Results:1.A total of 120 cases of diffuse large B-cell lymphoma were included in the study,including 8 cases lost to follow-up,and 112 cases with complete data:60 males and 52 females.were sampled,including 8 cases lost to follow-up,and 112 cases with complete data:60 males and 52 females.The median age was 54（16～79）years.Among 112 patients,there were 80 patients with specific molecular subtypes,51 patients with non-GCB and 29 patients with BCG.25 patients developed disease progression,and 14 died due to diffuse large B-cell lymphoma.The median PFS was 36 months（95%CI29.465～42.535）,and the rates of PFS at 1,3,5 years were respectively 90.2%,39.3%and 16.1%;the median OS was 35 months（95%CI 29.368～40.712）,and the 1,3,5-years survival rates were 94.6%,42.9%and 19.6%,respectively.2.The threshold of interim PET/CT parameters by ROC:when PFS was used as the research endpoint,the threshold values of SUV_max,MTV,TMTV,TLG,TTLG and SPD were 1.75,2.30cm³,6.40cm³,6.10g,9.30g and 3.53cm²,respectively;when OS was the endpoint of the study,the threshold were 3.75,7.05cm³,17.80cm³,18.5g,19.05g and 5.67cm²,respectively.LD_max lacks diagnostic efficacy in prognosis of DLBCL patients.3.Kaplan-Meier survival function was used to analyze the relationship between PET/CT parameters and prognosis when PFS was used as the study endpoint:the prognosis of the high-value group(SUV_max≥1.75,MTV_max≥2.3cm³,TMTV≥6.4cm³,TLG≥6.1g,TTLG≥9.3g and SPD≥3.53cm²)was worse than that of the low-value group(SUV_max<1.75,MTV<2.3cm³,TMTV<6.4cm³,TLG<6.1g,TTLG<6.4g and SPD<3.53cm²).There were statistically significant differences in PFS（P=0.006,P=0.011,P=0.001,P=0.001,P=0.001,P=0.00）.With OS as the end point,the prognosis of the high-value group(SUV_max≥3.75,MTV≥7.05cm³,TMTV≥17.8cm³,TLG≥18.5g,TTLG≥19.05g and SPD≥5.67cm²)was worse than that of the low-value group(SUV_max<3.75,MTV<7.05cm³,TMTV<17.8cm³,TLG<18.5g,TTLG<19.05g and SPD<5.67cm²),and the difference of OS among all groups was statistically significant（P=0.001,P=0.000,P=0.000,P=0.000,P=0.000）.The median PFS and OS（26 and 28.5 months,respectively）of patients in DS positive group（DS 4～5 score）were shorter than those in the negative group（DS 1～3 score）（29 and 32.5 months,respectively）,and the differences were statistically significant（PFS P=0.000and OS P=0.009）.4.Patients were grouped by combining clinical factors and PET/CT parameters.Kaplan-Meier survival function analysis was used to compare PFS and OS in each group.When PFS was used as the endpoint of the study:combining with age and SUV_max,the median PFS of four groups of young and low SUV_max(age<60 and SUV_max<1.75),young and high SUV_max(age<60 and SUV_max≥1.75),old and low SUV_max(age≥60 and SUV_max<1.75),old and high SUV_max(age≥60 and SUV_max≥1.75)were 27,35,32,19 months,respectively,the difference was statistically significant（P=0.0004）;combining stage and TTLG:the median PFS of four groups with early stage and low TTLG（Ⅰ,Ⅱperiod and TTLG<9.3g）,early stage and high TTLG（Ⅰ,Ⅱperiod and TTLG≥9.3g）,later period and low TTLG（Ⅲ,Ⅳperiod and TTLG<9.3g）,later period and high TTLG（Ⅲ,Ⅳperiod and TTLG≥9.3g）were 31,29,27.5,24.5 months,and the difference has statistical significance（P=0.001）.Combined with IPI and TMTV,the patients were divided into four groups with statistically significant differences in PFS（P=0.000）:the median PFS of low IPI and low TMTV（IPI 0～2 and TMTV<6.4cm³）,low IPI and high TMTV（IPI 0～2 and TMTV≥6.4cm³）,high IPI and low TMTV（IPI 3～5 and TMTV<6.4cm³）,high IPI and high TMTV（IPI 3～5 and TMTV≥6.4cm³）were33,36,26,22 months,respectively.Taking OS as the end point of the study,the group was divided according to above methods:the median OS of four groups of young and low SUV_max(age<60 and SUV_max<3.75),young and high SUV_max(age<60 and SUV_max≥3.75),old and low SUV_max(age≥60 and SUV_max<3.75),old and high SUV_max(age≥60 and SUV_max≥3.75)were 31,37,31.5 and 17months,respectively,with statistical significance（P=0.000）;early stage and low TTLG（Ⅰ,Ⅱperiod and TTLG<19.05g）,early stage and high TTLG（Ⅰ,Ⅱperiod and TTLG≥19.05g）,later period and low TTLG（Ⅲ,Ⅳperiod and TTLG<19.05g）,later period and high TTLG（Ⅲ,Ⅳperiod and TTLG≥19.05g）four groups of OS also statistically difference（median OS is respectively 32,32,31,27.5 months,P=0.000）.Combined with IPI and TMTV,the median OS of low IPI and low TMTV（IPI 0～2 and TMTV<17.8cm³）,low IPI and high TMTV（IPI 0～2 and TMTV≥17.8cm³）,high IPI and low TMTV（IPI 3～5 and TMTV<17.8cm³）,high IPI and high TMTV（IPI 3～5 and TMTV≥17.8cm³）were 35,41.5,26,19 months,respectively,and the differences among all groups were statistically significant（P=0.000）.5.Univariate analysis showed that interim PTE/CT parameters(including SUV_max,MTV,TMTV,TLG,TTLG and SPD)were both related to patients’PFS and OS,and were prognostic factors in DLBCL patients.Age,ECOG score,IPI and NCCN-IPI were correlated with PFS and OS,and they were prognostic factors for DLBCL patients,while LDH was only a prognostic factor for OS and lacked of diagnostic performance for PFS.Multivariate analysis showed that only age,ECOG score and TLG of the lesion with maximum SUV_max were independent prognostic factors for DLBCL patients.Conclusions:1.All the parameters of interim PET/CT(SUV_max,MTV,TMTV,TLG,TTLG and SPD)were correlated with the prognosis of patients.Patients higher than the optimal ROC curve threshold had a poor prognosis,while patients lower than the ROC curve threshold had a relatively good prognosis,which indicated that interim PET/CT parameters had a certain value in the prognosis evaluation of DLBCL patients,and TLG of the lesion with maximum SUV_max was an independent prognostic factor for DLBCL patients.2.Patients in groups with age≥60 years,ECOG score≥2,high-,high-intermediate-risk according to IPI and NCCN-IPI had worse prognosis than that of patients with age<60 years,ECOG score<2,low-,low-intermediate-risk according to IPI and NCCN-IPI,which indicating that age,ECOG score,IPI and NCCN-IPI were correlated with the prognosis of patients in DLBCL.Age≥60 years,ECOG score≥2 were independent adverse prognostic factors for disease progression or death during follow-up.3.Interim PET/CT parameters were combined with clinically relevant prognostic factors:PFS and OS of patients in group with age≥60 years and high SUV_max,Ⅲ、Ⅳperiod and high TTLG,high-,high-intermediate-risk according to IPI and high TMTV were the shortest.indicating that the combination of the two factors can improve risk stratification of patients,and has a certain predictive value for the prognosis of patients with different stratification.