A Series Of Studies On Radionuclide Imaging And Targeted Therapy Of Neuroendocrine Tumor

Project ⅠA prospective head-to-head comparison of 68Ga-NOTA-3P-TATERGD and 68Ga-DOTATATE in patients with gastroenteropancreatic neuroendocrine tumoursPurpose:The aim of this study was to compare 68Ga-NOTA-3P-TATE-RGD,a dual somatostatin receptor 2-and integrin αvβ3-targeting tracer,to 68Ga-DOTATATE in a single group of patients with gastroenteropancreatic(GEP)-neuroendocrine tumours(NETs).Methods:Thirty-five patients with histologically confirmed GEP-NETs(5 Grade 1,28 Grade 2,and 2 Grade 3 tumors)were prospectively enrolled with informed consent.The primary tumour mainly originated from pancreas and rectum.All patients were scanned with both 68Ga-NOTA-3P-TATE-RGD PET/CT and 68Ga-DOTATATE PET/CT within a week and compared on a head-to-head basis.Sixteen patients also had conventional 18F-FDG PET/CT.Images were evaluated semi-quantitatively using maximum standardized uptake values(SUVmax)of tumour and tumour-to-background ratio.Results:All patients had at least one positive lesion on each of the two scans.A total of 1190 and 1106 lesions were detected on 68Ga-NOTA-3P-TATE-RGD images and 68Ga-DOTATATE images,respectively(P=0.152).68Ga-NOTA-3P-TATE-RGD PET/CT revealed significantly more lesions in the liver than 68Ga-DOTATATEPET/CT(634 vs.532,P=0.021).Both tracers produced comparable results for detecting primary tumours(20 vs.20,P=1.000),lymph node metastases(101 vs.102,P=0.655),and bone metastases(381 vs.398,P=0.244).The tumour SUVmax in 12 patients was significantly higher for 68Ga-NOTA-3P-TATE-RGD than for 68Ga-DOTATATE(27.2±13.6 vs.19.5± 10.0,P<0.001);among them,9 had 18F-FDG PET/CT and all were found to be FDG-positive.The remaining 23 patients had significantly higher 68GaDOTATATE uptake than 68Ga-NOTA-3P-TATE-RGD(22.3±16.4 vs.11.9 ±7.5,P<0.001);among them,7 had 18F-FDG PET/CT and 6 were FDG-negative.Generally,68Ga-DOTATATE demonstrated higher tumour SUVmax than 68Ga-NOTA-3P-TATERGD(20.8 ±16.0 vs.14.2±8.9,P<0.001),including primary tumours,liver lesions,lymph node lesions,and bone lesions.However,the tumour-to-background ratio of liver lesions was significantly higher when using 68Ga-NOTA-3P-TATE-RGD compared with 68Ga-DOTATATE(8.4 ± 5.5 vs.4.7±3.7,P<0.001).Conclusion:68Ga-NOTA-3P-TATE-RGD performed better than 68Ga-DOTATATE in detection of liver metastases with a higher tumour-to-background ratio.Moreover,68Ga-NOTA-3P-TATE-RGD tended to demonstrate higher uptake over 68GaDOTATATE in FDG-avid NETs.Project ⅡSafety and efficacy of peptide receptor radionuclide therapy with 177Lu-DOTA-EB-TATE in patients with metastatic neuroendocrine tumorsRationale:This study aimed to assess the safety,efficacy,and survival of 177Lu-DOTAEB-TATE in patients with metastatic neuroendocrine tumors(NETs).Methods:Thirty patients with metastatic NETs were prospectively enrolled and treated with 177Lu-DOTA-EB-TATE(3 intended cycles at 8 to 12-week intervals,3.7 GBq/cycle).Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE),version 5.0.The treatment response was graded according to RECIST 1.1 and PERCIST 1.0 criteria.Kaplan-Meier analysis was performed to calculate progression-free survival(PFS)and overall survival(OS).Results:Patients tolerated therapy well without acute adverse effects.During peptide receptor radionuclide therapy(PRRT),no grade 4 toxicity was observed in any of the patients;grade 3 hematotoxicity was recorded in 4 patients,including grade 3 thrombocytopenia in 4 patients(13.3%)and grade-3 anemia in 1 patient(3.3%);grade 3 hepatotoxicity was recorded in 1(3.3%)patient,and no grade 2/3/4 nephrotoxicity was observed.On long-term follow-up,none of the patients developed grade 4 hematotoxicity or nephrotoxicity of any grade,reversible grade 3 hematotoxicity(thrombocytopenia)occurred in 1 patient.There was no incidence of leukemia or myelodysplastic syndrome for the duration of follow-up.Of 27 patients with RECISTmeasurable disease,partial response and stable disease were seen in 9 and 14 patients,respectively,resulting in a response rate of 33.3%and disease control rate of 85.2%.Of 29 patients evaluable for response on 68Ga-DOTATATE PET/CT,14 had partial response and 11 had stable disease,with a response rate of 48.3%and disease control rate of 86.2%.The follow-up period ranged from 5 to 57 months after the first 177LuDOTA-EB-TATE PRRT with a median follow-up of 46 months.The median PFS was 36 months,and the median OS was not reached.Ki-67 index of greater than 10%was associated with poorer PFS(P=0.012).Conclusions:Our results suggest that PRRT with approximately 3.7 GBq 177LuDOTA-EB-TATE has acceptable toxicity profile and is effective in treating metastatic NET with high disease control rate.In addition,177Lu-DOTA-EB-TATE achieved a favorable survival outcome with encouraging PFS.Project ⅢSafety,Biodistribution and Dosimetry of a Long-Acting Radiolabeled Somatostatin Analogue 177Lu-DOTA-EB-TATE with and without Amino Acid InfusionPurpose:Kidney is considered to be one of the dose-limiting organs in peptide receptor radionuclide therapy(PRRT).Amino acid cocktail infusion has been applied to reduce renal absorbed dose by inhibiting the proximal tubular reabsorption of the radiopeptide.An Evans blue-modified 177Lu-labeled octreotate(177Lu-DOTA-EB-TATE)has an extended circulation in the blood,which may make the amino acid infusion unnecessary.The aim of this study was to evaluate the safety,biodistribution and dosimetry of 177LuDOTA-EB-TATE with and without amino acid infusion.Methods:Ten patients with metastatic neuroendocrine tumors(NETs)were randomly divided into 2 groups.The effect of amino acid infusion on renal uptake was assessed in a crossover randomized setting.Group A received 177Lu-DOTA-EB-TATE at a dose of 3.7 GBq without amino acid infusion for the first cycle and with amino acid infusion for the second cycle;group B received 177Lu-DOTA-EB-TATE at a dose of 3.7 GBq with amino acid infusion for the first cycle and without amino acid infusion for the second cycle.All patients underwent serial whole-body planar imaging at 1,24,96 and 168 h and SPECT scan at 24 h after radioligand administration.Abdominal CT was performed 2 days before PRRT for SPECT/CT fusion.The dosimetry was calculated using the HERMES software.Dosimetry evaluation were compared on a betweengroup and intra-patient basis.Results:Administrations of 177Lu-DOTA-EB-TATE with or without amino acids were well tolerated.No grade 4 hematotoxicity was observed in any of the patients.Grade 3 thrombocytopenia was reported in 1 patient.No grade 2/3/4 nephrotoxicity was recorded.No significant difference was observed in creatinine(75.1 ± 21.7 vs.67.5±18.1,P=0.128),blood urea nitrogen(4.5± 0.8 vs.5.1±1.4,P=0.612),or GFR(109.3±25.2 ml/min vs.96.9±29.0 ml/min,P=0.237)before and after PRRT.For each cycle,there was no significant difference in whole-body effective dose,kidney effective dose,as well as residence time of the kidneys between group A and B(P>0.05).By intrapatient comparison,without and with amino acid infusion also did not show significant difference in whole-body effective dose(0.14±0.05 vs.0.12± 0.04,P=0.612),kidney effective dose(1.09±0.42 vs.0.73±0.31 mSv/MBq,P=0.093),and residence time of the kidneys(2.95±1.58 vs.3.13±1.11,P=0.674).Conclusion:177Lu-DOTA-EB-TATE PRRT with and without amino acid infusion demonstrated a favorable safety profile in NET patients.Administration of 177LuDOTA-EB-TATE without amino acid infusion has acceptable slightly increased kidney absorbed dose and residence time of the kidneys,and does not affect kidney function.Further investigation in a larger cohort and long-term follow-up are warranted.Project ⅣPrognostic Value of FDG PET/CT in Patients With Neuroendocrine Carcinoma of the Uterine CervixPurpose:We evaluated the prognostic value of metabolic parameters measured on pretreatment FDG PET/CT in patients with cervical neuroendocrine carcinomas(NECs).Methods:A total of 22 patients with cervical NECs who underwent pretreatment FDG PET/CT were retrospectively reviewed.The SUVmax,metabolic tumor volume(MTV),total lesion glycolysis(TLG)of the primary lesion were measured.The association between prognostic factors and progression-free survival(PFS)and overall survival(OS)were investigated using the Kaplan-Meier method,log-rank test,and Univariate and multivariate cox proportional hazards model.Results:Of the 22 patients,12 developed disease progression and 5 died during the follow-up period.Univariate analyses revealed that MTV,TLG,and the International Federation of Gynecology and Obstetrics(FIGO)stage were significantly associated with PFS(all P<0.05).While SUVmax did not show a significant correlation with PFS.Kaplan-Meier survival curves revealed that patients with MTV>31.9 cm3(log-rank,P<0.001),TLG>154.3(log-rank,P<0.001),and higher FIGO stage(log-rank,P=0.026)had significantly shorter PFS.In the multivariate analyses,MTV(P=0.017,HR=7.298,95%CI 1.427-37.316)and TLG(P=0.003,HR=15.175,95%CI 2.470-93.244)were independent prognostic factors.While for OS,the univariate analysis revealed that only TLG>154.3 showed statistical significance(P=0.043,HR=9.821,95%CI,1.080-89.290).Conclusions:MTV and TLG on FDG PET/CT were the significant prognostic factors of PFS in patients with cervical NECs.Patients with high MTV and TLG had worse clinical outcomes.In addition,TLG may also be a predictor of OS.