| Part Ⅰ Somatostatin receptor targeted imagingProject Ⅰ Head-to-Head Comparison of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT in Localizing Tumors with Ectopic Adrenocorticotropic Hormone SecretionObjective:Localizing the source of ectopic adrenocorticotropic hormone(ACTH)tumor is challenging.This study compared the diagnostic value of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT in ectopic ACTH tumor.Methods:Thirty-six patients with a suspicion of ectopic ACTH tumor were enrolled to undergo both 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT within 4 weeks for comparison.Twenty-three patients underwent surgical resection or biopsy.Immunohistochemical staining for SSTR2(somatostatin receptor 2)and ACTH was performed.Results:Ectopic ACTH tumors were observed in 20/23 patients.Among the 20 patients with histologically proven ACTH tumors,68Ga-DOTATATE PET/CT correctly identified the tumor in 15(75.0%),with an SUVmax ranging from 1.4 to 20.7(6.7±5.5).18F-FDG PET/CT correctly identified the tumor in 12(60.0%)patients,with an SUVmax ranging from 1.8 to 10.0(4.0±2.1).Moreover,68Ga-DOTATATE PET/CT unmasked the sources of ectopic ACTH tumor in 6 patients with no 18F-FDG uptake,and 18F-FDG PET/CT unmasked the sources in 3 patients with negative 68Ga-DOTATATE uptake,resulting in ectopic ACTH tumors being identified in 18(90%)patients by combining 68GaDOTATATE PET/CT and 18F-FDG PET/CT.Conclusions:68Ga-DOTATATE PET/CT and 18F-FDG PET/CT are complementary in localizing and discriminating the source of ectopic ACTH tumor.68Ga-DOTATATE PET/CT combined with 18F-FDG PET/CT had higher detection rate than each alone.Part Ⅱ Somatostatin receptor targeted radionuclide therapyProject Ⅱ Dose Escalation of an Evans Blue-modified Radiolabeled Somatostatin Analog 177Lu-DOTA-EB-TATE in the Treatment of Metastatic Neuroendocrine TumorsObjective:To evaluate the safety and efficacy of 177Lu-DOTA-EB-TATE,a radiolabeled somatostatin analog modified by Evans blue,at escalating doses,was used to increase tumor retention in patients with progressive metastatic neuroendocrine tumors(NETs).Methods:Thirty-three patients with metastatic NETs were prospectively enrolled into four groups:group A(n=6,43±12 years)administered approximately 3.7 GBq(100 mCi)177Lu-DOTATATE as controls;group B(n=7,55±7 years)administered approximately 1.11 GBq(30 mCi)177Lu-DOTA-EB-TATE;group C(n=6,55±10 years)administered approximately 1.85 GBq(50 mCi)177Lu-DOTA-EB-TATE;group D(n=14,50±10 years)administered approximately 3.7 GBq(100 mCi)177Lu-DOTA-EB-TATE.Treatmentrelated adverse events were graded according to the CTCAE v.5.0.68Ga-DOTATATE PET/CT were performed at baseline and 2-3 months after treatment for response evaluation.Results:Administration was well tolerated.No CTC 3/4 hematotoxicity,nephrotoxicity,or hepatotoxicity was observed during or after treatment in groups A-C.In group D,CTC3 hematotoxicity was recorded in 2 patients with multicourse chemotherapy previously.After one-cycle treatment,the SUVmax decreased in group C(ΔSUVmax%=-17.4±29.3%)and group D(ΔSUVmax%=-15.1 ± 39.1%),but greatly increased in group B(ΔSUVmax%=30.0 ± 68.0%)and mildly increased in group A(ΔSUVmax%=5.4±45.9%).Referring to EORTC criteria,16.7%(1/6),0%(0/7),50%(3/6),and 50%(7/14)were evaluated as partial response in groups A,B,C,and D,respectively.When selecting lesions with comparable baseline SUVmax ranging from 15 to 40,SUVmax showed no significant decrease in group B(ΔSUVmax%=-7.3±24.5%)(P=0.214),significant decrease in group C(ΔSUVmax%=34.9±12.4%)(P=0.001),and in group D(ΔSUVmax%=-17.9±19.7%)(P=0.012)in contrast to the increased SUVmax in group A(ΔSUVmax%=8.4±48.8%).SUVmax significantly decreased in the EBTATE groups(groups B-D combined)(ΔSUVmax%=-19.0±21.5%)as compared with the TATE group(P=0.045).Conclusions:177Lu-DOTA-EB-TATE is well tolerated and is more effective than 177LuDOTATATE.Both 1.85 GBq(50 mCi)and 3.7 GBq(100 mCi)doses appear to be more effective than 1.11 GBq(30 mCi)dose.Further investigation with more cycles of 177Lu-DOTA-EB-TATE treatment and longer follow-up is warranted.Project Ⅲ Peptide Receptor Radionuclide Therapy of Late-stage Neuroendocrine Tumor Patients with Multiple Cycles of 177LuDOTA-EB-TATEObjective:This study aimed to evaluate the safety and efficacy of multiple cycles of 177LuDOTA-EB-TATE peptide receptor radionuclide therapy(PRRT)at escalating doses in neuroendocrine tumors(NETs).Methods:Thirty-two NET patients were enrolled and divided into 3 groups and treated with escalating doses:group A(1.17 ± 0.09 GBq/cycle);group B(1.89 ± 0.53 GBq/cycle);group C(3.97 ± 0.84 GBq/cycle).The treatment was planned up to three cycles.Treatmentrelated adverse events(AEs)were graded according to the National Cancer Institute CTCAE v.5.0.Treatment response was referred to EORTC criteria and modified PERCIST criteria.Results:Administration of PRRT was well tolerated without life-threatening(CTC-4)AEs.CTC-3 hematotoxicity was recorded in 1 patient(16.6%)in group B(thrombocytopenia)and 3 patients(21.4%)in group C(thrombocytopenia in 3,anemia in 1).CTC-3 hepatotoxicity was recorded in 1 patient in group A(8.3%)and C(7.1%),respectively with elevated AST.No nephrotoxicity was observed.When referring to EORTC criteria,the overall disease response rates(DRR)were similar in groups A-C(50.0%,50.0%,and 42.9%),and the overall disease control rates(DCR)were higher in group B(83.3%)and C(71.5%)than that in group A(66.7%).When referring to modified PERCIST criteria,lower DRR but similar DCR was found.When selecting comparable baseline SUVmax ranging from 15 to 40,the ΔSUVmax%had slight increase in group A(ΔSUVmax%=2.1±40.8)but significant decrease in groups B and C(ΔSUVmax%=-38.7 ± 10.0 and-14.7±20.0)after the 1st PRRT(P=0.001),and had decrease in all three groups after the 3rd PRRT(groups A-C,ΔSUVmax%=-6.9±42.3,-49.2±30.9,-11.9 ±37.9,P=0.044).Conclusions:Escalated doses of 177Lu-DOTA-EB-TATE up to 3.97 GBq/cycle seem to be well tolerated.1.89 GBq/cycle and 3.97 GBq/cycle 177Lu-DOTA-EB-TATE were both effective in tumor control and more effective than 1.17 GBq/cycle 177Lu-DOTA-EB-TATE.Project Ⅳ Peptide Receptor Radionuclide Therapy in Patients with Advanced Progressive Medullary Thyroid Cancer:Safety,Efficacy and Survival DataObjective:There are few therapeutic options for progressive metastatic medullary thyroid carcinoma(MTC).PRRT has demonstrated remarkable success in the management of gastroenteropancreatic NETs and has also been suggested to treatment of MTC.However,evidence on its effectivity and long-term outcome for this indication is still limited.This study aimed to evaluate the safety and efficacy of PRRT in SSTR-positive patients with advanced,progressive MTC and to determine survival.Methods:Twenty-eight patients(15 men;mean age,49 ± 14 years)with progressive,somatostatin receptor-positive,advanced MTC received PRRT with 177Lu-or 90Y-labeled somatostatin analogs.Treatment-related adverse events were graded according to the National Cancer Institute CTCAE v.5.0.Treatment response was evaluated according to RECIST 1.1 as well as molecular imaging criteria(EORTC).Kaplan-Meier analysis was used to calculate PFS and OS,defined from the start of PRRT.Cox regression analyses were performed to identify parameters associated with PFS and OS.Results:Seventy-seven cycles of PRRT were administered(mean accumulative administered activity,16.0±7.8 GBq).No acute or long-term grade 3/4 toxicity was recorded with a follow-up of 3-140 months,except for one(4%)patient who suffered for grade 3 anemia.According to RECIST criteria,the disease control rate(DCR)after 3-4 months of PRRT was 56.0%(partial remission,12.0%;stable disease,44.0%).The DCR(72.0%)was higher by molecular response evaluation.Median OS and PFS were 63.7 months and 10.1 months,respectively.The annual OS rates at 1 year was 84%,3 years 65%,5 years 57%,and 10 years 18%.The annual PFS rate at 1 year was 42%,at 2 years 21%,and at 5 years 13%.Patients with bone metastases had poorer OS and PFS than those without metastases(median OS,58.7 months vs 92.3 months,P=0.035[HR,2.7;95%CI,0.92-7.84];median PFS,8.5 months vs 12.8 months,P=0.592[HR,1.2;95%CI,0.562.76]).Conclusions:PRRT was well tolerated and effective in patients with advanced,aggressive MTC.Bone metastases was an independent negative prognostic factor for OS.Part Ⅲ The prognosis of somatostatin receptor targeted radionuclide therapyProject Ⅴ Prognostic Value of 18F-FDG PET/CT in a Large Cohort of Patients with Advanced Neuroendocrine Neoplasms Treated with Peptide Receptor Radionuclide TherapyObjective:This retrospective study aimed to determine the role of 18F-FDG PET/CT in a large cohort of 495 patients with metastatic NETs who were treated with PRRT.Methods:The 495 patients were treated with 177Lu-and/or 90Y-PRRT.All subjects received both 68Ga-SSTR and 18F-FDG PET/CT prior to treatment and were followed 3189 months.Kaplan-Meier analysis,log-rank test and Cox regression analysis were performed for OS and PFS.Results:18F-FDG PET/CT was positive in 382(77.2%)patients and 113(22.8%)were FDG-negative before PRRT,while 100%were 68Ga-SSTR positive.For all patients,the median PFS and OS,defined from start of PRRT,were 19.6 months and 58.7 months,respectively.Positive 18F-FDG predicted shorter PFS(18.5 months vs 24.1 months,P=0.002)and OS(53.2 months 83.1 months,P<0.001)than negative 18F-FDG.Amongst the pancreatic NET,the median OS was 52.8 months in 18F-FDG positive and 114.3 months in 18F-FDG negative subjects(P<0.001).For all patients with positive 18F-FDG uptake,and a ratio of the highest SUVmax on 68Ga-SSTR PET to the most 18F-FDG-avid tumor lesions>2,the median OS was 53.0 months,compared to 43.4 months in those patients with a ratio<2(P=0.030).For patients with no 18F-FDG uptake(complete "mismatch"imaging pattern),the median OS was 108.3 months vs 76.9 months for SUVmax>15.0 and≤15.0 on "Ga-SSTR PET/CT,respectively.Conclusions:The presence of FDG-positive lesions is an independent prognostic factor.18F-FDG PET/CT compliments the molecular imaging aspect of 68Ga-SSTR PET/CT for the prognosis.High SSTR expression combined with negative 18F-FDG PET/CT imaging is associated with the most favorable long-term prognosis. |
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