title: Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: a multiparametric response evaluation correlating with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics.
abstract: OBJECTIVE
  To assess the performance of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in metastatic gastroenteropancreatic neuroendocrine tumor (GEP-NET) and correlate it with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics.
  
  
  METHODS
  Fifty patients (M : F 33 : 17, age: 26-71 years) with histopathologically confirmed metastatic/inoperable NETs who had undergone at least three cycles of PRRT with Lu-DOTATATE were included in the analysis. As part of the pretreatment evaluation, they underwent either Tc-HYNIC TOC (n=40)/Ga-DOTATATE PET (n=10) or fluorine-18-fluorodeoxyglucose (F-FDG) PET-computed tomography (CT). Response was assessed after three and five cycles PRRT on the basis of three parameters: (a) symptomatic and subjective scale, (b) biochemical tumor marker level, and (c) objective imaging (F-FDG/Ga DOTATATE PET/CT, Tc-HYNIC TOC, ceCT), and was categorized using predefined criteria (detailed in methods). Stable disease on imaging assessment with response on symptomatic or biochemical tumor marker scales or both were included in the responder group.
  
  
  RESULTS
  The study population was broadly classified into (a) metastatic GEP-NET with known primary (n=43 i.e. 86%), which was further subclassified according to the site of primary and (b) those with unknown primary (n=7 i.e. 14%). Symptomatic response: 96% of patients showed a symptomatic response or improvement in health-related quality of life, irrespective of tumor proliferation index, dual tracer imaging characteristics, and response or progression of disease in the scan. Biochemical tumor marker response: 83% of scan responders showed a decrease, 10% showed a stable value, and 7% showed an increase in tumor marker levels. Among the scan nonresponders, 67% patients showed a corresponding increase in the tumor marker level, 22% patient showed a decrease, whereas 11% showed stable values. Scan response: 31 out of total 50 patients (62%) showed a partial scan response with either a decrease in the number of somatostatin receptor (SSTR)-positive lesions or metabolic activity in F-FDG/Ga-DOTATATE PET-CT or both, 10 patients (20%) showed stable disease, and nine patients (18%) showed progressive disease. The higher objective partial scan response documented can be explained by the introduction of the F-FDG-PET/CT parameter as a determinant criterion. Among the responders category (n=41), 32 (78.04%) showed discordance between F-FDG-PET/CT-based and SSTR-based imaging, whereas eight out of nine patients with nonresponse category (88.89%) showed concordance between SSTR-based imaging and F-FDG-PET/CT. Conversely, 32 of 33 patients (96.97%) with SSTR/F-FDG discordance and nine out of 17 (52.94%) with concordance were finally classified as responders, whereas the remaining, that is, 1/33 (3.03%) in the 'discordant' category and 8/17 (47.06%) with imaging concordance were classified as nonresponders, respectively.
  
  
  CONCLUSIONS
  Our data show that high pretherapy F-FDG maximum standardized uptake values were associated with increased chances of treatment refractoriness in GEP-NETs. However, symptomatic improvement was observed in most cases irrespective of grade and F-FDG uptake. High pretherapy F-FDG maximum standardized uptake value in both low-grade and high-grade NET predicted a poor outcome and was associated with disease progression. Introduction of F-FDG-PET/CT parameter as a determinant of response classification increases the percentage of objective scan responders among patients with grades I and II GEP-NETs as F-FDG activity was observed to decrease before SSTR-based imaging and more frequently compared with the latter.
authors.affiliation: aRadiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe Departments of bMedical Oncology cSurgical Oncology, Gastrointestinal and Hepato-Pancreato-Biliary Service, Tata Memorial Hospital, Mumbai, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Thapa
authors.forename: Rohit
authors.initials: R
authors.lastname: Ranade
authors.forename: Vikas
authors.initials: V
authors.lastname: Ostwal
authors.forename: Shailesh V
authors.initials: SV
authors.lastname: Shrikhande
authors.forename: Mahesh
authors.initials: M
authors.lastname: Goel
authors.forename: Sandip
authors.initials: S
authors.lastname: Basu
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000528:radiation effects; D005260:Female; D006801:Humans; D007414:Intestinal Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D015282:Octreotide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009942:Organometallic Compounds / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D000072078:Positron Emission Tomography Computed Tomography; D011849:Radioactive Tracers; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D009942:Organometallic Compounds; D011849:Radioactive Tracers; D017481:Receptors, Somatostatin; C447941:lutetium Lu 177 dotatate; D015282:Octreotide