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Objectives: This practice parameter (PP) for Lutetium-177 (Lu-177) DOTATATE peptide receptor radionuclide therapy (PRRT) aims to guide authorized users in selection of appropriate adult candidates with gastroeneropancreatic neuroendocrine tumors (GEP-NETs) from foregut, midgut, and hindgut. The essential selection criteria include somatostatin receptor-positive GEP-NETs, which are usually inoperable and progressed despite standard therapy. Lu-177 DOTATATE is a radiopharmaceutical with high avidity for somatostatin receptors that are overexpressed by these tumors. This document ensures safe handling of Lu-177 DOTATATE by the authorized users and safe management of affected patients. Methods: The document was developed according to the systematic process developed by the American College of Radiology (ACR) and described on the ACR Web site (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards). The PP development was led by 2 ACR Committees on Practice Parameters (Nuclear Medicine and Molecular Imaging and Radiation Oncology) collaboratively with the American College of Nuclear Medicine, American Society of Radiation Oncology, and Society of Nuclear Medicine and Molecular Imaging. Results: The Lu-177 DOTATATE PP reviewed pharmacology, indications, adverse effects, personnel qualifications, and required clinical evaluation before starting the treatment, as well as the recommended posttherapy monitoring, quality assurance, documentation, and appropriate radiation safety instructions provided in written form and explained to the patients. Conclusions: Lu-177 DOTATATE is available for therapy of inoperable and/or advanced GEP-NETs when conventional therapy had failed. It can reduce tumor size, improve symptoms, and increase the progression free survival. The PP document provides clinical guidance for authorized users to assure an appropriate, consistent, and safe practice of Lu-177 DOTATATE.

Objectives This practice parameter (PP) for Lutetium-177 (Lu-177) DOTATATE peptide receptor radionuclide therapy (PRRT) aims to guide authorized users in selection of appropriate adult candidates with gastroeneropancreatic neuroendocrine tumors (GEP-NETs) from foregut, midgut, and hindgut. The essential selection criteria include somatostatin receptor-positive GEP-NETs, which are usually inoperable and progressed despite standard therapy. Lu-177 DOTATATE is a radiopharmaceutical with high avidity for somatostatin receptors that are overexpressed by these tumors. This document ensures safe handling of Lu-177 DOTATATE by the authorized users and safe management of affected patients. Methods The document was developed according to the systematic process developed by the American College of Radiology (ACR) and described on the ACR Web site (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards). The PP development was led by 2 ACR Committees on Practice Parameters (Nuclear Medicine and Molecular Imaging and Radiation Oncology) collaboratively with the American College of Nuclear Medicine, American Society of Radiation Oncology, and Society of Nuclear Medicine and Molecular Imaging. Results The Lu-177 DOTATATE PP reviewed pharmacology, indications, adverse effects, personnel qualifications, and required clinical evaluation before starting the treatment, as well as the recommended posttherapy monitoring, quality assurance, documentation, and appropriate radiation safety instructions provided in written form and explained to the patients. Conclusions Lu-177 DOTATATE is available for therapy of inoperable and/or advanced GEP-NETs when conventional therapy had failed. It can reduce tumor size, improve symptoms, and increase the progression free survival. The PP document provides clinical guidance for authorized users to assure an appropriate, consistent, and safe practice of Lu-177 DOTATATE.

4111 Background: The primary statistical analysis for the NETTER-1 trial showed a clinically and statistically significant PFS benefit with 177Lu-DOTATATE vs. high-dose octreotide. 177Lu-DOTATATE treatment was also correlated with a significant delay in time to deterioration in HRQoL. In addition to HRQoL questionnaires, patients were asked to record presence or absence of a range of symptoms in a daily diary. Methods: A Mixed Model Repeated Measures (MMRM) was used to analyze the change, compared to baseline, of the occurrence of abdominal Pain, diarrhea and cutaneous flushing as these symptoms were regarded as the most relevant to judge the overall disease status. For each visit (week = 0, 4, 8, etc.) the number of days with symptoms during the previous period was calculated. At baseline, the number of days with symptoms was counted over the previous 6 weeks, whereas the time frame between visits lasted 4 weeks. Results: The estimated number of days with symptoms declined significantly more in the 177Lu-dotatate arm compared to the octreotide arm. The difference in change and the confidence intervals for the symptoms abdominal pain, diarrhea and flushing of skin are, respectively: -3.11 [-4.88; -1.34], -3.11 [-5.04; -1.18] and -1.98 [-3.88; -0.08]. Conclusions: Analysis of symptom diaries confirms that 177Lu-Dotatate can palliate clinically relevant symptoms when compared to high-dose octreotide.

348 Background: Neuroendocrine tumor progression is associated with decline in quality of life, both due to tumor and hormone-related symptoms. The Phase III NETTER-1 trial randomized patients with advanced, progressive midgut NETs to receive treatment with 177Lu-DOTATATE (177Lu; Lutathera) versus high-dose (60 mg) Octreotide LAR (Oct). EORTC questionnaires C30 and GINET21 were assessed during the trial in order to determine the impact of treatment on health-related quality of life (HRQoL). Methods: Patients completed EORTC QLQ-30 and QLQ-G.I.NET21 questionnaires at baseline and every 12 weeks thereafter until disease progression. Raw scores were converted to a 100-point scale and individual changes from baseline scores were assessed. Clinically relevant ( ≥ 10 point) deterioration/improvement was considered clinically significant. Results: Clinically and statistically significant improvements in QoL were observed in the 177Lu arm versus the Oct arm at certain time points in key domains of HRQoL including global health status and diarrhea. In mean, global health status improved in 28% of patients on 177Lu arm vs. 15% on Oct, and worsened in 18% of patients on 177Lu vs. 26% on Oct. Diarrhea improved in 39% of patients on 177Lu vs. 23% on Oct, and worsened in 19% of patients on 177Lu vs. 23% on Oct. There was a trend towards improvement in pain that was not statistically significant. Flushing appeared to improve compared to baseline in both arms of the study with no clear advantage to treatment with 177Lu vs. Oct. Conclusions: QoL analysis suggests benefit in important domains associated with 177Lu treatment compared to high-dose octreotide in patients with advanced midgut NETs, and confirms the treatment value of 177Lu on patient QoL, in addition to the meaningful increase in progression-free survival already reported. Clinical trial information: NCT01578239.

194 Background: Currently, there are limited therapeutic options for patients with advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog therapy. Methods: NETTER-1 is the first Phase III multicentric, randomized, controlled trial evaluating 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) in patients with inoperable, progressive, somatostatin receptor positive midgut NETs. 230 patients with Grade 1-2 metastatic midgut NETs were randomized to receive Lutathera 7.4 GBq every 8 weeks (x4 administrations) versus Octreotide LAR 60 mg every 4-weeks. The primary endpoint was PFS per RECIST 1.1 criteria, with objective tumor assessment performed by an independent reading center every 12 weeks. Secondary objectives included objective response rate, overall survival, toxicity, and health-related quality of life. Results: Enrolment was completed in February 2015, with a target of 230 patients randomized (1:1) in 36 European and 15 sites in the United States. At the time of statistical analysis, the number of centrally confirmed disease progressions or deaths was 23 in the Lutathera group and 67 in the Octreotide LAR 60 mg group. The median PFS was not reached for Lutathera and was 8.4 months with 60 mg Octreotide LAR [95% CI: 5.8-11.0 months], p < 0.0001, with a hazard ratio of 0.21 [95% CI: 0.13-0.34]. Within the current evaluable patient dataset for tumor responses (n = 201), the number of CR+PR was 19 (18.8%) in the Lutathera group and 3 (3.0%) in the Octreotide LAR 60 mg group (p < 0.0004). Although the OS data were not mature enough for a definitive analysis, the number of deaths was 13 in the Lutathera group and 22 in the Octreotide LAR 60 mg group (p < 0.019 at interim analysis) which suggests an improvement in overall survival. Conclusions: The Phase III NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS and ORR, and also suggests a survival benefit in patients with advanced midgut NETs treated with Lutathera. Clinical trial information: NCT01578239.