Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors

IMPORTANCE Data about the optimal timing for the initiation of peptide receptor radionuclidetherapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumorsare lacking.OBJECTIVE To evaluate the association of upfront PRRT vs upfront chemotherapy or targetedtherapy with progression-free survival (PFS) among patients with advanced enteropancreaticneuroendocrine tumors who experienced disease progression after treatment with somatostatinanalogues (SSAs).DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study analyzed theclinical records from 25 Italian oncology centers for patients aged 18 years or older who hadunresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreaticneuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy afterexperiencing disease progression after treatment with SSAs between January 24, 2000, and July 1,2020. Propensity score matching was done to minimize the selection bias.EXPOSURES Upfront PRRT or upfront chemotherapy or targeted therapy.MAIN OUTCOMES AND MEASURES The main outcome was the difference in PFS among patientswho received upfront PRRT vs among those who received upfront chemotherapy or targetedtherapy. A secondary outcome was the difference in overall survival between these groups. Hazardratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust forrelevant factors associated with PFS and were corrected for interaction with these factors.RESULTS Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329(64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targetedtherapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8]years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in thechemotherapy or targeted therapy group in the unmatched (2.5 years [95%CI, 2.3-3.0 years] vs 0.7years [95%CI, 0.5-1.0 years]; HR, 0.35 [95%CI, 0.28-0.44; P < .001]) and matched (2.2 years [95%CI, 1.8-2.8 years] vs 0.6 years [95%CI, 0.4-1.0 years]; HR, 0.37 [95%CI, 0.27-0.51; P < .001])populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95%CI, 10.7-14.1 years] vs11.6 years [95%CI, 9.1-13.4 years]; HR, 0.81 [95%CI, 0.62-1.06; P = .11]) and matched (12.2 years [95%CI, 9.1-14.2 years] vs 11.5 years [95%CI, 9.2-17.9 years]; HR, 0.83 [95%CI, 0.56-1.24; P = .36])populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37;95%CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction,upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning:adjusted HR [aHR], 0.39 [95%CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95%CI, 0.16-0.56]), gradeof 1 to 2 (grade 1: aHR, 0.21 [95%CI, 0.12-0.34]; grade 2: aHR, 0.52 [95%CI, 0.29-0.73]), and site oftumor origin (pancreatic: aHR, 0.41 [95%CI, 0.24-0.61]; intestinal: aHR, 0.19 [95%CI, 0.11-0.43])(P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95%CI,0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95%CI,0.29-1.43; P = .31).CONCLUSIONS AND RELEVANCE In this cohort study, treatment with upfront PRRT in patientswith enteropancreatic neuroendocrine tumors who had experienced disease progression with SSAtreatment was associated with significantly improved survival outcomes compared with upfrontchemotherapy or targeted therapy. Further research is needed to investigate the correct strategy,timing, and optimal specific sequence of these therapeutic options.