Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors
Authors: Sara Pusceddu, Natalie Prinzi, Salvatore Tafuto, Toni Ibrahim, Angelina Filice, Maria Pia Brizzi, Francesco Panzuto, Sergio Baldari, Chiara M. Grana, Davide Campana, Maria Vittoria Davì, Dario Giuffrida, Maria Chiara Zatelli, Stefano Partelli, Paola Razzore, Riccardo Marconcini, Sara Massironi, Fabio Gelsomino, Antongiulio Faggiano, Elisa Giannetta, Emilio Bajetta, Franco Grimaldi, Mauro Cives, Fernando Cirillo, Vittorio Perfetti, Francesca Corti, Claudio Ricci, Luca Giacomelli, Luca Porcu, Massimo Di Maio, Ettore Seregni, Marco Maccauro, Secondo Lastoria, Alberto Bongiovanni, Annibale Versari, Irene Persano, Maria Rinzivillo, Salvatore Antonio Pignata, Paola Anna Rocca, Giuseppe Lamberti, Sara Cingarlini, Ivana Puliafito, Maria Rosaria Ambrosio, Isabella Zanata, Alessandra Bracigliano, Stefano Severi, Francesca Spada, Valentina Andreasi, Roberta Modica, Federica Scalorbi, Massimo Milione, Giovanna Sabella, Jorgelina Coppa, Riccardo Casadei, Maria Di Bartolomeo, Massimo Falconi, Filippo de Braud
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. <h3>Objective</h3> To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). <h3>Design, Setting, and Participants</h3> This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. <h3>Exposures</h3> Upfront PRRT or upfront chemotherapy or targeted therapy. <h3>Main Outcomes and Measures</h3> The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. <h3>Results</h3> 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 targeted therapy. 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 the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44;<i>P</i> &lt; .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;<i>P</i> &lt; .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] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06;<i>P</i> = .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;<i>P</i> = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51;<i>P</i> &lt; .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]), grade of 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 of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (<i>P</i> &lt; .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37;<i>P</i> = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43;<i>P</i> = .31). <h3>Conclusions and Relevance</h3> In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.