open57noIMPORTANCE Data about the optimal timing for the initiation of peptide receptor radionuclide
therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors
are lacking.
OBJECTIVE 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).
DESIGN, SETTING, AND PARTICIPANTS 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.
EXPOSURES Upfront PRRT or upfront chemotherapy or targeted therapy.
MAIN OUTCOMES AND MEASURES 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.
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 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; 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] vs
11.6 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]), 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])
(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 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.openPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, FilippoPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, Filipp