Efficacy and Safety of Non-Surgical Treatments for Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis

Abstract

Background: Pancreatic neuroendocrine tumor (pNET) is a rare and complex disease that requires careful management and treatment. Currently, a range of treatments, including surgery, somatostatin analogs (SSA), peptide receptor radionuclide therapy (PRRT), targeted drugs, cytotoxic chemotherapy, and immunotherapy, exist for pNETs. However, determining the optimal treatment strategies remains challenging. Aim: To evaluate the efficacy and safety of non-surgical therapies, such as somatostatin analogs (SSA), peptide receptor radionuclide therapy (PRRT), targeted drugs, cytotoxic chemotherapy, and immunotherapy in treating pNETs. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science databases for relevant studies published from inception until August 2025. Randomized clinical trials (RCTs), non-randomized clinical trials, and prospective studies were included in this meta-analysis if they evaluated the efficacy and safety of any treatment of interest in patients with pNETs. Results: Thirty-three studies involving 2374 pNET patients were analyzed. Targeted therapies showed modest objective response rates (ORRs) but high disease control rates (DCRs): everolimus (ORR 7%, 95% CI: 3-10%; DCR 81%, 95% CI: 75-87%), sunitinib (ORR 12%, 95% CI: 5-19%; DCR 79%, 95% CI: 70-88%), surufatinib (ORR 19%, 95% CI: 12-27%; DCR 81%, 95% CI: 73-89%). Cytotoxic chemotherapy demonstrated higher ORRs: dacarbazine-based (32%, 95% CI: 21-43%), streptozocin-based (40%, 95% CI: 25-54%), temozolomide-based (42%, 95% CI: 29-55%). PRRT showed varying efficacy: ¹⁷⁷Lu-DOTATATE (ORR 36%, 95% CI: 27-44%; DCR 84%, 95% CI: 76-92%), ⁹⁰Y-DOTATOC (ORR 27%, 95% CI: 18-36%; DCR 73%, 95% CI: 63-83%). SSAs had low ORRs but high DCRs: lanreotide (ORR 0%, DCR 67%, 95% CI: 57-77%), octreotide (ORR 23%, 95% CI: 15-31%; DCR 75%, 95% CI: 66-84%). Immunotherapy with pembrolizumab showed limited efficacy (ORR 7%, 95% CI: 0-14%). Treatment-related adverse events were common across therapies, with specific toxicity profiles for each modality. Conclusions: Cytotoxic chemotherapy offers better response rates than other treatment modalities. However, toxicity management is crucial. PRRT also shows robust antitumor activity and disease control, while SSAs and targeted therapies are effective treatment options for disease stabilization. Immunotherapy demonstrated limited antitumor activity, and further research is needed to establish its role in pNET treatment.

Keywords: cytotoxic chemotherapy; non-surgical treatments; pancreatic neuroendocrine tumor; peptide receptor radionuclide therapy; somatostatin analogs.

Figure 1

PRISMA flow diagram for study selection.

Figure 2

Forest plot showing the pooled ORR for patients treated with targeted therapies, i.e., everolimus, palbociclib, sunitinib, and surufatinib [13,14,15,16,17,18,19,20].

Figure 3

Forest plot showing the pooled DCR for patients treated with targeted therapies, i.e., everolimus, palbociclib, sunitinib, and surufatinib [13,14,15,16,17,18,19,20].

Figure 4

Forest plot showing the pooled ORR for patients treated with cytotoxic chemotherapy, i.e., dacarbazine-, streptozocin-, and temozolomide-based therapies [21,22,23,24,25,26,27,28,29,30,31].

Figure 5

Forest plot showing the pooled DCR for patients treated with cytotoxic chemotherapy, i.e., dacarbazine-, streptozocin-, and temozolomide-based therapies [21,22,23,24,25,26,27,28,29,30,31].

Figure 6

Forest plot showing the pooled ORR for patients treated with PRRT, i.e., 177Lu-DOTATATE, 90Y-DOTATATE, 90Y-DOTATOC, and combination of 177Lu-DOTATATE and 90Y-DOTATOC [33,34,35,36,37,38,39].

Figure 7

Forest plot showing the pooled DCR for patients treated with PRRT, i.e., 177Lu-DOTATATE, 90Y-DOTATATE, 90Y-DOTATOC, and combination of 177Lu-DOTATATE and 90Y-DOTATOC [33,34,35,36,37,38,39].

Figure 8

Forest plot showing the pooled ORR for patients treated with SSAs, i.e., lanreotide and octreotide [27,41,43].

Figure 9

Forest plot showing the pooled DCR for patients treated with SSAs, i.e., lanreotide and octreotide [27,41,43].

Figure 10

Forest plot showing the pooled ORR for patients treated with immunotherapy, specifically pembrolizumab [44,45].

Figure 11

Summary of risk of bias using the RoB-2 tool [13,14,15,16,17,18,19,22,42].

Figure 12

Summary of risk of bias using the ROBINS-I tool [15,19,20,21,23,24,25,26,27,28,29,34,35,36,37,38,39,40,41,43,44,45].