(336) Safety of Combined Radioligand and Systemic Therapies in Neuroendocrine Tumors: A Systematic Review

Background: : Radioligand therapy (RLT) delivers targeted radiation to cancer cells via tumor-specific molecules. Among RLT options, 177Lu-DOTATATE with long-acting octreotide has been the only FDA-approved therapy for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) since 2018. Combining RLT with systemic therapies such as chemotherapy, immunotherapy, and kinase inhibitors may enhance efficacy through complementary mechanisms and resistance mitigation. However, these combinations can amplify toxicity risks, including cumulative myelosuppression, renal injury, and overlapping organ-specific adverse effects, which make safety evaluation critical. Evidence synthesizing these risks across clinical contexts remains limited.

Objective: : To systematically review and evaluate the safety of RLT when used in combination with other systemic therapies for the treatment of NETs.

Methods: : A systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials was conducted from database inception to November 2024. Studies evaluating RLT combined with systemic drug therapies for NETs and reporting safety outcomes were included. Extracted data included study design, patient population, tumor characteristics, adverse event criteria, and safety results. This review’s methods adhered to PRISMA guidelines. Risk of bias was assessed using Cochrane Risk of Bias 2 (RoB2) for clinical trials, ROBINS-I for non-randomized studies, and the Newcastle-Ottawa Scale for cohort and case-control studies.

Results: : Of 1412 records screened, 44 publications met inclusion: 13 single-arm prospective studies, 10 prospective studies with comparators, and 21 retrospective observational studies. Treatments included RLT with radiosensitizing chemotherapy (n=19, using capecitabine+/-temozolomide), dual RLTs (n=18), RLT with somatostatin analogues (n=5), and RLT with targeted therapies (n=2, using everolimus or nivolumab). Sample sizes ranged from 6 to 1535 patients (median: 37.5). Most studies included NET (n=23) and neuroendocrine neoplasm (n=3) without tumor origin restriction. Others included GEP-NET (n=8), midgut NET (n=3), and misc. (n=7). Hematologic, nephrologic, gastrointestinal, and hepatic toxicities were most common while discontinuations, toxicity-related deaths, and endocrine adverse events were rare. Overall risk-of-bias was low, with 26 studies rated low risk, 16 moderate, and 2 serious across study designs.

Conclusions: : Future meta-analyses quantitatively comparing hematologic, nephrologic, gastrointestinal, and hepatic toxicities will better inform the comparative safety profiles of different RLT combinations.

Sponsorship:: None