Combination Treatment Strategies With Peptide Receptor Radionuclide Therapy

The landscape of systemic treatment for patients with neuroendocrine tumors (NET) is continuously evolving due to discovery of various molecular pathways involvement in tumor growth and the clinical availability of several therapeutic agents against these pathways. Among these agents, peptide receptor radionuclide therapy (PRRT) serves as the cornerstone for the treatment of well-differentiated metastatic/advanced NETs that express somatostatin receptors (SSTR). However, complete response and longer survival rates with progression-free disease status after PRRT are rarely observed. Therefore, a combination of PRRT with other antitumor agents exhibiting synergistic effects is necessary to augment PRRT efficacy without increasing the toxicity profile. Various combinations of PRRT with antitumor agents or surgical intervention have been employed, including somatostatin analogs (SSAs), radiosensitizing chemotherapy, cytotoxic chemotherapy, different therapeutic isotopes, transarterial radioembolization (TARE), targeted molecular drugs, immune-checkpoint inhibitors (ICIs), and neoadjuvant PRRT before surgery. This review will explore various combinations of PRRT with other antitumor agents, highlighting their fundamental mechanisms of action for synergistic effects. It will also focus on protocols for combined PRRT approaches, provide an overview of existing literature and ongoing clinical trials, discuss the future directions and perspectives, and offer insights into the practical use of combination strategies in various clinical scenarios to assist clinicians in planning effective and safe combined treatment regimens for the management of NET patients.