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Theranostics 2024; 14(1):133-142. doi:10.7150/thno.88619 This issue Cite

Research Paper

Peptide receptor radionuclide therapy (PRRT) in metastatic neuroendocrine tumors of unknown primary (CUP-NETs)

Richard P. Baum^1,2#, Peipei Wang^3,4,5#, Vivianne Jakobsson^3,4,6, Tianzhi Zhao^3,4,6, Christiane Schuchardt², Pek-Lan Khong^3,4, Jingjing Zhang^3,4,6✉

1. CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, Wiesbaden, Germany.
2. Theranostics Center for Molecular Radiotherapy and Precision Oncology, ENETS Center of Excellence, Zentralklinik Bad Berka, Bad Berka, Germany.
3. Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
4. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
5. Department of Nuclear Medicine, Peking Union Medical College Hospital. Chinese Academy of Medical Science and Peking Union Medical College, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China.
6. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
^#Contributed equally to this work.

✉ Corresponding author: Jingjing Zhang, MD, PhD. Department of Diagnostic Radiology, National University of Singapore. Centre for Translational Medicine (MD6), 14 Medical Drive, #B1-01, Singapore 117599, Singapore. Phone: +65 84353534. E-mail: j.zhangedu.sg. More

Abstract

Rationale: Peptide receptor radionuclide therapy (PRRT) for the treatment of neuroendocrine tumors (NETs) has been explored for more than two decades, but there are only limited data on the treatment of NETs of unknown primary site (CUP-NETs). This study aimed to analyze the long-term outcome, efficacy, and safety of PRRT in patients with CUP-NETs.

Methods: Patients with pathologically confirmed metastatic CUP-NET who received lutetium-177 (¹⁷⁷Lu) and/or yttrium-90 (⁹⁰Y) labeled somatostatin analogs between March 2001 and March 2019 were retrospectively reviewed; those patients were referred as cCUP-NETs (clinical CUP-NETs). Eighty-one patients had unknown primary tumors even after [⁶⁸Ga]Ga-SSTR and [¹⁸F]FDG PET/CT and were classified as pCUP-NETs (PET CUP-NETs). Treatment response was assessed according to RECIST 1.1 and PERCIST. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier analysis, and adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Results: A total of 575 PRRT cycles were administered to 156 patients (76 men and 80 women) evaluable for analysis: these patients were monitored for a median period of 92.3 mo (range, 4.0-169.1 mo). The disease control rate was 41.4% (43.4%) by RECIST and 40.2% (40.8%) by PERCIST in cCUP-NENs (pCUP-NETs). The objective response rate (ORR) with PRRT was 29.4% and 32.2% in cCUP-NENs and pCUP-NETs, respectively. The median PFS and OS for the entire cohort were 17.4 mo (95% confidence interval [95% CI], 11.4-23.4) and 67.4 mo (95% CI, 47.2-87.2) for all patients, respectively. The median OS for G3 tumors was significantly lower (15 mo) than for patients with G1 NET (85.5 mo), G2 (71.7 mo), and for patients with unknown grade (63.3 mo) NETs (P = 0.186, HR: 10.6, 95% CI: 3.87, 28.97, P = 0.09). PRRT was well tolerated by all patients. During treatment and long-term follow-up, CTCAE grade 3 and grade 4 thrombocytopenia and leukocytopenia were observed in only 3 patients (1.9%); there was no evidence of renal or hepatic toxicity.

Conclusion: In a large cohort of patients with advanced CUP-NETs treated with PRRT in a real-world scenario and followed up to 14 years after the commencement, PRRT has demonstrated favorable and clinically significant efficacy and survival with minimal and acceptable side effects. Our results indicate that PRRT is a well-tolerated and effective treatment option for patients with metastatic CUP-NETs expressing somatostatin receptors.

Keywords: NETs of unknown primary site (CUP-NETs), peptide receptor radionuclide therapy (PRRT), somatostatin receptor (SSTR), efficacy, ¹⁷⁷Lu, ⁹⁰Y

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