PURPOSE: 177Lu-DOTA(0)-Tyr(3)-octreotate (177Lu-DOTATATE) is a somatostatin receptor (SSTR)-targeting radiopharmaceutical that shows promise for treating metastatic pheochromocytomas/paragangliomas (PPGLs), a rare SSTR-expressing tumor. METHODS: In the first stage of this two-stage Simon phase II trial, 36 PPGL patients with RECIST 1.1 progression within 12 months were prospectively recruited into two genetic cohorts (succinate dehydrogenase [SDHx]-mutated v apparent sporadic, 18 per cohort) and treated with four cycles of 177Lu-DOTATATE. The primary end point was progression-free survival (PFS) rate at 6 months (from initiation of treatment). Secondary end points included safety, overall survival (OS), response rate, imaging/serum biomarkers, and antihypertensive medication reduction. Computed tomography/magnetic resonance imaging (CT/MRIs) and positron emission tomography (PET)-CTs (68Ga-DOTATATE and 18F-labeled fluorodeoxyglucose) were obtained after two and four cycles, then every 3 (CT/MRIs) to 6 months (PET/CTs). Patients with systolic blood pressure (SBP) > 200 mmHg despite medical management were treated in the intensive care unit (ICU). RESULTS: Six-month PFS rate for all patients was 0.861 (95% CI, 0.755 to 0.982), which was significantly lower (P = .009) for SDHx at 0.72 (95% CI, 0.542 to 0.962) versus sporadic at 1.00 (95% CI, 1.0 to 1.0). Median PFS was 19.9 months (12.9 months SDHx v 24.3 months sporadic) and median OS was 51.7 months (31.2 months SDHx v not reached in sporadic). Best response was achieved on average 11.0 months after completing 177Lu-DOTATATE. A 17% incidence of grade 3+ catecholamine release syndrome (CRS) was noted, which may benefit from preemptive ICU admission. Plasma chromogranin A and normetanephrine were the best tumor-marker surrogates and correlated well with changes in RECIST sum and total tumor lesion uptake on serial 68Ga-DOTATATE PET-CT scans. CONCLUSION: 177Lu-DOTATATE demonstrated effectiveness and acceptable safety profile for progressive, metastatic PPGL. CRS may occur but can be mitigated through pretreatment with antihypertensives, and, when appropriate, intensified monitoring in the ICU with intravenous antihypertensives.

AKESO Center for Adrenal Endocrine Tumors Prague Czech Republic

Developmental Therapeutics Branch National Institutes of Health National Cancer Institute Center for Cancer Research Bethesda MD

Division of Cancer Therapy and Diagnosis Biometric Research Program National Institutes of Health National Cancer Institute Bethesda MD

Division of Nuclear Medicine National Institutes of Health Clinical Center Bethesda MD

Metabolic Diseases Branch National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases Bethesda MD

Molecular Imaging Branch National Institutes of Health National Cancer Institute Center for Cancer Research Bethesda MD

National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda MD

PET Department National Institutes of Health Clinical Center Bethesda MD

Uniformed Services University of the Health Sciences Bethesda MD

J Clin Oncol. 2025 Nov;43(31):3427. doi: 10.1200/JCO-25-02180. PubMed

Zobrazit více v PubMed

Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas. Endocr Pathol 2022;33(1):90–114. (In eng). DOI: 10.1007/s12022-022-09704-6. PubMed DOI

Hamidi O, Young WF, Iñiguez-Ariza NM Jr., et al. Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years. J Clin Endocrinol Metab 2017;102(9):3296–3305. (In eng). DOI: 10.1210/jc.2017-00992. PubMed DOI PMC

Nölting S, Bechmann N, Taieb D, et al. Personalized Management of Pheochromocytoma and Paraganglioma. Endocr Rev 2022;43(2):199–239. (In eng). DOI: 10.1210/endrev/bnab019. PubMed DOI PMC

Hescot S, Curras-Freixes M, Deutschbein T, et al. Prognosis of Malignant Pheochromocytoma and Paraganglioma (MAPP-Prono Study): A European Network for the Study of Adrenal Tumors Retrospective Study. J Clin Endocrinol Metab 2019;104(6):2367–2374. (In eng). DOI: 10.1210/jc.2018-01968. PubMed DOI

Janssen I, Chen CC, Millo CM, et al. PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2016;43(10):1784–91. (In eng). DOI: 10.1007/s00259-016-3357-x. PubMed DOI PMC

Han S, Suh CH, Woo S, Kim YJ, Lee JJ. Performance of (68)Ga-DOTA-Conjugated Somatostatin Receptor-Targeting Peptide PET in Detection of Pheochromocytoma and Paraganglioma: A Systematic Review and Metaanalysis. J Nucl Med 2019;60(3):369–376. (In eng). DOI: 10.2967/jnumed.118.211706. PubMed DOI

Kong G, Schenberg T, Yates CJ, et al. The Role of 68Ga-DOTA-Octreotate PET/CT in Follow-Up of SDH-Associated Pheochromocytoma and Paraganglioma. J Clin Endocrinol Metab 2019;104(11):5091–5099. (In eng). DOI: 10.1210/jc.2019-00018. PubMed DOI

Taïeb D, Garrigue P, Bardiès M, Abdullah AE, Pacak K. Application and Dosimetric Requirements for Gallium-68-labeled Somatostatin Analogues in Targeted Radionuclide Therapy for Gastroenteropancreatic Neuroendocrine Tumors. PET Clin 2015;10(4):477–86. (In eng). DOI: 10.1016/j.cpet.2015.06.001. PubMed DOI PMC

Kong G, Grozinsky-Glasberg S, Hofman MS, et al. Efficacy of Peptide Receptor Radionuclide Therapy for Functional Metastatic Paraganglioma and Pheochromocytoma. J Clin Endocrinol Metab 2017;102(9):3278–3287. (In eng). DOI: 10.1210/jc.2017-00816. PubMed DOI

Janssen I, Blanchet EM, Adams K, et al. Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma. Clin Cancer Res 2015;21(17):3888–95. (In eng). DOI: 10.1158/1078-0432.Ccr-14-2751. PubMed DOI PMC

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

Fishbein L, Del Rivero J, Else T, et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. Pancreas 2021;50(4):469–493. (In eng). DOI: 10.1097/mpa.0000000000001792. PubMed DOI

Hescot S, Leboulleux S, Amar L, et al. One-year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 2013;98(10):4006–12. (In eng). DOI: 10.1210/jc.2013-1907. PubMed DOI

Taïeb D, Nölting S, Perrier ND, et al. Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement. Nat Rev Endocrinol 2024;20(3):168–184. (In eng). DOI: 10.1038/s41574-023-00926-0. PubMed DOI

Araujo-Castro M, García Sanz I, Mínguez Ojeda C, et al. Local recurrence and metastatic disease in pheochromocytomas and sympathetic paragangliomas. Front Endocrinol (Lausanne) 2023;14:1279828. (In eng). DOI: 10.3389/fendo.2023.1279828. PubMed DOI PMC

Baudin E, Goichot B, Berruti A, et al. Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial. Lancet 2024;403(10431):1061–1070. (In eng). DOI: 10.1016/s0140-6736(23)02554-0. PubMed DOI

Jimenez C, Habra MA, Campbell MT, et al. Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial. Lancet Oncol 2024;25(5):658–667. (In eng). DOI: 10.1016/s1470-2045(24)00133-5. PubMed DOI

Phelps TE, Del Rivero J, Chertow DS, Rosing D, Pacak K, Lin FI. Managing Catecholamine Release Syndrome During and Following Lu-177-DOTATATE in High-Risk Pheochromocytoma Patients. JCEM Case Rep 2024;2(4):luae049. (In eng). DOI: 10.1210/jcemcr/luae049. PubMed DOI PMC

Gubbi S, Al-Jundi M, Auh S, et al. Early short-term effects on catecholamine levels and pituitary function in patients with pheochromocytoma or paraganglioma treated with [(177)Lu]Lu-DOTA-TATE therapy. Front Endocrinol (Lausanne) 2023;14:1275813. (In eng). DOI: 10.3389/fendo.2023.1275813. PubMed DOI PMC

Prado-Wohlwend S, Del Olmo-García MI, Bello-Arques P, Merino-Torres JF. Response to targeted radionuclide therapy with [(131)I]MIBG AND [(177)Lu]Lu-DOTA-TATE according to adrenal vs. extra-adrenal primary location in metastatic paragangliomas and pheochromocytomas: A systematic review. Front Endocrinol (Lausanne) 2022;13:957172. (In eng). DOI: 10.3389/fendo.2022.957172. PubMed DOI PMC

Zandee WT, Feelders RA, Smit Duijzentkunst DA, et al. Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177Lu-DOTATATE. Eur J Endocrinol 2019;181(1):45–53. (In eng). DOI: 10.1530/eje-18-0901. PubMed DOI

Severi S, Bongiovanni A, Ferrara M, et al. Peptide receptor radionuclide therapy in patients with metastatic progressive pheochromocytoma and paraganglioma: long-term toxicity, efficacy and prognostic biomarker data of phase II clinical trials. ESMO Open 2021;6(4):100171. (In eng). DOI: 10.1016/j.esmoop.2021.100171. PubMed DOI PMC

Bhatt RS, Landis DM, Zimmer M, et al. Hypoxia-inducible factor-2alpha: effect on radiation sensitivity and differential regulation by an mTOR inhibitor. BJU Int 2008;102(3):358–63. (In eng). DOI: 10.1111/j.1464-410X.2008.07558.x. PubMed DOI PMC

FDA Label for Lutathera. April/23/2024. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/208700s031lbl.pdf).

Sundlöv A, Sjögreen-Gleisner K, Tennvall J, et al. Pituitary Function after High-Dose 177Lu-DOTATATE Therapy and Long-Term Follow-Up. Neuroendocrinology 2021;111(4):344–353. (In eng). DOI: 10.1159/000507761. PubMed DOI PMC

Teunissen JJ, Krenning EP, de Jong FH, et al. Effects of therapy with [177Lu-DOTA 0,Tyr 3]octreotate on endocrine function. Eur J Nucl Med Mol Imaging 2009;36(11):1758–66. (In eng). DOI: 10.1007/s00259-009-1151-8. PubMed DOI PMC

Brabander T, van der Zwan WA, Teunissen JJM, et al. Long-Term Efficacy, Survival, and Safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res 2017;23(16):4617–4624. (In eng). DOI: 10.1158/1078-0432.Ccr-16-2743. PubMed DOI

Qui JZ J; Cai L; Kong W; Xue W; Zhang J; Dong P; Liu J; Li W; Li N; Naik G; Gong K Belzutifan monotherapy in Chinese patients (pts) with von Hippel-Lindau (VHL) disease–associated tumors: Results of LITESPARK-015 study. Journal of Clinical Oncology 2025;43:5_suppl.

FDA approves belzutifan for pheochromocytoma or paraganglioma. May 14th, 2025. (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma).

Pacak K, Taieb D, Lin FI, Jha A. Approach to the Patient: Concept and Application of Targeted Radiotherapy in the Paraganglioma Patient. J Clin Endocrinol Metab 2024;109(9):2366–2388. (In eng). DOI: 10.1210/clinem/dgae252. PubMed DOI PMC

Jimenez C, Chin BB, Noto RB, et al. Biomarker response to high-specific-activity I-131 meta-iodobenzylguanidine in pheochromocytoma/paraganglioma. Endocr Relat Cancer 2023;30(2) (In eng). DOI: 10.1530/erc-22-0236. PubMed DOI PMC