Metastatic or unresectable pheochromocytomas and paragangliomas (PPGLs) remain rare but clinically challenging neuroendocrine neoplasms with limited curative options. Traditionally managed with surgery, radionuclide therapy, or cytotoxic chemotherapy, systemic treatments have historically achieved disease stabilization, rather than durable remissions. In recent years, however, the therapeutic landscape has evolved substantially. Radiopharmaceuticals such as 131I-MIBG and 177Lu-DOTATATE continue to play a pivotal role, achieving disease control in many patients. Cytotoxic regimens, particularly temozolomide, remain relevant, with some studies suggesting that SDHB-mutated PPGLs demonstrate a heightened sensitivity associated with MGMT promoter hypermethylation and reduced MGMT expression. Targeted agents are increasingly important: multi-kinase inhibitors such as sunitinib, anlotinib, and cabozantinib have shown meaningful activity. The landmark approval of belzutifan, a HIF-2α inhibitor, in 2025 represents the first oral targeted therapy for advanced/metastatic PPGL, which is particularly relevant for pseudohypoxic Cluster 1 tumors. Immunotherapy has yielded modest responses with checkpoint inhibitor monotherapy, but ongoing studies of dual checkpoint blockade and TKI-ICI combinations hold promise. Novel approaches, including PARP inhibition, metabolic targeting strategies, and cancer vaccines, are under investigation, especially for aggressive SDHB-related disease. Optimal sequencing of these therapies is emerging as a central challenge, with treatment strategies increasingly tailored to molecular genotype, tumor behavior, and functional imaging phenotype. This review summarizes current evidence and highlights ongoing clinical trials, underscoring a paradigm shift toward precision medicine and rational combination strategies. Collectively, these advances bring cautious optimism that metastatic PPGLs may soon become a more manageable chronic disease with improved survival and quality of life.

Center for Adrenal Endocrine Tumors AKESO 155 00 Prague Czech Republic

Developmental Therapeutics Clinic National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD 20892 USA

Molecular Imaging Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

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Al Subhi A.R., Boyle V., Elston M.S. Systematic Review: Incidence of Pheochromocytoma and Paraganglioma over 70 Years. J. Endocr. Soc. 2022;6:bvac105. doi: 10.1210/jendso/bvac105. PubMed DOI PMC

Neumann H.P.H., Young W.F., Eng C. Pheochromocytoma and Paraganglioma. N. Engl. J. Med. 2019;381:552–565. doi: 10.1056/NEJMra1806651. PubMed DOI

Lenders J.W.M., Duh Q.-Y., Eisenhofer G., Gimenez-Roqueplo A.-P., Grebe S.K.G., Murad M.H., Naruse M., Pacak K., Young W.F., Jr. Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2014;99:1915–1942. doi: 10.1210/jc.2014-1498. PubMed DOI

Casey R.T., Hendriks E., Deal C., Waguespack S.G., Wiegering V., Redlich A., Akker S., Prasad R., Fassnacht M., Clifton-Bligh R., et al. International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents. Nat. Rev. Endocrinol. 2024;20:729–748. doi: 10.1038/s41574-024-01024-5. PubMed DOI

Horton C., LaDuca H., Deckman A., Durda K., Jackson M., Richardson M.E., Tian Y., Yussuf A., Jasperson K., Else T. Universal Germline Panel Testing for Individuals With Pheochromocytoma and Paraganglioma Produces High Diagnostic Yield. J. Clin. Endocrinol. Metab. 2022;107:e1917–e1923. doi: 10.1210/clinem/dgac014. PubMed DOI PMC

Sukrithan V., Perez K., Pandit-Taskar N., Jimenez C. Management of metastatic pheochromocytomas and paragangliomas: When and what. Curr. Probl. Cancer. 2024;51:101116. doi: 10.1016/j.currproblcancer.2024.101116. PubMed DOI

Fishbein L., Del Rivero J., Else T., Howe J.R., Asa S.L., Cohen D.L., Dahia P.L.M., Fraker D.L., Goodman K.A., Hope T.A., et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. Pancreas. 2021;50:469–493. doi: 10.1097/MPA.0000000000001792. PubMed DOI

Wang K., Crona J., Beuschlein F., Grossman A.B., Pacak K., Nölting S. Targeted Therapies in Pheochromocytoma and Paraganglioma. J. Clin. Endocrinol. Metab. 2022;107:2963–2972. doi: 10.1210/clinem/dgac471. PubMed DOI PMC

Pacak K., Wimalawansa S.J. Pheochromocytoma and paraganglioma. Endocr. Pract. 2015;21:406–412. doi: 10.4158/EP14481.RA. PubMed DOI

Mete O., Asa S.L., Gill A.J., Kimura N., de Krijger R.R., Tischler A. Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas. Endocr. Pathol. 2022;33:90–114. doi: 10.1007/s12022-022-09704-6. PubMed DOI

Juhlin C.C. Challenges in Paragangliomas and Pheochromocytomas: From Histology to Molecular Immunohistochemistry. Endocr. Pathol. 2021;32:228–244. doi: 10.1007/s12022-021-09675-0. PubMed DOI PMC

Amar L., Pacak K., Steichen O., Akker S.A., Aylwin S.J.B., Baudin E., Buffet A., Burnichon N., Clifton-Bligh R.J., Dahia P.L.M., et al. International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers. Nat. Rev. Endocrinol. 2021;17:435–444. doi: 10.1038/s41574-021-00492-3. PubMed DOI PMC

Calsina B., Piñeiro-Yáñez E., Martínez-Montes Á.M., Caleiras E., Fernández-Sanromán Á., Monteagudo M., Torres-Pérez R., Fustero-Torre C., Pulgarín-Alfaro M., Gil E., et al. Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma. Nat. Commun. 2023;14:1122. doi: 10.1038/s41467-023-36769-6. PubMed DOI PMC

Fishbein L., Leshchiner I., Walter V., Danilova L., Robertson A.G., Johnson A.R., Lichtenberg T.M., Murray B.A., Ghayee H.K., Else T., et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;31:181–193. doi: 10.1016/j.ccell.2017.01.001. PubMed DOI PMC

Calsina B., Currás-Freixes M., Buffet A., Pons T., Contreras L., Letón R., Comino-Méndez I., Remacha L., Calatayud M., Obispo B., et al. Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients. Genet. Med. 2018;20:1652–1662. doi: 10.1038/s41436-018-0068-7. PubMed DOI PMC

de Bresser C.J.M., de Krijger R.R. The Molecular Classification of Pheochromocytomas and Paragangliomas: Discovering the Genomic and Immune Landscape of Metastatic Disease. Endocr. Pathol. 2024;35:279–292. doi: 10.1007/s12022-024-09830-3. PubMed DOI PMC

Kumar S., Lila A.R., Memon S.S., Sarathi V., Patil V.A., Menon S., Mittal N., Prakash G., Malhotra G., Shah N.S., et al. Metastatic cluster 2-related pheochromocytoma/paraganglioma: A single-center experience and systematic review. Endocr. Connect. 2021;10:1463–1476. doi: 10.1530/EC-21-0455. PubMed DOI PMC

Nölting S., Bechmann N., Taieb D., Beuschlein F., Fassnacht M., Kroiss M., Eisenhofer G., Grossman A., Pacak K. Personalized Management of Pheochromocytoma and Paraganglioma. Endocr. Rev. 2022;43:199–239. doi: 10.1210/endrev/bnab019. PubMed DOI PMC

Aygun N., Uludag M. Pheochromocytoma and Paraganglioma: From Treatment to Follow-up. Şişli Etfal Hastan. Tip Bülteni. 2020;54:391–398. doi: 10.14744/SEMB.2020.58998. PubMed DOI PMC

Roman-Gonzalez A., Zhou S., Ayala-Ramirez M., Shen C., Waguespack S.G., Habra M.A., Karam J.A., Perrier N., Wood C.G., Jimenez C. Impact of Surgical Resection of the Primary Tumor on Overall Survival in Patients With Metastatic Pheochromocytoma or Sympathetic Paraganglioma. Ann. Surg. 2018;268:172–178. doi: 10.1097/SLA.0000000000002195. PubMed DOI

Zawadzka K., Tylec P., Małczak P., Major P., Pędziwiatr M., Pisarska-Adamczyk M. Total versus partial adrenalectomy in bilateral pheochromocytoma—A systematic review and meta-analysis. Front. Endocrinol. 2023;14:1127676. doi: 10.3389/fendo.2023.1127676. PubMed DOI PMC

Pinto D., Parameswaran R. Adrenal insufficiency post unilateral adrenalectomy in non-cortisol secreting tumours. Gland. Surg. 2023;12:1328–1331. doi: 10.21037/gs-23-335. PubMed DOI PMC

Kamath A.S., Singh K. StatPearls. StatPearls Publishing; Treasure Island, FL, USA: 2025. [(accessed on 9 September 2025)]. Perioperative Management of Pheochromocytoma. Available online: http://www.ncbi.nlm.nih.gov/books/NBK589634/ PubMed

Fagundes G.F.C., Almeida M.Q. Perioperative Management of Pheochromocytomas and Sympathetic Paragangliomas. J. Endocr. Soc. 2022;6:bvac004. doi: 10.1210/jendso/bvac004. PubMed DOI PMC

Taïeb D., Nölting S., Perrier N.D., Fassnacht M., Carrasquillo J.A., Grossman A.B., Clifton-Bligh R., Wanna G.B., Schwam Z.G., Amar L., et al. Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: An international expert Consensus statement. Nat. Rev. Endocrinol. 2024;20:168–184. doi: 10.1038/s41574-023-00926-0. PubMed DOI

Ye W., Yang W., Guo C., Dong C., Shi F., Liang C., Ye W., Yang W., Guo C., Dong C., et al. The effect of MWA protocols upon morphology and IVIM parameters of hepatic ablation zones—A preliminary in vivo animal study with an MRI-compatible microwave ablation device. Diagn. Interv. Radiol. 2022;28:115–123. doi: 10.5152/dir.2022.20292. PubMed DOI PMC

Ceppa E.P., Collings A.T., Abdalla M., Onkendi E., Nelson D.W., Ozair A., Miraflor E., Rahman F., Whiteside J., Shah M.M., et al. SAGES/AHPBA Guidelines for the Use of Microwave and Radiofrequency Liver Ablation for the Surgical Treatment of Hepatocellular Carcinoma or Colorectal Liver Metastases less than 5 cm. Surg. Endosc. 2023;37:8991–9000. doi: 10.1007/s00464-023-10468-1. PubMed DOI

Lubner M.G., Brace C.L., Ziemlewicz T.J., Hinshaw J.L., Lee F.T. Microwave Ablation of Hepatic Malignancy. Semin. Intervent Radiol. 2013;30:56–66. doi: 10.1055/s-0033-1333654. PubMed DOI PMC

Kohlenberg J., Welch B., Hamidi O., Callstrom M., Morris J., Sprung J., Bancos I., Young W. Efficacy and Safety of Ablative Therapy in the Treatment of Patients with Metastatic Pheochromocytoma and Paraganglioma. Cancers. 2019;11:195. doi: 10.3390/cancers11020195. PubMed DOI PMC

Kariyasu T., Machida H., Nishina Y., Tambo M., Miyagawa S., Rakue T., Sumitani Y., Yasuda K., Shibahara J., Yokoyama K. Emergent transcatheter arterial embolization to control critical blood pressure fluctuation associated with hypercatecholaminemic crisis in a patient with an unruptured retroperitoneal paraganglioma. Radiol. Case Rep. 2021;16:2065–2071. doi: 10.1016/j.radcr.2021.05.018. PubMed DOI PMC

Ichikawa T., Oyabu C., Minamida M., Ichijo Y., Hashimoto Y., Asano M., Iwase H., Tanaka T., Fukui M. Changes in the Size of a Ruptured Pheochromocytoma after Transcatheter Arterial Embolization. Case Rep. Med. 2021;2021:5568978. doi: 10.1155/2021/5568978. PubMed DOI PMC

Jimenez C., Baudrand R., Uslar T., Bulzico D. Perspective review: Lessons from successful clinical trials and real-world studies of systemic therapy for metastatic pheochromocytomas and paragangliomas. Ther. Adv. Med. Oncol. 2024;16:17588359241301359. doi: 10.1177/17588359241301359. PubMed DOI PMC

Fischer A., Kloos S., Maccio U., Friemel J., Remde H., Fassnacht M., Pamporaki C., Eisenhofer G., Timmers H.J.L.M., Robledo M., et al. Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses. J. Clin. Endocrinol. Metab. 2023;108:2676–2685. doi: 10.1210/clinem/dgad166. PubMed DOI PMC

Leijon H., Remes S., Hagström J., Louhimo J., Mäenpää H., Schalin-Jäntti C., Miettinen M., Haglund C., Arola J. Variable somatostatin receptor subtype expression in 151 primary pheochromocytomas and paragangliomas. Hum. Pathol. 2019;86:66–75. doi: 10.1016/j.humpath.2018.11.020. PubMed DOI PMC

Gomes-Porras M., Cárdenas-Salas J., Álvarez-Escolá C. Somatostatin Analogs in Clinical Practice: A Review. Int. J. Mol. Sci. 2020;21:1682. doi: 10.3390/ijms21051682. PubMed DOI PMC

Massironi S., Albertelli M., Hasballa I., Paravani P., Ferone D., Faggiano A., Danese S. “Cold” Somatostatin Analogs in Neuroendocrine Neoplasms: Decoding Mechanisms, Overcoming Resistance, and Shaping the Future of Therapy. Cells. 2025;14:245. doi: 10.3390/cells14040245. PubMed DOI PMC

Rinke A., Müller H.-H., Schade-Brittinger C., Klose K.-J., Barth P., Wied M., Mayer C., Aminossadati B., Pape U.-F., Bläker M., et al. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors: A Report From the PROMID Study Group. JCO. 2009;27:4656–4663. doi: 10.1200/JCO.2009.22.8510. PubMed DOI

Caplin M.E., Pavel M., Ćwikła J.B., Phan A.T., Raderer M., Sedláčková E., Cadiot G., Wolin E.M., Capdevila J., Wall L., et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. N. Engl. J. Med. 2014;371:224–233. doi: 10.1056/NEJMoa1316158. PubMed DOI

Fojo A. Exploratory Phase II Study of LAnreotide in Metastatic Pheochromocytoma/PARAganglioma (LAMPARA). clinicaltrials.gov, Clinical Trial Registration NCT03946527. February 2025. [(accessed on 9 September 2025)]; Available online: https://clinicaltrials.gov/study/NCT03946527.

Wolin E.M., Jarzab B., Eriksson B., Walter T., Toumpanakis C., Morse M.A., Tomassetti P., Weber M.M., Fogelman D.R., Ramage J., et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des. Dev. Ther. 2015;9:5075–5086. doi: 10.2147/DDDT.S84177. PubMed DOI PMC

Bolanowski M., Kałużny M., Witek P., Jawiarczyk-Przybyłowska A. Pasireotide—A novel somatostatin receptor ligand after 20 years of use. Rev. Endocr. Metab. Disord. 2022;23:601–620. doi: 10.1007/s11154-022-09710-3. PubMed DOI PMC

Vyakaranam A.R., Crona J., Norlén O., Granberg D., Garske-Román U., Sandström M., Fröss-Baron K., Thiis-Evensen E., Hellman P., Sundin A. Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE. Cancers. 2019;11:909. doi: 10.3390/cancers11070909. PubMed DOI PMC

Severi S., Bongiovanni A., Ferrara M., Nicolini S., Di Mauro F., Sansovini M., Lolli I., Tardelli E., Cittanti C., Di Iorio V., 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;6:100171. doi: 10.1016/j.esmoop.2021.100171. PubMed DOI PMC

Kornerup L.S., Andreassen M., Knigge U., Arveschoug A.K., Poulsen P.L., Kjær A., Oturai P.S., Grønbæk H., Dam G. Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study. Cancers. 2024;16:1349. doi: 10.3390/cancers16071349. PubMed DOI PMC

Gubbi S., Al-Jundi M., Auh S., Jha A., Zou J., Shamis I., Meuter L., Knue M., Turkbey B., Lindenberg L., et al. Early short-term effects on catecholamine levels and pituitary function in patients with pheochromocytoma or paraganglioma treated with [177Lu]Lu-DOTA-TATE therapy. Front. Endocrinol. 2023;14:1275813. doi: 10.3389/fendo.2023.1275813. PubMed DOI PMC

Duan H., Ferri V., Moradi F., Nguyen J., Franc B.L., Iagaru A., Aparici M. Peptide Receptor Radionuclide Therapy (PRRT) in Advanced Pheochromocytoma and Paraganglioma From a Single Institution Experience. [(accessed on 17 November 2025)];2021 Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927907/

Lin F.I., del Rivero J., Carrasquillo J.A., Jha A., Zou J., Shamis I., Talvacchio S., Turkbey B., Huang E.P., Shih J., et al. Phase II Study of 177Lu-DOTATATE for Progressive Metastatic Pheochromocytomas and Paragangliomas: Interim Analysis of Efficacy, Safety, and Biomarkers. J. Clin. Oncol. 2025;43:3102–3112. doi: 10.1200/JCO-25-00791. PubMed DOI PMC

Tsang E.S., Funk G., Leung J., Kalish G., Kennecke H.F. Supportive Management of Patients with Advanced Pheochromocytomas and Paragangliomas Receiving PRRT. Curr. Oncol. 2021;28:2823–2829. doi: 10.3390/curroncol28040247. PubMed DOI PMC

Dillon J.S., Bushnell D., Laux D.E. High-specific-activity 131iodine-metaiodobenzylguanidine for therapy of unresectable pheochromocytoma and paraganglioma. Future Oncol. 2021;17:1131–1141. doi: 10.2217/fon-2020-0625. PubMed DOI PMC

Pryma D.A., Chin B.B., Noto R.B., Dillon J.S., Perkins S., Solnes L., Kostakoglu L., Serafini A.N., Pampaloni M.H., Jensen J., et al. Efficacy and Safety of High-Specific-Activity 131I-MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma. J. Nucl. Med. 2019;60:623–630. doi: 10.2967/jnumed.118.217463. PubMed DOI PMC

Jimenez C., Chin B.B., Noto R.B., Dillon J.S., Solnes L., Stambler N., DiPippo V.A., Pryma D.A. Biomarker response to high-specific-activity I-131 meta-iodobenzylguanidine in pheochromocytoma/paraganglioma. Endocr. Relat. Cancer. 2022;30:e220236. doi: 10.1530/ERC-22-0236. PubMed DOI PMC

Center for Drug Evaluation and Research FDA Approves Iobenguane I 131 for Rare Adrenal Gland Tumors. FDA, August 2024. [(accessed on 9 September 2025)]; Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-iobenguane-i-131-rare-adrenal-gland-tumors.

Carrasquillo J.A., Pandit-Taskar N., Chen C.C. I-131 Metaiodobenzylguanidine Therapy of Pheochromocytoma and Paraganglioma. Semin. Nucl. Med. 2016;46:203–214. doi: 10.1053/j.semnuclmed.2016.01.011. PubMed DOI

Jha A., Taïeb D., Carrasquillo J.A., Pryma D.A., Patel M., Millo C., de Herder W.W., Del Rivero J., Crona J., Shulkin B.L., et al. High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma. Clin. Cancer Res. 2021;27:2989–2995. doi: 10.1158/1078-0432.CCR-20-3703. PubMed DOI PMC

Prado-Wohlwend S., del Olmo-García M.I., Bello-Arques P., Merino-Torres J.F. [177Lu]Lu-DOTA-TATE and [131I]MIBG Phenotypic Imaging-Based Therapy in Metastatic/Inoperable Pheochromocytomas and Paragangliomas: Comparative Results in a Single Center. Front. Endocrinol. 2022;13:778322. doi: 10.3389/fendo.2022.778322. PubMed DOI PMC

Zandee W.T., Feelders R.A., Smit Duijzentkunst D.A., Hofland J., Metselaar R.M., Oldenburg R.A., van Linge A., Kam B.L.R., Teunissen J.J.M., Korpershoek E., et al. Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177Lu-DOTATATE. Eur. J. Endocrinol. 2019;181:45–53. doi: 10.1530/EJE-18-0901. PubMed DOI

Carrasquillo J.A., Chen C.C., Jha A., Pacak K., Pryma D.A., Lin F.I. Systemic Radiopharmaceutical Therapy of Pheochromocytoma and Paraganglioma. J. Nucl. Med. 2021;62:1192–1199. doi: 10.2967/jnumed.120.259697. PubMed DOI PMC

Ilanchezhian M., Jha A., Pacak K., Del Rivero J. Emerging Treatments for Advanced/Metastatic Pheochromocytoma and Paraganglioma. Curr. Treat. Options Oncol. 2020;21:85. doi: 10.1007/s11864-020-00787-z. PubMed DOI PMC

Zhou Y., Cui Y., Zhang D., Tong A. Efficacy and Safety of Tyrosine Kinase Inhibitors in Patients with Metastatic Pheochromocytomas/Paragangliomas. J. Clin. Endocrinol. Metab. 2023;108:755–766. doi: 10.1210/clinem/dgac657. PubMed DOI

Raymond E., Dahan L., Raoul J.-L., Bang Y.-J., Borbath I., Lombard-Bohas C., Valle J., Metrakos P., Smith D., Vinik A., et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med. 2011;364:501–513. doi: 10.1056/NEJMoa1003825. PubMed DOI

Baudin E., Goichot B., Berruti A., Hadoux J., Moalla S., Laboureau S., Nölting S., de la Fouchardière C., Kienitz T., Deutschbein T., 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;403:1061–1070. doi: 10.1016/S0140-6736(23)02554-0. PubMed DOI

Ayala-Ramirez M., Chougnet C.N., Habra M.A., Palmer J.L., Leboulleux S., Cabanillas M.E., Caramella C., Anderson P., Al Ghuzlan A., Waguespack S.G., et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J. Clin. Endocrinol. Metab. 2012;97:4040–4050. doi: 10.1210/jc.2012-2356. PubMed DOI PMC

Deschler-Baier B., Konda B., Massarelli E., Hu M.I., Wirth L.J., Xu X., Wright J., Clifton-Bligh R.J. Clinical Activity of Selpercatinib in RET-mutant Pheochromocytoma. J. Clin. Endocrinol. Metab. 2024;110:e600–e606. doi: 10.1210/clinem/dgae283. PubMed DOI PMC

Burotto Pichun M.E., Edgerly M., Velarde M., Bates S.E., Daerr R., Adams K., Pacak K., Fojo T. Phase II clinical trial of axitinib in metastatic pheochromocytomas and paraganlgiomas (P/PG): Preliminary results. J. Clin. Oncol. 2015;33:457. doi: 10.1200/jco.2015.33.7_suppl.457. DOI

Jimenez C., Habra M.A., Campbell M.T., Tamsen G., Cruz-Goldberg D., Long J., Bassett R., Dantzer R., Balderrama-Brondani V., Varghese J., 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;25:658–667. doi: 10.1016/S1470-2045(24)00133-5. PubMed DOI

Tian R., Yao X., Song J., Wang J., Fu J., Shi L., Yu F., Zhang P., Zhang C., Ni Y., et al. Anlotinib for Metastatic Progressed Pheochromocytoma and Paraganglioma: A Retrospective Study of Real-World Data. J. Endocr. Soc. 2024;8:bvae061. doi: 10.1210/jendso/bvae061. PubMed DOI PMC

Keiser H.R., Goldstein D.S., Wade J.L., Douglas F.L., Averbuch S.D. Treatment of malignant pheochromocytoma with combination chemotherapy. Hypertension. 1985;7:I18–I24. doi: 10.1161/01.HYP.7.3_Pt_2.I18. PubMed DOI

Averbuch S.D., Steakley C.S., Young R.C., Gelmann E.P., Goldstein D.S., Stull R., Keiser H.R. Malignant pheochromocytoma: Effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann. Intern. Med. 1988;109:267–273. doi: 10.7326/0003-4819-109-4-267. PubMed DOI

Huang H., Abraham J., Hung E., Averbuch S., Merino M., Steinberg S.M., Pacak K., Fojo T. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: Recommendation from a 22-year follow-up of 18 patients. Cancer. 2008;113:2020–2028. doi: 10.1002/cncr.23812. PubMed DOI PMC

Niemeijer N.D., Alblas G., van Hulsteijn L.T., Dekkers O.M., Corssmit E.P.M. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: Systematic review and meta-analysis. Clin. Endocrinol. 2014;81:642–651. doi: 10.1111/cen.12542. PubMed DOI

Asai S., Katabami T., Tsuiki M., Tanaka Y., Naruse M. Controlling tumor progression with cyclophosphamide, vincristine, and dacarbazine treatment improves survival in patients with metastatic and unresectable malignant pheochromocytomas/paragangliomas. Horm. Cancer. 2017;8:108–118. doi: 10.1007/s12672-017-0284-7. PubMed DOI PMC

Kulke M.H., Stuart K., Enzinger P.C., Ryan D.P., Clark J.W., Muzikansky A., Vincitore M., Michelini A., Fuchs C.S. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J. Clin. Oncol. 2006;24:401–406. doi: 10.1200/JCO.2005.03.6046. PubMed DOI

Hadoux J., Favier J., Scoazec J.-Y., Leboulleux S., Al Ghuzlan A., Caramella C., Déandreis D., Borget I., Loriot C., Chougnet C., et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int. J. Cancer. 2014;135:2711–2720. doi: 10.1002/ijc.28913. PubMed DOI

Perez K., Jacene H., Hornick J.L., Ma C., Vaz N., Brais L.K., Alexander H., Baddoo W., Astone K., Esplin E.D., et al. SDHx mutations and temozolomide in malignant pheochromocytoma and paraganglioma. Endocr.-Relat. Cancer. 2022;29:533–544. doi: 10.1530/ERC-21-0392. PubMed DOI

Urquhart C., Fleming B., Harper I., Aloj L., Armstrong R., Hook L., Long A.-M., Jackson C., Gallagher F.A., McLean M.A., et al. The use of temozolomide in paediatric metastatic phaeochromocytoma/paraganglioma: A case report and literature review. Front. Endocrinol. 2022;13:1066208. doi: 10.3389/fendo.2022.1066208. PubMed DOI PMC

Jimenez C., Subbiah V., Stephen B., Ma J., Milton D., Xu M., Zarifa A., Akhmedzhanov F.O., Tsimberidou A., Habra M.A., et al. Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas. Cancers. 2020;12:2307. doi: 10.3390/cancers12082307. PubMed DOI PMC

National Cancer Institute (NCI) DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors. clinicaltrials.gov, Clinical trial registration NCT02834013, September 2025. [(accessed on 9 September 2025)]; Available online: https://clinicaltrials.gov/study/NCT02834013.

Economides M.P., Shah A.Y., Jimenez C., Habra M.A., Desai M., Campbell M.T. A Durable Response With the Combination of Nivolumab and Cabozantinib in a Patient With Metastatic Paraganglioma: A Case Report and Review of the Current Literature. Front. Endocrinol. 2020;11:594264. doi: 10.3389/fendo.2020.594264. PubMed DOI PMC

Hadrava Vanova K., Uher O., Meuter L., Ghosal S., Talvacchio S., Patel M., Neuzil J., Pacak K. PD-L1 expression and association with genetic background in pheochromocytoma and paraganglioma. Front. Oncol. 2022;12:1045517. doi: 10.3389/fonc.2022.1045517. PubMed DOI PMC

Yu A., Xu X., Pang Y., Li M., Luo J., Wang J., Liu L. PD-L1 Expression is Linked to Tumor-Infiltrating T-Cell Exhaustion and Adverse Pathological Behavior in Pheochromocytoma/Paraganglioma. Lab. Investig. 2023;103:100210. doi: 10.1016/j.labinv.2023.100210. PubMed DOI

Celada L., Cubiella T., San-Juan-Guardado J., Gutiérrez G., Beiguela B., Rodriguez R., Poch M., Astudillo A., Grijalba A., Sánchez-Sobrino P., et al. Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype. J. Pathol. 2023;259:103–114. doi: 10.1002/path.6026. PubMed DOI PMC

Center for Drug Evaluation and Research FDA Approves Belzutifan for Pheochromocytoma or Paraganglioma. FDA, May 2025. [(accessed on 9 September 2025)]; Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma.

Jimenez C., Andreassen M., Durand A., Moog S., Hendifar A., Welin S., Spada F., Sharma R., Wolin E., Ruether J., et al. Belzutifan for Advanced Pheochromocytoma or Paraganglioma. [(accessed on 17 November 2025)];N. Engl. J. Med. 2025 :NEJMoa2504964. doi: 10.1056/NEJMoa2504964. Available online: https://www.nejm.org/doi/abs/10.1056/NEJMoa2504964. PubMed DOI

FDA Grants Priority Review to Merck’s Application for WELIREG® (Belzutifan) for the Treatment of Patients with Advanced Pheochromocytoma and Paraganglioma (PPGL), Merck.com. [(accessed on 10 September 2025)]. Available online: https://www.merck.com/news/fda-grants-priority-review-to-mercks-application-for-welireg-belzutifan-for-the-treatment-of-patients-with-advanced-pheochromocytoma-and-paraganglioma-ppgl/

Moog S., Salgues B., Braik-Djellas Y., Viel T., Balvay D., Autret G., Robidel E., Gimenez-Roqueplo A.-P., Tavitian B., Lussey-Lepoutre C., et al. Preclinical evaluation of targeted therapies in Sdhb-mutated tumors. Endocr.-Relat. Cancer. 2022;29:375–388. doi: 10.1530/ERC-22-0030. PubMed DOI

Hadrava Vanova K., Yang C., Meuter L., Neuzil J., Pacak K. Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma. Cancers. 2021;13:3769. doi: 10.3390/cancers13153769. PubMed DOI PMC

Enterome A Phase 1/2 Trial of a Novel Therapeutic Vaccine (EO2401) in Combination with Immune Check Point Blockade, for Treatment of Patients with Locally Advanced or Metastatic Adrenocortical Carcinoma, or Malignant Pheochromocytoma/Paraganglioma. clinicaltrials.gov, Clinical Trial Registration NCT04187404, November 2024. [(accessed on 10 September 2025)]; Available online: https://clinicaltrials.gov/study/NCT04187404.

Baudin E., Grisanti S., Fassnacht M., C.W. der Houven van Oordt M.-V., Haak H., de la Fouchardiere C., Subbiah V., Jimenez C., Castillon J.C., Granberg D., et al. 2MO EO2401 (EO) therapeutic vaccine for patients (pts) with adrenocortical carcinoma (ACC) and malignant pheochromocytoma/paraganglioma (MPP): Phase I/II SPENCER study. Ann. Oncol. 2022;33:S545–S546. doi: 10.1016/j.annonc.2022.07.023. DOI

University College, London A Phase I Trial of Vandetanib Combined with 131I-mIBG Radiotherapy in Patients with Neuroendocrine Tumours, Advanced Phaeochromocytoma and Paraganglioma. clinicaltrials.gov, Clinical TRIAL REGIStration NCT01941849, December 2015. [(accessed on 10 September 2025)]; Available online: https://clinicaltrials.gov/study/NCT01941849.

National Cancer Institute (NCI) A Prospective, Multi-Institutional Phase II Trial Evaluating Temozolomide vs. Temozolomide and Olaparib for Advanced Pheochromocytoma and Paraganglioma. clinicaltrials.gov, Clinical Trial Registration NCT04394858, June 2025. [(accessed on 10 September 2025)]; Available online: https://clinicaltrials.gov/study/NCT04394858.

Ambrosini V., Kunikowska J., Baudin E., Bodei L., Bouvier C., Capdevila J., Cremonesi M., de Herder W.W., Dromain C., Falconi M., et al. Consensus on Molecular Imaging and Theranostics in Neuroendocrine Neoplasms. Eur. J. Cancer. 2021;146:56–73. doi: 10.1016/j.ejca.2021.01.008. PubMed DOI PMC

Nguyen C.B., Oh E., Bahar P., Vaishampayan U.N., Else T., Alva A.S. Novel Approaches with HIF-2α Targeted Therapies in Metastatic Renal Cell Carcinoma. Cancers. 2024;16:601. doi: 10.3390/cancers16030601. PubMed DOI PMC

Lantheus to Discontinue Production of Azedra. [(accessed on 2 November 2025)]. Available online: https://snmmi.org/Web/Web/News/Articles/Lantheus-to-Discontinue-Production-of-Azedra.aspx?utm_source=chatgpt.com.