# Metastatic pheochromocytoma and paraganglioma

Source: https://onco.cc/cancers/metastatic-ppgl/  
OnCo record `metastatic-ppgl` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Metastatic pheochromocytoma and paraganglioma is disease that has spread to bone, lymph nodes, liver or lungs, the only way these adrenaline-producing tumours are called malignant. It is often slow, so treatment starts with blood pressure control and watching, then moves through radioactive drugs that home to the tumour, the kinase inhibitor sunitinib, chemotherapy and, since 2025, belzutifan.

## Summary

No pathological feature reliably separates benign from malignant pheochromocytoma and paraganglioma; malignancy is defined by metastases at sites where chromaffin tissue does not normally occur, above all bone, lymph nodes, liver and lung. Metastatic disease occurs in about a tenth of adrenal tumours and a much larger share of extra-adrenal sympathetic paragangliomas, and SDHB mutation, large size, extra-adrenal site and a noradrenergic or dopaminergic profile are the main risk factors. The course is heterogeneous: some patients live for decades with stable bone metastases, others progress within months, so the first decision is whether to treat at all. Catecholamine excess is controlled throughout with alpha-blockade (phenoxybenzamine or doxazosin) and beta-blockade added second, with metyrosine for refractory cases, and any procedure, including biopsy and embolisation, is done under blockade to avoid a hypertensive crisis. Somatostatin receptor PET (68Ga-DOTATATE) and 123I-MIBG scintigraphy stage the disease and, by showing uptake, select patients for the corresponding radionuclide therapy.

Treatment is sequenced by pace. Indolent disease is watched or treated locally with surgery, radiotherapy, ablation or embolisation of dominant lesions. For progressive disease, radionuclide therapy is the first systemic step: high-specific-activity 131I-MIBG (iobenguane, Azedra) was approved in 2018 after a phase 2 trial in which a quarter of patients halved their antihypertensive medication and about a fifth had tumour responses, though the manufacturer withdrew it from the market in 2024, and lutetium-177 dotatate, approved for gastroenteropancreatic neuroendocrine tumours, is used for somatostatin-receptor-positive disease on the strength of retrospective series and phase 2 trials. Sunitinib is the one systemic drug with randomised evidence: FIRSTMAPPP (Lancet 2024), an academic phase 2 trial that took twelve years to enrol 78 patients, showed 12-month progression-free survival of 36 percent against 19 percent on placebo. Cyclophosphamide, vincristine and dacarbazine (CVD) chemotherapy, in use since 1988, and temozolomide, which is active particularly in SDHB-mutant tumours, are the cytotoxic options, and cabozantinib showed activity in the phase 2 NATALIE trial. Belzutifan, the HIF-2 alpha inhibitor, was approved in the United States in May 2025 for adults and children over 12 with locally advanced, unresectable or metastatic disease after a response rate of 26 percent in the LITESPARK-015 cohort, the first approval for the disease in seven years and the first to exploit the pseudohypoxia biology of cluster 1 tumours; the imipridone ONC206 and radioligand combinations are in trials. Bone metastases, the commonest site, are treated with denosumab or bisphosphonates and palliative radiotherapy.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: Malignant pheochromocytoma; Metastatic paraganglioma; Advanced PPGL; Unresectable pheochromocytoma and paraganglioma
- Tags: subtype-page; endocrine
- Group: endocrine
- Burden: About one in ten pheochromocytomas and up to a third or more of sympathetic paragangliomas, especially SDHB-related ones, metastasise to bone, lymph nodes, liver and lung; the course ranges from indolent over decades to rapidly fatal.
- Subtypes: Indolent metastatic pheochromocytoma or paraganglioma (bone-predominant, observation or local therapy); Progressive somatostatin-receptor-positive metastatic paraganglioma (lutetium-177 dotatate); MIBG-avid metastatic pheochromocytoma (131I-MIBG where available); SDHB-related metastatic paraganglioma (temozolomide-sensitive, belzutifan candidate); Rapidly progressive metastatic pheochromocytoma or paraganglioma (CVD chemotherapy); Metastatic pheochromocytoma or paraganglioma with uncontrolled catecholamine excess
- Biomarkers: Plasma or urinary metanephrines and 3-methoxytyramine (secretory profile, monitoring); Germline and somatic SDHB, VHL and other cluster status (prognosis, belzutifan and temozolomide sensitivity); 68Ga-DOTATATE PET uptake (lutetium-177 dotatate eligibility); 123I-MIBG uptake (131I-MIBG eligibility); Rate of progression on serial imaging (decides when to treat); Bone scan or FDG-PET for skeletal disease

## Standard of care

- All patients: Alpha-blockade with beta-blockade added second; metyrosine for refractory symptoms; blockade before every procedure; bone-protective agents for skeletal metastases. ([Adrenalectomy](https://onco.cc/terms/adrenalectomy/))
- Staging: 68Ga-DOTATATE PET, 123I-MIBG scintigraphy where 131I-MIBG is available, CT or MRI, FDG-PET for SDHB-related disease; germline testing. ([Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://onco.cc/technologies/sstr-pet/), [MIBG imaging and 131I-MIBG therapy](https://onco.cc/technologies/mibg-theranostics/), [FDG PET](https://onco.cc/technologies/fdg-pet/), [MRI](https://onco.cc/technologies/mri/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/))
- Indolent disease: Active surveillance; resection, radiotherapy, thermal ablation or embolisation of dominant or symptomatic lesions. ([Active surveillance](https://onco.cc/technologies/active-surveillance/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/))
- Progressive disease, radionuclide therapy: Lutetium-177 dotatate for somatostatin-receptor-positive disease; 131I-MIBG for MIBG-avid disease where still available (approved 2018, withdrawn from market 2024). ([Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/), [Peptide receptor radionuclide therapy (PRRT)](https://onco.cc/technologies/prrt/), [Radioligand therapy (beta emitters)](https://onco.cc/technologies/radioligand-therapy/), [131I-MIBG (iobenguane I-131) therapy](https://onco.cc/drugs/i131-mibg/), [MIBG imaging and 131I-MIBG therapy](https://onco.cc/technologies/mibg-theranostics/))
- Progressive disease, systemic drugs: Belzutifan (approved 2025); sunitinib (FIRSTMAPPP); cabozantinib; cyclophosphamide, vincristine and dacarbazine or temozolomide for rapidly progressive or SDHB-related disease. ([Belzutifan](https://onco.cc/drugs/belzutifan/), [Sunitinib](https://onco.cc/drugs/sunitinib/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Vincristine](https://onco.cc/drugs/vincristine/), [Temozolomide](https://onco.cc/drugs/temozolomide/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/))
- Trials: ONC206, radioligand combinations and next-generation HIF-2 alpha inhibitors. ([Study of ONC206 (JZP3507) in Advanced Pheochromocytoma and Paraganglioma](https://onco.cc/trials/nct07282587/), [Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL](https://onco.cc/trials/nct04924075/))

## State of the art

- Belzutifan is the first approved targeted drug and the first to act on the tumour's own hypoxia biology.
- FIRSTMAPPP proved that randomised trials are possible in this ultra-rare disease and validated sunitinib.
- Radionuclide therapy gives durable control to patients whose tumours take up the tracer.

## Open problems

- No randomised trial has compared radionuclide therapy with drugs or defined their order.
- Azedra's withdrawal leaves MIBG-avid, somatostatin-receptor-negative patients without a radionuclide option in many countries.
- Catecholamine crises during treatment remain dangerous.
- The disease is too rare and too slow for conventional trial designs.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Pheochromocytoma
- FIRSTMAPPP (Lancet 2024): https://doi.org/10.1016/S0140-6736(23)02554-0
- Endocrine Society PPGL guideline 2014: https://doi.org/10.1210/jc.2014-1498
- Wikipedia: https://en.wikipedia.org/wiki/Pheochromocytoma

## Connected records

- cancers: [Advanced and metastatic adrenocortical carcinoma (ENSAT stage IV or unresectable)](https://onco.cc/cancers/advanced-adrenocortical-carcinoma/), [Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)](https://onco.cc/cancers/hereditary-ppgl/), [Pheochromocytoma and paraganglioma (PPGL)](https://onco.cc/cancers/pheochromocytoma-paraganglioma/), [Small intestinal neuroendocrine tumours](https://onco.cc/cancers/small-intestinal-net/)
- technologies: [Active surveillance](https://onco.cc/technologies/active-surveillance/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [FDG PET](https://onco.cc/technologies/fdg-pet/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [MIBG imaging and 131I-MIBG therapy](https://onco.cc/technologies/mibg-theranostics/), [MRI](https://onco.cc/technologies/mri/), [Peptide receptor radionuclide therapy (PRRT)](https://onco.cc/technologies/prrt/), [Radioligand therapy (beta emitters)](https://onco.cc/technologies/radioligand-therapy/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://onco.cc/technologies/sstr-pet/), [Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/)
- targets: [HIF-2α](https://onco.cc/targets/hif2a/), [Somatostatin receptor 2](https://onco.cc/targets/sstr2/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [131I-MIBG (iobenguane I-131) therapy](https://onco.cc/drugs/i131-mibg/), [Belzutifan](https://onco.cc/drugs/belzutifan/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/), [Sunitinib](https://onco.cc/drugs/sunitinib/), [Temozolomide](https://onco.cc/drugs/temozolomide/), [Vincristine](https://onco.cc/drugs/vincristine/)
- terms: [Adrenalectomy](https://onco.cc/terms/adrenalectomy/), [Rare cancers](https://onco.cc/terms/rare-cancers/), [SDH deficiency (SDHB immunohistochemistry loss)](https://onco.cc/terms/sdh-deficiency/)
- trials: [Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL](https://onco.cc/trials/nct04924075/), [Study of ONC206 (JZP3507) in Advanced Pheochromocytoma and Paraganglioma](https://onco.cc/trials/nct07282587/)
- key papers: [Efficacy and safety of high-specific-activity 131I-MIBG therapy in advanced pheochromocytoma or paraganglioma](https://onco.cc/key-papers/paper-pryma-high-specific-activity-i131-mibg-ppgl-jnm-2019/), [FIRSTMAPPP: sunitinib for metastatic progressive pheochromocytomas and paragangliomas](https://onco.cc/key-papers/paper-firstmappp-sunitinib-metastatic-ppgl-lancet-2024/), [Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline](https://onco.cc/key-papers/paper-endocrine-society-pheochromocytoma-paraganglioma-guideline-jcem-2014/)

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