Systemic Therapy Selection for Metastatic Pheochromocytoma and Paraganglioma

Authored by Natalia Gandur, published on 2026-06-22 20:45:15.0

The algorithm is broadly aligned with contemporary management of metastatic PPGL by emphasizing symptom stabilization, careful selection between observation vs treatment, and use of functional imaging (MIBG/SSTR) and molecular features to guide therapy. It appropriately incorporates newer prospective evidence for TKIs (sunitinib, cabozantinib) and the emergence of belzutifan for PPGL, while maintaining established options (HSA 131I-MIBG, CVD, temozolomide) and prioritizing clinical trials. Key limitations are the still-sparse randomized data for many sequences and heterogeneity across genotypes/imaging phenotypes, meaning several branches remain supported mainly by phase II/retrospective evidence and consensus guidance.

  1. Confirmed metastatic PPGL
    Confirm metastatic pheochromocytoma or paraganglioma before systemic treatment selection. This pathway applies to patients with metastatic PPGL being considered for observation, systemic therapy, targeted therapy, radiopharmaceutical therapy, or clinical trial participation. Key baseline considerations: Disease burden and sites of metastases Disease tempo Catecholamine secretion and blood pressure control Performance status and comorbidities Prior local/systemic therapy Molecular profile, including RET/MEN2 and pseudohypoxia-associated biology when available Functional imaging avidity, including MIBG and/or DOTATATE when relevant Multidisciplinary review with oncology, endocrinology, nuclear medicine, radiology, and cardiology when indicated Baseline evaluation: CBC with differential CMP including AST/ALT, bilirubin, creatinine/eGFR, electrolytes Blood pressure assessment and cardiovascular risk review Plasma free metanephrines or 24-hour urine fractionated metanephrines/catecholamines when clinically informative Review catecholamine-related symptoms: hypertension, palpitations, headache, sweating, constipation, cardiomyopathy, pain Baseline neuropathy assessment if considering vincristine or TKI therapy Bone marrow reserve and prior radiation/radiopharmaceutical exposure Molecular testing review, including RET/MEN2 and pseudohypoxia-associated alterations when available Functional imaging review, including MIBG and/or DOTATATE depending on treatment context
    • Need systemic therapy now?
      Radiographic progression, clinically meaningful tumor burden, threatened organ function, or uncontrolled hormonal symptoms. Systemic therapy may be appropriate when there is radiographic progression, clinically meaningful tumor burden, threatened organ function, symptomatic disease, or catecholamine-related morbidity not adequately controlled with medical therapy. Observation is reasonable when disease is not progressing and hormonal symptoms are absent or controlled. Patients without radiographic progression but with uncontrolled hormonal symptoms should undergo endocrine optimization and reassessment. Assessment before deciding systemic therapy need: Review interval imaging to confirm progression pattern Assess tumor burden and threatened organ function Review catecholamine-related symptoms and blood pressure control Consider plasma free metanephrines or 24-hour urine fractionated metanephrines/catecholamines when clinically informative Review CBC, CMP, renal function, marrow reserve, and performance status if systemic therapy may be needed Confirm functional imaging status when radiopharmaceutical therapy may be considered Review molecular profile, including RET/MEN2 and pseudohypoxia-associated biology when available Do not start systemic anticancer therapy before stabilizing acute catecholamine crisis or uncontrolled severe hypertension when urgent endocrine/cardiovascular management is required.
      • No
        • Observation / Continue surveillance
          Use when disease is not progressing, tumor burden is not clinically urgent, organ function is not threatened, and hormonal symptoms are absent or medically controlled. Monitoring: Interval imaging based on disease tempo and clinical context Biochemical markers when informative Blood pressure and symptom monitoring Reassess systemic therapy if progression, tumor-related morbidity, or uncontrolled hormonal symptoms develop
      • Yes
        • RET-altered disease?
          Assess for RET-altered or MEN2-associated MPPGL. If RET-driven disease is confirmed and selpercatinib is accessible and clinically appropriate, selpercatinib may be prioritized. If no actionable RET alteration is present, proceed according to disease tempo, functional imaging avidity, molecular profile, treatment urgency, prior therapy, toxicity risk, and access. Assessment: Review germline and/or somatic testing when available Confirm MEN2-associated disease when clinically relevant Consider broader molecular profiling if not previously performed Integrate RET status with disease tempo, tumor burden, symptoms, imaging phenotype, and patient fitness
          • No
            • Pace of progression?
              Classify disease tempo before choosing therapy. Rapid progression / urgent tumor control:Use when disease is fast-growing, symptomatic, associated with high tumor burden, threatening organ function, or when delayed response would be clinically unsafe. Slow-to-moderate progression:Use when disease is progressing but immediate cytoreduction is not required, allowing consideration of therapies with potentially slower but durable disease control. Assessment: Compare current and prior imaging Review symptom trajectory Assess threatened organ function Review catecholamine-related morbidity and blood pressure control Assess performance status, marrow reserve, renal function, and treatment access
              • Rapid progression
                For rapid progression or urgent tumor control, prioritize options that may provide earlier disease control, such as CVD chemotherapy or tyrosine kinase inhibitors. Before treatment: Optimize catecholamine blockade and blood pressure whenever feasible Involve endocrinology for hormonally active disease Assess performance status, marrow reserve, renal function, neuropathy, cardiovascular risk, and prior therapies Consider inpatient or high-acuity monitoring when catecholamine secretion is clinically high-risk Clinical caveat:Therapies with slower expected time to response may be less suitable when immediate cytoreduction is needed.
                • CVD chemotherapy
                  CVD chemotherapy refers to cyclophosphamide, vincristine, and dacarbazine. Potential use: Rapidly progressive disease Need for cytoreduction High tumor burden or threatened organ function Selected neoadjuvant or bridging contexts Monitoring / toxicity: CBC and CMP before treatment cycles Myelosuppression Nausea and fatigue Neuropathy and constipation, especially with vincristine Catecholamine crisis risk in hormonally active disease Blood pressure monitoring and endocrine optimization before therapy Clinical caveat:Evidence supports activity in selected patients, but optimal sequencing and survival impact remain uncertain.
                  • or Cabozantinib / Sunitinib
                    Cabozantinib or sunitinib may be considered for progressive MPPGL when tyrosine kinase inhibitor therapy is clinically appropriate. Potential use: Progressive metastatic disease Need for systemic disease control Patients for whom oral therapy is appropriate Situations where chemotherapy or radiopharmaceutical therapy is not preferred, unavailable, or unsuitable Monitoring / toxicity: Blood pressure Proteinuria Diarrhea Mucositis Hand-foot syndrome Fatigue Bleeding or thrombotic risk Fistula or wound-healing risk in selected patients Renal and hepatic function per institutional practice Clinical caveat:Hypertension may be challenging in catecholamine-secreting tumors; optimize blood pressure and endocrine management before and during therapy.
                    • Consider temozolomide
                      • Clinical trial
              • Slow-to-moderate progression
                Use when metastatic PPGL is progressing but immediate cytoreduction is not required. This setting allows consideration of therapies with potentially slower onset but durable disease control, including belzutifan in selected patients, radiopharmaceutical therapy when imaging-avid, TKI therapy, chemotherapy, temozolomide, or clinical trial participation. Assessment: Confirm progression pattern and pace Review tumor burden and symptoms Confirm hormonal activity and blood pressure control Review molecular profile, including RET/MEN2 and pseudohypoxia-associated biology Review current functional imaging: MIBG and/or DOTATATE when relevant Assess marrow reserve, renal function, performance status, prior therapy, and treatment access Clinical caveat: If disease tempo accelerates or organ function becomes threatened, reassess using the rapid progression pathway.
                • Cluster 1 / pseudohypoxia?
                  Cluster 1 / pseudohypoxia biology includes SDHx-related disease, VHL, EPAS1, FH/MDH-related biology, and related pseudohypoxia-associated molecular profiles. This biology may support consideration of belzutifan in slow-to-moderate progressive MPPGL when therapy is approved/accessible and rapid cytoreduction is not required. Do not use molecular cluster alone to determine therapy. Integrate disease tempo, symptoms, tumor burden, functional imaging, patient fitness, prior therapy, toxicity risk, and access. Assessment: Review germline and/or somatic testing Review hereditary syndrome context when known Confirm whether RET/MEN2-driven disease has already been addressed Consider functional imaging and patient-specific treatment constraints
                  • Yes
                    • Belzutifan
                      Consider belzutifan for slow-to-moderate progressive MPPGL, particularly in pseudohypoxia/Cluster 1 biology, when approved/accessible and when immediate cytoreduction is not required. Monitoring / toxicity: Hemoglobin and anemia Oxygen saturation Dyspnea or hypoxemia symptoms Fatigue Blood pressure and catecholamine-related symptoms Pregnancy prevention per prescribing information Clinical caveats: Belzutifan may not be optimal when rapid tumor shrinkage is needed.Access and regulatory approval may vary by country.Monitor closely in patients with baseline anemia, hypoxemia, or cardiopulmonary vulnerability.
                      • At progression
                        • Imaging-directed therapy
                          Before radiopharmaceutical therapy, confirm current functional imaging avidity. Avidity may differ between lesions and may change over time. Assess: MIBG avidity / norepinephrine transporter expression Somatostatin receptor positivity / DOTATATE avidity FDG avidity when clinically relevant Bone marrow reserve Renal function Prior radiation or radiopharmaceutical exposure Catecholamine-secreting status and need for monitored administration Clinical caveat:Radiopharmaceutical therapy should be selected based on current imaging phenotype, treatment availability, safety profile, and multidisciplinary review.
                          • MIBG avid?
                            • HSA 131I-MIBG
                              • Cabozantinib or Sunitinib
                                • or CVD chemotherapy
                                  • or Temozolomide
                                    • Clinical trial
                          • SSTR positive?
                            • PRRT (177Lu-DOTATATE)
                              • Cabozantinib or Sunitinib
                                • or CVD chemotherapy
                                  • or Temozolomide
                                    • Clinical trial
                  • No
                    • Imaging-directed therapy
                      • MIBG avid?
                        • HSA 131I-MIBG
                          Consider MIBG-directed therapy only for MIBG-avid disease when available and clinically appropriate. Clinical considerations: Confirm current MIBG avidity before treatment Assess disease burden, symptoms, disease tempo, and treatment goals Assess marrow reserve and prior radiation/radiopharmaceutical exposure Review renal function and overall fitness Consider catecholamine-secreting status and need for monitored administration Monitoring / toxicity: CBC and marrow reserve Blood pressure and catecholamine-related symptoms Fatigue, nausea, and cytopenias Long-term marrow risk when clinically relevant Clinical caveats: Availability may vary by country and institution.Repeat functional imaging may be needed because avidity can change over time.This option is not appropriate for non–MIBG-avid disease.
                          • Cabozantinib or Sunitinib
                            • or CVD chemotherapy
                              • or Temozolomide
                                Temozolomide may be considered in selected patients with metastatic PPGL, including situations where oral therapy is preferred or other options are unsuitable, unavailable, or exhausted. Clinical considerations: Consider in selected progressive disease May be particularly relevant in some SDHB-associated or MGMT-low / MGMT-methylated contexts, when available Review prior alkylator exposure and marrow reserve Do not select solely on genotype; integrate disease tempo, burden, symptoms, access, and patient fitness Monitoring / toxicity: CBC before each cycle and as clinically indicated Nausea and fatigue Myelosuppression Infection risk in selected patients Cumulative marrow reserve Antiemetic and infection prophylaxis per institutional practice when indicated Clinical caveat:Evidence is limited and heterogeneous; use should be individualized.
                                • Clinical trial
                                  Clinical trial participation should be considered whenever available. Rationale:MPPGL is rare, biologically heterogeneous, and has limited prospective sequencing data. Treatment choice should be individualized by disease tempo, tumor biology, functional imaging, symptom burden, prior therapy, toxicity risk, treatment access, patient goals, and multidisciplinary judgment. Consider clinical trial especially when: Disease has progressed after available standard options Molecular or imaging phenotype suggests investigational targeted therapy The patient has rare or high-risk biology Optimal sequencing is uncertain Standard therapies are unavailable, unsuitable, or poorly tolerated This pathway should support, not replace, multidisciplinary expert judgment.
                      • SSTR positive?
                        • PRRT (177Lu-DOTATATE)
                          • Cabozantinib or Sunitinib
                            • or CVD chemotherapy
                              • or Temozolomide
                                Temozolomide may be considered in selected patients with metastatic PPGL, including situations where oral therapy is preferred or other options are unsuitable, unavailable, or exhausted. Clinical considerations: Consider in selected progressive disease May be particularly relevant in some SDHB-associated or MGMT-low / MGMT-methylated contexts, when available Review prior alkylator exposure and marrow reserve Do not select solely on genotype; integrate disease tempo, burden, symptoms, access, and patient fitness Monitoring / toxicity: CBC before each cycle and as clinically indicated Nausea and fatigue Myelosuppression Infection risk in selected patients Cumulative marrow reserve Antiemetic and infection prophylaxis per institutional practice when indicated Clinical caveat:Evidence is limited and heterogeneous; use should be individualized.
                                • Clinical trial
                                  Clinical trial participation should be considered whenever available. Rationale:MPPGL is rare, biologically heterogeneous, and has limited prospective sequencing data. Treatment choice should be individualized by disease tempo, tumor biology, functional imaging, symptom burden, prior therapy, toxicity risk, treatment access, patient goals, and multidisciplinary judgment. Consider clinical trial especially when: Disease has progressed after available standard options Molecular or imaging phenotype suggests investigational targeted therapy The patient has rare or high-risk biology Optimal sequencing is uncertain Standard therapies are unavailable, unsuitable, or poorly tolerated This pathway should support, not replace, multidisciplinary expert judgment.
          • Yes
            • Selpercatinib
              Consider selpercatinib for RET-altered or MEN2-associated metastatic PPGL when available and clinically appropriate. Clinical considerations: Confirm actionable RET alteration or MEN2-associated disease Review prior therapy and contraindications Monitor per prescribing information and institutional practice At progression or if not a candidate, reassess imaging-directed therapy, TKI, chemotherapy, temozolomide, or clinical trial options Monitoring considerations: Blood pressure Liver function tests QT interval risk when clinically relevant Drug interactions Diarrhea, fatigue, edema, dry mouth, rash, and other adverse events per label/institutional practice
              • At progression or if not candidate
                • Imaging-directed therapy
                  • MIBG avid? SSTR positive?
                    • MIBG avid? → HSA 131I-MIBG
                      • Cabozantinib or Sunitinib or CVD chemotherapy or Temozolomide
                        • Clinical Trial
                    • SSTR positive? → PRRT (177Lu-DOTATATE)
                      • Cabozantinib or Sunitinib or CVD chemotherapy or Temozolomide
                        • Clinical Trial
tosprivacyGlover et al. Approach to the patient with metastatic pheochromocytoma and paraganglioma: advances in systemic therapy. J Clin Endocrinol Metab. 2026.NANETS Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. Pancreas. 2021.Lenders et al. Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2014.Taïeb et al. Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHx pathogenic variants. Lancet Diabetes Endocrinol. 2023.Deschler-Baier et al. Clinical Activity of Selpercatinib in RET-mutant Pheochromocytoma. J Clin Endocrinol Metab. 2025.Efficacy of RET inhibitors in the management of advanced RET-mutated pheochromocytoma and paraganglioma. Endocrine. 2025.Yoshida et al. Controlling Tumor Progression With Cyclophosphamide, Vincristine, and Dacarbazine Treatment Improves Survival in Patients With Metastatic and Unresectable Malignant Pheochromocytomas/Paragangliomas. Horm Cancer. 2017.Niemeijer et al. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clin Endocrinol. 2014.Jimenez et al. Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma: the NATALIE trial. Lancet Oncol. 2024.Baudin et al. Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: FIRSTMAPPP. Lancet. 2024.Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: FIRSTMAPPP. PubMed.FDA approves belzutifan for pheochromocytoma or paraganglioma. U.S. Food and Drug Administration. 2025.FDA fast-track approval of belzutifan is a milestone in rare cancer. Nat Rev Endocrinol. 2025.LITESPARK-015: Belzutifan in advanced pheochromocytoma and paraganglioma. Ann Oncol. 2025.Lin et al. Phase II study of 177Lu-DOTATATE for progressive metastatic pheochromocytomas and paragangliomas. J Clin Oncol. 2025.Pryma et al. Efficacy and safety of high-specific-activity 131I-MIBG therapy in patients with advanced pheochromocytoma or paraganglioma. J Nucl Med. 2019.Lin et al. Phase II Study of 177Lu-DOTATATE for Progressive Metastatic Pheochromocytomas and Paragangliomas. J Clin Oncol. 2025.ClinicalTrials.gov NCT03206060: Lu-177-DOTATATE in Inoperable SSTR-Positive Pheochromocytoma or Paraganglioma.Hadoux et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer. 2014.Li et al. A novel strategy for predicting the efficacy of temozolomide treatment in metastatic pheochromocytoma/paraganglioma. J Endocrinol Invest. 2024.Temozolomide Is a Potential Therapeutic Tool for Patients With Metastatic Pheochromocytoma/Paraganglioma. Front Endocrinol. 2020.