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Management of malignant (metastatic) paraganglioma and pheochromocytoma

Management of malignant (metastatic) paraganglioma and pheochromocytoma
Author:
William F Young, Jr, MD, MSc
Section Editor:
Patrick Y Wen, MD
Deputy Editor:
Sonali M Shah, MD
Literature review current through: Apr 2025. | This topic last updated: Oct 18, 2024.

INTRODUCTION — 

Pheochromocytomas and paragangliomas are catecholamine-secreting neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla (in the case of pheochromocytomas) and from neuroendocrine cells of the extra-adrenal autonomic paraganglia (in the case of paragangliomas). While pheochromocytomas and paragangliomas share overlapping histopathology, epidemiology, and molecular pathogenesis, they have different clinical behavior, metastatic potential, biochemical findings, and association with inherited genetic syndromes (table 1).

This topic review will discuss the treatment for advanced malignant (metastatic) pheochromocytoma or paraganglioma. Related topics on pheochromocytoma and paraganglioma are discussed separately.

●(See "Clinical presentation and diagnosis of pheochromocytoma".)

●(See "Epidemiology, clinical presentation, and diagnosis of paragangliomas".)

●(See "Treatment of pheochromocytoma in adults".)

●(See "Locoregional management of paragangliomas".)

●(See "Pheochromocytoma and paraganglioma in genetic disorders".)

CLINICAL PRESENTATION

Incidence — Malignant (metastatic) pheochromocytomas and paragangliomas are uncommon tumors. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Epidemiology' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Epidemiology'.)

●Pheochromocytoma – Among all patients with pheochromocytoma, approximately 10 percent have metastatic disease. Metastatic disease can present as local invasion into the surrounding tissues and organs (eg, kidney and liver) or distant metastases to lymph nodes, bones, liver, and lungs [1]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Malignant potential'.)

Among pheochromocytomas/paragangliomas related to multiple endocrine neoplasia type 2 (MEN2), only 3 to 5 percent are metastatic. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Pheochromocytoma' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'MEN2'.)

●Paraganglioma – Among all patients with paragangliomas, between 20 to 25 percent have metastatic disease. Malignant skull base and neck paragangliomas most frequently metastasize to the cervical lymph nodes. By contrast, paragangliomas below the skull base and neck more frequently have distant metastases to the bones, liver, and lungs. (See "Locoregional management of paragangliomas", section on 'Risk of malignancy' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Overview'.)

The highest rates of metastatic disease are seen in paragangliomas associated with inherited pathogenic variants in the B subunit of the succinate dehydrogenase (SDHB) gene, which are usually abdominal and secretory. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Familial paraganglioma and SDH pathogenic variants'.)

Symptoms — Metastatic pheochromocytoma and catecholamine-secreting paragangliomas often present with symptoms of catecholamine excess such as hypertension, episodic headache, sweating, tremor, and forceful palpitations. These are often the same symptoms as those associated with benign (localized) tumors. Abdominal pain may also develop due to metastatic growth of the tumor into the adjacent tissues and organs (eg, kidney and liver) [2]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Clinical presentation' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Clinical presentation and diagnosis'.)

By contrast, some paragangliomas (particularly those arising in the skull base and neck) do not present with symptoms of catecholamine excess and frequently are asymptomatic. However, intratumoral metabolism of catecholamines to metanephrines (ie, norepinephrine to normetanephrine, and epinephrine to metanephrine, respectively) can still occur independently of catecholamine release.

Timing of metastases — Although metastatic disease can be diagnosed at initial presentation (ie, synchronous metastases), it is more common to manifest during long-term surveillance following initial therapy for locoregional disease (ie, metachronous metastases). (See "Locoregional management of paragangliomas", section on 'Posttreatment surveillance' and "Treatment of pheochromocytoma in adults", section on 'Prognosis and monitoring'.)

In a retrospective series of 272 patients with metastatic pheochromocytoma or paraganglioma, synchronous and metachronous metastases were diagnosed in 35 and 65 percent of patients, respectively [3]. Metachronous metastases developed at a median of 5.5 years from the initial diagnosis. However, some metastases can also present as late as 50 years or more after the original diagnosis [3].

DIAGNOSIS — 

The diagnosis of malignant (metastatic) pheochromocytoma or paraganglioma is made based on tissue sampling and histopathologic confirmation of tumor deposits in tissues that do not normally contain chromaffin cells (eg, lymph nodes, liver, bones, lungs, and other distant metastatic sites) (picture 1 and picture 2). The histopathology of pheochromocytoma and paraganglioma are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Histology and malignant potential'.)

PRETREATMENT EVALUATION

Imaging studies and biochemical assays — The pretreatment evaluation of malignant (metastatic) paraganglioma and pheochromocytoma, which is typically performed as part of the initial diagnostic evaluation, includes biochemical testing to assess for catecholamine secretion (plasma fractionated metanephrines and/or 24-hour urinary excretion of fractionated metanephrines, 3-methoxytyramine, and catecholamines) and imaging studies to assess the baseline extent of disease and surgical resectability (algorithm 1). These studies can be used as a baseline to assess treatment response. (See 'Assessing treatment response' below.)

Further details on the diagnostic evaluation of these tumors are discussed separately. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Epidemiology, clinical presentation, and diagnosis of paragangliomas".)

Genetic testing — Germline genetic testing is also recommended for all patients with metastatic paraganglioma and pheochromocytoma since these tumors can either be sporadic or associated with various inherited genetic syndromes (table 1) [4-6]. Germline pathogenic variants that contribute to the development of pheochromocytoma and paraganglioma are classified into three general "clusters" [7,8]:

●Cluster 1 – Germline pathogenic variants in genes that encode proteins that function in the cellular response to hypoxia. These include: VHL, SDHD, SDHC, SDHB, SDHAF2, SDHA EGLN1 (PHD2), KIF1, IDH1, TMEM127, SDHA, MAX, EPAS1 (HIF2A), FH gene encoding fumarate hydratase, EGLN1 (PHD2), EGLN2 (PHD1), and KIF1B.

Cluster 1 tumors are mostly extra-adrenal paragangliomas (except in VHL where most tumors are localized to the adrenal) and nearly all have a noradrenergic biochemical phenotype.

●Cluster 2 – Germline pathogenic variants in genes that encode proteins that activate kinase signaling. These include: RET, NF1, MAX, TMEM127, and HRAS.

Cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic biochemical phenotype.

●Cluster 3 – Germline pathogenic variants in genes that encode proteins associated with Wnt-signaling. Germline pathogenic variants include: CSDE1 and UBTF::MAML3 fusions.

Cluster 3 tumors can have a noradrenergic or adrenergic biochemical phenotype.

Further details on hereditary pheochromocytoma and paraganglioma syndromes are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Genetic testing' and "Pheochromocytoma and paraganglioma in genetic disorders".)

GENERAL PRINCIPLES OF THERAPY — 

There are no curative treatments for malignant (metastatic) pheochromocytoma or paraganglioma [9]. The goals of therapy include controlling tumor burden, palliating tumor-related symptoms, improving quality of life, and prolonging overall survival (OS).

Management of catecholamine secretion — All patients with metastatic pheochromocytoma or paraganglioma that is confirmed to be catecholamine-secreting must receive appropriate alpha- and beta-adrenergic blockage prior to initiating therapy for the primary tumor and associated metastatic disease using the same approach as those with benign (localized) disease. Such medical management is necessary to block the effects from possible massive catecholamine secretion from the tumor upon intervention. (See "Treatment of pheochromocytoma in adults", section on 'Combined alpha and beta-adrenergic blockade'.)

Management of the primary tumor — Following appropriate medical management, treatment of the primary tumor is usually addressed prior to proceeding with treatment of metastatic disease. For patients undergoing surgical resection of both the primary tumor and metastatic sites, the operations may be coordinated. (See 'Resectable metastases' below.)

●Patients with metastatic pheochromocytoma undergo surgical resection (adrenalectomy) of the primary tumor. Further details are discussed separately. (See "Treatment of pheochromocytoma in adults", section on 'Adrenalectomy'.)

●For patients with metastatic paragangliomas, locoregional management of the primary tumor is the same regardless of whether the tumor is localized or metastatic. Surgical resection of the primary tumor is the preferred approach for most patients. Radiation therapy (RT) is an alternative option in select cases of cervical and jugulotympanic skull base and neck paragangliomas. Further details are discussed separately. (See "Locoregional management of paragangliomas", section on 'Therapeutic approach at specific sites and outcomes'.)

In a retrospective study of 272 patients with malignant pheochromocytoma or paraganglioma, not undergoing primary tumor resection was associated with worsened OS [3].

Selection of therapy for metastatic disease — Selection of therapy for sites of metastatic disease is based on surgical resectability, symptoms, disease burden and location, and rate of disease progression (algorithm 2). A multidisciplinary approach to management is necessary and includes input from medical oncology, surgical oncology, and radiation oncology [9,10]. Clinical trial enrollment is encouraged where available.

RESECTABLE METASTASES — 

For most patients with malignant (metastatic) pheochromocytoma or paraganglioma and resectable metastases, we suggest surgical resection of all metastatic lesions rather than systemic therapy or other treatment approaches. We perform a complete surgical resection, if feasible; if not achievable, we perform incomplete cytoreductive resection with or without locoregional therapies such as radiation therapy (RT) or ablation. Surgical intervention should only be performed in centers of excellence for pheochromocytoma and paraganglioma.

Surgical resection of metastatic disease improves symptoms, reduces hormone secretion, prevents complications related to the tumor in a critical anatomic location, and improves the response to subsequent therapies [11-14]. Limited data also suggest that surgery (including incomplete resections/debulking procedures) is associated with prolonged overall survival (OS) and minimal morbidity [15-17].

As an example, in a retrospective study of 34 patients treated with surgery for malignant pheochromocytoma or paraganglioma, complete (R0) resection was achieved in 14 patients (41 percent) and incomplete resection in 30 patients (59 percent) [14]. For the entire study population, at a median follow-up of six years, five-year OS was 90 percent (median OS of 11 years). For those with R0 resection, 10-year disease-free survival (DFS) was 49 percent (median DFS of 4.6 years). Among the 23 patients with elevated preoperative fractionated metanephrines or catecholamines, 13 patients (56 percent) demonstrated normalized markers postoperatively, and most either remained fully off antihypertensive medications (11 patients) or had significant reductions in the number of medications required (seven patients). Symptom relief was also reported in 15 of 18 patients (76 percent) who were symptomatic prior to surgery. There was no perioperative mortality. Morbidity rate was 15 percent (5 of 34 patients) including complications of colocutaneous fistula, small bowel obstruction, lymphocele, empyema, and ureteral obstruction (one patient each).

●Medical management prior to surgery – Medical preparation prior to surgery to control excessive adrenergic stimulation from the tumor and perioperative hemodynamic management are discussed separately. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery' and "Locoregional management of paragangliomas", section on 'General surgical principles'.)

●Coordinating resection of the primary tumor and metastases – For patients who are also undergoing resection of the primary tumor, coordinating resection with metastatic disease depends upon the location of the metastases and the length of the necessary anesthesia session. Primary tumors and metastatic disease that are proximally located can typically be resected during the same operation. For disease that is not completely resectable, one option for tumor debulking is cytoreductive (R2) resection, with or without locoregional therapies, such as RT or ablative therapies.

●Open surgical procedure – Open surgical procedures are typically performed in cases of proven or suspected metastatic disease [18]. Although laparoscopic approach to resection is generally preferred for benign (localized) pheochromocytomas or abdominal paragangliomas, metastatic tumors are often large or located in areas that are difficult to remove laparoscopically. If a primary tumor is also being resected, the capsule should not be entered surgically, if possible, as this predisposes to recurrence [19].

LIMITED UNRESECTABLE METASTASES — 

Patients with limited unresectable malignant (metastatic) disease may be appropriate candidates for locoregional therapies. Examples include those whose metastatic disease is isolated to a limited number of sites such as the liver, lungs, soft tissue, or bones.

●For patients with limited, unresectable metastases <1 cm that are asymptomatic, we suggest surveillance rather than locoregional or systemic therapy, given the lack of aggressive behavior of such tumors. (See 'Asymptomatic disease (surveillance)' below.)

●For patients with limited metastases that are ≥1 cm or symptomatic/progressive, we suggest locoregional therapy rather than surveillance or systemic therapy to improve symptoms and extend survival. Selection of therapy is based on tumor size and location, patient and provider preference, and treatment availability. As examples, for patients with bony metastases, options include radiation therapy (RT) or percutaneous thermal ablation, whereas for those with liver metastases, options include RT, percutaneous thermal ablation therapy, or transarterial chemoembolization (TACE).

The primary tumor should be treated prior to initiating locoregional therapy. (See 'Management of the primary tumor' above.)

Radiation therapy — RT at doses greater than 40 gray can provide local tumor control and relief of symptoms for metastatic tumors at a variety of sites, including the soft tissues, liver, and bone metastases [20,21]. Patients need to be monitored during RT, because RT-induced inflammation of the lesion can, in rare circumstances, induce massive catecholamine secretion and hypertensive crisis [22].

An observational study evaluated the use of RT in 41 patients with either primary paraganglioma (63 percent) or pheochromocytoma (37 percent) and 107 sites of disease [20]. Treatment intent was curative in 20 patients (30 lesions) and palliative in 21 patients (77 lesions). Treatment sites included bone (69 percent), soft tissue (30 percent), and liver (1 percent). The median (range) RT dose was 40 (range 6.5 to 70) gray. In the entire study population, five-year overall survival (OS) was 65 percent. For patients treated with curative and palliative intent, OS was 79 and 50 percent, respectively. Local control at five years was 81 percent for all lesions. External beam RT also improved symptoms in a majority (94 percent) of those with symptomatic lesions. There were no acute grade ≥3 treatment-related adverse events, including no hypertensive crises [20].

Local ablative therapy — Several nonsurgical, local ablative therapies are available for patients with metastases, including radiofrequency ablation, cryoablation, and percutaneous ethanol injection.

Percutaneous tumor ablation is most effective when limited to patients with one or a few relatively small (ideally, <3 to 4 cm) tumors. With careful attention to periprocedural management, percutaneous ablation may be safely performed for metastatic lesions at a variety of sites, including soft tissue, bone, lung, and liver [23-30]. As with other forms of local therapy including surgery and RT, any form of local ablation can induce massive catecholamine secretion and a hypertensive crisis; preprocedure medical preparation is needed. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery' and "Locoregional management of paragangliomas", section on 'Medical preparation for surgery'.)

In a retrospective observational study of 31 patients with metastatic pheochromocytoma or paraganglioma, 123 lesions were treated with various nonsurgical ablative therapies (42 with radiofrequency ablation; 23 with cryoablation; and 4 with percutaneous ethanol injection [30]). At a median follow-up of 60 months, radiographic local control was achieved in 69 of 80 lesions (86 percent). Improvement in metastasis-related pain or symptoms of catecholamine excess was achieved in 12 of 13 procedures (92 percent). Thirty-three procedures (67 percent) had no known complications. Clavien-Dindo grade I, II, IV, and V complications occurred after seven (14 percent), seven (14 percent), one (2 percent), and one (2 percent) procedure(s), respectively [30].

Transarterial chemoembolization for liver metastases — For patients with multiple liver metastases that are not amenable to resection or nonsurgical methods of ablation, isolated case reports suggest benefit (decreased tumor bulk and improved symptom control) from transarterial chemoembolization (TACE) [31-35]. As with other forms of local therapy, TACE can induce massive catecholamine secretion and a hypertensive crisis; preprocedure medical preparation is needed. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery' and "Locoregional management of paragangliomas", section on 'Medical preparation for surgery'.)

DIFFUSE UNRESECTABLE METASTASES — 

Some patients with malignant (metastatic) paraganglioma and pheochromocytoma may not have disease that is amenable to surgery or alternate locoregional therapies due to diffuse or widespread metastatic disease. For such patients, management options include surveillance or systemic therapy.

The primary tumor should generally be treated prior to initiating therapy. (See 'Management of the primary tumor' above.)

Asymptomatic disease (surveillance) — For patients who have asymptomatic, indolent disease, we suggest surveillance rather than systemic therapy, as treatment-related side effects may exceed the potential benefits of therapy [9]. Treatment may be initiated upon the development of symptoms and/or progressive disease.

The optimal surveillance schedule is not established. We monitor blood pressure and obtain biochemical testing (plasma-fractionated metanephrines or 24-hour urinary excretion of fractionated metanephrines, catecholamines, and 3-methoxytyramine) every three to four months. Patients who are symptomatic and/or have increases in their biochemical markers should be imaging with gadolinium-enhanced magnetic resonance imaging (MRI) or gallium Ga-68 dotatate positron emission tomography (PET)-computed tomography (CT) to evaluate for disease progression and initiation of systemic therapy. Patients with stable disease and no new symptoms may forego or undergo less frequent surveillance imaging and biochemical testing. (See 'Assessing treatment response' below.)

Symptomatic or progressive disease — For patients with disease that is symptomatic or progressive, we suggest initial treatment with cyclophosphamide, vincristine, and dacarbazine (CVD) rather than other systemic agents due to its high objective response rates (ORRs). (See 'Cyclophosphamide, vincristine, dacarbazine' below.)

For patients who are ineligible for or decline chemotherapy, alternative options for initial treatment include:

●Moderate to rapidly progressive disease – Sunitinib, cabozantinib, or radionuclide therapy. (See 'Sunitinib' below and 'Cabozantinib' below and 'Radionuclide therapy' below.)

●Slowly progressive disease – Somatostatin analogs (SSAs) (for somatostatin receptor [SSTR] positive disease only). (See 'Somatostatin analogs' below.)

Cyclophosphamide, vincristine, dacarbazine — CVD is the preferred initial systemic therapy for metastatic, progressive pheochromocytoma and paraganglioma due to its high and durable tumor response rates (particularly in those with high tumor burden or numerous bone metastases), reduction in tumor-specific and biochemical symptoms, and good tolerability profile.

●Efficacy – In a single-arm nonrandomized trial, 14 patients with metastatic pheochromocytoma were treated with CVD (cyclophosphamide at 750 mg/m2 intravenously [IV] on day 1, vincristine at 1.4 mg/m2 IV on day 1, and dacarbazine at 600 mg/m2 IV on days 1 and 2 of each 21- to 28-day cycle) [36,37]. At extended follow-up (median of 22 years) for this same cohort along with four other patients who met the original eligibility criteria, complete or partial objective responses were seen in 10 of 18 patients (56 percent) [36]. Biochemical responses were seen in 13 patients (72 percent). Patients with complete or partial tumor response received a mean of 27 cycles of CVD (median of 23 cycles). The median duration of response was 20 months, and the median overall survival (OS) was 3.3 years. All patients also experienced symptomatic improvement in performance status and blood pressure [37].

Observational studies have demonstrated similar efficacy for CVD or alternative formulations (eg, with or without vincristine and/or doxorubicin) [38-40]. As an example, in one retrospective series, 52 patients with progressive metastatic pheochromocytoma or sympathetic paraganglioma were treated with a variety of chemotherapy regimens, including cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CyVADIC; 19 patients); cyclophosphamide, doxorubicin, and dacarbazine (CyADIC; 12 patients); cyclophosphamide, vincristine, and dacarbazine (CyVDic; 10 patients); or other regimens (11 patients) [38]. Among the 52 evaluable patients, 17 patients (33 percent) responded to initial chemotherapy, including 13 with an objective tumor response (25 percent), and four with normalization of blood pressure. In two patients with initially unresectable tumors, the response to chemotherapy was sufficient to permit subsequent surgical excision. Responders, all of whom received a chemotherapy regimen that contained dacarbazine and cyclophosphamide, survived longer than nonresponders (median 6.4 versus 3.7 years). However, nonresponders also had significantly larger tumors (10 versus 5 cm) and a higher percentage of extra-adrenal primaries, two factors that are associated with decreased OS in pheochromocytoma or paraganglioma [41]. The five-year OS rate of the entire cohort was 51 percent.

●Toxicity – Treatment with CVD is generally well tolerated. The most common toxicities are mild myelosuppression, peripheral neuropathy, and gastrointestinal toxicity [37].

Sunitinib — Sunitinib is an appropriate alternative to chemotherapy in patients with metastatic paraganglioma/pheochromocytoma and moderate to rapidly progressive disease. Sunitinib also demonstrated a nonstatistically significant trend towards improved progression-free survival (PFS) in a placebo-controlled randomized phase II trial [42].

We offer sunitinib at a dose of 37.5 mg orally daily until disease progression or unacceptable toxicity [42]. Although hypertension is a common side effect of sunitinib, it can safely be used to treat metastatic pheochromocytoma and secretory paraganglioma. Sunitinib should be initiated only after normal or near-normal blood pressure is achieved with combined alpha- and beta-adrenergic blockade. Patients must also have close follow-up visits and appropriate dose adjustments to antihypertensive agents, which are usually required after initiating sunitinib [43]. Further details on the management of hypertension and other toxicities associated with sunitinib are discussed separately. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Class side effects of all VEGF inhibitors' and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Initial observational studies and single-arm phase II clinical trials suggested clinical efficacy for sunitinib in malignant pheochromocytoma or paraganglioma [43-49]. Based on these data, sunitinib was evaluated in a placebo-controlled randomized phase II trial (FIRSTMAPP) [42]. In this study, 78 patients with metastatic progressive pheochromocytoma or paraganglioma (either sporadic or associated with an inherited syndrome) were randomly assigned to either oral sunitinib at 37.5 mg daily or placebo. Approximately one-third (32 percent) had a germline pathogenic variant in SDHx. Most patients (69 percent) had also received prior therapies (chemotherapy, iobenguane I-131 metaiodobenzylguanidine [MIBG] therapy, RT, ablative therapies, everolimus, interferon, SSAs, and/or peptide receptor radionuclide therapy). At a median follow-up of 30 months, results were as follows [42]:

●Entire study population – Sunitinib demonstrated a nonstatistically significant trend towards improved PFS relative to placebo (median PFS 8.9 [95% CI 5.5-12.7] versus 3.6 [95% CI 3.1-6.1] months; two-year PFS 17.6 [95% CI 8.7-32.5] versus 8.4 [median 2.7-23.7] percent), which would be clinically meaningful if true [42]. The difference in OS between the treatment arms was not statistically significant (median 26 versus 50 months; two-year OS 57 versus 58 percent). ORRs were higher for sunitinib than placebo (36 versus 8 percent), all of which were partial responses. Median duration of response with sunitinib was 12 months.

●Treatment-naïve disease – In subgroup analyses of patients with treatment-naïve disease, sunitinib demonstrated a trend towards improved PFS (hazard ratio [HR] 0.50) and higher ORR (27 versus 15 percent) relative to placebo [42].

●Treatment-refractory disease – In a subgroup analysis of patients who received prior therapy, sunitinib also demonstrated a trend towards improved PFS (HR 0.79) and higher ORR (43 versus 4 percent) relative to placebo.

●Other patient subgroups – Trends towards PFS benefit for sunitinib over placebo were also seen for those with SDHB pathogenic variants, bone metastases, and arterial hypertension.

The most frequent grade 3 or 4 toxicities for sunitinib and placebo were asthenia (18 versus 3 percent), hypertension (13 versus 10 percent), and back or bone pain (3 versus 8 percent). No new toxicity profiles were noted for sunitinib.

Cabozantinib — Cabozantinib is an appropriate alternative to chemotherapy for patients with metastatic paraganglioma/pheochromocytoma and moderately to rapidly progressive disease. In a phase II trial of 17 patients with malignant pheochromocytoma or paraganglioma, cabozantinib, a multikinase inhibitor that targets vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, demonstrated an ORR of 25 percent [50].

Radionuclide therapy — Systemic radionuclide treatment is an appropriate alternative to chemotherapy for patients with metastatic paraganglioma or pheochromocytoma and moderately to rapidly progressive disease. Radionuclide therapy employs beta-emitting isotopes that are coupled to either SSAs (ie, peptide receptor radionuclide therapy) or MIBG.

Peptide receptor radionuclide therapy — Patients with metastatic or recurrent pheochromocytoma or paraganglioma and moderately progressive disease whose tumors express SSTRs may benefit from peptide receptor radionuclide therapy with lutetium Lu-177 dotatate [51-56]. Treatment benefits include objective tumor responses and reduction in symptoms of catecholamine secretion. SSTR expression is determined by positive uptake on an SSTR-based imaging study, such as Ga-68 dotatate PET-CT [57-59]. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Somatostatin receptor-based imaging'.)

Pheochromocytomas and extra-adrenal paragangliomas express SSTRs at a level that is similar to that of neuroendocrine neoplasms [60-63]. Lu-177 dotatate is approved by the US Food and Drug Administration for the treatment of SSTR-expressing gastroenteropancreatic neuroendocrine tumors. Use of Lu-177 dotatate in SSTR-positive metastatic paraganglioma or pheochromocytoma is considered off-label since treatment approval has not been extended to pheochromocytoma and paraganglioma. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Lutetium Lu-177 dotatate'.)

Peptide receptor radiotherapy (PRRT) was evaluated in a meta-analysis of 12 observational studies that included 201 patients with advanced paraganglioma or pheochromocytoma. Most patients had received prior treatment such as surgery, chemotherapy, radiation therapy (RT), or other systemic therapies [56]. The ORR and disease control rates were 25 and 84 percent, respectively. Clinical and biochemical responses were seen in 61 and 64 percent of the patients, respectively. Similar tumor response rates were seen for therapy with Yttrium Y-90 and Lu-177 dotatate. Treatment was well tolerated with minimal grade 3 to 4 toxicity. Toxicities of PRRT are discussed separately. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Toxicity and risks'.)

Iobenguane I-131 MIBG — Although iobenguane I-131 MIBG is effective in the treatment of metastatic pheochromocytoma and paraganglioma, it has been discontinued from the United States market for commercial reasons; it may remain available in other areas.

●Patient selection – Treatment with iobenguane I-131 (therapeutic) is an option in patients with good uptake of iobenguane I-123 (diagnostic) by dosimetry who fall into one of the following clinical categories [64]:

•Unresectable, moderately progressive pheochromocytoma or paraganglioma

•Symptoms from disease that are not amenable to locoregional methods of control

•A high tumor burden and a low number of bone metastases

●Dosing, schedule, and toxicity – The optimal dose and treatment schedule of iobenguane I-131 (therapeutic) is not established. Most studies use different doses and schedules and include only a few patients [64]. There are no randomized trials comparing high-dose versus fractionated-medium doses of iobenguane I-131 (therapeutic) [11]. Some institutions with extensive experience use high-dose iobenguane I-131 (therapeutic) for selected patients with aggressive disease who can tolerate it. Thyroidal uptake of free iodide is prevented by giving an oral saturated solution of potassium iodide at 24 hours prior to planned administration and daily for 10 days post-therapy. At other institutions, medium-dose iobenguane I-131 (therapeutic) is used for patients with relatively indolent disease, with chemotherapy preferred over high-dose iobenguane I-131 (therapeutic) for those with more aggressive disease. (See 'Cyclophosphamide, vincristine, dacarbazine' above.)

Iobenguane I-131 (therapeutic) treatment can be repeated, usually at six-month intervals [65]. The optimal dosimetry is not established. Most studies have used single-therapy doses between 100 to 200 millicurie, with cumulative doses ranging from 557 to 2322 millicurie and averaging 400 and 600 millicurie [2,65-71]. At these doses, treatment is generally well tolerated with the main side effects being transient mild leukopenia and thrombocytopenia. Hypothyroidism was reported in 3 of 28 patients receiving cumulative doses of 111 to 916 millicurie in one series [70], and in 2 of 10 patients in a second report (average cumulative dose 310 millicurie) [72].

Patients should be counseled about the potential risks of long-term myelosuppression [69,73,74] and a possible increase in myelodysplasia and acute leukemia in long-term survivors [74,75]. It is not clear whether these risks are limited to those who receive high-dose therapy.

●Efficacy – The diagnostic and therapeutic value of MIBG is based upon its structural similarity with noradrenaline and a high affinity to (and uptake in) chromaffin cells. Radioactive iodine (I131) is attached to the MIBG molecule to produce iobenguane I-131 (therapeutic), which functions as a semiselective agent for malignant pheochromocytoma or paraganglioma. This treatment only works for the approximately 60 percent of tumors that take up MIBG as determined by iobenguane I-123 (diagnostic) scintigraphy [76-78]. A lower fraction of dopamine-secreting paragangliomas take up iobenguane I-123 (diagnostic) [79-81].

For patients with metastatic disease whose tumors secrete catecholamines and take up MIBG, the therapeutic value of iobenguane I-131 (therapeutic) to achieve symptom palliation and tumor regression or stabilization has been shown in observational case series [2,65-72,78,82,83]. ORRs are approximately 30 percent, and another 40 percent of tumors remain stable; less than 5 percent have a complete remission. Hormonal response (ie, decrease in catecholamine secretion) is reported in 45 to 67 percent of cases [2,69,70,78]. In general, better objective responses are achieved in patients with limited disease and in those with soft tissue rather than bone metastases [2].

There is some evidence that higher-dose regimens (single doses 500 to 800 millicurie) can result in sustained complete response in a small number of patients, albeit with a higher risk of potentially serious side effects [75,82]:

•In a phase II trial, 50 patients with metastatic pheochromocytoma or paraganglioma received single iobenguane I-131 (therapeutic) doses ranging from 492 to 1160 millicurie (6 to 19 millicurie/kg, median 12 millicurie/kg); cumulative doses ranged from 492 to 3191 millicurie [75]. Patients had to have successful peripheral blood stem cell harvest to receive >12 millicurie/kg. Overall, a complete response was achieved in 10 percent, a partial response in 20 percent, and 39 percent had stable disease/minor response (69 percent disease control rate). The five-year OS rate was 64 percent.

Toxicities included grade 3 to 4 neutropenia in 87 percent and grade 3 or 4 thrombocytopenia in 87 percent; four patients experienced prolonged myelosuppression that required autologous hematopoietic cell rescue. Other serious toxicities included grade 4 acute respiratory distress syndrome and cryptogenic organizing pneumonia in two patients each, and myelodysplastic syndrome and concurrent acute leukemia in two patients who received multiple infusions of iobenguane I-131 (therapeutic). Hypothyroidism was not reported, although large doses of potassium iodide were administered to prevent uptake of iobenguane I-131 (therapeutic) by the thyroid, and three became hyperthyroid.

•In a retrospective study, 125 patients with metastatic pheochromocytoma or paraganglioma were treated with a median dose of 18,800 megabecquerels I-131 MIBG [84]. In these patients, median survival posttreatment was approximately four years.

-Among 88 patients with follow-up imaging, complete and partial response rates were 1 and 33 percent, whereas stable disease and disease progression rates were 53 and 13 percent, respectively. Median PFS was two years.

-Among 54 patients, over half (59 percent) demonstrated biochemical response, although half of these relapsed, with a median time to biochemical progression of 2.8 years.

-Among 83 patients, a majority (75 percent) reported improvement in pretreatment symptoms, consisting primarily of pain (42 percent), fatigue (27 percent), and hypertension (14 percent). At a median of 1.8 years, most experienced subsequent symptomatic progression (61 percent) [84].

Somatostatin analogs — A trial of SSA therapy (octreotide long-acting release or lanreotide) is an option to stabilize disease or palliate symptoms in patients with malignant SSTR-positive pheochromocytoma or paraganglioma who are ineligible for or decline other treatment options, based on limited data. SSTR expression is determined by positive uptake on an SSTR-based imaging study, such as Ga-68 dotatate PET-CT [57-59]. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Somatostatin receptor-based imaging'.)

Data for the use of octreotide for metastatic pheochromocytoma or paraganglioma are limited to case reports and observational studies. While most data suggest that the main benefit for octreotide is disease stabilization rather than objective tumor regression [85-91], a few studies report objective responses and short-term reduction of catecholamine secretion [92-94]. Studies with lanreotide also demonstrate mainly disease stabilization [95].

Other regimens — Other chemotherapy regimens with modest objective response rates in metastatic pheochromocytoma and paraganglioma include temozolomide monotherapy [96] (particularly among those with succinate dehydrogenase [SDH] B pathogenic variants, which are associated with hypermethylation of the promoter for O6-methylguanine-deoxyribonucleic acid [DNA] methyltransferase [MGMT] [97]); temozolomide plus thalidomide [98] or capecitabine [99]; single-agent gemcitabine [100]; gemcitabine plus docetaxel [101] or paclitaxel [102]; doxorubicin plus streptozocin [103]; or paclitaxel alone [104].

ASSESSING TREATMENT RESPONSE — 

Response assessment in patients being treated for malignant (metastatic) pheochromocytoma or paraganglioma is usually performed using both imaging studies and serial biochemical assays. Biochemical testing (eg, plasma-fractionated metanephrines and/or 24-hour urine-fractionated metanephrines, catecholamines, and 3-methoxytyramine) and imaging studies are usually assessed three months after initiating systemic therapy or radionuclide therapy; and approximately six months following radiation therapy (RT) or the initiation of a somatostatin analog (SSA).

●Imaging studies – Imaging studies that can be used for response assessment include gadolinium-enhanced MRI of the primary tumor site, and somatostatin receptor (SSTR)-based imaging with gallium Ga-68 dotatate positron emission tomography (PET)-CT.

•MRI – One of the unique features of metastatic pheochromocytoma or paraganglioma is their slow response to therapy, particularly to RT [20]. These tumors are known to regress slowly and usually partially after RT, and successfully treated tumors demonstrate residual masses, the presence of which does not necessarily indicate treatment failure. Paragangliomas are vascular tumors, and the malignant cells constitute only a small part of the tumor mass. It is thought that the vascular elements constitute the bulk of the tumor undergoing fibrosis after treatment. Stabilization or reduction in tumor size, decreased enhancement, and reduced T2 signal intensity on MRI have all been described and are indicative of local control [20,105].

•SSTR-based imaging – Functional SSTR-based imaging can also be used to assess tumor burden not seen on standard imaging modalities. SSTR-based imaging using Ga-68 dotatate PET-CT is frequently obtained as part of the diagnostic evaluation for metastatic pheochromocytoma and paraganglioma and offers a better option for assessing treatment response than other imaging studies [106-112]. Further details on diagnostic imaging studies for metastatic pheochromocytoma and paraganglioma are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Screening for synchronous and metastatic disease' and "Clinical presentation and diagnosis of pheochromocytoma", section on 'Additional imaging'.)

●Biochemical testing – Biochemical assays can be used to assess treatment response. Such assays include plasma-fractionated metanephrines or 24-hour urinary excretion of fractionated metanephrines, catecholamines, 3-methoxytyramine, and serum chromogranin A (CgA). As with other neuroendocrine tumors, serum CgA levels correlate with disease burden, and serial measurements of this biomarker are mostly used to monitor response to treatment [113-118]. However, because of limited specificity, CgA is not useful for diagnostic purposes (table 2).

PROGNOSIS — 

For patients with malignant (metastatic) pheochromocytoma or paraganglioma, the average five-year overall survival (OS) is approximately 50 percent [16,17,38,41,66,119-125]. Prognosis is also influenced by primary tumor site, disease burden, and location of metastases, among other clinical factors.

●Metastatic pheochromocytoma – For patients with metastatic pheochromocytoma, five-year OS ranges between 34 to 60 percent, with some studies reporting 10-year OS rates of 25 percent [114]. However, other studies suggest that survival outcomes may be poorer with pheochromocytomas compared with paraganglioma, regardless of functionality. In one longitudinal observational study over two decades, pheochromocytoma presented more often with distant metastases and was associated with worsened five-year OS relative to paraganglioma (58 versus 80 percent) [126].

●Metastatic paraganglioma – For patients with malignant paragangliomas of the skull base and neck, survival outcomes are the most variable with five-year OS ranging between 12 to 84 percent [16,121,125]. In an observational study from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database of 86 cases of malignant (metastatic) head and neck paraganglioma, the five-year survival rate was 65 percent overall. For patients with regionally confined metastases, five-year OS was higher for those with confined versus distant metastases (82 versus 41 percent) [125]. Survival outcomes were also more favorable for primary carotid body tumors than other primary tumor sites (five-year OS 87 versus 48 percent).

●Prognostic factors – Other poor prognostic factors include male sex, older age, synchronous metastases, larger primary tumor size, elevated dopamine levels, and not undergoing primary tumor resection [3]. There was no difference in survival according to the presence or absence of an SDHB pathogenic variant. Patients with brain, liver, and lung metastases have a worse prognosis than those with isolated bone lesions [11].

The prognostic implications of molecular alterations for metastatic pheochromocytoma and paraganglioma are poorly understood. In a genomic profiling study of patients with metastatic disease, high mutational load, microsatellite instability, and somatic copy-number alteration burden were associated with alpha thalassemia/mental retardation-X linked (ATRX) and telomerase reverse transcriptase (TERT) gene alterations, which may serve as prognostic markers [127]. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Histology and malignant potential'.)

INVESTIGATIONAL AGENTS

●Tyrosine kinase inhibitors – A study evaluating pazopanib, in patients with metastatic pheochromocytoma or paraganglioma was terminated due to slow accrual [128]. Other select tyrosine kinase inhibitors undergoing evaluation in clinical trials include axitinib and lenvatinib.

●Mechanistic target of rapamycin inhibitors – Studies are ongoing examining the benefit of everolimus, which inhibits the mechanistic target of rapamycin pathway. In one early study, five of seven patients with pheochromocytoma or paraganglioma exhibited disease stabilization, although there were no objective responses [129].

●Hypoxia-inducible factor 2 alpha (HIF2A) inhibitors – HIF2A is a main oncogenic driver of paraganglioma and pheochromocytoma [130]. HIF2A inhibitors, such as belzutifan, are active in cancers associated with von Hippel-Lindau disease [131] and are being investigated in those with paraganglioma and pheochromocytoma. As an example, belzutifan has activity in Pacak-Zhuang syndrome, a rare disease characterized by early-onset polycythemia vera and multiple paragangliomas [132]. (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera", section on 'EPAS1' and "Epidemiology, clinical presentation, and diagnosis of paragangliomas", section on 'Molecular pathogenesis'.)

The use of HIF2A inhibitors to treat other tumors associated with von Hippel-Lindau disease is discussed separately. (See "Surveillance and management of von Hippel-Lindau disease".)

●Immunotherapy – Immune checkpoint inhibitors may have potential treatment efficacy in metastatic pheochromocytoma and paraganglioma. This approach remains investigational, and further randomized trials are necessary.

Many pheochromocytoma and paraganglioma tumors express programmed cell death ligand 1 (PD-L1), suggesting a role for immune checkpoint inhibitors [133]. Additionally, in the subgroup of tumors with pseudohypoxia-related molecular alterations, such as HIF2A, PD-L1 expression is increased via an HIF-dependent mechanism that affects T-cells activity repression in the tumor microenvironment [134,135]. (See "Principles of cancer immunotherapy", section on 'Immune checkpoint inhibitors'.)

In a phase II trial, 11 patients with metastatic pheochromocytoma and paragangliomas were treated with the PD-1 inhibitor pembrolizumab [136]. At a median follow-up of 18 months, the objective response, nonprogression, and clinical benefit rates were 9, 40, and 73 percent, respectively. Median progression-free and overall survival were 6 and 19 months respectively.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pheochromocytoma and paraganglioma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (See "Patient education: Pheochromocytoma (The Basics)".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation

•Symptoms – Malignant (metastatic) pheochromocytomas and paragangliomas are uncommon tumors that present with symptoms of catecholamine excess such as hypertension, episodic headache, sweating, tremor, forceful palpitations, and/or abdominal pain. (See 'Incidence' above and 'Symptoms' above.)

•Timing of metastases – Although metastatic disease can be diagnosed at initial presentation (synchronous metastases), it is more common to manifest during long-term surveillance following initial therapy for locoregional disease (metachronous metastases). (See 'Timing of metastases' above.)

●Pretreatment evaluation – Pretreatment evaluation includes biochemical testing to assess for catecholamine secretion, imaging studies to assess the baseline extent of disease and surgical resectability, and genetic testing. (See 'Pretreatment evaluation' above.)

●Management of catecholamine secretion – All patients with metastatic pheochromocytoma or paraganglioma that is confirmed to be catecholamine-secreting must receive appropriate alpha- and beta-adrenergic blockage prior to initiating therapy for the primary tumor and associated metastatic disease, using the same approach as those with benign (localized) disease. (See 'Management of catecholamine secretion' above.)

●Management of the primary tumor – Following appropriate medical management, treatment of the primary tumor (with either surgery or radiation therapy [RT]) is usually addressed prior to proceeding with treatment of metastatic disease. For patients undergoing surgical resection of both the primary tumor and metastatic sites, the operations may be coordinated. (See 'Management of the primary tumor' above and 'Resectable metastases' above.)

•Patients with metastatic pheochromocytoma undergo surgical resection (adrenalectomy) of the primary tumor. (See "Treatment of pheochromocytoma in adults", section on 'Adrenalectomy'.)

•For patients with paraganglioma, locoregional management of the primary tumor is the same regardless of whether the tumor is localized or metastatic. Surgical resection of the primary tumor is the preferred approach for most patients. RT is an alternative option in select cases of cervical and jugulotympanic skull base and neck paragangliomas. Further details are discussed separately. (See "Locoregional management of paragangliomas", section on 'Therapeutic approach at specific sites and outcomes'.)

●Management of metastases – Selection of therapy for sites of metastatic disease is based on surgical resectability, symptoms, disease burden and location, and rate of disease progression (algorithm 2). Multidisciplinary management is necessary. Clinical trial enrollment is encouraged where available.

•Resectable metastases – For most patients with resectable metastases, we suggest surgical resection of all metastatic lesions rather than systemic therapy or other treatment approaches (Grade 2C). We perform a complete surgical resection, if feasible; if not achievable, we perform an incomplete cytoreductive resection with or without locoregional therapies such as RT or ablation. Surgical intervention should only be performed in centers of excellence for pheochromocytoma and paraganglioma. Surgical resection of metastatic disease improves symptoms, reduces hormone secretion, prevents complications related to tumor in a critical anatomic location, and improves the response to subsequent therapies. Limited data also suggest that surgery (including incomplete resection/debulking procedures) is associated with prolonged overall survival (OS) and minimal morbidity. (See 'Resectable metastases' above.)

•Limited unresectable metastases

-For patients with limited, unresectable metastases <1 cm that are asymptomatic, we suggest surveillance rather than locoregional or systemic therapy (Grade 2C) given the lack of aggressive behavior of such tumors. (See 'Limited unresectable metastases' above.)

For patients with limited metastases that are ≥1 cm or symptomatic/progressive, we suggest locoregional therapy rather than surveillance or systemic therapy (Grade 2C) to improve symptoms and extend survival. Selection of therapy is based on tumor size and location, patient and provider preference, and treatment availability. As examples, for patients with bony metastases, options include RT or percutaneous thermal ablation, whereas for those with liver metastases, options include RT, percutaneous thermal ablation therapy, or transarterial chemoembolization (TACE).

•Diffuse unresectable metastases – For patients with diffuse unresectable metastases, management is based on symptoms and the rate of disease progression. (See 'Diffuse unresectable metastases' above.)

-Asymptomatic disease – For patients with asymptomatic, indolent disease, we suggest surveillance rather than systemic therapy (Grade 2C). (See 'Asymptomatic disease (surveillance)' above.)

-Symptomatic and progressive disease – For patients with symptomatic or progressive disease, we suggest initial treatment with cyclophosphamide, vincristine, and dacarbazine (CVD) rather than other systemic agents (Grade 2C), due to high objective response rates. (See 'Cyclophosphamide, vincristine, dacarbazine' above.)

For those who are ineligible for or decline chemotherapy, alternate options include sunitinib, cabozantinib, or radionuclide therapy (for moderately to rapidly progressive disease) and somatostatin analogs (SSAs; for slowly progressive, somatostatin receptor [SSTR]-positive disease only). (See 'Sunitinib' above and 'Cabozantinib' above and 'Radionuclide therapy' above and 'Somatostatin analogs' above.)

●Treatment response – Treatment response is assessed using both imaging studies (gadolinium-enhanced MRI of the primary tumor site and gallium Ga-68 dotatate positron emission tomography [PET]-CT) and biochemical testing (eg, plasma-fractionated metanephrines and/or 24-hour urine-fractionated metanephrines, catecholamines, and 3-methoxytyramine). These studies are usually assessed three months after initiating systemic therapy or radionuclide therapy; and approximately six months following RT or the initiation of an SSA. (See 'Assessing treatment response' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Sally E Carty, MD, FACS, and Aymen Elfiky, MD, MPH, MSc, MBA, who contributed to earlier versions of this topic review.

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Topic 86953 Version 41.0

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124 : Survival of patients with metastatic malignant pheochromocytoma and efficacy of combined cyclophosphamide, vincristine, and dacarbazine chemotherapy.

125 : Malignant head and neck paragangliomas: treatment efficacy and prognostic indicators.

126 : Malignant pheochromocytoma and paraganglioma: a population level analysis of long-term survival over two decades.

127 : Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma.

128 : Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma.

129 : Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas.

130 : HIF-2alpha: Achilles' heel of pseudohypoxic subtype paraganglioma and other related conditions.

131 : Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

132 : Belzutifan, a Potent HIF2αInhibitor, in the Pacak-Zhuang Syndrome.

133 : Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: Relationship with the hypoxic response, immune evasion and malignant behavior.

134 : Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer.

135 : Emerging Therapies in Pheochromocytoma and Paraganglioma: Immune Checkpoint Inhibitors in the Starting Blocks.

136 : Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas.