Supportive management of patients with pheochromocytoma/paraganglioma undergoing noninvasive treatment

Abstract

Purpose of Review

Many publications review perioperative management of pheochromocytomas/paragangliomas (PPGLs); however, a large population, including 10–20% of metastatic PPGL patients, have inoperable disease. This has necessitated the development of noninvasive treatments (e.g., radio/chemotherapy), which, in affording disease-modification, have led to an ever-growing population of surviving patients with inoperable PPGL. These patients experience debilitating symptoms arising from discomforts related to the masses themselves (e.g., pain from osseous metastasis) and symptoms from tumoral catecholamine production and release. Unfortunately, management of these conditions is not yet well-defined. Adding further insult-to-injury, these noninvasive treatments can trigger catecholamine release, worsening catecholamine-induced symptoms. Herein, we detail these ailments and their management especially while patients receive these noninvasive treatments.

Recent Findings

Improved diagnostic evaluations have allowed for earlier detection of PPGL, prolonging survival in patients with inoperable PPGLs. Accordingly, noninvasive treatment strategies have rapidly evolved alongside state-of-the-art theranostics and genetic determinants which inform ongoing management and therapeutic response.

Summary

While treatments afford improved survival, there must be a corresponding attention to quality-of-life. This is ensured by employing supportive management which mitigates debilitating symptoms. This is best accomplished with a multidisciplinary approach and familiarity with genetic and biochemical determinants which guide patient education and management.

Introduction

Pheochromocytomas and paragangliomas (PPGLs) are rare chromaffin cell tumors with most releasing catecholamines. These lead to catecholamine-induced symptoms (elaborated upon below). The gold standard/method-of-choice for treatment is surgical resection. Nonetheless, many patients have inoperable disease with a subset being those with metastasis (10–25% have metastatic disease [1,2*,3**]) and others that may have solitary tumors that are not amenable to surgery given location, size, or comorbidities. Recently, with the advancement of diagnostic and genetic techniques, there is earlier and more frequent detection of inoperable PPGL, growing the population of patients requiring non-surgical interventions for better survival. Further, the underlying disease and therapies these patients receive are associated with various symptoms and signs, most commonly those related to catecholamine-release (e.g., ileus, hypertension, tachycardia), metastatic/mass effect (e.g., pain due to osseous metastasis and/or attendant nerve impingement), and deleterious effects of treatments themselves (e.g., nausea or myelosuppression from chemotherapy/radiotherapy).

Given these complications are common, there is a lack of guidance pertaining to their management, and with the many recent advances in treatment and genetic testing, a timely review is necessary. First, genetic determinants will be discussed as they provide a foundation that often guides management.

Genetic Testing

As the most heritable of known tumors, approximately 80% of PPGLs may be classified according to their germline or somatic mutations. Therefore, at diagnosis, or upon learning of a past history of PPGL, each patient should have genetic testing and counseling [2*,3**,4]. When tested, 35–40% of these patients have associated germline mutations in one of the 20 or more genes linked to PPGL with testing of somatic tumor tissue revealing about another 40% of linked mutations [1,2*]. It is critical to identify these genetic determinants as they direct multiple aspects of patient care, most importantly: the frequency of disease monitoring, the selection of functional imaging (e.g., which modality of imaging is best), and the degree of treatment intensity [1,2*,3**,5]. Further, these mutations can be grouped into clusters (pseudohypoxia cluster 1, kinase-signaling cluster 2, or Wnt-signaling cluster 3) which subsequently define the biochemical profile of catecholamines—norepinephrine (NE), epinephrine (EPI), and dopamine—these tumors secrete (or their biochemical phenotypes). Given that NE/EPI have differing affinities for their cognate adrenoceptors, which themselves are expressed with different spatial densities upon target organs, the catecholamine profile or biochemical phenotype therefore translates to which catecholamine-induced symptoms are observed. Moreover, with the availability of agents that selectively oppose these adrenoceptors (for example α_1- or β_1-selective adrenoceptor blocking agents) these biochemical phenotypes consequently determine medication management. These secretory biochemical phenotypes are classified into three types based on the surrogate metabolites of NE, EPI, and dopamine, which are normetanephrine, metanephrine, and methoxytyramine, respectively, and the elevation of each of these metabolites as compared to the summed total elevation of all measured above the normal limits. Cluster 1 phenotypes include noradrenergic (almost exclusively normetanephrine elevations compared to metanephrine elevations, with <10% of metanephrine contributing to the total increase) and/or dopaminergic (elevations of methoxytyramine higher compared to normetanephrine, >5% of plasma methoxytyramine contributing to the total increase) [2*,6,7,8]. Cluster 2 usually demonstrates the adrenergic phenotype (metanephrine increase >10% of total normetanephrine/metanephrine increase) [6,7]. Cluster 3 is still unknown [2*]. Some tumors are non-secretory [2*,6]. Subsequently, the most appropriate functional imaging (e.g., [¹⁸F]-Fluorodopa – FDOPA –PET/CT for cluster 1 PPGLs, somatostatin receptor – SSTR – PET/CT for cluster 2 PPGLs) can be selected based upon the genetic cluster of a particular tumor [2*,9]. Imaging can be used in place of biopsy confirmation of every new lesion and is especially useful when disease progression is suspected. Genetic clusters can also guide screening practices for family members with heritable mutations. Such considerations (whereby genetic mutations may direct clinical management) are exemplified by newly published guidelines for patients who are carriers of succinate dehydrogenase mutations (SDHx) [10*].

Patient Education

A patient’s understanding of their disease and the required follow-up is absolutely essential for successful management. Patients must first understand that available treatments for inoperable PPGL are non-curative.

Although compared to other cancer types PPGL can be very stable or slow to grow, it is unpredictably so—some patients can be monitored for years without intervention, whereas others have rapidly progressive metastatic disease requiring equally aggressive treatment. Average 5-year survival of metastatic disease is 50–70% [3**]. Risk factors that increase likelihood of metastasis are SDHB mutations, extra-adrenal location, tumor size ≥5cm, and three-fold elevated methoxytyramine [2*].

Unfortunately, even after resection of a PPGL screening is required, recognizing the potential for metastasis, recurrence, and multiplicity. Currently no pathologic scoring system possesses the desired accuracy to suitably predict this risk [2*,3**]. For these reasons, regular follow-up and vigilance are requisite for early detection and sequent management.

Catecholamine surges can substantially impact cardiovascular (CV) and gastrointestinal (GI) function incurring sometimes near-fatal derangements (e.g., hemorrhagic stroke, paralytic ileus with pursuant perforation, distributive shock, or cardiac arrest). Patients must therefore understand circumstances, medications, and operations that incur catecholamine release (as elaborated in Tables 1 and 2) [3**,11] both for the purpose of advocating to their providers as well as ensuring accurate biochemical testing. In managing catecholamine-induced conditions (discussed in the next section), patients need to be counseled on how to measure an accurate blood pressure and heart rate at home, consistently at least 1–2 times daily, in a log that can be shared with their physicians.

Table 1:

Education Prior to the Measurement of Biochemistries, What to Avoid

Stop 14 Days Prior
Sleep aids	Zolpidem (Ambien), eszopiclone (Lunesta)
MAO inhibitors	Phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl/Emsam), isocarboxazid (Marplan)
Tricyclic anti-depressants	Amitriptyline (Elavil), imipramine (Topfranil), nortriptyline (Aventyl)
Other anti-depressants/anti-anxiety	Escitalopram (Lexapro), paroxetine (Paxil), fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), bupropion (Wellbutrin), duloxetine (Cymbalta), venlafaxine (Effexor)
Anti-histamines	Diphenhydramine (Benadryl), Loratadine (Claritin), Fexofenadine (Allegra), Cetirizine (Zyrtec), Levocetirizine (Xyzal) OTC formulations containing the above anti-histamines
Decongestants	Guaifenesin (Robitussin, Mucinex)
DDC	Carbidopa/levodopa (Sinemet, Parcopa, Atamet)
Stimulants	Amphetamine/dextroamphetamine (Adderall), methylphenidate (Ritalin, Concerta), dexmethylphenidate (Focalin), dextroamphetamine (Dexedrine), lisdexamfetamine (Vyvanse)
All H2-blockers/PPIs1	Esomeprazole (Nexium), famotidine (Pepcid), ranitidine (Zantac), lansoprazole (Prevacid), omeprazole (Prilosec), nizatidine (Axid), cimetidine (Tagamet)
Stop 5 Days Prior 2
Acetaminophen	Acetaminophen (Tylenol/Paracetamol), acetaminophen/aspirin/caffeine (Excedrin), acetaminophen/oxycodone (Percocet), acetaminophen/tramadol (Ultracet), acetaminophen/hydrocodone (Vicodin)
Anti-hypertensives3/anti-arrhythmics	Labetalol, methyldopa, sotalol
Stop 24 Hours Prior and Throughout
Foods/dietary/habitual: caffeine or decaf products, alcohol, spicy foods, smoking/nicotine
Stop 8 Hours Prior
Fasting except for water	OK to take regular morning medications with water as long as not on the above lists

¹If also testing chromogranin A simultaneously with metanephrines/catecholamines;

²Only if catecholamines and metanephrines are measured by HPLC;

³Most morning anti-hypertensives can be taken. However, at high doses these medications can cause false positive results.

Abbreviations: MAO = monoamine oxidase; OTC = over-the-counter; DDC = dopa decarboxylase; H2 blockers = histamine H₂ antagonists; PPIs = proton pump inhibitors; HPLC: high performance liquid chromatography

Table 2:

Education Summary and Handout

Terminology	Definition	Significance	Take-home message for patients
Pheochromocytoma vs paraganglioma terminology	Both are neuroendocrine tumors of chromaffin cells; difference is location (pheochromocytomas = adrenal tumors, paragangliomas = extra-adrenal tumors, or anywhere other than the adrenal gland).	Changes how easy it is to remove surgically and other treatment options; likelihood of recurrence/metastasis; different genetics influence where the tumors will occur.	Knowing what you had/have and what the physician reports are describing can help you communicate it accurately to other providers.
Metanephrines vs catecholamines	Biological chemicals given off normally by adrenal glands and at nerves, but often at increased levels and at unpredictable times by PPGL tumors; (catecholamines = norepinephrine or noradrenaline, epinephrine or adrenaline, dopamine; metanephrines = their byproducts, normetanephrine, metanephrine, methoxytyramine, respectively).	These biological chemicals cause the “classic” symptoms (sweating, flushing, headaches, high BP, high HR, anxiety, tremors) and the most severe consequences associated with PPGL; critical to measure for diagnosis and before receiving any treatment or surgery; can also guide what treatment or medication will be best for symptoms.	Measurement of both can be informative, but metanephrines are superior to catecholamines for diagnosis/management.
24-hour urine vs blood (plasma)	Metanephrines/catecholamines may be measured via a 24-hour urine collection or via a blood draw.	Though plasma preferred over urine if it is collected correctly (lying completely flat on your back for 20–30 minutes with an IV catheter already in place to draw the sample after resting), logistics at your facility may dictate one over the other, and preparation must be done well for both to be interpreted correctly (see Table 1).	The preparation and execution of how the labs are taken are very influential on the results—guidelines should be followed carefully, always ask your provider before stopping/pausing any medications. Plasma metanephrines are recommended as the preferred test.
CT/MRI vs PET imaging	CTs/MRIs are considered anatomic imaging that is very sensitive but not specific. PET scans with various radionucleotides are functional imaging, very specific for the detection of PPGL.	Anatomic = precise location/size Functional = receptor/cellular characteristics, including imprecise location/activity.	Anatomic and functional imaging can complement each other, but serve different purposes. Your doctor can consult published guidelines over when to do one or the other, or compare both. Functional imaging may help to characterize a new tumor without doing a biopsy.
Alpha (α)-adrenoceptor blockers vs other BP medications	To control effects of excessive catecholamine levels, α-adrenoceptor blocking agents such as phenoxybenzamine or doxazosin are typically used first, though other BP and HR medications may be used at the same time.	If PPGL is present, β-adrenoceptor blocking agents should not be started first/used alone without α-adrenoceptor blocking agents, except in very specific cases of some epinephrine-secreting tumors; side effects of all BP/HR medications should be monitored.	Always have a list of current medications with you including dosages, and be aware that BP/HR issues due to PPGL are not always treated the same as other causes. Report all side effects, especially dizziness or lightheadedness on standing, to your prescriber.
Accuracy of blood pressure and heart rate records	BP and HR measurements are largely influenced by how they are measured.	BP/HR medications are titrated, or incrementally changed, to prevent dangerous outcomes. Regular measurements make these changes more accurate; can help avoid side effects from over-medicating; especially important prior to surgery to avoid complications during the operation.	BP and HR are only as accurate as the measurement techniques—sit calm and still in a chair for 5 minutes, feet flat on the floor, arms supported beside you before checking; use an arm cuff, not wrist; be consistent and regular about home measurements; keep a log and share with your providers.
Medications to Avoid or Carefully Monitor	Check with a physician prior to taking the following medications: metoclopramide; glucocorticoids (also known as steroids) should be at lowest doses possible; anti-depressants; including monoamine oxidase inhibitors; tricyclic anti-depressants; selective serotonin/norepinephrine reuptake inhibitors—can be taken but must be monitored as these medications cause elevated catecholamines with subsequent elevation of BP and HR; opioids (pain medications); naloxone; glucagon (a treatment commonly used for low blood sugar); linezolid or tedizolid; obesity management medications like phentermine and sibutramine; chemotherapy—must be carefully considered if given to any patient with PPGL.	Certain medications can increase circulating catecholamines, making it more likely to precipitate a hypertensive crisis or elevated BP and HR on a long-term basis.	These medications should be avoided if possible, or discussed in detail in the context of current levels of catecholamines/metanephrines and careful BP/HR monitoring prior to starting and while taking to avoid risks associated with high catecholamine levels.

Abbreviations: PPGL: pheochromocytoma/paraganglioma; HR: heart rate; BP: blood pressure; CT: computed tomography; MRI: magnetic resonance imaging; PET: positron emission tomography; IV: intravenous.

Catecholamine Excess and Management: CV-System

The most common CV manifestations of NE and EPI are hypertension (68–83% of PPGL patients) [1,4] and tachyarrhythmias (10.9%) [12], with 71% of mortality in PPGL due to CV causes [12]. For these reasons patients should have a baseline echocardiogram (echo) and electrocardiogram (EKG) to rule out other cardiac complications prior to starting noninvasive treatments with repeat echo/EKG in the presence of CV symptoms and/or every 3–5 years for serial assessment [3**].

For medication control of catecholamine-induced hypertension and tachyarrhythmias, always start with α-adrenoceptor blocking agents prior to starting β-adrenoceptor blocking agents to avoid unopposed α-adrenoceptor-mediated vasoconstriction (leading to further hypertension or pulmonary edema) [1,2*,3**,4,11,12,13]. The choice of α-adrenoceptor blocking agent should be individualized—phenoxybenzamine, a nonselective/noncompetitive α_1/2-adrenoceptor blocking agent, is more effective but with more side effects, while doxazosin, a selective/competitive α₁-adrenoceptor blocking agent, has less side effects but requires more titration and adjustment [2*]. Notably, doxazosin (preferred in its class, in our practice and included in more PPGL-specific studies), or terazosin and prazosin, are more affordable and readily available compared to phenoxybenzamine in the United States [11]. Phenoxybenzamine is started at 10 mg once or twice daily, whereas doxazosin is started at 1–4 mg once or twice daily (in our practice often 1–2 mg daily), depending on baseline blood pressures, and both titrated as needed. [3**,11,13].

β₁-specific adrenoceptor blocking agents such as atenolol or metoprolol may be added for continuing tachyarrhythmias (with atenolol avoided in patients with severe kidney dysfunction). Having the adrenergic biochemical phenotype as mentioned with genetic cluster 2 is the exception; in these patients, hypotension with tachycardia may occur when α-adrenoceptor blockade is implemented. This occurs as EPI (the most influential catecholamine secreted in cluster 2 patients) has 20-fold the affinity for β₂-adrenoceptors compared to NE, and catecholamines may bind to β₂-adrenoceptors preferentially in the setting of α₁-adrenoceptor inhibition [12]. This excessive stimulation of β₂-adrenoceptors on blood vessels in the absence of adequate opposing α₁-adrenoceptor-mediated vasoconstriction can lead to profound vasodilation and hypotension. Thus, after other causes of hypotension have been evaluated and addressed, propranolol without initial α-adrenoceptor blockade can be an effective first-line treatment for these patients [12].

Metyrosine is the only medication in its class that blocks tyrosine hydroxylase, the rate-limiting step of catecholamine synthesis [12]. Due to both significant cost/lack of availability as well as significant side effects, it still should be initiated after α-adrenoceptor blocking agents have been started [3**,11]. Drowsiness/sedation are the most common side effects, seen in almost all patients (up to 96% in one study), though patients must be monitored for other side effects such as extrapyramidal symptoms (such as tremors/drooling/speech difficulty, 10%), psychiatric changes (such as depression and disorientation), diarrhea (10%), and crystalluria [11,14]. Adverse effects are usually dose-dependent. For this reason, we recommend starting with 250 mg once daily, titrating up by 250 mg up to 1 g at most daily in our practice, watching carefully for severe symptoms. We rarely approach a daily dose of 2 g and almost never the manufacturer maximum dose of 4 g daily [11,14]. Patients should monitor their blood pressure and heart rate when starting or changing doses of metyrosine.

Upon treatment with vasodilating anti-hypertensives the vascular compartment expands, leaving an insufficient intravascular effective circulating volume as a consequence of the initial profound vasoconstriction by catecholamines which leads to a reduction in circulating volume (often by a compensatory diuresis) [15]. This leads to hypotension that can be preempted/corrected with fluids and increased salt intake. α/β-adrenoceptor blocking agents should be held for blood pressures <90/60 mmHg with further evaluation (e.g., for infection or cardiogenic shock) if hypotension persists.

In patients chronically living with secretory PPGLs causing catecholamine-induced hypertension (as established by elevated metanephrines in the setting of hypertension), initiate adrenoceptor blockade and titrate periodically to achieve a goal blood pressure below 130/80 mmHg with heart rate between 60–80 beats per minute [1,2*,3**,4]. In contrast, in the 7–14 days leading up to and 2–3 weeks after noninvasive treatments that may lead to catecholamine release from tumor(s) we favor more aggressive blockade in order to avoid inadequate coverage in the event such treatments incur a surge in catecholamines. Thus, we favor aggressive fluid and salt intake and compression stockings if orthostatic hypotension occurs to avoid down-titration of adrenoceptor blockade in the acute treatment period. We often only make adjustments to adrenoceptor blockade if orthostatic symptoms, despite the previously mentioned interventions, lead to recurring or severe dysfunction (e.g., persistent dizziness, overt debilitation, and/or syncope) [2*,3**].

Catecholamine Excess and Management: GI-System

Excess catecholamines suppress gut motility, leading to frequent complaints of constipation, or in the extreme paralytic ileus with perforation [3**,16]. Abdominal discomfort is often overlooked in the face of cardiac sequelae. Constipation is the result of catecholamines and noninvasive treatments (Table 3), leading to abdominal discomfort. Pain can then lead to further release of catecholamines which in-turn worsens constipation in a vicious cycle. Therefore, constipation should be addressed promptly beginning with routine lifestyle prevention techniques with pharmacotherapy as elaborated upon in Table 3. If constipation is severe, start pharmacotherapy with stool softeners (e.g., docusate), then osmotic laxatives (e.g., polyethylene glycol), then enemas/suppositories (preferably tap water) avoiding forceful cramp-inducing stimulants (e.g., senokot, bisacodyl) and emollients (e.g., mineral oil) as the later hinders absorption of many lipid-soluble medications [16]. Additionally, metyrosine may also treat constipation by reducing the levels of offending catecholamines.

Table 3:

Management of Common Treatment Side effects

Side Effect	Treatment Modalities	Treatment Options
Nausea/vomiting	1. CVD chemotherapy 2. Some amino acid co-infusion with PRRT with 177Lu-Dotatate (Lutathera®) – given for renal protection 3. 131I-MIBG radiation (conventional and HSA) 4. Temozolomide 5. Metyrosine 6. Cold SSAs (mild, often temporary) – e.g., octreotide, lanreotide 7. TKIs – e.g., sunitinib, axitinib, cabozantinib	• 5-HT3 receptor antagonist plus neurokinin-1 receptor antagonist, plus dexamethasone at lowest dose if required • For amino acid co-infusion with PRRT, using L-arginine and L-lysine containing mixtures along with prophylactic anti-emetic regimens Precaution: avoid dopamine receptor antagonists like metoclopramide and prochlorperazine, and omit dexamethasone if not needed for individual patient or use lowest dose due to concerns for catecholamine increase
Diarrhea	1. Cold SSAs	• Decrease dosage of SSAs • Loperamide (Imodium) starting at 4 mg (available in 2 mg tablets), can increase up to 4 mg four times daily—monitor for QTc prolongation • And/or diphenoxylate/atropine (Lomotil) 2.5 mg/0.025 mg tablets, up to two tablets four times daily
Cholelithiasis		• Decrease dosage or stop SSAs • Monitor liver function tests • If suspected obtain right upper quadrant ultrasound • If identified, consult gastroenterology/general surgery for possible cholecystectomy
Constipation	1. Vincristine, part of CVD chemotherapy 2. Temozolomide 3. Chronic elevations in catecholamine levels/surges 4. Opioid pain medications	Maintenance: • Lifestyle changes: 25–40 g of dietary fiber daily, 2 quarts of fluid intake daily, regular meals throughout day • Stool softeners (like docusate) and osmotic laxatives (like polyethylene glycol) Severe constipation: • Enemas (preferably tap water) and suppositories • Avoid stimulant laxatives (like Senokot)
Peripheral neuropathies	1. Vincristine, part of CVD chemotherapy	• Avoid cold exposure with appropriate clothing • Capsaicin cream 0.075%, or single-application 8% capsaicin patch • Gabapentin (Neurontin) or Pregabalin (Lyrica)
Fatigue/weakness	1. Temozolomide 2. PRRT with 177Lu-Dotatate (Lutathera®) 3. 131I-MIBG* 4. TKIs* *Can cause hypothyroidism	• Check thyroid and adrenal function • If taking metyrosine consider reducing the dose or shifting the timing to evening
Dry mouth	1. 131I-MIBG	• Avoid or stop anti-cholinergic agents if possible • Increase hydration, avoid desiccants • Consider throat lozenges and OTC lubricating mouthwashes (such as Biotene) • If persistent consider pro-cholinergic agents such as pilocarpine at 5 mg three to four times daily or cevimeline at 30 mg three times daily • Regular dental evaluation for dental caries
Myelosuppression	1. CVD chemotherapy (leukopenia, MDS, leukemia) 2. 131I-MIBG conventional radiation (neutropenias, thrombocytopenias) 3. HSA-131I-MIBG (Azedra®) (thrombocytopenia, neutropenia, leukopenia, anemia, leukemias/MDS) 4. PRRT with 177Lu-Dotatate (Lutathera®) (lymphopenia, thrombocytopenia, neutropenia, MDS/leukemia) 5. Temozolomide (lymphopenia, anemia) 6. TKIs (thrombocytopenia)	• CBC checked prior to every treatment • For substantial cytopenia’s: packed red blood cell transfusions, platelet transfusions, granulocyte colony-stimulating factor, or erythropoietin therapy depending on specific cell affected • Consider previous therapies used given compounding myelosuppression

Abbreviations: CVD: cyclophosphamide, vincristine, dacarbazine; PRRT: peptide receptor radionucleotide therapy; ¹³¹I-MIBG: [131-I]-metaiodobenzylguanidine; SSAs: somatostatin analogs; TKIs: tyrosine kinase inhibitors; QTc: corrected QT; OTC: over-the-counter; HSA: high-specific-activity; CBC: complete blood count; MDS: myelodysplastic syndrome

Nausea and vomiting (N/V) are usually not directly catecholamine-induced. Rather, they are common side effects of noninvasive therapy. The severity ranges based on treatment, with cold somatostatin analogs (like octreotide or lanreotide) and metyrosine generally being mild compared to cyclophosphamide, vincristine, dacarbazine (CVD) chemotherapy and tyrosine kinase inhibitors (like sunitinib, cabozantinib, and axitinib) which cause the most severe N/V. The treatment of N/V in PPGL should avoid dopamine receptor antagonists (e.g., metoclopramide or prochlorperazine) and dexamethasone as a corticosteroid should be introduced at the lowest required dosages as these drugs can worsen catecholamine release. Instead, start with 5-HT₃ receptor antagonists (e.g., ondansetron). However, beware of catecholamine-induced QTc prolongation and avoid 5-HT₃ receptor antagonists as the QTc interval approaches >500 ms [17]. Neurokinin-1 receptor antagonists (e.g., aprepitant) which antagonize the binding of substance P, though costly, may be particularly useful as an antiemetic in these patients, as chromaffin tumors may secrete substance P [18,19,20].

Metastatic Disease Management

Metastasis of PPGL is defined by the World Health Organization as the presence of chromaffin cells within tissue otherwise lacking native chromaffin cells. By definition, this includes lymph nodes and bones and most of the time disease can be considered metastases if in the lung or liver. Even if unable to differentiate between multiple primary tumors/recurrence compared to metastasis, if unresectable, they are often treated with the same approach as a metastatic lesion [1,2*,3**,4]. Many outstanding publications discuss treatment of metastatic disease in general; however, this discussion will focus on management of discomforts caused by mass-effect, particularly in osseous metastasis. If determined that noninvasive intervention is needed, management for the side effects of these therapies is outlined in Table 3.

For patients with metastatic disease, osseous tumors are common with 20% of patients having tumors almost exclusively within bones and 60–70% having some tumors within bones [3**,21]. These lesions may cause bone pain, impingement of neurologic structures (especially compression of the spinal cord), pathologic fractures, and myelosuppression. Management techniques can address multiple elements at the same time. A multidisciplinary approach including pain management, neurosurgery, radiation oncology, and orthopedics is invaluable depending on the tumor location and resultant symptoms. This is principally relevant to lesions that are intimately close to neurologic structures, particularly when they begin to cause compression and/or when they cause pathologic fractures, as such circumstances largely mandate surgical intervention. Such lesions are also amenable to localized external radiotherapy for reduction of mass-effect symptoms [3**]. When osseous lesions are extensive/diffuse and/or associated with multifocal symptoms, systemic therapy can also be used. Steroids and opiates are commonly prescribed, especially when patients have neurogenic impingement. Both agents should be used sparingly, however, given they can worsen catecholamine release.

Although there is minimal evidence that catecholamine excess correlates with decreased bone mineral density [3**,21,22], prevention of osseous sequelae and osteogenic pain can also be treated with bisphosphonates (with 1–4 mg of zoledronic acid given intravenously every 3 months) or denosumab (with 120 mg given subcutaneously every 3 months, note denosumab is generally preferred in patients with renal impairment) [3**,23]. These agents can be initiated once it is established that multiple osseous lesions are present/growing. The administration of these agents may be complicated (more commonly by denosumab compared to zoledronic acid) by hypocalcemia, jaw necrosis, or vertebral rebound fractures. Patients should therefore be monitored for these adverse effects. Finally, myelosuppression from both infiltration of the metastases as well as from chemotherapy or systemic radiation requires serial monitoring of complete blood counts.

To avoid potentially serious side effects of treatments, and due to the non-curative nature of inoperable disease, surveillance with imaging and biochemical markers is a well-accepted strategy in those with stable disease, low tumor burden, and minimal catecholamine-induced symptoms [4]. We recommend anatomical cross-sectional imaging via computed tomography (CT) or magnetic resonance imaging (MRI) every 3–6 months for the first year after diagnosis, then 6–12 months thereafter, along with functional studies if growth is suspected and/or insufficiently characterized by anatomic imaging. Trending biochemical studies with assessment of plasma-free or 24-h urine every 6 months in secretory patients can also be useful as a surrogate of disease progression (but should not be relied upon as a sole-determinant) [3**]. Due to the rarity and complexity of this condition, consultation and treatment via a multidisciplinary center with experience in PPGL is recommended.

Conclusion

Given the growing population of patients with inoperable PPGL, symptomatic management is a priority, even more so while patients receive noninvasive treatment. As previously mentioned, symptoms arising from catecholamine excess, metastatic disease, and treatment side effects often demand a multidisciplinary approach. Knowledge of a patient’s genetic cluster can advise a targeted approach to individual disease management and obviate the most common and potentially harmful CV and GI symptoms they may experience. Patient education is also a major priority as it empowers understanding and collaboration throughout treatment, allowing for more favorable outcomes.

Key Points.

• Noninvasive treatment of patients with PPGL is largely based on genetic, biochemical, and imaging determinants.

• Noninvasive treatments can lead to catecholamine release and debilitating catecholamine-induced CV/GI symptoms. Treatment of these symptoms improves quality of life.

• A multidisciplinary approach is essential when treating discomforts directly arising from masses themselves (e.g., osseous metastasis).

• Patient involvement and education on their condition is essential for optimal management.