Pheochromocytoma medical therapy

Pharmacological medical therapies for pheochromocytoma incldue treatment with alpha blockers (for example, phenoxybenzamine) followed by beta blockers (for example, atenolol) before surgery. Other drugs can be used such as calcium channel blockers and metyrosine. Adjunctive chemotherapy and radiation are used in metastatic disease. Hypertensive crisis can be managed by using sodium nitroprusside, phentolamine and nicardipine.

Pharmacological medical therapy is recommended in all patients with pheochromocytoma undergoing surgery to control hypertension and reduce morbidity.

• All patients undergoing surgery need preoperative treatment to control hypertension during surgery and hypotension after it.
• According to Endocrine Society’s 2014 Clinical Practice Guidelines, there are three medical regimens for preoperative management of pheochromocytoma:^[1][2]
  • Combined alpha followed by beta-adrenergic blockers
  • Calcium channel blockers
  • Metyrosine

• It is used to counteract hypertension and the beta-1 adrenoceptor antagonist atenolol to reduce cardiac output. They can block the sudden release of adrenaline during surgical stress and prevent hypertensive crisis. The patient is ready for surgery after 10 to 14 days of initiation of alpha-adrenergic blockade. Patients should take high sodium diet to prevent orthostatic hypotension due to alpha blockers. After adequate alpha-adrenergic blockade has been achieved, a beta-adrenergic blocker is initiated 3 days before surgery.

Beta-adrenergic blocker

• It should never be started first because unopposed alpha-adrenergic receptor stimulation can lead to the brisk increase in blood pressure. It should be used with caution due to the risk of heart failure, pulmonary edema, and asthma.

• It is used to control blood pressure preoperatively and an intravenous injection is given intraoperatively.
• Its main use is controlling blood pressure in case of failed alpha and beta blockers regimen or unaccepted side effects in that regimen.^[3]

• It is the last medical line of treatment. It inhibits catecholamine synthesis.
• It is used in case of failure of other medical lines of treatment or in patients who cannot tolerate them.
• Clinicians use combined treatment in difficult cases and if radiofrequency ablation for metastatic foci will be used. Metyrosine side effects include crystalluria, extrapyramidal manifestations, and high cost.^[4]

The following dosage regimen may be used:

• Preferred regimen (1): IV Sodium nitroprusside 0.3 to 0.5 mcg/kg/minute; maximum dose of 10 mcg/kg/minute for 10 minutes. The rate of a prolonged infusion should be no more than 3 mcg/kg/minute to avoid cyanide toxicity.
• Preferred regimen (2): IV Phentolamine (non-selective alpha-adrenergic blocker) 1 to 5 mg bolus; maximum single dose: 15 mg. The response to phentolamine is maximal in two to three minutes after starting of the initial dose.
• Preferred regimen (3): IV Nicardipine (calcium channel blocker) ^[5]

• Phenoxybenzamine use is safe but beta-adrenergic blockers use has been associated with intrauterine growth retardation.^[6]
• Resection of the tumor can often be performed safely during the second trimester.^[7]
• Tumor resection can be combined with a cesarean section during delivery.
• Careful monitoring is needed to mother and fetus.

• Preoperative evaluation should include testing for associated tumors.

Serum calcium must be measured to exclude medullary thyroid cancer. It should be removed first if it is found. Thyroidectomy is the only way to treat medullary thyroid related to MEN.^[8] Surgical treatment has low morbidity, even in children. Thyroid replacement is started directly after surgery.

• Primary hyperparathyroidism and pheochromocytoma are features of MEN2B syndrome.

• Asymptomatic patients who do not undergo surgery need follow up only.

• If patients are symptomatic, hyperparathyroidism surgery is the only definitive treatment.^[9]
• Surgery for pheoochromocytoma should be done first if both pheochromocytoma and hyperparathyroidism are found together.

• Preoperative localization is preferred by CT scan, ultrasound, and sestamibi scan (resection of the enlarged glands only is the preferred procedure in this situation).
• Subtotal parathyroidectomy and total parathyroidectomy, carry the risk of hypoparathyroidism.^[10]
• Complication and recurrence rate is low^[11]
• Family members should undergo RET mutation screening.

• For asymptomatic patients, follow up is better than intervention due to high risk of complications in surgeries.

• For symptomatic patients, open procedures are recommended due to large tumor size and high vascularity. Primary and metastatic lesions should be resected if possible.

• Some authors suggest administration of 131-iodine-labeled meta-iodo-benzylguanidine (131I-MIBG) after resection. ^[12]
• There are many types of local therapy:
  • External beam radiation therapy (EBRT)
  • Radio frequency ablation
  • Cryoablation
  • Ethanol injection

• External beam radiation therapy (EBRT) can relieve symptoms and decrease pain in non-resectable cases. It may induce massive catecholamine secretion and a hypertensive crisis. All of them need preoperative medical management to decrease chances of hypertensive crisis.
• Other ablation procedures (radiofrequency ablation, cryoablation, or ethanol injection) are based on the lesion target location; head, neck, thorax or retroperitoneal.
• Liver tumors are treated with either radioferequency ablation, ethanol injection or transarterial chemoembolization. These procedures may be used in patients with multiple liver metastases.
• Percutaneous tumor ablation is limited to patients with one or a few small tumors.^[13]

• Metastatic pheochromocytoma is treated with Averbuc protocol, which is a combination of cyclophosphamide, vincristine, dacarbazine and doxorubicin.^[14]
• For patients with rapidly progressive tumors or bone-predominant extensive disease, chemotherapy is a preferred option even if 123I-MIBG scintigraphy is positive.
• Chemotherapy should be considered for patients with unresectable and rapidly growing pheochromocytoma and a large number of metastases.
• The median duration of response is 20 months with median survival of 3.3 years.^[15]
• Most common side effects are gastrointestinal upset, peripheral neuropathy and bone marrow suppression.^[16]

• Sunitinib is a tyrosine kinase receptor inhibitor and vascular endothelial growth factor receptors inhibitor.

• Pazopanib is tyrosine kinase receptors inhibitor.

• ¹³¹I-MIBG radiation therapy may be used for the treatment of MIBG-avid metastases.^[14]
• Patients with a good uptake of ¹³¹I-MIBG in cases of unresectable progressive pheochromocytoma lead to a lower number of metastases. Therapy can be repeated for recurrent cases.^[17]
• High doses show serious side effects including, leukopenia, thrombocytopenia due to bone marrow depression, hypothyroidism and acute leukemia.^[18][19]
• Pheochromocytomas express somatostatin receptors. Patients with metastatic or recurrent pheochromocytoma may benefit from radiolabeled somatostatin analogs.^[20]Long-term potential side effects of therapy with radiolabeled somatostatin analogs may include loss of renal function, pancytopenia, and myelodysplastic syndrome.^[19]

Pheochromocytoma is considered an absolute contraindication to the use of the following medications:

• Atomoxetine
• Glucagon
• Minoxidil
• Metoclopramide

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