Pheochromocytoma medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2]
Overview
Treatment with alpha blockers (example: phenoxybenzamine) followed by beta blockers (example: atenolol) is required before surgery. Adjunctive chemotherapy and radiation are used in metastatic disease.
Medical Therapy
Preoperative medical therapy:
All patients doing surgery need preoperative treatment to control hypertension during surgery and hypotension after it. There are three medical regimens for treatment; Combined alpha and beta-adrenergic blockade, calcium channel blockers, and metyrosine[1]:
Aalpha adrenoceptor blocker (phenoxybenzamine) are used to counteract hypertension and the beta-1 adrenoceptor antagonist atenolol to reduce cardiac output. They can block sudden release of adrenaline during surgery and prevent hypertensive crisis. Patient is ready for surgery in 10 to 14 days after initiation of alpha-adrenergic blockade. Patients should take high sodium diet to antagonize orthostatic hypotension of alpha blockers.After adequate alpha-adrenergic blockade has been achieved, beta-adrenergic blockade is initiated 3 days before surgery. Beta-adrenergic blocker should never be started first because unopposed alpha-adrenergic receptor stimulation can lead to brisky increase in blood pressure. It should be used with caution due to risk of heart failure, pulmonary edema and asthma.
Second line of treatment is calcium channel blocker which is used to control blood pressure preoperatively and intravenous injection intraoperatively.
Its main use is controlling blood pressure in case of failed alpha and beta blockers regimen or unaccepted side effects in the that regimen.
Metyrosine 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. Additionally, clinicans use combined treatment in difficult cases and if radiofrequency ablation for metastatic foci will be used. Metyrosine side effects include: crystaluria , extrapyramidal manifestations and high cost.
Management of hypertensive crisis
- Sodium nitroprusside is the first line of treatment because of its rapid onset of action and short duration of effect. The rate of a prolonged infusion should be no more than 3 mcg/kg per minute to avoid cyanide toxicity.
- Phentolamine is nonselective alpha-adrenergic blocker. The response to phentolamine is maximal in two to three minutes after starting of initial dose.
- Nicardipine is calcium channel blocker and the last line of treatment after failure of previous two lines.
Management of malignant pheochromocyotma
Asymptomatic patients, follow up is better than intervention due to high risk of complications in surgeries.
Symptomatic patients Open procedures are recommended [34] [35] due to large tumor size and high vascularity. Primary and metastatic lesions should be resected if possible.[30]
Local therapy
- Some authors suggest administration of 131-iodine-labeled meta-iodobenzylguanidine (131I-MIBG) after resection [36]. [4,18].
- There are many types of local therapy: external beam radiation therapy (EBRT), radio frequency ablation, , cryoablation, or ethanol injection.
- External beam radiation therapy (EBRT) can relieve symptoms and decrease pain in non resectable cases. It can induce massive catecholamine secretion and a hypertensive crisis [39]. All of them need preoperative medical management to decrease chances of hypertensive crisis .
- Other ablation procedure (RFA, cryoablation, or ethanol injection) was based upon the lesion target location; head, neck ,thorax or retroperitoneal.
- Liver tumors were treated with either RFA or ethanol injection or transarterial chemoembolization for liver For patients with multiple liver metastases is available option for patients not fit for surgeries.
- Percutaneous tumor ablation is limited to patients with one or a few small tumors. 47-51
Systemic therapy
131I-MIBG treatment can be repeated, usually at six-month intervals [36]. [63].
High doses show serious side effects include: leukopenia, thrombocytopenia due to bone marrow depression and hypothyroidism.
Treatment with 131I-MIBG should be considered in patients with good uptake of 123I-MIBG Unresectable progressive pheochromocytoma/paraganglioma
●A high tumor burden and a low number of bone metastases
For patients with rapidly progressive tumors or bone-predominant extensive disease, chemotherapy is a preferred option even if 123I-MIBG scintigraphy is positive [4].
Patients should be counseled about the potential risks of long-term myelosuppression [60,66,67], and a possible increase in myelodysplasia and acute leukemia in long-term survivors [65,67]. It is not clear whether these risks are limited to those who receive high-dose therapy.
Peptide receptor radioligand therapy — Pheochromocytomas and extra-adrenal paragangliomas express somatostatin receptors at a level that is similar to that of other neuroendocrine tumors, including gastroenteropancreatic neuroendocrine tumors [68-71]. As with other neuroendocrine tumors, patients whose metastatic or recurrent pheochromocytoma/paragangliomaexpresses somatostatin receptors (as determined by positive uptake with 111In-pentetreotide or where available, positron emission tomography [PET] imaging using gallium-68-labeled somatostatin analogs such as 68-Ga-DOTATATE [72-74]) may benefit from therapy using radiolabeled somatostatin analogs. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Radiolabeled somatostatin analogs' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Radiolabeled somatostatin analogs'.)
Long-term potential side effects of therapy with radiolabeled somatostatin analogs may include loss of renal function, pancytopenia, and myelodysplastic syndrome [66].
Based upon this limited amount of data, the utility of somatostatin analog therapy for tumor control or palliation of symptoms in patients with malignant pheochromocytoma/paraganglioma remains unclear. However, a therapeutic trial of octreotide could be considered in a patient who is not yet a candidate for more toxic systemic treatment options.
Cytotoxic chemotherapy — Systemic chemotherapy should be considered for patients with unresectable and rapidly progressive pheochromocytoma/paraganglioma and patients with high tumor burden or a large number of bone metastases. The most extensive data are from studies using various combinations of cyclophosphamide, dacarbazine, vincristine, and doxorubicin [9,86-88].
The median duration of response was 20 months median survival for all patients was 3.3 years from the start of chemotherapy [87]. Treatment was well tolerated, with the most prominent side effects being "mild" myelosuppression, peripheral neuropathy, and gastrointestinal toxicity [89].
Molecularly targeted therapy — Sunitinib is a potent inhibitor of multiple tyrosine kinase receptors, including vascular endothelial growth factor receptors (VEGFRs)
Pazopanib, another inhibitor of VEGRs
Chemotherapy
Metastatic pheochromocytoma is treated with Averbuc protocol which is a combination of cyclophosphamide, vincristine, and dacarbazine.[2]
Radiation
131I-MIBG radiation therapy has been used for the treatment of MIBG-avid metastases.[2]
Contraindicated medications
Pheochromocytoma is considered an absolute contraindication to the use of the following medications:
References
- ↑ Tauzin-Fin P, Sesay M, Gosse P, Ballanger P (2004). "Effects of perioperative alpha1 block on haemodynamic control during laparoscopic surgery for phaeochromocytoma". Br J Anaesth. 92 (4): 512–7. doi:10.1093/bja/aeh083. PMID 14766711.
- ↑ 2.0 2.1 National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq#link/_179_toc