Pheochromocytoma medical therapy: Difference between revisions

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Latest revision as of 00:29, 29 July 2020

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2] Mohammed Abdelwahed M.D [3]

Overview

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.

Medical Therapy

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

Preoperative medical therapy

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

Aalpha adrenoceptor blocker

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.

Calcium channel blocker

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]

Metyrosine

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]

Dosing[2]

The following dosage regimen may be used:

Drug	Initial dose	Final dose
Phenoxybenzamine	10 mg b.i.d.	1 mg/kg/d
Propranolol	1 20 mg t.i.d.	40 mg TID
Nifedipine	30 mg/d	60 mg/d

Management of hypertensive crisis

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]

Management of pheochromocytoma during pregnancy

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.

Management of familial pheochromocytoma

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:

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.

Management of malignant pheochromocytoma

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.

Local therapy

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]

Systemic therapy

Chemotherapy

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]

Molecular Therapy

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

Pazopanib is tyrosine kinase receptors inhibitor.

Radiation therapy

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]

Contraindicated medications

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

References

↑ Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH; et al. (2014). "Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline". J Clin Endocrinol Metab. 99 (6): 1915–42. doi:10.1210/jc.2014-1498. PMID 24893135.
↑ 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.
↑ Lebuffe G, Dosseh ED, Tek G, Tytgat H, Moreno S, Tavernier B; et al. (2005). "The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas". Anaesthesia. 60 (5): 439–44. doi:10.1111/j.1365-2044.2005.04156.x. PMID 15819762.
↑ Steinsapir J, Carr AA, Prisant LM, Bransome ED (1997). "Metyrosine and pheochromocytoma". Arch Intern Med. 157 (8): 901–6. PMID 9129550.
↑ Varon J, Marik PE (2003). "Clinical review: the management of hypertensive crises". Crit Care. 7 (5): 374–84. doi:10.1186/cc2351. PMC 270718. PMID 12974970.
↑ Butters L, Kennedy S, Rubin PC (1990). "Atenolol in essential hypertension during pregnancy". BMJ. 301 (6752): 587–9. PMC 1663720. PMID 2242456.
↑ Junglee N, Harries SE, Davies N, Scott-Coombes D, Scanlon MF, Rees DA (2007). "Pheochromocytoma in Pregnancy: When is Operative Intervention Indicated?". J Womens Health (Larchmt). 16 (9): 1362–5. doi:10.1089/jwh.2007.0382. PMID 18001193.
↑ Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF; et al. (2015). "Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma". Thyroid. 25 (6): 567–610. doi:10.1089/thy.2014.0335. PMC 4490627. PMID 25810047.
↑ Herfarth KK, Bartsch D, Doherty GM, Wells SA, Lairmore TC (1996). "Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A". Surgery. 120 (6): 966–73, discussion 973-4. PMID 8957482.
↑ Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF; et al. (2015). "Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma". Thyroid. 25 (6): 567–610. doi:10.1089/thy.2014.0335. PMC 4490627. PMID 25810047.
↑ Wells SA, Donis-Keller H (1994). "Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes". Endocrinol Metab Clin North Am. 23 (1): 215–28. PMID 7913027.
↑ Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K; et al. (2010). "The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer". Pancreas. 39 (6): 775–83. doi:10.1097/MPA.0b013e3181ebb4f0. PMC 3419007. PMID 20664475.
↑ Watanabe D, Tanabe A, Naruse M, Tsuiki M, Torii N, Noshiro T; et al. (2006). "Transcatheter arterial embolization for the treatment of liver metastases in a patient with malignant pheochromocytoma". Endocr J. 53 (1): 59–66. PMID 16543673.
↑ ^14.0 ^14.1 National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq#link/_179_toc
↑ Huang H, Abraham J, Hung E, Averbuch S, Merino M, Steinberg SM; et al. (2008). "Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients". Cancer. 113 (8): 2020–8. doi:10.1002/cncr.23812. PMID 18780317.
↑ Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R; et al. (1988). "Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine". Ann Intern Med. 109 (4): 267–73. PMID 3395037.
↑ Mukherjee JJ, Kaltsas GA, Islam N, Plowman PN, Foley R, Hikmat J; et al. (2001). "Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG]". Clin Endocrinol (Oxf). 55 (1): 47–60. PMID 11453952.
↑ Sze WC, Grossman AB, Goddard I, Amendra D, Shieh SC, Plowman PN; et al. (2013). "Sequelae and survivorship in patients treated with (131)I-MIBG therapy". Br J Cancer. 109 (3): 565–72. doi:10.1038/bjc.2013.365. PMC 3738119. PMID 23860527.
↑ ^19.0 ^19.1 Gulenchyn KY, Yao X, Asa SL, Singh S, Law C (2012). "Radionuclide therapy in neuroendocrine tumours: a systematic review". Clin Oncol (R Coll Radiol). 24 (4): 294–308. doi:10.1016/j.clon.2011.12.003. PMID 22221516.
↑ Hubalewska-Dydejczyk A, Trofimiuk M, Sowa-Staszczak A, Gilis-Januszewska A, Wierzchowski W, Pach D; et al. (2008). "[Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas]". Przegl Lek. 65 (9): 405–7. PMID 19140390.

Template:WS Template:WH

[pmid248931352-1] Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH; et al. (2014). "Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline". J Clin Endocrinol Metab. 99 (6): 1915–42. doi:10.1210/jc.2014-1498. PMID 24893135.

[pmid14766711-2] 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.

[pmid15819762-3] Lebuffe G, Dosseh ED, Tek G, Tytgat H, Moreno S, Tavernier B; et al. (2005). "The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas". Anaesthesia. 60 (5): 439–44. doi:10.1111/j.1365-2044.2005.04156.x. PMID 15819762.

[pmid9129550-4] Steinsapir J, Carr AA, Prisant LM, Bransome ED (1997). "Metyrosine and pheochromocytoma". Arch Intern Med. 157 (8): 901–6. PMID 9129550.

[pmid12974970-5] Varon J, Marik PE (2003). "Clinical review: the management of hypertensive crises". Crit Care. 7 (5): 374–84. doi:10.1186/cc2351. PMC 270718. PMID 12974970.

[pmid2242456-6] Butters L, Kennedy S, Rubin PC (1990). "Atenolol in essential hypertension during pregnancy". BMJ. 301 (6752): 587–9. PMC 1663720. PMID 2242456.

[pmid18001193-7] Junglee N, Harries SE, Davies N, Scott-Coombes D, Scanlon MF, Rees DA (2007). "Pheochromocytoma in Pregnancy: When is Operative Intervention Indicated?". J Womens Health (Larchmt). 16 (9): 1362–5. doi:10.1089/jwh.2007.0382. PMID 18001193.

[pmid25810047-8] Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF; et al. (2015). "Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma". Thyroid. 25 (6): 567–610. doi:10.1089/thy.2014.0335. PMC 4490627. PMID 25810047.

[pmid8957482-9] Herfarth KK, Bartsch D, Doherty GM, Wells SA, Lairmore TC (1996). "Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A". Surgery. 120 (6): 966–73, discussion 973-4. PMID 8957482.

[pmid258100472-10] Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF; et al. (2015). "Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma". Thyroid. 25 (6): 567–610. doi:10.1089/thy.2014.0335. PMC 4490627. PMID 25810047.

[pmid7913027-11] Wells SA, Donis-Keller H (1994). "Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes". Endocrinol Metab Clin North Am. 23 (1): 215–28. PMID 7913027.

[pmid20664475-12] Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K; et al. (2010). "The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer". Pancreas. 39 (6): 775–83. doi:10.1097/MPA.0b013e3181ebb4f0. PMC 3419007. PMID 20664475.

[pmid16543673-13] Watanabe D, Tanabe A, Naruse M, Tsuiki M, Torii N, Noshiro T; et al. (2006). "Transcatheter arterial embolization for the treatment of liver metastases in a patient with malignant pheochromocytoma". Endocr J. 53 (1): 59–66. PMID 16543673.

[cancergov-14] 14.0 ^14.1 National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq#link/_179_toc

[pmid18780317-15] Huang H, Abraham J, Hung E, Averbuch S, Merino M, Steinberg SM; et al. (2008). "Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients". Cancer. 113 (8): 2020–8. doi:10.1002/cncr.23812. PMID 18780317.

[pmid3395037-16] Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R; et al. (1988). "Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine". Ann Intern Med. 109 (4): 267–73. PMID 3395037.

[pmid11453952-17] Mukherjee JJ, Kaltsas GA, Islam N, Plowman PN, Foley R, Hikmat J; et al. (2001). "Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG]". Clin Endocrinol (Oxf). 55 (1): 47–60. PMID 11453952.

[pmid23860527-18] Sze WC, Grossman AB, Goddard I, Amendra D, Shieh SC, Plowman PN; et al. (2013). "Sequelae and survivorship in patients treated with (131)I-MIBG therapy". Br J Cancer. 109 (3): 565–72. doi:10.1038/bjc.2013.365. PMC 3738119. PMID 23860527.

[pmid22221516-19] 19.0 ^19.1 Gulenchyn KY, Yao X, Asa SL, Singh S, Law C (2012). "Radionuclide therapy in neuroendocrine tumours: a systematic review". Clin Oncol (R Coll Radiol). 24 (4): 294–308. doi:10.1016/j.clon.2011.12.003. PMID 22221516.

[pmid19140390-20] Hubalewska-Dydejczyk A, Trofimiuk M, Sowa-Staszczak A, Gilis-Januszewska A, Wierzchowski W, Pach D; et al. (2008). "[Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas]". Przegl Lek. 65 (9): 405–7. PMID 19140390.

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@@ Line 1: / Line 1: @@
 __NOTOC__
 {{Pheochromocytoma}}
-{{CMG}}; {{AE}} {{AAM}}
+{{CMG}}; {{AE}} {{AAM}} {{MAD}}
 ==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.
+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 blocker|calcium channel blockers]] and [[metyrosine]]. Adjunctive [[chemotherapy]] and [[radiation]] are used in metastatic disease. [[Hypertensive crisis]] can be managed by using [[Sodium nitroprusside|sodium nitroprusside,]] [[phentolamine]] and [[nicardipine]].
 ==Medical Therapy==
-'''Preoperative medical therapy:'''
+Pharmacological medical therapy is recommended in all patients with pheochromocytoma undergoing surgery to control [[hypertension]] and reduce [[morbidity]].
-All patients going to 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<ref name="pmid14766711">{{cite journal| author=Tauzin-Fin P, Sesay M, Gosse P, Ballanger P| title=Effects of perioperative alpha1 block on haemodynamic control during laparoscopic surgery for phaeochromocytoma. | journal=Br J Anaesth | year= 2004 | volume= 92 | issue= 4 | pages= 512-7 | pmid=14766711 | doi=10.1093/bja/aeh083 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14766711  }}</ref> according to  Endocrine Society’s 2014 Clinical Practice Guidelines:
+=== Preoperative medical therapy ===
-* <u>[[alpha blocker|Aalpha adrenoceptor blocker]] ([[phenoxybenzamine]])</u> 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.'''<ref name="pmid24893135">{{cite journal| author=Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH et al.| title=Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2014 | volume= 99 | issue= 6 | pages= 1915-42 | pmid=24893135 | doi=10.1210/jc.2014-1498 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24893135  }}</ref>'''It''' should be used with caution due to risk of heart failure, pulmonary edema and asthma.
+* 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:<ref name="pmid248931352">{{cite journal| author=Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH et al.| title=Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. | journal=J Clin Endocrinol Metab | year= 2014 | volume= 99 | issue= 6 | pages= 1915-42 | pmid=24893135 | doi=10.1210/jc.2014-1498 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24893135  }}</ref><ref name="pmid14766711">{{cite journal| author=Tauzin-Fin P, Sesay M, Gosse P, Ballanger P| title=Effects of perioperative alpha1 block on haemodynamic control during laparoscopic surgery for phaeochromocytoma. | journal=Br J Anaesth | year= 2004 | volume= 92 | issue= 4 | pages= 512-7 | pmid=14766711 | doi=10.1093/bja/aeh083 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14766711  }}</ref>
+** Combined [[Alpha blocker|alpha]] followed by [[beta-adrenergic blockers]]
+** [[Calcium channel blocker|Calcium channel blockers]]
+** [[Metyrosine]]
-* <u>Second line of treatment is [[calcium channel blocker]]</u> which is used to control blood pressure preoperatively and intravenous injection intraoperatively.
+==== [[alpha blocker|'''Aalpha adrenoceptor blocker''']] ====
-Its main use is controlling blood pressure in case of failed alpha and beta blockers regimen or unaccepted side effects in the that regimen.<ref name="pmid15819762">{{cite journal| author=Lebuffe G, Dosseh ED, Tek G, Tytgat H, Moreno S, Tavernier B et al.| title=The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. | journal=Anaesthesia | year= 2005 | volume= 60 | issue= 5 | pages= 439-44 | pmid=15819762 | doi=10.1111/j.1365-2044.2005.04156.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15819762  }}</ref>
+* It is used to counteract [[hypertension]] and the [[Beta blockers|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 blocking agent|alpha-adrenergic blockade]]. Patients should take high [[sodium]] diet to prevent [[orthostatic hypotension]] due to [[Alpha blocker|alpha blockers]]. After adequate [[Alpha-adrenergic blocker|alpha-adrenergic blockade]] has been achieved, a [[beta-adrenergic blocker]] is initiated 3 days before surgery.
-* <u>[[Metyrosine]] is the last medical line of treatment</u>. 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 symptom|extrapyramidal]] manifestations and high cost.<ref name="pmid9129550">{{cite journal| author=Steinsapir J, Carr AA, Prisant LM, Bransome ED| title=Metyrosine and pheochromocytoma. | journal=Arch Intern Med | year= 1997 | volume= 157 | issue= 8 | pages= 901-6 | pmid=9129550 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9129550  }}</ref>
+'''[[Beta blockers|Beta-adrenergic blocker]]'''
+* It should never be started first because unopposed [[Alpha-adrenergic agonist|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]].
+==== [[Calcium channel blocker]] ====
+* 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 blocker|alpha]] and [[beta blockers]] regimen or unaccepted side effects in that regimen.<ref name="pmid15819762">{{cite journal| author=Lebuffe G, Dosseh ED, Tek G, Tytgat H, Moreno S, Tavernier B et al.| title=The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. | journal=Anaesthesia | year= 2005 | volume= 60 | issue= 5 | pages= 439-44 | pmid=15819762 | doi=10.1111/j.1365-2044.2005.04156.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15819762  }}</ref>
+==== [[Metyrosine]] ====
+* 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|crystalluria,]] [[Extrapyramidal symptom|extrapyramidal]] manifestations, and high cost.<ref name="pmid9129550">{{cite journal| author=Steinsapir J, Carr AA, Prisant LM, Bransome ED| title=Metyrosine and pheochromocytoma. | journal=Arch Intern Med | year= 1997 | volume= 157 | issue= 8 | pages= 901-6 | pmid=9129550 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9129550  }}</ref>
+==== Dosing[[Pheochromocytoma medical therapy#cite note-pmid248931352-2|[2]]] ====
+The following dosage regimen may be used:
+{| class="wikitable"
+!align="center" style="background:#4479BA; color: #FFFFFF;" + |Drug
+!align="center" style="background:#4479BA; color: #FFFFFF;" + |Initial dose
+!align="center" style="background:#4479BA; color: #FFFFFF;" + |Final dose
+|-
+|[[Phenoxybenzamine]]
+|10 mg b.i.d.
+|1 mg/kg/d
+|-
+|[[Propranolol]]
+|1 20 mg t.i.d.
+|40 mg TID
+|-
+|[[Nifedipine]]
+|30 mg/d
+|60 mg/d
+|}
 == 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.
+* 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.
-* Phentolamine is nonselective alpha-adrenergic blocker. The response to phentolamine is maximal in two to three minutes after starting of initial dose.
+* Preferred regimen (2): IV [[Phentolamine]] ([[Alpha blocker|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.
-* Nicardipine is calcium channel blocker and the last line of treatment after failure of previous two lines.
+* Preferred regimen (3): IV [[Nicardipine]] ([[calcium channel blocker]]) <ref name="pmid12974970">{{cite journal| author=Varon J, Marik PE| title=Clinical review: the management of hypertensive crises. | journal=Crit Care | year= 2003 | volume= 7 | issue= 5 | pages= 374-84 | pmid=12974970 | doi=10.1186/cc2351 | pmc=270718 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12974970  }} </ref>
+== Management of pheochromocytoma during pregnancy ==
+* [[Phenoxybenzamine]] use is safe but [[beta-adrenergic blockers]] use has been associated with [[intrauterine growth retardation]].<ref name="pmid2242456">{{cite journal| author=Butters L, Kennedy S, Rubin PC| title=Atenolol in essential hypertension during pregnancy. | journal=BMJ | year= 1990 | volume= 301 | issue= 6752 | pages= 587-9 | pmid=2242456 | doi= | pmc=1663720 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2242456  }}</ref>
+* Resection of the [[tumor]] can often be performed safely during the [[second trimester]].<ref name="pmid18001193">{{cite journal| author=Junglee N, Harries SE, Davies N, Scott-Coombes D, Scanlon MF, Rees DA| title=Pheochromocytoma in Pregnancy: When is Operative Intervention Indicated? | journal=J Womens Health (Larchmt) | year= 2007 | volume= 16 | issue= 9 | pages= 1362-5 | pmid=18001193 | doi=10.1089/jwh.2007.0382 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18001193  }}</ref>
+* [[Tumor]] resection can be combined with a cesarean section during [[delivery]].
+* Careful monitoring is needed to mother and [[fetus]].
-== Management of familiar pheochromocytoma ==
+== Management of familial pheochromocytoma ==
-* Preoperative evaluation should include testing for associated tumors.
+* Preoperative evaluation should include testing for associated [[Tumor|tumors]].
-* '''Medullary thyroid tumor''' :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.<ref name="pmid25810047">{{cite journal| author=Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF et al.| title=Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. | journal=Thyroid | year= 2015 | volume= 25 | issue= 6 | pages= 567-610 | pmid=25810047 | doi=10.1089/thy.2014.0335 | pmc=4490627 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25810047  }}</ref>
+=== [[Medullary thyroid cancer]]: ===
+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 cancer|medullary thyroid]] related to [[Multiple endocrine neoplasia|MEN]].<ref name="pmid25810047">{{cite journal| author=Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF et al.| title=Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. | journal=Thyroid | year= 2015 | volume= 25 | issue= 6 | pages= 567-610 | pmid=25810047 | doi=10.1089/thy.2014.0335 | pmc=4490627 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25810047  }}</ref> Surgical treatment has low [[morbidity]], even in children. [[Thyroid hormone|Thyroid]] replacement is started directly after surgery.
-* '''Primary hyperparathyroidism'''  is part of MEN2A only:
+=== '''[[Primary hyperparathyroidism]]:''' ===
+* [[Primary hyperparathyroidism]] and pheochromocytoma are features of [[MEN2b|MEN2B]] syndrome.
-* Asymptomatic patients who do not undergo surgery and need follow up only.
+* Asymptomatic patients who do not undergo surgery need follow up only.
-* If patients are  symptomatic, hyperparathyroidism surgery is the only defenetive treatment.<ref name="pmid8957482">{{cite journal| author=Herfarth KK, Bartsch D, Doherty GM, Wells SA, Lairmore TC| title=Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. | journal=Surgery | year= 1996 | volume= 120 | issue= 6 | pages= 966-73; discussion 973-4 | pmid=8957482 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8957482  }}</ref>
+* If patients are symptomatic, [[hyperparathyroidism]] surgery is the only definitive treatment.<ref name="pmid8957482">{{cite journal| author=Herfarth KK, Bartsch D, Doherty GM, Wells SA, Lairmore TC| title=Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. | journal=Surgery | year= 1996 | volume= 120 | issue= 6 | pages= 966-73; discussion 973-4 | pmid=8957482 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8957482  }}</ref>
-* If both pheochromocytoma and hperparathyroidism are found together, pheochromocytoma surgery should be done first.
+* Surgery for pheoochromocytoma should be done first if both pheochromocytoma and [[hyperparathyroidism]] are found together.
-* Preoperative localization is preferred by CT, US and sistamibi scan so resection of the enlarged glands only is the preferred procedure in this situation.
+* 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,carryrisk of hypoparathyroidism.<ref name="pmid258100472">{{cite journal| author=Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF et al.| title=Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. | journal=Thyroid | year= 2015 | volume= 25 | issue= 6 | pages= 567-610 | pmid=25810047 | doi=10.1089/thy.2014.0335 | pmc=4490627 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25810047  }}</ref>
+* Subtotal parathyroidectomy and total parathyroidectomy, carry the risk of [[hypoparathyroidism]].<ref name="pmid258100472">{{cite journal| author=Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF et al.| title=Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. | journal=Thyroid | year= 2015 | volume= 25 | issue= 6 | pages= 567-610 | pmid=25810047 | doi=10.1089/thy.2014.0335 | pmc=4490627 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25810047  }}</ref>
-* Complication and recurrence rate are low<ref name="pmid7913027">{{cite journal| author=Wells SA, Donis-Keller H| title=Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. | journal=Endocrinol Metab Clin North Am | year= 1994 | volume= 23 | issue= 1 | pages= 215-28 | pmid=7913027 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7913027  }}</ref>
+* Complication and recurrence rate is low<ref name="pmid7913027">{{cite journal| author=Wells SA, Donis-Keller H| title=Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. | journal=Endocrinol Metab Clin North Am | year= 1994 | volume= 23 | issue= 1 | pages= 215-28 | pmid=7913027 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7913027  }}</ref>
-* family members should undergo ''RET'' mutation screening.
+* Family members should undergo [[RET gene|RET]] [[mutation]] [[Screening (medicine)|screening]].
-== Management of malignant pheochromocyotma ==
+== Management of malignant pheochromocytoma ==
-* Asymptomatic patients, follow up is better than intervention due to high risk of complications in surgeries.
+* For [[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.
+* For [[symptomatic]] patients, open procedures are recommended due to large [[tumor]] size and high [[vascularity]]. Primary and [[metastatic]] lesions should be resected if possible.
-====== '''Local therapy''' ======
+=== '''Local therapy''' ===
-* Some authors suggest administration of 131-iodine-labeled meta-iodobenzylguanidine (131I-MIBG) after resection <ref name="pmid20664475">{{cite journal| author=Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K et al.| title=The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. | journal=Pancreas | year= 2010 | volume= 39 | issue= 6 | pages= 775-83 | pmid=20664475 | doi=10.1097/MPA.0b013e3181ebb4f0 | pmc=3419007 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20664475  }}</ref>
+* Some authors suggest administration of 131-iodine-labeled meta-iodo-benzylguanidine (131I-MIBG) after resection. <ref name="pmid20664475">{{cite journal| author=Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K et al.| title=The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. | journal=Pancreas | year= 2010 | volume= 39 | issue= 6 | pages= 775-83 | pmid=20664475 | doi=10.1097/MPA.0b013e3181ebb4f0 | pmc=3419007 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20664475  }}</ref>
-* There are many types of local therapy: external beam radiation therapy (EBRT), radio frequency ablation, , cryoablation, or ethanol injection.
+* There are many types of local therapy:
+** [[External beam radiotherapy|External beam radiation therapy]] ([[External beam radiation therapy|EBRT]])
+** [[Radiofrequency ablation|Radio frequency ablation]]
+** [[Cryoablation]]
+** [[Ethanol]] injection
-* <u>External beam radiation therapy (EBRT</u>)  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 .
+* <u>[[External beam radiotherapy|External beam radiation therapy]] (EBRT</u>)  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 procedure (RFA, cryoablation, or ethanol injection) was based upon the lesion target location; head, neck ,thorax or retroperitoneal.
+* Other ablation procedures ([[radiofrequency ablation]], [[cryoablation]], or [[ethanol]] injection) are based on 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.
+* [[Liver]] [[Tumor|tumors]] are treated with either [[Radiofrequency ablation|radioferequency ablation]], [[ethanol]] injection or [[Chemoembolization|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. <ref name="pmid16543673">{{cite journal| author=Watanabe D, Tanabe A, Naruse M, Tsuiki M, Torii N, Noshiro T et al.| title=Transcatheter arterial embolization for the treatment of liver metastases in a patient with malignant pheochromocytoma. | journal=Endocr J | year= 2006 | volume= 53 | issue= 1 | pages= 59-66 | pmid=16543673 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16543673  }}</ref>
+* [[Percutaneous]] [[tumor]] [[ablation]] is limited to patients with one or a few small tumors.<ref name="pmid16543673">{{cite journal| author=Watanabe D, Tanabe A, Naruse M, Tsuiki M, Torii N, Noshiro T et al.| title=Transcatheter arterial embolization for the treatment of liver metastases in a patient with malignant pheochromocytoma. | journal=Endocr J | year= 2006 | volume= 53 | issue= 1 | pages= 59-66 | pmid=16543673 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16543673  }}</ref>
 === '''Systemic therapy''' ===
-==== Chemotherapy ====
+==== [[Chemotherapy]] ====
-* Metastatic pheochromocytoma is treated with Averbuc protocol which is a combination of [[cyclophosphamide]], [[vincristine]], [[dacarbazine]].<ref name="cancergov">National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq#link/_179_toc</ref> and [[doxorubicin]].
+* [[Metastasis|Metastatic]] pheochromocytoma is treated with Averbuc protocol, which is a combination of [[cyclophosphamide]], [[vincristine]], [[dacarbazine]] and [[doxorubicin]].<ref name="cancergov">National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq#link/_179_toc</ref>
-* For patients with rapidly progressive tumors or bone-predominant extensive disease, chemotherapy is a preferred option even if 123I-MIBG scintigraphy is positive [4].
+* For patients with rapidly progressive [[tumors]] or [[bone]]-predominant extensive disease, [[chemotherapy]] is a preferred option even if 123I-[[Scintigraphy|MIBG scintigraphy]] is positive.
-* Chemotherapy should be considered for patients with unresectable and rapidly growing  pheochromocytoma and large number of metastases.
+* [[Chemotherapy]] should be considered for patients with unresectable and rapidly growing pheochromocytoma and a large number of [[metastases]].
-* [9,86-88].
+* The median duration of response is 20 months with median survival of 3.3 years.<ref name="pmid18780317">{{cite journal| author=Huang H, Abraham J, Hung E, Averbuch S, Merino M, Steinberg SM et al.| title=Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. | journal=Cancer | year= 2008 | volume= 113 | issue= 8 | pages= 2020-8 | pmid=18780317 | doi=10.1002/cncr.23812 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18780317  }}</ref>
-* The median duration of response was 20 months with median survival  3.3 years.<ref name="pmid18780317">{{cite journal| author=Huang H, Abraham J, Hung E, Averbuch S, Merino M, Steinberg SM et al.| title=Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. | journal=Cancer | year= 2008 | volume= 113 | issue= 8 | pages= 2020-8 | pmid=18780317 | doi=10.1002/cncr.23812 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18780317  }}</ref>
+* Most common side effects are [[gastrointestinal]] upset, [[peripheral neuropathy]] and [[bone marrow suppression]].<ref name="pmid3395037">{{cite journal| author=Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R et al.| title=Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. | journal=Ann Intern Med | year= 1988 | volume= 109 | issue= 4 | pages= 267-73 | pmid=3395037 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3395037  }}</ref>
-* Most common side effects are GIT upset, peripheral neuropathy and BM supression.<ref name="pmid3395037">{{cite journal| author=Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R et al.| title=Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. | journal=Ann Intern Med | year= 1988 | volume= 109 | issue= 4 | pages= 267-73 | pmid=3395037 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3395037  }}</ref>
-* '''Molecularly therapy''': sunitinib and pazopanib are tyrosine kinase receptors inhibitor, vascular endothelial growth factor receptors (VEGFRs)
+==== '''[[Molecule|Molecular Therapy]]''' ====
+* [[Sunitinib]] is a [[tyrosine kinase]] receptor inhibitor and [[VEGF receptors|vascular endothelial growth factor receptors inhibitor]].
+* [[Pazopanib]] is [[Tyrosine kinase inhibitors|tyrosine kinase receptors inhibitor]].
-==== Radiation ====
+==== [[Radiation therapy]] ====
-* <sup>131</sup>I-MIBG radiation therapy has been used for the treatment of MIBG-avid metastases;<ref name="cancergov" /> patients with good uptake of 123I-MIBG Unresectable progressive pheochromocytoma and low number of metastases. Therapy can be repeated for recuurent cases. <ref name="pmid11453952">{{cite journal| author=Mukherjee JJ, Kaltsas GA, Islam N, Plowman PN, Foley R, Hikmat J et al.| title=Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG]. | journal=Clin Endocrinol (Oxf) | year= 2001 | volume= 55 | issue= 1 | pages= 47-60 | pmid=11453952 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11453952  }}</ref>
+* <sup>131</sup>I-MIBG [[radiation therapy]] may be used for the treatment of MIBG-avid [[metastases]].<ref name="cancergov" />
-* High doses show serious side effects include: leukopenia, thrombocytopenia due to bone marrow depression <ref name="pmid22221516">{{cite journal| author=Gulenchyn KY, Yao X, Asa SL, Singh S, Law C| title=Radionuclide therapy in neuroendocrine tumours: a systematic review. | journal=Clin Oncol (R Coll Radiol) | year= 2012 | volume= 24 | issue= 4 | pages= 294-308 | pmid=22221516 | doi=10.1016/j.clon.2011.12.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22221516  }}</ref> and hypothyroidism and  acute leukemia <ref name="pmid23860527">{{cite journal| author=Sze WC, Grossman AB, Goddard I, Amendra D, Shieh SC, Plowman PN et al.| title=Sequelae and survivorship in patients treated with (131)I-MIBG therapy. | journal=Br J Cancer | year= 2013 | volume= 109 | issue= 3 | pages= 565-72 | pmid=23860527 | doi=10.1038/bjc.2013.365 | pmc=3738119 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23860527  }}</ref>
+* Patients with a good uptake of <sup>131</sup>I-MIBG in cases of unresectable progressive pheochromocytoma lead to a lower number of [[metastases]]. Therapy can be repeated for recurrent cases.<ref name="pmid11453952">{{cite journal| author=Mukherjee JJ, Kaltsas GA, Islam N, Plowman PN, Foley R, Hikmat J et al.| title=Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG]. | journal=Clin Endocrinol (Oxf) | year= 2001 | volume= 55 | issue= 1 | pages= 47-60 | pmid=11453952 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11453952  }}</ref>
-* Pheochromocytomas  express somatostatin receptors patients with metastatic or recurrent pheochromocytoma may benefit from
+* High doses show serious side effects including, [[leukopenia]], [[thrombocytopenia]] due to [[Bone marrow suppression|bone marrow depression]], [[hypothyroidism]] and [[acute leukemia]].<ref name="pmid23860527">{{cite journal| author=Sze WC, Grossman AB, Goddard I, Amendra D, Shieh SC, Plowman PN et al.| title=Sequelae and survivorship in patients treated with (131)I-MIBG therapy. | journal=Br J Cancer | year= 2013 | volume= 109 | issue= 3 | pages= 565-72 | pmid=23860527 | doi=10.1038/bjc.2013.365 | pmc=3738119 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23860527  }}</ref><ref name="pmid22221516">{{cite journal| author=Gulenchyn KY, Yao X, Asa SL, Singh S, Law C| title=Radionuclide therapy in neuroendocrine tumours: a systematic review. | journal=Clin Oncol (R Coll Radiol) | year= 2012 | volume= 24 | issue= 4 | pages= 294-308 | pmid=22221516 | doi=10.1016/j.clon.2011.12.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22221516  }}</ref>
-* radiolabeled somatostatin analogs. <ref name="pmid19140390">{{cite journal| author=Hubalewska-Dydejczyk A, Trofimiuk M, Sowa-Staszczak A, Gilis-Januszewska A, Wierzchowski W, Pach D et al.| title=[Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas]. | journal=Przegl Lek | year= 2008 | volume= 65 | issue= 9 | pages= 405-7 | pmid=19140390 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19140390  }}</ref>Long-term potential side effects of therapy with radiolabeled somatostatin analogs may include loss of renal function, pancytopenia, and myelodysplastic syndrome.<ref name="pmid22221516" />
+* Pheochromocytomas express [[somatostatin receptors]]. Patients with [[metastatic]] or recurrent pheochromocytoma may benefit from [[Radiolabel|radiolabeled]] [[somatostatin]] analogs.<ref name="pmid19140390">{{cite journal| author=Hubalewska-Dydejczyk A, Trofimiuk M, Sowa-Staszczak A, Gilis-Januszewska A, Wierzchowski W, Pach D et al.| title=[Somatostatin receptors expression (SSTR1-SSTR5) in pheochromocytomas]. | journal=Przegl Lek | year= 2008 | volume= 65 | issue= 9 | pages= 405-7 | pmid=19140390 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19140390  }}</ref>Long-term potential side effects of therapy with [[Radiolabel|radiolabeled]] [[somatostatin]] analogs may include loss of [[renal]] function, [[pancytopenia]], and [[myelodysplastic syndrome]].<ref name="pmid22221516" />
 ===Contraindicated medications===