Pheochromocytoma medical therapy: Difference between revisions

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__NOTOC__
__NOTOC__
{{Pheochromocytoma}}
{{Pheochromocytoma}}
{{CMG}}; {{AE}} {{AAM}}
{{CMG}}; {{AE}} {{AAM}} {{MAD}}


==Overview==
==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==
==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 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<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>:
=== 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:<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>[[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. It''' should be used with caution due to risk of heart failure, pulmonary edema and asthma.  
==== [[alpha blocker|'''Aalpha adrenoceptor blocker''']] ====
* 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.
'''[[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]].


<u>Second line of treatment is [[calcium channel blocker]]</u> which is used to control blood pressure preoperatively and intravenous injection intraoperatively.
==== [[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>


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]] ====
* 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>


<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.
==== 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 ==
== 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 malignant pheochromocyotma ==
== 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]].


THERAPEUTIC OPTIONS — Initial observation coupled with frequent follow-up could be considered an option for asymptomatic patients, given the indolent course in some subgroups of patients. For many patients with indolent tumors, treatment-related side effects may exceed the potential benefit of therapy. (See 'Prognosis' above.)
== Management of familial pheochromocytoma ==
* Preoperative evaluation should include testing for associated [[Tumor|tumors]].  


However, for symptomatic patients or those with progressive metastatic disease, there are several therapeutic strategies for control of tumor burden. A multidisciplinary approach to management is optimal [29].
=== [[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.


Local therapy
=== '''[[Primary hyperparathyroidism]]:''' ===
* [[Primary hyperparathyroidism]] and pheochromocytoma are features of [[MEN2b|MEN2B]] syndrome.


Resection — There are no curative treatments for malignant pheochromocytoma/paraganglioma. However, both the primary and metastatic lesions should be resected, if possible [30]. Resection may improve symptoms, reduce hormone secretion, prevent complications related to a critical anatomic location, and improve the efficacy of subsequent therapies [18,31,32]. Resection may also possibly improve survival, although there are no clinical trial data to support this [33]. Although the five-year survival rate is less than 50 percent, many of these patients have prolonged survival and minimal morbidity [3,5].
* Asymptomatic patients who do not undergo surgery need follow up only.


Surgical intervention should only be performed in centers with experience in handling patients with malignant pheochromocytoma/paraganglioma. Preoperative control of the effects of excessive adrenergic stimulation, and preoperative, as well as intraoperative, volume expansion are necessary. General surgical principles, including medical preparation for surgery and intraoperative hemodynamic management, are addressed elsewhere. (See "Paragangliomas: Treatment of locoregional disease", section on 'General surgical principles'.)
* 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>
* Surgery for pheoochromocytoma should be done first if both pheochromocytoma and [[hyperparathyroidism]] are found together.


Although a laparoscopic approach to resection is generally preferred for benign pheochromocytomas/paragangliomas, malignant tumors are often large or located in areas that are difficult to remove laparoscopically. In cases of proven or suspected malignancy, open procedures are recommended [34]. If a primary tumor is being resected, the capsule should not be entered surgically, if possible, as this predisposes to recurrence [35].
* 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]].<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 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 gene|RET]] [[mutation]] [[Screening (medicine)|screening]].


Some authors suggest administration of 131-iodine-labeled meta-iodobenzylguanidine (131I-MIBG) after resection of a catecholamine-secreting pheochromocytoma/paraganglioma that takes up MIBG as determined by 123I-MIBG scanning [36]. However, there are no data demonstrating a survival or relapse-free survival benefit for "adjuvant" 131I-MIBG treatment after resection of metastatic disease. We suggest not pursuing this approach, which is in keeping with treatment guidelines for pheochromocytoma/paraganglioma from the National Comprehensive Cancer Network and others [4,18].
== Management of malignant pheochromocytoma ==
* For [[asymptomatic]] patients, follow up is better than intervention due to high risk of complications in surgeries.


Radiation therapy — It was previously thought that malignant pheochromocytomas/paragangliomas were relatively radioresistant [37]. However, external beam radiation therapy (EBRT) at doses >40 Gy can provide local tumor control and relief of symptoms for tumors at a variety of sites, including the soft tissues of the skull base and neck, abdomen, and thorax, as well as painful bone metastases. In a series of 17 patients with malignant paraganglioma who received EBRT, 76 percent had local control or clinically significant symptomatic relief for at least one year or until death [38]. Of the five patients with widespread systemic metastases and areas of bulky symptomatic tumor who received sequential 131I-MIBG and EBRT, all irradiated areas showed a durable objective response; all patients eventually experienced out of field systemic progression requiring other treatment.
* For [[symptomatic]] patients, open procedures are recommended due to large [[tumor]] size and high [[vascularity]]. Primary and [[metastatic]] lesions should be resected if possible.  


The use of EBRT for primary treatment of skull base and neck paragangliomas, and the utility of stereotactic radiosurgery for primary treatment of jugulotympanic skull base and neck paragangliomas is discussed in detail elsewhere. (See "Paragangliomas: Treatment of locoregional disease", section on 'Primary radiation therapy' and "Paragangliomas: Treatment of locoregional disease", section on 'Radiation therapy'.)
=== '''Local therapy''' ===
* 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 radiotherapy|External beam radiation therapy]] ([[External beam radiation therapy|EBRT]])
** [[Radiofrequency ablation|Radio frequency ablation]]
** [[Cryoablation]]
** [[Ethanol]] injection


Patients need to be monitored during RT, because RT-induced inflammation of the lesion can induce massive catecholamine secretion and a hypertensive crisis [39].
* <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 procedures ([[radiofrequency ablation]], [[cryoablation]], or [[ethanol]] injection) are based on the lesion target location; [[head]], [[neck]], [[thorax]] or [[retroperitoneal]].
* [[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>


Nonsurgical ablative therapy — Several nonsurgical, local ablative therapies are available for patients with metastases, including radiofrequency ablation (RFA), cryoablation, and percutaneous ethanol injection. Percutaneous ablation for metastatic lesions at a variety of sites, including soft tissue, bone, and liver, may be safely performed if there is careful attention to periprocedural management [40-46]. As with other forms of local therapy including surgery and RT, any form of local ablation can induce massive catecholamine secretion and a hypertensive crisis; preprocedure medical preparation is needed. (See "Paragangliomas: Treatment of locoregional disease", section on 'Medical preparation for surgery'.)
=== '''Systemic therapy''' ===


The safety and efficacy of percutaneous ablation was addressed in a series of 10 patients with metastatic pheochromocytoma/paraganglioma, all of whom were pretreated with alpha- and beta-adrenergic blockade as well as tyrosine hydroxylase inhibition with metyrosine [40]. The ablation procedure chosen (RFA, cryoablation, or ethanol injection) was based upon the lesion target location; bone, chest wall, and retroperitoneal lesions were treated with either RFA or cryoablation, while liver tumors were treated with either RFA or ethanol injection. For the lesions with follow-up imaging, successful ablation without evidence of recurrence was achieved in 15 of 27 primarily treated lesions (56 percent). Among the seven patients who had dedicated imaging performed after ablation (representing 31 treated tumors), the time to disease progression was relatively short (7.2 ± 4 months). However, amelioration of breakthrough hypertensive symptoms or metastasis-related pain was achieved in two of two and four of four patients, respectively.
==== [[Chemotherapy]] ====
* [[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-[[Scintigraphy|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.<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>


Results are best if percutaneous tumor ablation is limited to patients with one or a few relatively small (ideally, <3 to 4 cm) tumors.
==== '''[[Molecule|Molecular Therapy]]''' ====
* [[Sunitinib]] is a [[tyrosine kinase]] receptor inhibitor and [[VEGF receptors|vascular endothelial growth factor receptors inhibitor]].


Transarterial chemoembolization for liver metastases — For patients with multiple liver metastases that are not amenable to resection or nonsurgical methods of ablation, isolated case reports suggest benefit (decreased tumor bulk and improved symptom control) from transarterial chemoembolization (TACE) [47-51]. As with other forms of local therapy, TACE can induce massive catecholamine secretion and a hypertensive crisis; preprocedure medical preparation is needed. (See "Paragangliomas: Treatment of locoregional disease", section on 'Medical preparation for surgery'.)
* [[Pazopanib]] is [[Tyrosine kinase inhibitors|tyrosine kinase receptors inhibitor]].


Systemic therapy
==== [[Radiation therapy]] ====
 
* <sup>131</sup>I-MIBG [[radiation therapy]] may be used for the treatment of MIBG-avid [[metastases]].<ref name="cancergov" />
Radionuclide therapy — Systemic radionuclide treatment employs beta-emitting isotopes that are coupled to either MIBG or somatostatin analogs.
* 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>
 
* 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>
MIBG — The diagnostic and therapeutic value of MIBG is based upon its structural similarity with noradrenaline and a high affinity to, and uptake in, chromaffin cells. Radioactive iodine (I131) is attached to the MIBG molecule to produce 131I-MIBG, which functions as a semi-selective agent for malignant pheochromocytoma/paraganglioma. This treatment only works for the approximately 60 percent of tumors that take up MIBG as determined by 123I-MIBG scintigraphy [52,53]. A lower fraction of dopamine-secreting paragangliomas take up 123I-MIBG [54-56]. External beam RT abolishes the ability of these tumors to take up MIBG, making 131I-MIBG treatment ineffective in any irradiated site [8].
* 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" />
 
For patients with metastatic disease whose tumors secrete catecholamines and take up MIBG, the therapeutic value of 131I-MIBG to achieve symptom palliation and tumor regression or stabilization has been shown in many small case series [8,19,36,57-64]. Objective response rates are approximately 30 percent, and another 40 percent of tumors remain stable; less than 5 percent have a complete remission. Hormonal response (ie, decrease in catecholamine secretion) is reported in 45 to 67 percent of cases [19,60,61]. In general, better objective responses are achieved in patients with limited disease and in those with soft tissue rather than bone metastases [19].
 
131I-MIBG treatment can be repeated, usually at six-month intervals [36]. The optimal dosimetry is not established. Most of the published reports have used single therapy doses between 100 to 200 mCi, with cumulative doses ranging from 557 to 2322 mCi and averaging 400 and 600 mCi [8,19,36,57,58,60-62]. At these doses, treatment is generally well tolerated with the main side effects being transient mild leukopenia and thrombocytopenia. Hypothyroidism was reported in 3 of 28 patients receiving cumulative doses of 111-916 mCi in one series [61], and in 2 of 10 patients in a second report (average cumulative dose 310 mCi) [63].
 
There is some evidence that higher-dose regimens (single doses 500 to 800 mCi) can result in sustained complete response in a small number of patients, albeit with a higher risk of potentially serious side effects [59,65]:
 
●In one report, 12 patients with malignant pheochromocytoma received a single 131I-MIBG treatment with 12 to 18 mCi/kg;repeat treatments (median interval between treatments 4.4 months, range 3 to 7 months) were administered on a case-by-case basis to improve the overall response [59]. At a median follow-up of 45 months, two died without a response, three remained in a complete remission (two of whom had both soft tissue and skeletal metastases), and seven had a documented partial remission. However, 79 percent had grade 3 thrombocytopenia, 72 percent had grade 3 or 4 neutropenia, and one patient required autologous stem cell rescue for hematologic recovery. All patients received treatment with potassium iodide to prevent 131I uptake by the thyroid, and there were no cases of hypothyroidism.
 
●In a subsequent phase II study, 50 patients with metastatic pheochromocytoma/paraganglioma received single 131I-MIBG doses ranging from 492 to 1160 mCi (6 to 19 mCi/kg, median 12 mCi/kg); cumulative doses ranged from 492 to 3191 mCi [65]. Patients had to have successful peripheral blood stem cell harvest to receive >12 mCi/kg. Overall, a complete response was achieved in 10 percent, a partial response in 20 percent, and 39 percent had stable disease/minor response (69 percent disease control rate). The five-year overall survival rate was 64 percent. 
 
Toxicities included grade 3 to 4 neutropenia in 87 percent and grade 3 or 4 thrombocytopenia in 87 percent; four patients experienced prolonged myelosuppression that required autologous hematopoietic cell rescue. Other serious toxicity included grade 4 acute respiratory distress syndrome and cryptogenic organizing pneumonia in two patients each, and myelodysplastic syndrome and concurrent acute leukemia in two patients who received multiple infusions of 131I-MIBG. Hypothyroidism was not reported, although large doses of potassium iodide were administered to prevent uptake of 131I by the thyroid, and three became hyperthyroid.
 
Treatment with 131I-MIBG should be considered in patients with good uptake of 123I-MIBG by dosimetry who fall into one of the following categories:
 
●Unresectable progressive pheochromocytoma/paraganglioma
 
●Symptoms from disease that is not amenable to locoregional methods of control
 
●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].
 
Given the fact that most studies use different doses of 131I-MIBG and schedules, and include only a few patients, specific recommendations as to the best dose and treatment schedule cannot be made [4]. Multicenter studies are required to reach a consensus on the efficacy of high-dose versus fractionated medium doses of 131I-MIBG [18]. Some institutions with extensive experience with this compound use high-dose 131I-MIBG for selected patients with aggressive disease who are able to tolerate it. Thyroidal uptake of free iodide is prevented by giving an oral saturated solution of potassium iodide at 24 hours prior to planned administration and daily for 10 days post-therapy. At other institutions, medium-dose 131I-MIBG is used for patients with relatively indolent disease, with chemotherapy preferred over high-dose 131I-MIBG for those with more aggressive disease.
 
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].
 
The most commonly used radionuclides are Yttrium-90-labeled DOTA0-Tyr3-octreotide (90Y-edotreotide, 90Y-DOTA-TOC) and lutetium-177-DOTA0-Tyr3-octreotate (177Lu-DOTATATE). The efficacy of 90Y-DOTA-TOC and 177Lu-DOTATATE for malignant paraganglioma/pheochromocytoma has been described in isolated case reports and small series [75-78]. In the largest report, 28 patients with progressive, surgically-incurable pheochromocytoma/paraganglioma received 90Y-DOTA-TOC alone or sequentially with 177Lu-DOTATATE [78]. The best response was two partial remissions, five minor responses, and 13 cases of stable disease (disease control rate 71 percent). At a mean followup of 19 months, 10 of the 20 patients with an objective response or stable disease still had not progressed, and there were only two cases of mild hematologic toxicity and no renal insufficiency.
 
At least in the United States, the use of radiolabeled somatostatin analogs for the treatment of advanced neuroendocrine tumors, including malignant pheochromocytoma/paraganglioma, remains investigational.
 
Octreotide — The therapeutic effect of treating metastatic pheochromocytoma/paraganglioma with the somatostatin analog octreotide has been analyzed in a few studies with small patient numbers, and the results are mixed:
 
●Case reports suggest benefit for octreotide in producing objective responses in a small number of patients with advanced malignant paraganglioma [79,80] and for short-term reduction of catecholamine secretion in a patient with pheochromocytoma [81].
 
●On the other hand, others have failed to show benefit for short-term octreotide administration either for control of catecholamine secretion or for preoperative reduction in tumor size [82-85]. None of these studies reported rates of tumor stability; at least in the setting of metastatic gastroenteropancreatic neuroendocrine tumors, the main benefit of somatostatin analogs is in disease stabilization rather than objective tumor regression. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Benefits' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Somatostatin analogs'.)
 
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.
 
Most literature reports evaluating cytotoxic chemotherapy for progressive metastatic paraganglioma predominantly involve patients with retroperitoneal sympathetic catecholamine-secreting tumors. The most extensive data are from studies using various combinations of cyclophosphamide, dacarbazine, vincristine, and doxorubicin [9,86-88]. The following illustrates the range of findings:
 
●An early trial of CVD (cyclophosphamide [750 mg/m2 on day 1], vincristine [1.4 mg/m2 on day 1], and dacarbazine [600 mg/m2 on days 1 and 2] of each 21- to 28-day cycle) reported high response rates and symptomatic improvement with this regimen in 14 patients [89]. Details of the regimen and long-term outcomes (median follow-up 22 years) in this cohort, as well as four others who met the original eligibility criteria for the trial, were described in a later report [87]. Overall, 10 of 18 patients (56 percent) had a complete or partial objective response to therapy, and three others had a "minor response" [87]. Biochemical responses were seen in 13 (72 percent). Patients whose tumors were scored as complete or partial response received a mean of 27.4 cycles of CVD (median of 23 cycles). The median duration of response was 20 months (range 7 to 126 months), and the 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].
 
●The largest single-institution retrospective series of chemotherapy included 52 patients with progressive metastatic pheochromocytoma or sympathetic extra-adrenal paraganglioma who received a variety of chemotherapy regimens, including cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CyVADIC, n = 19); cyclophosphamide, doxorubicin, and dacarbazine (CyADIC, n = 12); cyclophosphamide, vincristine, and dacarbazine (CyVDic, n = 10); or a variety of other regimens (n = 11) [9]. Of the 52 evaluable patients, 17 (33 percent) responded to frontline chemotherapy, including 13 with an objective tumor response (25 percent), and four with normalization of blood pressure. In two patients with initially unresectable tumors, the response to chemotherapy was sufficient to permit subsequent surgical excision. Responders, all of whom received a chemotherapy regimen that contained dacarbazine and cyclophosphamide, survived longer than nonresponders (median 6.4 versus 3.7 years). However, nonresponders also had significantly larger tumors (10 versus 5 cm) and a higher percentage of extra-adrenal primaries, two factors that are associated with decreased overall survival in pheochromocytoma/paraganglioma [14]. The overall survival rate of the entire cohort at five years was 51 percent.
 
●Single case reports and small series suggest that these tumors may also respond to temozolomide alone [90], particularly among those with ''SDHB'' mutations, which are associated with hypermethylation of the promoter for O6-methylguanine-DNA methyltransferase [MGMT] [91]; temozolomide plus thalidomide [92] or capecitabine [93]; single agent gemcitabine [94]; gemcitabine plus docetaxel [95] or paclitaxel [96]; doxorubicin plus streptozocin [97]; or paclitaxel alone [98]. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Familial paraganglioma and SDH gene mutations'.)
 
Molecularly targeted therapy — Sunitinib is a potent inhibitor of multiple tyrosine kinase receptors, including vascular endothelial growth factor receptors (VEGFRs) 1 and 2, platelet-derived growth factor receptor (PDGFR) beta, KIT, FLT3, and RET. Early reports suggest utility for sunitinib in patients with malignant pheochromocytoma/paraganglioma [99-103]:
 
●In one report of three patients with metastatic paraganglioma treated with sunitinib (50 mg daily four weeks on, two weeks off), one patient achieved a near complete response, and two others had partial responses; two patients continued to benefit from the drug beyond 40 weeks [99].
 
●The largest retrospective series included 17 patients with progressive metastatic pheochromocytoma/sympatheticparaganglioma who were treated with sunitinib monotherapy [103]. Four patients had metastatic disease that was limited to the skeleton, and response assessment in this group consisted of (18)F-fluorodeoxyglucose PET (FDG-PET)/computedtomography (CT) only. Of 14 evaluable patients, three had a partial response (21 percent) and five had stable disease (36 percent). Median progression-free survival was 4.1 months. Of the 14 patients with hypertension secondary to excessive catecholamine secretion, six eventually improved and this correlated with a reduction in the dose and/or number of antihypertensive medications; however, blood pressure initially worsened in the three months after starting sunitinib in five. Besides hypertension, the most common side effects were diarrhea, hand-foot syndrome, sore mouth, and fatigue. The median overall survival of the entire group was 27 months.
 
Further information on the benefits of sunitinib should be forthcoming from an open label trial of sunitinib in patients with advanced malignant pheochromocytoma/paraganglioma (SNIPP trial) being coordinated by the University of Toronto in three Canadian centers and one in the Netherlands (NCT00843037), and a European randomized, placebo-controlled phase II trial of sunitinib in this same population (FIRST-MAPPP trial). Given the rarity of these conditions, eligible patients should be encouraged to enroll.
 
Although hypertension is one of the most common side effects of sunitinib, the drug can be safely used in patients with pheochromocytoma and secretory paragangliomas as long as strict follow-up and aggressive antihypertensive dosage adjustments are performed. Sunitinib should be initiated only after normal or near normal blood pressure is achieved with combined alpha- and beta-adrenergic blockade. After treatment initiation, additional antihypertensive drugs or dose increase are usually required.
 
Pazopanib, another inhibitor of VEGRs 1, 2, and 3, as well as KIT and PDGFR, is also under study for patients with malignant pheochromocytoma/paraganglioma (NCT01340794).
 
Studies are also ongoing examining the benefit of another molecularly targeted therapy, everolimus, which inhibits the mTOR (mammalian target of rapamycin) pathway. In an early study, five of seven patients with pheochromocytoma/paragangliomaexhibited disease stabilization, although there were no objective responses [104]
 
== Chemotherapy ==
Metastatic pheochromocytoma is treated with Averbuc protocol which is a combination of [[cyclophosphamide]], [[vincristine]], and [[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>
 
== Radiation ==
<sup>131</sup>I-MIBG radiation therapy has been used for the treatment of MIBG-avid metastases.<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>


===Contraindicated medications===
===Contraindicated medications===

Latest revision as of 00:29, 29 July 2020

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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] 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

Aalpha adrenoceptor blocker

Beta-adrenergic blocker

Calcium channel blocker

Metyrosine

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

Management of pheochromocytoma during pregnancy

Management of familial pheochromocytoma

  • Preoperative evaluation should include testing for associated tumors.

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 related to MEN.[8] Surgical treatment has low morbidity, even in children. Thyroid replacement is started directly after surgery.

Primary hyperparathyroidism:

  • 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.

Management of malignant pheochromocytoma

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

Local therapy

Systemic therapy

Chemotherapy

Molecular Therapy

Radiation therapy

Contraindicated medications

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

References

  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.
  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.
  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.
  4. ↑ Steinsapir J, Carr AA, Prisant LM, Bransome ED (1997). "Metyrosine and pheochromocytoma". Arch Intern Med. 157 (8): 901–6. PMID 9129550.
  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.
  6. ↑ Butters L, Kennedy S, Rubin PC (1990). "Atenolol in essential hypertension during pregnancy". BMJ. 301 (6752): 587–9. PMC 1663720. PMID 2242456.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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
  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.
  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.
  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.
  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.
  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.
  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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