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The mainstay of therapy for pheochromocytoma is surgery but patients need preoperative medical treatment to control hypertension and imnrpove morbidity.
The mainstay of therapy for pheochromocytoma is surgery but patients need preoperative medical treatment to control hypertension and imnrpove morbidity.


'''Preoperative medical therapy:'''
=== '''Preoperative medical therapy:''' ===
* 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:<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>


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:<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>
==== [[alpha blocker|'''Aalpha adrenoceptor blocker''']] ====
* [[alpha blocker|Aalpha adrenoceptor blocker]] ([[phenoxybenzamine]]) are used to counteract [[hypertension]] and the beta-1 adrenoceptor antagonist [[atenolol]] to reduce [[cardiac output]]. They can block sudden release of adrenaline during surgery and prevent hypertensive crisis. Patient is ready for surgery in 10 to 14 days after initiation of alpha-adrenergic blockade. Patients should take high sodium diet to antagonize orthostatic hypotension of alpha blockers.After adequate alpha-adrenergic blockade has been achieved, beta-adrenergic blockade is initiated 3 days before surgery. '''[[Beta blockers|Beta-adrenergic blocker]] should never be started first because unopposed [[Alpha-adrenergic agonist|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.  
* It is 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.


* Second line of treatment is [[calcium channel blocker]] which is used to control blood pressure preoperatively and intravenous injection intraoperatively.
* '''[[Beta blockers|Beta-adrenergic blocker]] should never be started first because unopposed [[Alpha-adrenergic agonist|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.
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>
 
* [[Metyrosine]] is the last medical line of treatment. It  inhibits catecholamine synthesis. It is used in case of failure of other medical lines of treatment or in patients who cannot tolerate them. Additionally, clinicans use combined treatment in difficult cases and if [[radiofrequency ablation]] for metastatic foci will be used. Metyrosine side effects include: [[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>
==== [[calcium channel blocker]] ====
* It is used to control blood pressure preoperatively and intravenous injection intraoperatively.
* Its main use is controlling blood pressure in case of failed alpha and beta blockers regimen or unaccepted side effects in the that regimen.<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.  
* Clinicans use combined treatment in difficult cases and if [[radiofrequency ablation]] for metastatic foci will be used. Metyrosine side effects include: [[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>


== Management of hypertensive crisis ==
== Management of hypertensive crisis ==
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* Preoperative evaluation should include testing for associated tumors.  
* Preoperative evaluation should include testing for associated 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 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>


* '''[[Primary hyperparathyroidism]]'''  is part of MEN2A only:
* '''[[Primary hyperparathyroidism]]'''  is part of MEN2A only:
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* 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.  
* 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.  


====== '''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-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>
* 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 radiation therapy (EBRT), radio frequency ablation, , cryoablation, or ethanol injection.
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=== '''Systemic therapy''' ===
=== '''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]].
* 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]].
* For patients with rapidly progressive tumors or bone-predominant extensive disease, chemotherapy is a preferred option even if 123I-[[Scintigraphy|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 [4].
* 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 large number of metastases.
* [9,86-88].
* 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>
* 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 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>
* 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)


==== Radiation ====
==== '''[[Molecule|Molecularl 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>
[[sunitinib]] is [[tyrosine kinase]] receptors inhibitor and [[vascular endothelial growth factor receptors]] (VEGFRs).
 
[[pazopanib]] is [[tyrosine kinase]] receptors inhibitor.
 
==== [[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>
* High doses show serious side effects include: leukopenia, thrombocytopenia due to [[Bone marrow suppression|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>
* High doses show serious side effects include: leukopenia, thrombocytopenia due to [[Bone marrow suppression|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>
* Pheochromocytomas  express somatostatin receptors patients with metastatic or recurrent pheochromocytoma may benefit from
* Pheochromocytomas  express somatostatin receptors patients with metastatic or recurrent pheochromocytoma may benefit from

Revision as of 15:57, 10 July 2017

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

Overview

Treatment with alpha blockers (example: phenoxybenzamine) followed by beta blockers (example: atenolol) is required before surgery. Adjunctive chemotherapy and radiation are used in metastatic disease.

Medical Therapy

The mainstay of therapy for pheochromocytoma is surgery but patients need preoperative medical treatment to control hypertension and imnrpove morbidity.

Preoperative medical therapy:

  • 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[1] according to Endocrine Society’s 2014 Clinical Practice Guidelines:[2]

Aalpha adrenoceptor blocker

  • It is 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.[3]It should be used with caution due to risk of heart failure, pulmonary edema and asthma.

calcium channel blocker

  • It is used to control blood pressure preoperatively and intravenous injection intraoperatively.
  • Its main use is controlling blood pressure in case of failed alpha and beta blockers regimen or unaccepted side effects in the that regimen.[4]

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.
  • Clinicans 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.[5]

Management of hypertensive crisis

  • Sodium nitroprusside is the first line of treatment because of its rapid onset of action and short duration of effect. The rate of a prolonged infusion should be no more than 3 mcg/kg per minute to avoid cyanide toxicity.
  • Phentolamine is nonselective alpha-adrenergic blocker. The response to phentolamine is maximal in two to three minutes after starting of initial dose.
  • Nicardipine is calcium channel blocker and the last line of treatment after failure of previous two lines.

Management of familiar 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.[6]
  • Asymptomatic patients who do not undergo surgery and need follow up only.
  • If patients are symptomatic, hyperparathyroidism surgery is the only defenetive treatment.[7]
  • If both pheochromocytoma and hperparathyroidism are found together, pheochromocytoma surgery should be done first.
  • Preoperative localization is preferred by CT, US and sistamibi scan so resection of the enlarged glands only is the preferred procedure in this situation.
  • Subtotal parathyroidectomy and total parathyroidectomy,carryrisk of hypoparathyroidism.[8]
  • Complication and recurrence rate are low[9]
  • family members should undergo RET mutation screening.

Management of malignant pheochromocyotma

  • Asymptomatic patients, follow up is better than intervention due to high risk of complications in surgeries.
  • Symptomatic patients Open procedures are recommended [34] [35] due to large tumor size and high vascularity. Primary and metastatic lesions should be resected if possible.

Local therapy

  • Some authors suggest administration of 131-iodine-labeled meta-iodobenzylguanidine (131I-MIBG) after resection [10]
  • There are many types of local therapy: external beam radiation therapy (EBRT), radio frequency ablation, , cryoablation, or ethanol injection.
  • External beam radiation therapy (EBRT) can relieve symptoms and decrease pain in non resectable cases. It can induce massive catecholamine secretion and a hypertensive crisis [39]. All of them need preoperative medical management to decrease chances of hypertensive crisis .
  • Other ablation procedure (RFA, cryoablation, or ethanol injection) was based upon the lesion target location; head, neck ,thorax or retroperitoneal.
  • Liver tumors were treated with either RFA or ethanol injection or transarterial chemoembolization for liver For patients with multiple liver metastases is available option for patients not fit for surgeries.
  • Percutaneous tumor ablation is limited to patients with one or a few small tumors. [11]

Systemic therapy

Chemotherapy

  • Metastatic pheochromocytoma is treated with Averbuc protocol which is a combination of cyclophosphamide, vincristine, dacarbazine.[12] and doxorubicin.
  • For patients with rapidly progressive tumors or bone-predominant extensive disease, chemotherapy is a preferred option even if 123I-MIBG scintigraphy is positive [4].
  • Chemotherapy should be considered for patients with unresectable and rapidly growing pheochromocytoma and large number of metastases.
  • The median duration of response was 20 months with median survival 3.3 years.[13]
  • Most common side effects are GIT upset, peripheral neuropathy and BM supression.[14]

Molecularl therapy

sunitinib is tyrosine kinase receptors inhibitor and vascular endothelial growth factor receptors (VEGFRs).

pazopanib is tyrosine kinase receptors inhibitor.

Radiation therapy

  • 131I-MIBG radiation therapy has been used for the treatment of MIBG-avid metastases;[12]
  • Patients with good uptake of 123I-MIBG Unresectable progressive pheochromocytoma and low number of metastases. Therapy can be repeated for recuurent cases. [15]
  • High doses show serious side effects include: leukopenia, thrombocytopenia due to bone marrow depression [16] and hypothyroidism and acute leukemia [17]
  • Pheochromocytomas express somatostatin receptors patients with metastatic or recurrent pheochromocytoma may benefit from
  • radiolabeled somatostatin analogs. [18]Long-term potential side effects of therapy with radiolabeled somatostatin analogs may include loss of renal function, pancytopenia, and myelodysplastic syndrome.[16]

Contraindicated medications

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

References

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  2. 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.
  3. 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.
  4. 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.
  5. Steinsapir J, Carr AA, Prisant LM, Bransome ED (1997). "Metyrosine and pheochromocytoma". Arch Intern Med. 157 (8): 901–6. PMID 9129550.
  6. 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.
  7. 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.
  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. 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.
  10. 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.
  11. 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.
  12. 12.0 12.1 National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq#link/_179_toc
  13. 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.
  14. 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.
  15. 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.
  16. 16.0 16.1 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.
  17. 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.
  18. 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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