Pheochromocytoma medical therapy: Difference between revisions

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* 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 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>
* family members should undergo ''[[RET gene|RET]]'' mutation screening.
* family members should undergo ''[[RET gene|RET]]'' mutation screening.
*
* Patients with MEN2 and a known familial ''RET'' mutation should be counseled that prenatal testing and preimplantation genetic testing are available options if they choose to pursue fertility [26]. Prenatal testing is performed in the first or second trimester via chorionic villus sampling or amniocentesis, respectively. Preimplantation genetic diagnosis (PGD) is done as part of in vitro fertilization (IVF); single embryonic cells are tested for the ''RET'' mutation. Only embryos without a ''RET'' mutation are then transferred to the uterus. The various reproductive options available to prospective parents require thoughtful discussion and genetic counseling.  Monitoring for MEN2-associated tumors — Affected family members require screening for multiple endocrine neoplasia type 2 (MEN2)-associated tumors.  When RET mutation is known — When the ''RET'' mutation is known, monitoring for MEN2-associated tumors is based upon the specific mutation and degree of risk it confers for MTC, pheochromocytoma, and primary hyperparathyroidism.  Medullary thyroid cancer — Children with certain ''RET'' mutations can develop clinically apparent MTC at an early age. The goal in patients with known ''RET'' mutations (but without clinically apparent disease) is to perform a prophylactic thyroidectomy before MTC develops or when it is still confined to the thyroid gland (table 6). (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Preventive surgery'.)  Children with the highest risk mutation (codon 918) should have thyroidectomy within the first year of life and, therefore, do not require monitoring.  For children with high-risk mutations (codons 634, 883), we begin monitoring at age three years, and for children with moderate risk mutations, we begin monitoring at age five years. We monitor with an annual physical examination, neck ultrasound, and measurement of serum calcitonin. The detection of a serum calcitonin level (basal or stimulated) above the upper limit of normal is an indication for surgery.  Pheochromocytoma — The risk of developing pheochromocytoma is variable depending upon genotype [62-64]. For children in the highest and high-risk categories, screening for pheochromocytoma should begin by age 11 years (table 5). For children in the moderate-risk category, we begin screening by age 16 years. Patients should be screened yearly by measuring plasma fractionated metanephrines or 24-hour urinary metanephrines and normetanephrines. If biochemical results are positive, adrenal imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is the next step. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Additional evaluation after biochemical diagnosis'.)  There is large variability in the penetrance of pheochromocytoma among different reported kindreds, depending upon the specific ''RET'' germline mutation. These findings help guide screening and therapy for MEN2 patients [65-69]. As an example, compared with families with mutations in codons 634 and 918, pheochromocytomas are rare in families with mutations in codons 533, 609, 611, 618, 620, 630, 633, 666, 768, 790, 791, 804, and 891, although they do still occur.  Due to screening programs, pheochromocytomas may be diagnosed at a young age and before symptoms are present.  Hyperparathyroidism — The hyperparathyroidism in MEN2A is often mild and asymptomatic. In one study, the mean age at diagnosis was 33 years, but children diagnosed as young as two years of age has been reported [1,27,70,71]. Biochemical screening for hyperparathyroidism should be performed yearly beginning at age 11 years in high-risk patients and 16 years in moderate-risk patients (patients in the highest risk category [MEN2B] are not at risk for developing hyperparathyroidism) (table 5) [1]. We measure serum calcium (corrected for albumin). If it is elevated, we measure intact parathyroid hormone (PTH). The diagnosis is established by finding high (or inappropriately normal) serum PTH concentrations in the presence of hypercalcemia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)  When RET mutation is unknown  Biochemical testing — For closely related MEN2 family members who refuse DNA analysis for themselves or their children, or for families who meet the clinical criteria for MEN2 but have negative sequencing of the entire ''RET'' coding region, biochemical testing can be performed to detect MEN2-related tumors. If biochemical testing is used, yearly testing starting at age five and continuing until at least age 35 years (or until a positive test occurs) is necessary [7]. For families with a clinical diagnosis of MTC prior to age five years, biochemical screening for MTC should begin at the youngest age of first diagnosis.  Either a pentagastrin or a calcium stimulation test can be used to screen for C-cell hyperplasia/MTC. Where available (not in the United States), pentagastrin is the preferred stimulation test. Testing should also include plasma fractionated metanephrines or 24-hour urinary metanephrines and normetanephrines (to screen for pheochromocytoma) and serum calcium (to screen for hyperparathyroidism).  Choice of biochemical test for MTC — Owing to the unavailability of pentagastrin in many countries, there is growing interest in the calcium stimulation test. However, there are few data using the calcium stimulation as a confirmatory test in patients with elevated basal calcitonin levels, and cut points for the discrimination of normal, C-cell hyperplasia, and medullary thyroid cancer (MTC) have not been standardized [72]. In one study, basal and stimulated calcitonin levels were measured in over 100 patients with thyroid disease (MTC in remission or persistence, ''RET'' gene mutation carriers, nodular goiter) and in 16 healthy volunteers [73]. In all groups, the levels of calcitonin stimulated by either pentagastrin or calcium were significantly correlated. In this study, calcium stimulated calcitonin levels above 32.6 pg/mL (females) and 192 pg/mL (males) had the best accuracy to differentiate normal subjects from patients with C-cell hyperplasia or MTC [73]. Criteria for abnormal calcitonin values may vary in local or commercial laboratories [74].  ●Pentagastrin stimulation test – The pentagastrin stimulation test uses a slow intravenous injection of pentagastrin (0.5 mcg/kg body weight) over three minutes. Blood samples for calcitonin are obtained at baseline and two and five minutes after pentagastrin infusion [75,76]. If stimulated calcitonin values are ≥200 pg/mL, MTC is likely and thyroidectomy and lymphadenectomy are required. If values are <100 pg/mL, the risk of MTC is low and periodic monitoring of basal and stimulated serum calcitonin levels is recommended. If the stimulated calcitonin values are between 100 and 200 pg/mL, the risk is uncertain. Such values could be indicative of C-cell hyperplasia or micro MTC. Some advise surgery [77,78], others observation (following calcitonin levels) [79].  Side effects of pentagastrin include abdominal cramping, extremity paresthesia, and feeling of warmth, lasting up to one to two minutes [76]. Pentagastrin is not available in many countries, including the United States.  ●Calcium stimulation test – The calcium stimulation test uses an infusion of calcium gluconate (2.5 mg elemental calcium/kg body weight over 30 seconds) administered in a fasting state (no food after midnight) [54,76]. Blood samples for calcitonin are obtained at baseline and two and five minutes after the stimulus. In one study, calcium-stimulated calcitonin levels above 32.6 pg/mL (females) and 192 pg/mL (males) had the best accuracy to differentiate normal subjects from patients with C-cell hyperplasia or MTC [73].  The most common side effects are temporary flushing and feeling of warmth (98 percent) [76]. Facial paresthesias are less common (20 percent).


== Management of malignant pheochromocyotma ==
== Management of malignant pheochromocyotma ==

Revision as of 18:12, 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. 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.[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.
  • 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.[4]

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.[5] It is low morbidity surgery, even in children and thyroid replacement is started directly after surgery.

  • Asymptomatic patients who do not undergo surgery and need follow up only.
  • If patients are symptomatic, hyperparathyroidism surgery is the only defenetive treatment.[6]
  • 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.[7]
  • Complication and recurrence rate are low[8]
  • 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 [9]
  • 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. 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. [10]

Systemic therapy

Chemotherapy

  • Metastatic pheochromocytoma is treated with Averbuc protocol which is a combination of cyclophosphamide, vincristine, dacarbazine.[11] 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.[12]
  • Most common side effects are GIT upset, peripheral neuropathy and BM supression.[13]

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;[11]
  • Patients with good uptake of 123I-MIBG Unresectable progressive pheochromocytoma and low number of metastases. Therapy can be repeated for recuurent cases. [14]
  • High doses show serious side effects include: leukopenia, thrombocytopenia due to bone marrow depression [15] and hypothyroidism and acute leukemia [16]
  • Pheochromocytomas express somatostatin receptors patients with metastatic or recurrent pheochromocytoma may benefit from
  • radiolabeled somatostatin analogs. [17]Long-term potential side effects of therapy with radiolabeled somatostatin analogs may include loss of renal function, pancytopenia, and myelodysplastic syndrome.[15]

Contraindicated medications

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

References

  1. ↑ Tauzin-Fin P, Sesay M, Gosse P, Ballanger P (2004). "Effects of perioperative alpha1 block on haemodynamic control during laparoscopic surgery for phaeochromocytoma". Br J Anaesth. 92 (4): 512–7. doi:10.1093/bja/aeh083. PMID 14766711.
  2. ↑ 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. ↑ 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. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 11.0 11.1 National Cancer Institute. Physician Data Query Database 2015. http://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq#link/_179_toc
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 15.0 15.1 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.
  16. ↑ 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.
  17. ↑ 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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