Multiple endocrine neoplasia type 2 medical therapy: Difference between revisions

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Latest revision as of 20:14, 17 June 2019

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

Overview

The mainstay of multiple endocrine neoplasia type 2 is surgery. Medical therapies for multiple endocrine neoplasia type 2 include vandetanib, external beam radiation therapy analogues, and intensity modulated radiation therapy.

Medical Therapy

The mainstay of multiple endocrine neoplasia type 2 is surgery. Medical management of multiple endocrine neoplasia type 2 depends on the type of tumor involved.

Medullary Thyroid Cancer

Pregnancy Management

Patients should be tested for pheochromocytoma prior to a planned pregnancy. If it is a case of unplanned pregnancy, the patient should be tested for pheochromocytoma as early as possible.

Target Therapy for Persistent Medullary Thyroid Cancer

Thirty percent of medullary thyroid cancer patients, especially in multiple endocrine neoplasia type 2B and 2A, are not cured by surgery. They remain affected and can develop, if not already present at the time of the diagnosis, distant metastasis in the lungs, liver, bone and, more rarely, brain. Several studies demonstrated that conventional therapies, such as chemotherapy and radiotherapy, did not determine any clinical benefit.^[1]^[2]
Until few years ago, patients with advanced and progressive medullary thyroid cancer were “orphan” of drugs. Recently, developed molecular therapeutics that target the RET pathway have shown very promising activity in clinical trials of patients with advanced medullary thyroid cancer.^[3] In the majority of cases, the drug is a multityrosine kinase inhibitor (TKI) with the ability to block not only RET but also one or more of the vascular endothelial growth factor receptors (VEGF-R) as well as C-MET and/or C-KIT or FLT3 and/or other kinases. Vandetanib has been recently approved both by FDA (Food and Drug Administration) and EMA (European Medical Agency) for the treatment of advanced and progressive medullary thyroid cancer.
Other TKIs, such as sorafenib, sunitinib, motesanib, lenvatinib, and cabozantinib, are still under investigation either in official phase II/III clinical trials or in “off-label” studies. Although very promising, further studies and longer follow-up are needed to better evaluate the clinical benefits in terms of progression-free survival and overall survival as compared to the discomfort determined by the side effects which is not negligible. Among several, the most severe and intolerable side effects are anorexia, weight loss, and fatigue, which are difficult to be controlled. Others, such as hypertension or skin lesions can be managed with standard care procedures.
Vandetanib has been recommended for the treatment of advanced metastatic medullary thyroid cancer.

Primary Hyperparathyroidism

Among patients with persistent or recurrent primary hyperparathyroidism (PHPT), the long-term oral administration of calcimimetic drugs as cinacalcet to achieve long-term reductions in serum calcium and parathyroid hormone concentration should be considered.

Radiation Therapy

External beam radiation therapy
Intensity modulated radiation therapy

Contraindicated Medications

References

↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. doi:10.1210/jc.2008-0923.
↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. doi:10.1016/j.clon.2010.03.014.
↑ Wells SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M; et al. (2012). "Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial". J Clin Oncol. 30 (2): 134–41. doi:10.1200/JCO.2011.35.5040. PMC 3675689. PMID 22025146.

Template:WikiDoc Sources

[pmidhttp://dx.doi.org/10.1210/jc.2008-0923-1] Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. doi:10.1210/jc.2008-0923.

[pmidhttp://dx.doi.org/10.1016/j.clon.2010.03.014-2] Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. doi:10.1016/j.clon.2010.03.014.

[pmid22025146-3] Wells SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M; et al. (2012). "Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial". J Clin Oncol. 30 (2): 134–41. doi:10.1200/JCO.2011.35.5040. PMC 3675689. PMID 22025146.

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[2]

[3]

@@ Line 2: / Line 2: @@
 {{Multiple endocrine neoplasia type 2}}
 {{CMG}}; {{AE}} {{Ammu}}
 ==Overview==
+The mainstay of multiple endocrine neoplasia type 2 is surgery. [[Medical]] [[Therapy|therapies]] for multiple endocrine neoplasia type 2 include [[vandetanib]], [[external beam radiation therapy]] [[Analog (chemistry)|analogues]], and [[Intensity of statin therapy in primary and secondary prevention|intensity]] [[Modularity (biology)|modulated]] [[radiation therapy]].
 ==Medical Therapy==
-Management of MEN2 patients includes thyroidectomy including cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved and selective resection of pathologic parathyroid glands for primary hyperparathyroidism.
+The mainstay of multiple endocrine neoplasia type 2 is surgery. Medical management of multiple endocrine neoplasia type 2 depends on the type of [[tumor]] involved.
-===Conventional Therapy===
+===Medullary Thyroid Cancer===
-* The treatment of choice for primary MTC, both sporadic or hereditary, is total thyroidectomy with systematic dissection of all lymph nodes of the central compartment. Total thyroidectomy is necessary as MTC is multicentric in 65–90% of patients in MEN 2 and extensive central lymph node dissection has been reported to improve survival and recurrence rates compared to less aggressive procedures. <ref name="pmid17665245">{{cite journal| author=Machens A, Hauptmann S, Dralle H| title=Increased risk of lymph node metastasis in multifocal hereditary and sporadic medullary thyroid cancer. | journal=World J Surg | year= 2007 | volume= 31 | issue= 10 | pages= 1960-5 | pmid=17665245 | doi=10.1007/s00268-007-9185-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17665245  }} </ref><ref name="pmid6128962">{{cite journal| author=Russell CF, Van Heerden JA, Sizemore GW, Edis AJ, Taylor WF, ReMine WH et al.| title=The surgical management of medullary thyroid carcinoma. | journal=Ann Surg | year= 1983 | volume= 197 | issue= 1 | pages= 42-8 | pmid=6128962 | doi= | pmc=PMC1352852 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6128962  }} </ref> Lymph node dissection of laterocervical compartments is not performed on principle but only when the neck ultrasound suggests the presence of metastatic nodes.
+====Pregnancy Management====
-* Endoscopic adrenal-sparing surgery has become the method of choice for the surgical therapy of PHEO. <ref name="pmid18784938">{{cite journal| author=Walz MK, Alesina PF| title=Single access retroperitoneoscopic adrenalectomy (SARA)--one step beyond in endocrine surgery. | journal=Langenbecks Arch Surg | year= 2009 | volume= 394 | issue= 3 | pages= 447-50 | pmid=18784938 | doi=10.1007/s00423-008-0418-z | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18784938  }} </ref>In cases with an asynchronous development of PHEO, the adrenal gland without PHEO can be preserved, but the patient must be aware that the probability to repeat the surgical treatment in the near future is very high. The advantage of a monolateral adrenal surgery is the possibility to avoid substitutive therapy until the second surgery will be performed.
+* [[Patient|Patients]] should be tested for [[pheochromocytoma]] prior to a planned [[pregnancy]]. If it is a case of unplanned [[pregnancy]], the [[patient]] should be tested for [[pheochromocytoma]] as early as possible.
-* The parathyroid glands are frequently found to be enlarged at the time of the thyroidectomy for MTC and should, therefore, be carefully evaluated. The goal in MEN 2 patients with PHPT is to excise the enlarged glands and to leave at least one apparently normal parathyroid gland intact. If all glands are enlarged, a subtotal parathyroidectomy or total parathyroidectomy with autotransplantation should be performed. In patients with persistent or recurrent PHPT, the long-term oral administration of calcimimetic drugs as cinacalcet to achieve long-term reductions in serum calcium and PTH concentration should be considered.
-===Prophylactic or Precocious Thyroidectomy in RET Gene Carrier===
+====Target Therapy for Persistent Medullary Thyroid Cancer====
-* Prophylactic thyroidectomy is advised in gene carriers to guarantee a definitive cure in these subjects. Four different risk levels (from A, the lowest, to D the highest) for RET mutations have been suggested by the American Thyroid Association task force, which developed the most recent guidelines for the management of MTC patients.<ref name="pmid19469690">{{cite journal| author=American Thyroid Association Guidelines Task Force. Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF et al.| title=Medullary thyroid cancer: management guidelines of the American Thyroid Association. | journal=Thyroid | year= 2009 | volume= 19 | issue= 6 | pages= 565-612 | pmid=19469690 | doi=10.1089/thy.2008.0403 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19469690  }} </ref> According to these guidelines, these levels of risk, which are related to the clinical aggressiveness of the corresponding MTC, should be taken into consideration when planning surgical treatment. In particular patients with a level D, RET mutation (i.e., Met918Thr) should be treated as soon as possible in the first year of life; patients with level B and C mutations (located in exons 10, 11, 13, 14, and 15) should be operated on before 5 years of age; only for patients with a level A mutation (exon 8 and 5 mutations), total thyroidectomy can be delayed after five years of age or until the CT positivity.
+* Thirty percent of [[medullary thyroid cancer]] patients, especially in multiple endocrine neoplasia type 2B and 2A, are not cured by [[surgery]]. They remain affected and can develop, if not already present at the time of the [[diagnosis]], distant [[metastasis]] in the [[lung]]s, [[liver]], [[bone]] and, more rarely, [[brain]]. Several studies demonstrated that conventional therapies, such as [[chemotherapy]] and [[radiotherapy]], did not determine any [[clinical]] benefit.<ref name="pmidhttp://dx.doi.org/10.1210/jc.2008-0923">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid= | doi=10.1210/jc.2008-0923 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref><ref name="pmidhttp://dx.doi.org/10.1016/j.clon.2010.03.014">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid= | doi=10.1016/j.clon.2010.03.014 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref>
-* Recently, some evidences in big series of RET gene carriers demonstrated that gene carriers with undetectable levels of basal CT have an almost null risk to have already developed the MTC.<ref name="pmid19801688">{{cite journal| author=Lau GS, Lang BH, Lo CY, Tso A, Garcia-Barcelo MM, Tam PK et al.| title=Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing. | journal=Hong Kong Med J | year= 2009 | volume= 15 | issue= 5 | pages= 326-31 | pmid=19801688 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19801688  }} </ref><ref name="pmidhttp://dx.doi.org/10.1210/jc.2010-1234">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.1210/jc.2010-1234 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref> Moreover, a serum Ct <30–40 pg/mL is always associated to an intrathyroidal micro-MTC without any evidence of lymph node metastases. Taking into account these observation, Elisei et al. <ref name="pmidhttp://dx.doi.org/10.1210/jc.2011-2046">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.1210/jc.2011-2046 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref> designed a study in which they operated on only RET gene carriers on the basis of basal and stimulated CT. According to their results, the time of surgical treatment could be personalized and safely planned when the stimulated serum CT becomes positive at the annual control, independently from the type of RET mutation and its associated level of risk. Of course, both cysteine RET mutations and older age are risk factors for having an earlier positive result for either basal or Pg-stimulated serum CT. For these reasons, the follow-up controls should be more or less frequent in cysteine or noncysteine RET-mutated gene carriers, respectively. This strategy obviously implies a high compliance of theRET gene carriers to the scheduled followup with the advantage that young children can be treated later, sometime even after the puberty, close to the adulthood.
+* Until few years ago, [[Patient|patients]] with advanced and progressive [[medullary thyroid cancer]] were “[[Orphan drug|orphan]]” of [[:Category:Drugs|drugs]]. Recently, developed [[molecular]] [[therapeutics]] that [[Target cell|target]] the [[RET gene|RET]] pathway have shown very promising [[Activity (chemistry)|activity]] in [[Clinical trial|clinical trials]] of [[Patient|patients]] with advanced [[medullary thyroid cancer]].<ref name="pmid22025146">{{cite journal| author=Wells SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M et al.| title=Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. | journal=J Clin Oncol | year= 2012 | volume= 30 | issue= 2 | pages= 134-41 | pmid=22025146 | doi=10.1200/JCO.2011.35.5040 | pmc=PMC3675689 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22025146  }} </ref> In the majority of cases, the [[drug]] is a multi[[tyrosine kinase inhibitor]] (TKI) with the ability to block not only [[RET gene|RET]] but also one or more of the [[vascular endothelial growth factor receptors]] ([[Vascular endothelial growth factor receptors|VEGF-R]]) as well as [[C-MET]] and/or [[C-KIT]] or [[FLT3]] and/or other [[kinases]]. [[Vandetanib]] has been recently approved both by [[Food and Drug Administration|FDA]] ([[Food and Drug Administration]]) and EMA (European [[Medical]] Agency) for the treatment of advanced and progressive [[medullary thyroid cancer]].
-===Target Therapy for Persistent MTC===
+* Other TKIs, such as [[sorafenib]], [[sunitinib]], motesanib, [[lenvatinib]], and [[cabozantinib]], are still under investigation either in official [[phase II]]/[[Phase III|III]] [[Clinical trial|clinical trials]] or in “[[off-label]]” studies. Although very promising, further studies and longer follow-up are needed to better evaluate the [[clinical]] benefits in terms of progression-free survival and overall survival as compared to the discomfort determined by the side effects which is not negligible. Among several, the most severe and intolerable side effects are [[anorexia]], [[weight loss]], and [[fatigue]], which are difficult to be controlled. Others, such as [[hypertension]] or [[skin]] lesions can be managed with standard care procedures.
-* Thirty percent of MTC patients, especially in MEN 2B and 2A, are not cured by surgery. They remain affected and can develop, if not already present at the time of the diagnosis, distant metastasis in the lungs, liver, bone and, more rarely, brain. Several studies demonstrated that conventional therapies, such as chemotherapy and radiotherapy, did not determine any clinical benefit.<ref name="pmidhttp://dx.doi.org/10.1210/jc.2008-0923">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.1210/jc.2008-0923 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref><ref name="pmidhttp://dx.doi.org/10.1016/j.clon.2010.03.014">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.1016/j.clon.2010.03.014 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref> Until few years ago, patients with advanced and progressive MTC were “orphan” of drugs. Recently, developed molecular therapeutics that target the RETpathway have shown very promising activity in clinical trials of patients with advanced MTC.<ref name="pmid22025146">{{cite journal| author=Wells SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M et al.| title=Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. | journal=J Clin Oncol | year= 2012 | volume= 30 | issue= 2 | pages= 134-41 | pmid=22025146 | doi=10.1200/JCO.2011.35.5040 | pmc=PMC3675689 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22025146  }} </ref> In the majority of cases, the drug is a multityrosine kinase inhibitor (TKI) with the ability to block not only retbutalsoone or more of the vascular endothelial growth factor receptors (VEGF-R) as well as C-MET and/or C-KIT or FLT3 and/or other kinases. Vandetanib has been recently approved both by FDA (Food and Drug Administration) and EMA (European Medical Agency) for the treatment of advanced and progressive MTC. Other TKIs, such as sorafenib, sunitinib, motesanib, lenvatinib, AND cabozantinib, are still under investigation either in official phase II/III clinical trials or in “off-label” studies [99]. Although very promising, further studies and longer followup are needed to better evaluate the clinical benefits in terms of progression-free survival and overall survival as compared to the discomfort determined by the side effects which is not negligible. Among several, the most severe and intolerable side effects are anorexia, weight loss, and fatigue, which are difficult to be controlled. Others, such as hypertension or skin lesions can be managed with standard care procedures.
+* [[Vandetanib]] has been recommended for the treatment of advanced [[metastatic]] [[medullary thyroid cancer]].
-==Reference==
-{{Reflist|2}}
+====Primary Hyperparathyroidism====
+* Among  [[Patient|patients]] with persistent or recurrent [[primary hyperparathyroidism]] (PHPT), the long-term [[oral]] administration of calcimimetic [[drugs]] as [[cinacalcet]] to achieve long-term [[Reduction|reductions]] in [[serum]] [[calcium]] and [[parathyroid hormone]] concentration should be considered.
+====Radiation Therapy====
+* [[External beam radiation therapy]]
+* Intensity modulated [[radiation therapy]]
+====Contraindicated Medications====
+* [[Dopamine]]: [[Dopamine receptor D2|D2 receptor]] [[antagonists]]
+* [[Beta adrenergic receptor]] [[antagonists]]
+==References==
+{{reflist|2}}
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