Multiple endocrine neoplasia type 2 medical therapy

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

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.

Conventional Therapy

• 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. Lymph node dissection of laterocervical compartments is not performed on principle but only when the neck ultrasound suggests the presence of metastatic nodes.
• Endoscopic adrenal-sparing surgery has become the method of choice for the surgical therapy of PHEO. 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.
• 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

• 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. 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.
• 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. 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. 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.

Target Therapy for Persistent MTC

• 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. 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. 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.