Multiple endocrine neoplasia type 1 medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [3]

Overview

Pharmacologic medical therapies for multiple endocrine neoplasia type 1 include management of individual components of MEN 1.

Medical Therapy

Pharmacologic medical therapies for multiple endocrine neoplasia type 1 include management of individual components of MEN 1 .

Pituitary adenoma

Treatment options depends on the type of tumor and on its size:

• Prolactinomas are most often treated with dopamine agonists such as bromocriptine and cabergoline. The latter, decreases tumor size as well as alleviates symptoms. Dopamine agonists are followed by serial imaging to detect the recurrence. If the adenoma is large, treatment may include radiation therapy and surgery. Efforts have been made to use a progesterone antagonist for the treatment of prolactinomas, but so far have not proved successful.
• Thyrotrophic adenomas respond to octreotide, a long-acting somatostatin analog, in many but not all cases according to a review of the medical literature. Unlike prolactinomas, thyrotrophic adenomas characteristically respond poorly to dopamine agonist treatment.
• Somatotrophic adenomas can be treated with somatostatin analogues, dopamine analogues, and the newer GH-receptor antagonists, such as pegvisomant.
• Adrenocorticotropic adenomas can be treated with ketoconazole, an inhibitor of steroidogenesis, it's considered as a drug of choice in adjunctive medical therapy for ACTH-producing adenomas.
• Recurrent macroadenoma can be treated with octreotide, a long-acting somatostatin analogue. This can result in both reduction of the size of the tumour and reduction in the serum levels of growth hormone.
• Clomifene is contraindicated in patient with pituitary adenoma.

Hyperparathyroidism 

Medical therapy for hyperparathyroidism should be considered in the following circumstances:

• Patients with hyperparathyroidism not meeting the guidelines for surgery.
• Patients with hyperparathyroidism having contraindications to surgery.
• Patient with hyperparathyroidism who have previous unsuccessful neck exploration.
• Patient with hyperparathyroidism who have not been cured by surgery.
• Patient with hyperparathyroidism refuses surgery.

Medical Management

• 1. Primary hyperparathyroidism
  • 1.1 Nutritional supplementation
    • 1.1.1 Low calcium intake
      • Preferred regimen (1): Elemental calcium 500 mg PO q24h

      Note: Dietary calcium restriction is not necessary in primary hyperparathyroidism.

    • 1.1.2 Vitamin D depletion
      • Preferred regimen (1): Cholecalciferol 600–1000 IU PO q24h

      Note(1): Vitamin D deficiency is considered when serum level of 25-hydroxy vitamin D is below 50 nM (20 ng/mL).

      Note(2): Serum calcium levels and urinary calcium excretion should be monitored during vitamin D supplementation. Vitamin D supplementation should be stopped if serum calcium levels is >11.6 mg/dL and/or urinary calcium excretion is >400 mg/24 h.

      Note(3): The goal of vitamin D supplementation is to keep 25-hydroxy vitamin D level between 50 nmol/L to 75 nmol/L.

  • 1.2 Pharmacotherapy
    • 1.2.1 Bisphosphonates
      • Preferred regimen (1): Alendronate 10 mg PO q24h
    • 1.2.2 Calcimimetics
      • Preferred regimen (1): Cinacalcet HCl 30-120 mg PO q12h

      Note(1): Cinacalcet may be used in patients with familial primary hyperparathyroidism as a treatment option for patients having recurrent or persistent hypercalcemia after parathyroidectomy.

      Note(2): A combination of bisphosphonates and calcimimetics may be used to reduce the serum calcium and improve bone mineral density.

    • 1.2.3 Estrogen receptor-targeted therapy (post-menopausal women)
      • Preferred regimen (1): Conjugated equine estrogen 0.625 mg q24h + medroxyprogesterone acetate 5mg q24h

      Note(1): The risk-benefit ratio should be assessed with respect to known relative or absolute contraindication to use of estrogen in each patient.

• 2. Secondary hyperparathyroidism
  • 2.1 Secondary hyperparathyroidism due to vitamin D deficiency
    • 2.1.1 Vitamin D analogs
      • Preferred regimen (1): Calcitriol
      • Preferred regimen (2): Paricalcitol
      • Preferred regimen (3): Doxercalciferol
  • 2.2 Secondary hyperparathyroidism due to Chronic renal failure
    • 2.2.1 Calcimimetics
      • Preferred regimen (1): Cinacalcet HCL 30-180 mg PO q24h
    • 2.2.2 Phosphate binders/phosphate restriction
    • 2.2.3 Vitamin D analogs
      • Preferred regimen (1): Calcitriol 0.5 μg thrice weekly
      • Preferred regimen (2): Paricalcitol 2 μg thrice weekly
      • Preferred regimen (3): Doxercalciferol 1 μg thrice weekly
• 3. Tertiary hyperparathyroidism
  • 3.1 Calcimimetic drugs

    • Preferred regimen (1): Cinacalcet HCL

Zollinger-Ellison Syndrome

• Pharmacotherapy of Zollinger-Ellison syndrome (ZES) includes aspects of management such as medical control of acid hypersecretion, diagnosis, localization and treatment directed at the gastrinoma.
• Widespread use of PPIs for many GI complaints is making the diagnosis of ZES more difficult and is delaying the diagnosis.
• Certain aspects of ZES require modifications of standard antisecretory treatment and are discussed (pregnancy, parenteral therapy, complicated disease)
• Patients with advanced disease require treatments directed against the gastrinoma, a number of which are recently shown effective or promising including new chemotherapy regimens, molecular targeted therapies, biotherapies, and peptide-radioreceptor therapy.
• As the widespread use of pharmacotherapy has become more prevalent, the management of ZES has transformed from a surgical therapy to medical therapy which has been observed to play a major role.
• Medical management is to treat symptoms and prevent complications from peptic ulcer disease. The preferred medical therapy is the use of high doses of proton pump inhibitors. PPI’s are preferred over H2 receptor blockers due to their higher potency and longer duration of action.

Pharmacotherapy for Zollinger-Ellison syndrome may includes the following:

• Proton pump inhibitors

• Preferred regimen (1): Omeprazole 60 mg per day
• Preferred regimen (2):Esomeprazole 120 mg per day
• Preferred regimen (3):Lansoprazole 45 mg per day
• Preferred regimen (4):Rabeprazole 60 mg per day
• Preferred regimen (5):Pantoprazole 120 mg per day

• H2-receptor antagonists

• Preferred regimen (1):Famotidine
• Preferred regimen (2):Ranitidine

• Chemotherapy used for tumors that can not be surgically resected

• Preferred regimen (1): Streptozotocin
• Preferred regimen (2)5-fluorouracil
• Preferred regimen (3): Doxorubicin

Hormonal therapy

• Octreotide can be used to slow down acid secretion. Somatostatin analogue octreotide is effective in controlling systemic effects related to multiple liver metastases from a gastrinoma.
• In the management of gastroenteropancreatic (GEP) neoplasia in hypergastrinemic MEN-1 patients, octreotide is considered as a safe and effective adjunct to surgical strategies.
• In patients with progressive malignant gastrinoma, octreotide is an effective antitumor treatment. In patients with progressive malignant gastrinoma, octreotide treatment helps replace chemotherapy as the standard treatment especially in patients with slow-growing tumors.

• In patients who are not suitable for surgery or in patients with widespread metastasis, conservative management with PPIs is also recommended.
• In patients with metastatic disease a limited efficacy has been observed with current treatment modalities. Chemotherapy may be advised for patients with widespread metastasis. The first-line treatment suggested is combined therapy with streptozotocin and 5-fluorouracil or doxorubicin. However, these treatments have been shown to result in limited responses and considerable toxicity.