Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

family history of MEN2

1st line – confirm carrier status ± surgery

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INITIAL
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family history of MEN2
1st line – 

confirm carrier status ± surgery

The degree of aggressiveness of medullary thyroid cancer is predicted by the causative mutation with foci developing as young as 2 years of age. As a consequence of this the optimal age for total thyroidectomy in a genetically screened case is moving earlier and determined by genotype.[7]

Patients with mutations conferring a high risk of aggressive disease are treated with prophylactic total thyroidectomy with central neck dissection.[7][86] Lymph node dissection of the ipsilateral or contralateral neck and/or mediastinal exploration may be performed concurrently. The optimal operation extent is undecided and remains controversial.[88]

Patients with mutations conferring an intermediate risk of aggressive disease are treated with prophylactic thyroidectomy before the age of 5 years.[87]

The need for central neck dissection is controversial in this group, as the risk of surgical complications (e.g., hypoparathyroidism and recurrent laryngeal nerve damage) may outweigh the likelihood of metastatic disease in patients at lower risk of aggressive disease, especially when the patient undergoes surgery at a young age.[87]

Patients with mutations conferring a low risk of aggressive disease are treated with prophylactic thyroidectomy at some stage during childhood; there is little consensus about the timing.

Consider – thyroid hormone replacement

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INITIAL
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family history of MEN2
Consider – 

thyroid hormone replacement

Treatment recommended for SOME patients in selected patient group

Long-term treatment post-thyroidectomy is necessary. Levothyroxine is titrated to normalize TSH level.

Primary options

levothyroxine: adults: 1.7 micrograms/kg/day orally

ONGOING

MEN1

1st line – hydration ± hypercalcemia pharmacotherapy

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ONGOING
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MEN1
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hyperparathyroidism
1st line – 

hydration ± hypercalcemia pharmacotherapy

Adequate hydration is first-line therapy (at least 3 L fluid per day).

Possible additions, if needed, include intermittent intravenous bisphosphonates, following adequate intravenous hydration. Bisphosphonates reduce hypercalcemia by inhibiting bone resorption. The calcium mimetic cinacalcet is being used increasingly as an alternative to bisphosphonates. It decreases parathyroid hormone production.[72][73]

Primary options

zoledronic acid 4 mg injection: adults: 4 mg intravenously every 3-4 weeks

OR

cinacalcet: adults: 30-90 mg orally twice daily

Consider – surgery

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ONGOING
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MEN1
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hyperparathyroidism
Consider – 

surgery

Treatment recommended for SOME patients in selected patient group

Parathyroid surgery is performed in symptomatic patients and includes exploration and identification of all parathyroid glands.[8] Subtotal parathyroidectomy (at least 3.5 glands) or total parathyroidectomy is recommended.[3][70] Small parathyroid remnants are either left in place (marked by clips) or can be autotransplanted into forearms. Retrospective studies and one prospective study have failed to show any difference in outcome when comparing subtotal parathyroidectomy with total parathyroidectomy and autotransplantation in patients with MEN1.[71] Prophylactic transcervical thymectomy has been recommended at the time of surgery, due to the increased incidence of thymic neuroendocrine tumors.[3]

It is debatable whether asymptomatic patients should receive this surgery to prevent bone loss and other symptoms or whether it should be deferred to make operative decision-making easier once glands have enlarged sufficiently to be easily identified.

1st line – proton-pump inhibitors

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ONGOING
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MEN1
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gastrinoma/Zollinger-Ellison syndrome
1st line – 

proton-pump inhibitors

First-line treatment is medical management aimed at controlling gastric acid production with high-dose proton-pump inhibitors.[8] Dose should be adjusted according to response.

Fifteen-year survival with this is >50%.

Primary options

omeprazole: adults: 40-60 mg orally twice daily

Plus – hydration ± hypercalcemia pharmacotherapy

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ONGOING
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MEN1
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gastrinoma/Zollinger-Ellison syndrome
Plus – 

hydration ± hypercalcemia pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Gastrin secretion is increased by calcium, making hyperparathyroidism control important in the treatment of gastrinoma.[77]

Adequate hydration is first-line therapy (at least 3 L fluid per day).

Possible additions, if needed, include intermittent intravenous bisphosphonates, following adequate intravenous hydration. Bisphosphonates reduce hypercalcemia by inhibiting bone resorption. The calcium mimetic cinacalcet is being used increasingly as an alternative to bisphosphonates. It decreases parathyroid hormone production.[72]

Loop diuretics increase urinary calcium excretion but should be used with caution, as intravascular depletion and hypercalciuria can worsen renal impairment and increase the risk of renal calculi.[75]

Primary options

zoledronic acid 4 mg injection: adults: 4 mg intravenously every 3-4 weeks

OR

cinacalcet: adults: 30-90 mg orally twice daily

Secondary options

furosemide: adults: 120 mg/day orally given in 1-3 divided doses

Consider – surgery

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ONGOING
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MEN1
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gastrinoma/Zollinger-Ellison syndrome
Consider – 

surgery

Treatment recommended for SOME patients in selected patient group

Surgical options include duodenopancreatectomy (Whipple procedure) for pancreatic head and neck lesions and pancreas-sparing procedures. Surgical opinions are required when considering these procedures.

1st line – octreotide

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ONGOING
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MEN1
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pancreatic lesion
1st line – 

octreotide

Octreotide injections can help to stabilize hormone production in patients with pancreatic neuroendocrine tumors that express somatostatin receptors.[80]​

Randomized controlled trials (not specific to MEN syndromes) have demonstrated an impact on progression free survival as well as on secretory syndromes from long-acting somatostatin analogs.[81][82] Octreotide efficacy may be attributable to an antiproliferative effect.[83]​[84]​​

Primary options

octreotide: adults: 50-200 micrograms subcutaneously every 8 hours

More

1st line – surgery

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ONGOING
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MEN1
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pancreatic lesion
1st line – 

surgery

Surgical options include distal pancreatectomy for pancreatic tail lesions and duodenopancreatectomy (Whipple procedure) for pancreatic head and neck lesions. Intraoperative ultrasound and manual pancreas palpation helps localize additional lesions, which may be individually resected by enucleation.

Surgical opinions are required when considering these procedures.

1st line – observation

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ONGOING
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MEN1
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nonfunctioning pituitary adenoma
1st line – 

observation

Nonfunctioning tumors are usually observed until mass effect threatens other structures such as the optic chiasm.

1st line – surgery

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ONGOING
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MEN1
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nonfunctioning pituitary adenoma
1st line – 

surgery

Surgery may be performed when mass effect threatens other structures such as the optic chiasm.

1st line – dopamine agonists

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ONGOING
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MEN1
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prolactinoma
1st line – 

dopamine agonists

Prolactinomas are generally managed medically with dopamine agonists to suppress prolactin production.[8]

Bromocriptine is taken daily and has more adverse effects. Nausea can be reduced by taking the tablet halfway through the main meal of the day.

Cabergoline can be effective in twice-weekly doses. Dopamine agonists used at high doses in the treatment of Parkinson disease can cause cardiac valve fibrosis. This has not been observed at the lower doses used to treat hyperprolactinemia. Currently it is recommended that all patients commencing dopamine agonist therapy should undergo a baseline echocardiogram. A multicenter trial is currently underway to investigate the risk of cardiac valve fibrosis in patients on dopamine agonist therapy for hyperprolactinemia.

Both medications are titrated to bring prolactin levels into the normal range.

Primary options

bromocriptine: adults: 1.25 to 2.5 mg orally once daily initially, increase by 2.5 mg/day increments every 2-7 days according to response, maximum 15 mg/day

OR

cabergoline: adults: 0.25 mg orally twice weekly initially, increase by 0.25 mg/dose increments every 4 weeks according to response, maximum 1 mg/dose

1st line – surgery

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ONGOING
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MEN1
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adrenocorticotropic hormone- or growth hormone-producing tumor
1st line – 

surgery

Transsphenoidal surgery is the preferred initial approach to patients with adrenocorticotropic or growth hormone-producing tumors. Adrenocorticotropin-producing tumors are often small and difficult to localize on imaging. Petrosal sinus catheters can provide additional information on tumor location to guide surgery.

To optimize patients for surgery, medical control of hypercortisolemia can be achieved with adrenal suppression using metyrapone and/or ketoconazole.

Occasionally transcranial approaches are required due to tumor location or size.

MEN2

1st line – hydration ± hypercalcemia pharmacotherapy

Back
ONGOING
|
MEN2
|
hyperparathyroidism
1st line – 

hydration ± hypercalcemia pharmacotherapy

Adequate hydration is first-line therapy (at least 3 L fluid per day).

Possible additions, if needed, include intermittent intravenous bisphosphonates, following adequate intravenous hydration. Bisphosphonates reduce hypercalcemia by inhibiting bone resorption. The calcium mimetic cinacalcet is being used increasingly as an alternative to bisphosphonates. It decreases parathyroid hormone production.[72]

Primary options

zoledronic acid 4 mg injection: adults: 4 mg intravenously every 3-4 weeks

OR

cinacalcet: adults: 30-90 mg orally twice daily

Consider – surgery

Back
ONGOING
|
MEN2
|
hyperparathyroidism
Consider – 

surgery

Treatment recommended for SOME patients in selected patient group

Parathyroid surgery is performed in symptomatic patients and includes exploration and identification of all parathyroid glands.[70] All parathyroid tissue identified is removed (parathyroidectomy and subtotal thymectomy) to maximize the chance of cure. Small parathyroid remnants are either left in place (marked by clips) or can be autotransplanted into forearms.[37]

It is debatable whether asymptomatic patients should receive this surgery to prevent bone loss and other symptoms or whether it should be deferred to make operative decision-making easier once glands have enlarged sufficiently to be easily identified.

1st line – surgery

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ONGOING
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MEN2
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operable medullary thyroid cancer
1st line – 

surgery

Ideally, patients will be diagnosed genetically and on the basis of family screening before pathology develops and this can enable early prophylactic thyroidectomy.[7] The recommended age for this surgery depends on the pathogenicity of the RET mutation carried by the patients.[5]

Total thyroidectomy and neck dissection is the preferred treatment for localized disease.

In cases where there are multiple tumors or metastatic disease it may be performed if symptomatic debulking is required.

Lymph node dissection of ipsilateral or contralateral neck and/or mediastinal exploration may be performed concurrently.

Plus – thyroid hormone replacement

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ONGOING
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MEN2
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operable medullary thyroid cancer
Plus – 

thyroid hormone replacement

Treatment recommended for ALL patients in selected patient group

Long-term treatment post-thyroidectomy is necessary.

Levothyroxine is titrated to normalize thyroid-stimulating hormone level.

Primary options

levothyroxine: adults: 1.7 micrograms/kg/day orally

1st line – symptom control

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ONGOING
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MEN2
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inoperable medullary thyroid cancer
1st line – 

symptom control

Includes patients with locally invasive inoperable disease but that is nonmetastic.

Symptoms such as chronic diarrhea are treated when surgical cure is not possible.

A range of targeted chemotherapy options are available with further clinical trials ongoing.

Primary options

loperamide: adults: 4 mg orally initially, followed by 2 mg after each loose stool, maximum 16 mg/day

1st line – symptom control

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ONGOING
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MEN2
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metastatic medullary thyroid cancer
1st line – 

symptom control

Symptoms such as chronic diarrhea are treated when surgical cure is not possible.

A range of targeted chemotherapy options are available with further clinical trials ongoing.

Primary options

loperamide: adults: 4 mg orally initially, followed by 2 mg after each loose stool, maximum 16 mg/day

Consider – debulking surgery

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ONGOING
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MEN2
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metastatic medullary thyroid cancer
Consider – 

debulking surgery

Treatment recommended for SOME patients in selected patient group

Recurrent debulking can help to reduce symptomatic calcitonin levels and protect threatened neck structures.[89] Urgency is weighed against increased scarring that will decrease the ability to reoperate at a later date.

Consider – tracheal stenting

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ONGOING
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MEN2
|
metastatic medullary thyroid cancer
Consider – 

tracheal stenting

Treatment recommended for SOME patients in selected patient group

Recurrent tracheal stenting can treat or prevent tracheal compression.

1st line – surgery

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ONGOING
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MEN2
|
pheochromocytoma
1st line – 

surgery

Unilateral adrenalectomy is usually performed. Bilateral adrenalectomy may be performed if bilateral disease is present. If bilateral adrenalectomy is performed, the patient will require lifelong hydrocortisone and fludrocortisone replacement. However, bilateral adrenalectomy is very unusual and only performed if there is a genetic condition, if the contralateral adrenal had been removed for another reason, and/or in the presence of a second contralateral tumor. Even in the latter case, cortical-sparing surgery is often considered. Surgical techniques preserving the adrenal cortex during bilateral adrenalectomy for bilateral pheochromocytoma allow some patients to remain off corticosteroids after surgery while continuing to be monitored for recurrent disease.[90][91][92] Adrenal cortical-sparing surgery is a successful treatment option and is associated with a reduced risk of adrenal insufficiency.[90]

Plus – preoperative adrenergic blockade

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ONGOING
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MEN2
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pheochromocytoma
Plus – 

preoperative adrenergic blockade

Treatment recommended for ALL patients in selected patient group

Reduces the risk of hypertensive crises during surgery.

After alpha-blockade is maximized, short-acting beta-adrenergic antagonists, such as propranolol, are added to achieve heart rates between 60 and 80 bpm.

Should be started 7 to 10 days before surgery and then titrated until blood pressure is controlled.

Primary options

phenoxybenzamine: adults: 10 mg orally twice daily initially, increase gradually according to response, maximum 120 mg/day

and

propranolol hydrochloride: adults: 60 mg/day orally (immediate-release) given in 2-4 divided doses, increase gradually according to response

Consider – long-term hydrocortisone and fludrocortisone replacement

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ONGOING
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MEN2
|
pheochromocytoma
Consider – 

long-term hydrocortisone and fludrocortisone replacement

Treatment recommended for SOME patients in selected patient group

If bilateral adrenalectomy is performed, the patient will require lifelong hydrocortisone and fludrocortisone replacement .

Primary options

hydrocortisone: 10-25 mg/square meter of body surface area orally daily given in 2-3 divided doses; usual dose is a larger dose in the morning (10-15 mg) and a smaller dose in the late afternoon (5-10 mg)

and

fludrocortisone: 0.1 to 0.3 mg orally once daily

2nd line – short-term alpha-1 antagonists + short-acting beta-adrenergic antagonists

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ONGOING
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MEN2
|
pheochromocytoma
2nd line – 

short-term alpha-1 antagonists + short-acting beta-adrenergic antagonists

Adrenergic blockade with alpha-1 antagonists is continued postoperatively after unsuccessful surgery. Phenoxybenzamine is used first-line, as this is a noncompetitive alpha-antagonist. Doxazosin (a competitive alpha-antagonist) may be used second-line if phenoxybenzamine is not tolerated due to adverse effects such as nasal congestion. Short-acting beta-adrenergic antagonists are added once alpha-blockade is maximized. This helps to maximize adrenergic blockade and achieve heart rates between 60 and 80 bpm.

Primary options

phenoxybenzamine: adults: 10 mg orally twice daily initially, increase gradually according to response, maximum 120 mg/day

and

propranolol hydrochloride: adults: 60 mg/day orally (immediate-release) given in 2-4 divided doses, increase gradually according to response

Secondary options

doxazosin: adults: 1 mg orally (immediate-release) once daily initially, increase according to response, maximum 16 mg/day

and

propranolol hydrochloride: adults: 60 mg/day orally (immediate-release) given in 2-4 divided doses, increase gradually according to response

Plus – attempt switch to long-term alpha-1 antagonists + long-acting beta-adrenergic antagonists

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ONGOING
|
MEN2
|
pheochromocytoma
Plus – 

attempt switch to long-term alpha-1 antagonists + long-acting beta-adrenergic antagonists

Treatment recommended for ALL patients in selected patient group

Adrenergic blockade with alpha-1 antagonists such as doxazosin may be suitable for long-term medical therapy. Once adequate beta-blockade is achieved with short-acting agents, longer-acting beta-adrenergic antagonists may be substituted in place of short-acting preparations such as propranolol.

Primary options

doxazosin: adults: 1 mg orally (immediate-release) once daily initially, increase according to response, maximum 16 mg/day

-- AND --

metoprolol tartrate: adults: 25 mg orally (immediate-release) twice daily initially, increase according to response, maximum 200 mg/day

or

atenolol: adults: 25 mg orally once daily initially, increase according to response, maximum 100 mg/day

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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