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

hypertensive crisis

1st line – antihypertensive therapy

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INITIAL
|
hypertensive crisis
1st line – 

antihypertensive therapy

May be a presenting feature or an intra-operative complication if the patient has not received adequate preoperative medical therapy.

A hypertensive crisis may be precipitated by drugs that inhibit catecholamine uptake, such as tricyclic antidepressants and cocaine; opiates; anaesthesia induction; and x-ray contrast media. Possible consequences of a hypertensive crisis include cerebral haemorrhage, cardiac arrhythmias, myocardial infarction, encephalopathy, and heart failure.[82]

Treatment includes immediate alpha blockade with an alpha-1 blocker (e.g., terazosin, doxazosin, or prazosin) or with the non-selective alpha-blocker, phenoxybenzamine. Intravenous agents (nitroprusside, phentolamine, or nicardipine) are short-acting and titratable, and can be used first line.[63] Nitroprusside, phentolamine, or nicardipine can be added, as required, to an oral alpha-1 blocker prescribed in the initial management of hypertensive crisis.[48]

Clinical presentation will inform prescribing decisions. Consult a specialist when deciding on the most appropriate regimen.

Primary options

terazosin: 1 mg orally once daily at bedtime, increase gradually according to response, maximum 20 mg/day in 1-2 divided doses

or

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

or

prazosin: 1 mg orally two to three times daily, increase gradually according to response, maximum 20 mg/day

or

phenoxybenzamine: 10 mg orally twice daily initially, increase gradually according to response, maximum 120 mg/day in 2-3 divided doses

-- AND / OR --

nitroprusside: 0.3 to 0.5 micrograms/kg/minute intravenous infusion initially, increase by 0.5 micrograms/kg/minute every 5 minutes according to response, maximum 10 micrograms/kg/minute

More

or

phentolamine: 5 mg intravenously every 10 minutes when required according to response

or

nicardipine: 5 mg/hour intravenous infusion initially, increase by 2.5 mg/hour every 5-15 minutes according to response, maximum 15 mg/hour

ACUTE

without hypertensive crisis

1st line – alpha-blocker

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ACUTE
|
without hypertensive crisis
1st line – 

alpha-blocker

The first step in medical management is to block the effects of catecholamine excess by controlling hypertension and expanding intravascular volume.[1] This is achieved by first establishing adequate alpha blockade.[48]

Alpha-1 blockers (e.g., terazosin, doxazosin, or prazosin), or the non-selective alpha-blocker phenoxybenzamine, are recommended for initial pre-treatment blockade.[48][49] These drugs lower blood pressure (BP) by decreasing peripheral vascular resistance.[64]

A major disadvantage of phenoxybenzamine is that it blocks presynaptic alpha-2 receptors enhancing the release of noradrenaline (norepinephrine), resulting in a reflex tachycardia.

Alpha-1 blockers have a shorter duration of action than phenoxybenzamine, making them particularly useful in the perioperative period. The dose of alpha-1 blocker can be rapidly titrated, avoiding postoperative hypotension. These drugs do not enhance the release of noradrenaline and therefore do not cause a reflex tachycardia.

Primary options

terazosin: 1 mg orally once daily at bedtime, increase gradually according to response, maximum 20 mg/day in 1-2 divided doses

OR

doxazosin: 1 mg orally once daily at bedtime, increase gradually according to response, maximum 16 mg/day

OR

prazosin: 1 mg orally two to three times daily, increase gradually according to response, maximum 20 mg/day

OR

phenoxybenzamine: 10 mg orally twice daily initially, increase gradually according to response, maximum 120 mg/day in 2-3 divided doses

Plus – beta-blocker (after alpha blockade)

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ACUTE
|
without hypertensive crisis
Plus – 

beta-blocker (after alpha blockade)

Treatment recommended for ALL patients in selected patient group

Following adequate alpha blockade, which may take 3-4 days of therapy, beta blockade can be added to manage tachycardia.[3][28][48][67]

The commonly employed agents are beta-1 selective agents such as atenolol and metoprolol.

Beta-blockers must only be used after adequate alpha blockade is achieved preoperatively, as they can cause unopposed stimulation of alpha receptors, leading to vasoconstriction and a possible hypertensive crisis.

Adverse effects include bradycardia, bronchospasm, hypotension, and vasoconstriction; therefore, caution is needed when commencing patients with asthma, cardiomyopathies (this is particularly important as cardiomyopathy is a complication of prolonged catecholamine exposure), heart failure, or atrioventricular (AV) conduction abnormalities on beta-blockers.

Primary options

atenolol: 25-100 mg orally once daily

OR

metoprolol: 50 mg orally (immediate-release) twice daily initially, increase according to response, maximum 450 mg/day

Plus – hydration and high-salt diet (>5 g per day)

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ACUTE
|
without hypertensive crisis
Plus – 

hydration and high-salt diet (>5 g per day)

Treatment recommended for ALL patients in selected patient group

Hydration and a high-salt diet (>5 g/day) are given for 7-14 days (or until the patient is stable) to offset the effects of catecholamine-induced volume contraction associated with alpha blockade.[48]

All patients should be volume expanded with isotonic saline. In surgical patients, postoperative hypotension may be avoided by adequate intravenous fluid replacement preoperatively.

Consider – calcium-channel blocker or metirosine

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ACUTE
|
without hypertensive crisis
Consider – 

calcium-channel blocker or metirosine

Additional treatment recommended for SOME patients in selected patient group

Dihydropyridine calcium-channel blockers can supplement alpha blockade if additional BP control is required.[48]

Monotherapy with dihydropyridine calcium-channel blockers is not recommended, but may be an option if the patient is unable to tolerate alpha blockade.[48] Nifedipine and amlodipine are commonly recommended calcium-channel blockers in the setting of perioperative phaeochromocytoma BP control.

Calcium-channel blockers lower BP by relaxing smooth muscle in peripheral arteries. This is achieved by inhibition of the noradrenaline-mediated release of intracellular calcium in vascular smooth muscle.

They do not cause orthostatic hypertension and, therefore, have a role in patients with episodic hypertension.

Metirosine can be used in conjunction with alpha blockade to stabilise BP.[48] Metirosine, an inhibitor of tyrosine hydroxylase, inhibits catecholamine synthesis. In patients with phaeochromocytomas, metirosine can reduce the biosynthesis of catecholamines by 35% to 80%.[65] This is particularly useful in patients with very high circulating levels of catecholamines, which can be cytotoxic to myocardial cells.

Metirosine should be started 2 weeks prior to surgery. It can also be used when surgery is contraindicated.

Adverse effects of metirosine often limit the use of this drug and include crystalluria, fatigue, diarrhoea, depression, nightmares, and extrapyramidal signs.[83]

Patients should be instructed on maintaining an adequate fluid intake in order to avoid metirosine crystalluria.

Primary options

nifedipine: 30-60 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 120 mg/day

OR

amlodipine: 5-10 mg orally once daily

Secondary options

metirosine: 250 mg orally four times daily initially, increase by 250-500 mg/day increments according to response, maximum 4000 mg/day

Plus – surgical excision of tumour

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ACUTE
|
without hypertensive crisis
|
resectable tumour: following initial medical treatment
Plus – 

surgical excision of tumour

Treatment recommended for ALL patients in selected patient group

Surgical excision of the entire adrenal gland remains the mainstay of treatment for benign and malignant phaeochromocytoma.[48] If appropriate, minimally invasive resection of the tumour is preferred.[48][49]

The American Association of Endocrine Surgeons (AAES) recommends laparoscopic transabdominal or posterior retroperitoneal adrenalectomy.[68] The North American Neuroendocrine Tumor Society (NANETS) recommends open resection if there is evidence of local invasion, malignancy, or recurrence.[49] Minimally invasive adrenalectomy appears to be safe in patients with malignant phaeochromocytoma tumour size <6 cm.[69]

Cortical-sparing adrenalectomy should be considered in patients with bilateral phaeochromocytoma (recommended by the AAES and NANETS) and familial phaeochromocytoma (recommended by NANETS).[49][68] This method can avoid the need for lifelong corticosteroid therapy; however, patients need to be monitored postoperatively for local recurrence.[68]

Paragangliomas are extra-adrenal tumours. They require specialised surgical approaches depending on the various locations of origin.[70]

Plus – continued medical treatment

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ACUTE
|
without hypertensive crisis
|
unresectable benign tumour: following initial medical treatment
Plus – 

continued medical treatment

Treatment recommended for ALL patients in selected patient group

Patients with benign tumours who are unable to undergo surgery - for example, due to a high surgical risk because of heart failure - should receive long-term blood pressure control using alpha blockade, as well as calcium-channel blockers or beta blockade if needed.[48]

Metirosine is a less-preferred option for controlling hypertension.

Consider – iobenguane I-131

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ACUTE
|
without hypertensive crisis
|
unresectable benign tumour: following initial medical treatment
Consider – 

iobenguane I-131

Additional treatment recommended for SOME patients in selected patient group

Iobenguane I-131 (also known as I-131 metaiodobenzylguanidine [MIBG]) may be considered in patients with an unresectable secreting tumour if I-123 MIBG scintigraphy was positive.[48]

See local specialist protocol for dosing guidelines.

Primary options

iobenguane I 131

Plus – continued medical treatment

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ACUTE
|
without hypertensive crisis
|
locally unresectable catecholamine-secreting tumour: following initial medical treatment
Plus – 

continued medical treatment

Treatment recommended for ALL patients in selected patient group

Continued alpha blockade, with calcium-channel blockers or beta blockade if needed, facilitates blood pressure control in patients with unresectable secreting tumours.[48][49]

Adjustments to the blood pressure treatment regimen may be required should additional therapy be prescribed.[48]

Consider – radiotherapy ± cytoreductive resection

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ACUTE
|
without hypertensive crisis
|
locally unresectable catecholamine-secreting tumour: following initial medical treatment
Consider – 

radiotherapy ± cytoreductive resection

Additional treatment recommended for SOME patients in selected patient group

Radiotherapy with or without cytoreductive resection is a treatment option for patients with locally unresectable disease.[28][48][49]

Risks, benefits, and alternatives to surgery should be considered.[28]

Consider – postsurgical chemotherapy

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ACUTE
|
without hypertensive crisis
|
locally unresectable catecholamine-secreting tumour: following initial medical treatment
Consider – 

postsurgical chemotherapy

Additional treatment recommended for SOME patients in selected patient group

Chemotherapy is given to some patients with metastatic disease after surgery.

Chemotherapy regimens usually comprise cyclophosphamide plus vincristine plus dacarbazine (CVD), or temozolomide.[48][71]

Temozolomide, an alkylating drug and an alternative to dacarbazine, can be used as monotherapy or in combination with other antineoplastic drugs in patients with malignant phaeochromocytomas and SDHB mutations.[72][73]

See local specialist protocol for dosing guidelines.

Primary options

cyclophosphamide

and

vincristine

and

dacarbazine

Secondary options

temozolomide

Consider – iobenguane I-131 or radiotherapy

Back
ACUTE
|
without hypertensive crisis
|
locally unresectable catecholamine-secreting tumour: following initial medical treatment
Consider – 

iobenguane I-131 or radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Additional therapy may be required in some patients with residual tumour, such as multifocal or metastatic disease.[84]

The radiopharmaceutical iobenguane I-131 (also known as I-131 metaiodobenzylguanidine [MIBG]) may be considered if I-123 MIBG scintigraphy was positive.[48][49]

External beam radiotherapy provides local tumour control and relief of symptoms at both soft tissue sites of metastases, and painful bone metastases.[74][75]

Primary options

iobenguane I 131

Consider – enrolment in clinical trial

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ACUTE
|
without hypertensive crisis
|
locally unresectable catecholamine-secreting tumour: following initial medical treatment
Consider – 

enrolment in clinical trial

Additional treatment recommended for SOME patients in selected patient group

Potential enrolment in a clinical trial should be discussed with the patient.

Somatostatin analogues (octreotide, lanreotide) or peptide receptor radionuclide therapy ([PRRT] with lutetium Lu 177 dotatate) can be considered for patients with somatostatin receptor positive disease.[48]

Sunitinib, a tyrosine kinase inhibitor, demonstrated anti-tumour efficacy in a phase 2 randomised, placebo-controlled trial that included patients with metastatic phaeochromocytoma.[76]

Other clinical trial options may include immunotherapy (e.g., pembrolizumab) or hypoxia-inducible factor 2 alpha inhibitors (e.g., belzutifan).[84][85]

Plus – continued medical treatment

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ACUTE
|
without hypertensive crisis
|
catecholamine-secreting distant metastases: following initial medical treatment
Plus – 

continued medical treatment

Treatment recommended for ALL patients in selected patient group

Continued alpha blockade, with calcium-channel blockers or beta blockade if needed, facilitates blood pressure control in patients with unresectable secreting tumours.[48][49]

Adjustments to the blood pressure treatment regimen may be required should additional therapy be prescribed.[48]

Consider – cytoreductive resection

Back
ACUTE
|
without hypertensive crisis
|
catecholamine-secreting distant metastases: following initial medical treatment
Consider – 

cytoreductive resection

Additional treatment recommended for SOME patients in selected patient group

Cytoreductive resection is a treatment option in patients with catecholamine-secreting distant metastases.[48]

Risks, benefits, and alternatives to surgery should be considered.[28]

Consider – postsurgical chemotherapy

Back
ACUTE
|
without hypertensive crisis
|
catecholamine-secreting distant metastases: following initial medical treatment
Consider – 

postsurgical chemotherapy

Additional treatment recommended for SOME patients in selected patient group

Chemotherapy is given to some patients with metastatic disease after surgery.

Chemotherapy regimens usually comprise cyclophosphamide plus vincristine plus dacarbazine (CVD), or temozolomide.[48][71]

Temozolomide, an alkylating drug and an alternative to dacarbazine, can be used as monotherapy or in combination with other antineoplastic drugs in patients with malignant phaeochromocytomas and SDHB mutations.[72][73]

See local specialist protocol for dosing guidelines.

Primary options

cyclophosphamide

and

vincristine

and

dacarbazine

Secondary options

temozolomide

Consider – iobenguane I-131, radiation, or ablative therapy

Back
ACUTE
|
without hypertensive crisis
|
catecholamine-secreting distant metastases: following initial medical treatment
Consider – 

iobenguane I-131, radiation, or ablative therapy

Additional treatment recommended for SOME patients in selected patient group

Additional therapy may be required in some patients with residual tumour, such as multifocal or metastatic disease.[84]

The radiopharmaceutical iobenguane I-131 (also known as I-131 metaiodobenzylguanidine [MIBG]) may be considered if I-123 MIBG scintigraphy was positive.[48][49] See local specialist protocol for dosing guidelines.

Palliative external beam radiotherapy may be considered for oligometastatic disease or limited metastases of the liver.[48]

Radiofrequency ablation of hepatic and bone metastases may also be effective.[49][77]

Primary options

iobenguane I 131

Consider – enrolment in clinical trial

Back
ACUTE
|
without hypertensive crisis
|
catecholamine-secreting distant metastases: following initial medical treatment
Consider – 

enrolment in clinical trial

Additional treatment recommended for SOME patients in selected patient group

Potential enrolment in a clinical trial should be discussed with the patient.

Somatostatin analogues (octreotide, lanreotide) or peptide receptor radionuclide therapy ([PRRT] with lutetium Lu 177 dotatate) can be considered for patients with somatostatin receptor positive disease.[48]

Sunitinib, a tyrosine kinase inhibitor, demonstrated anti-tumour efficacy in a phase 2 randomised, placebo-controlled trial that included patients with metastatic phaeochromocytoma.[76]

Other clinical trial options may include immunotherapy (e.g., pembrolizumab) or hypoxia-inducible factor 2 alpha inhibitors (e.g., belzutifan).[84][85]

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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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