Acromegaly Xử trí

Pharmacological therapy is recommended when surgery is not suitable or in patients with persistent disease after surgical resection of the adenoma.

Somatostatin Analogs (SSA) or Somatostatin Receptor Ligands (SRL)  

The first-generation SSA includes Lanreotide and Octreotide, while Pasireotide is a second-generation SSA. SSAs are analogs of naturally occurring somatostatin with similar pharmacological actions but with prolonged duration of action. They bind to somatostatin receptor subtypes 2 and 5 on GH-secreting adenomas to suppress GH secretion. The first-generation SRLs are the first-line pharmacotherapy agents. They may be used after surgery has failed to achieve biochemical control. They may provide full or partial disease control, in the time between administration of radiation therapy and the onset of maximum benefit attained from radiation therapy. These are available in long-acting release (LAR) depot, short-acting subcutaneous (SC), and oral preparations. Pasireotide LAR may be used in patients with clinically relevant residual tumor not suitable for resection and inadequately controlled by first-generation SRL.  

Somatostatin analogs may be combined with dopamine agonists to improve therapeutic efficacy and are effective in normalizing GH and IGF-1 levels. Advantages of SSAs include rapid onset, continued efficacy, and proven safety record. Common side effects of SSAs include cramping and abdominal bloating which are reduced over the first few months of treatment. Lastly, to properly assess adequacy of treatment and the need for dose titration, it is recommended to have patients remain on the same dose for 3 months (if tolerated by the patient).

Dopamine Agonists  

Example drugs: Bromocriptine, Cabergoline, Quinagolide  

Dopamine agonists may be considered particularly in patients with mild biochemical activity (eg modestly elevated serum IGF-1 in the absence or concomitant presence of somatostatin analog therapy). They bind to D2 dopamine receptors expressed on GH-secreting adenoma and reduce GH production. Advantages of dopamine agonists include their low cost, and that they are the only orally administered medications available for acromegaly. They may also be a first-line therapy postsurgery in selected patients (eg those with markedly elevated prolactin levels and/or modestly elevated GH and IGF-1 levels). Cabergoline may be considered in patients with persistent disease after surgery or added to SRL if IGF-1 levels are <2.5 times the upper limit of normal. 

Dopamine agonists are an additive therapy to somatostatin analogs in patients partially responsive to a maximum somatostatin analog dose. With combination therapy, approximately 50% of such patients may achieve control of IGF-1 and GH levels. Bromocriptine was shown to provide benefit in a minority of patients with acromegaly in earlier studies but Cabergoline, a more selective dopamine-2 receptor agonist, may be effective in a larger percentage of patients. Repeated prolactin, GH and IGF-1 levels should be determined 4 to 6 weeks after each dosage change of dopamine agonist. Potential side effects of dopamine agonists include gastrointestinal upset, orthostatic hypotension, headache, and nasal congestion. 

Growth Hormone Receptor Antagonist (GHRA)  

Pegvisomant competes with endogenous GH for its receptor and prevents functional dimerization and signal transduction by the GH receptor. It is indicated in patients with persistently elevated IGF-1 levels despite maximal therapy with other treatment modalities. It is effective in normalizing IGF-1 levels in >90% of patients, including those who are partially or completely resistant to other medical therapies. It is often used as medical therapy in patients with inadequate response to or partial tolerability to somatostatin analogs. Potential side effects of Pegvisomant include flu-like illness, allergic reactions, and elevated liver enzymes. It is recommended that serial liver function test monitoring be done (monthly for the first 6 months, quarterly for the next 6 months, then biannually). Patients with elevated baseline liver function tests require more frequent monitoring. It must be noted that serum GH levels are not specific and should not be monitored in patients receiving Pegvisomant. Notably, endogenous GH levels increase with Pegvisomant administration, and it may be cross-measured in GH assays. Pegvisomant may also be used as first-line daily monotherapy.

Combination Therapy  

In patients with partial or inadequate response to somatostatin analog therapy, Cabergoline may be useful for further lowering of IGF-1 or GH levels. In patients with a partial response to somatostatin analog therapy, the addition of daily, weekly, or twice-weekly Pegvisomant may be beneficial.

Radiotherapy is considered as an adjunctive treatment in patients not fully responding to surgical or pharmacological therapy. It should generally be reserved as a third-line treatment in patients who have not achieved tumor growth control or normalization of hormone levels with surgery and/or medical therapy. It may also be used in patients receiving GHRA (who have failed other medical therapies) and are at risk of tumor growth. Other endocrinologists have used radiotherapy in patients controlled on medical therapy to allow termination of such therapy, which is potentially life-long. Conventional radiotherapy can normalize IGF-1 and lower GH levels in >60% of patients. However, maximum response is achieved 10 to 15 years after administration of radiotherapy. Medical therapy with somatostatin analogs is usually required during this latency period.  

It must be noted that the choice of technique depends on the tumor characteristics. For example, conventional radiotherapy is preferred for large tumor remnants or tumors that are near the optic pathways, while stereotactic radiotherapy is the choice for smaller tumor size or if convenience for the patient is desired. However, the main limitation of radiation therapy is safety, with hypopituitarism observed in up to 60% of patients. Hence, patients are advised that serial pituitary function follow-up is needed to evaluate for hypopituitarism. Additionally, follow-up includes assessment of thyroid, adrenal, and gonadal functions at least annually. Lastly, conventional radiotherapy may carry the risk of second tumors or cerebrovascular events due to radiation vasculopathy.