NEWSLETTER
Management of Acromegaly – What does medical treatment offer?
Dr. Aisha Sheikh — Consultant endocrinologist
Introduction
Acromegaly is a rare pituitary disorder with an estimated incidence of three to four cases per million people per year. Because it is a chronic and slowly developing disease, clinically progressive disfigurements or disabilities go unnoticed, and the diagnosis can be delayed. It is a severe systemic disease, because the GH/insulin-like growth factor-I (IGF-I) excess causes impairment of cardiac and respiratory functions that contribute to the increased mortality and morbidity. As a result, almost all patients should be treated, even those who are asymptomatic and those in whom the disorder does not seem to be progressing.
Goals of Therapy in Acromegaly
The goals of therapy are to normalize biochemical disease markers, eradicate or control tumor mass without harming normal pituitary function, relieve signs and symptoms, and restore life expectancy to that of the general population.
The serum insulin-like growth factor-I (IGF-I) concentration should be lowered to within the reference range for the patient's age and gender and the serum GH concentration should go down to <1 ng/mL (1 mcg/L) as measured by immuno-radiometric or chemiluminescent assay after a glucose load.
With normalization of serum IGF-1 concentrations, the life expectancy of acromegalic patients is similar to that of the general population. Therapy should also ameliorate symptoms, if any, due to the size of the somatotroph adenoma, but it should not cause hypopituitarism.
Transsphenoidal surgery and/or radiotherapy are still considered the treatment of choice, but despite recent advances in both these forms of treatment, the overall surgical cure rate remains around 60%, and radiotherapy may take 5–10 yr to lower GH to an acceptable level.
Medical Treatment
Medical therapy options include the use of dopamine agonists, Somatostatin receptor ligand (SRL) or somatostatin analog therapy, and pegvisomant. Pharmacologic treatment is used when surgery alone has not reduced serum GH and IGF-I to normal, but its role as primary therapy has not yet been clearly established.
Patients for whom a medication can be considered as primary therapy include those who have unacceptable surgical risk, refuse surgery, or have adenomas that are unlikely to be cured surgically. One disadvantage of somatostatin analogs is high cost.
Somatostatin analogs
Somatostatin analogs have been used as an adjunct to surgery and/or radiotherapy, but they are increasingly being used as first line therapy in the treatment of acromegaly.
Somatostatin receptor-2 and -5 subtypes expressed on the somatotroph cell are predominantly responsible for mediation of GH suppression by SRLs. Available formulations (octreotide and lanreotide) selectively bind to these two receptor subtypes on human pituitary tissue. Octreotide is 45 times more potent, has a long half-life (~120 min after sc injection), and lacks rebound hypersecretion, compared with endogenous somatostatin. The usual dose is 100–400 µg sc every 8 h. Long-acting octreotide acetate (octreotide LAR) is a longer-acting depot preparation requiring im injection by a health care professional.
Circulating drug levels peak 28 d after administration of 20–30 mg, and GH levels remain persistently suppressed for up to 7 wk. The im formulation of lanreotide (SR) is injected as a 30-mg dose every 7–14 d, and the deep sc formulation (i.e. Autogel) is injected every 28 d.
Somatostatin analogs efficacy
Somatostatin analogs suppress GH and IGF-I levels effectively and safely. GH levels reach their nadir within 2 h of an sc octreotide injection. A review of SRLs reported that 56% of patients treated with octreotide LAR and 49% of patients treated with lanreotide SR had adequately suppressed GH levels. Similarly, IGF-I levels were reduced in 66 and 48% of octreotide LAR- and lanreotide SR-treated patients, respectively. Approximately 30% of patients receiving SRLs exhibit significant tumor shrinkage, with most SRL studies reporting tumor size reductions of 20–50%.
Somatostatin analogs: safety and tolerability Almost 20 yr of clinical experience with SRLs has proven them to be safe and well tolerated. The most common adverse events associated with these agents are gastrointestinal events (including diarrhea, abdominal discomfort, loose stools, and nausea). Most events were mild in nature and disappeared with continued treatment.
In summary, SRL therapy results in decreases in GH and/or IGF-I levels with significant symptom relief and improved morbidity in a majority of patients. The disadvantages of SRL therapy include gastrointestinal and gallbladder effects, the ongoing cost of treatment, and the lack of tight biochemical control in 36–52% of patients. These drugs do not provide a permanent cure. Long-term treatment and a high level of patient compliance are needed.
Dopamine agonists
Overall, only a small percentage of patients, usually those with only minimal IGF-I elevations, will be controlled by dopamine agonists.
Dopamine agonists: efficacy
Dopamine agonists are orally active agents that bind to D2 receptors in the pituitary and suppress GH secretion in patients with acromegaly. The clinical and biochemical response to dopamine agonists in patients with acromegaly is variable. Prolactin (PRL)-cosecreting tumors show a more favorable response to dopamine agonist therapy. In the past, bromocriptine has been used extensively to treat acromegaly. Although bromocriptine improves clinical signs and symptoms and lowers GH levels in some patients, only 20% of patients (112 of 549) achieved a GH level less than 5 µg/liter, and only 10% of patients (12 of 116) achieved a normal IGF-I level. Large doses of bromocriptine (20 mg/d or more) may be required to obtain these responses. Cabergoline has a prolonged duration of action, is more effective and better tolerated than bromocriptine. In the largest study to date, cabergoline therapy for 3–40 months normalized IGF-I levels (defined as IGF-I <300 µg/liter) in 35% of 48 patients with pure GHsecreting tumors and suppressed GH levels to less than 2 µg/liter in 44%. As expected, efficacy was greater in patients with GH-PRL-cosecreting tumors, of whom 50% had IGF-I normalization and 56% had GH suppression (<2 µg/ liter) with cabergoline therapy.
GH receptor antagonist - Pegvisomant
Pegvisomant acts on peripheral GH receptors to block GH action. Because the drug acts by blocking GH receptors, the efficacy of pegvisomant is independent of tumor characteristics. Pegvisomant does not attempt to lower circulating GH levels, and therefore, GH is not useful as a marker of disease activity in patients being treated with pegvisomant. Thus, the primary biochemical goal of therapy with pegvisomant is to normalize serum IGF-I levels. GH concentrations increase during the first 2 wk of therapy; however, because GH receptors are occupied by pegvisomant, these elevations are not considered clinically relevant.
Pegvisomant efficacy
Pegvisomant has been shown to normalize IGF-I in almost all patients with acromegaly. In a randomized, double-blind, placebo-controlled trial in 112 patients with active disease, normal IGF-I levels were achieved in 89% of patients receiving the highest dose (20 mg/d sc) of pegvisomant. Patients were randomly assigned to receive placebo or pegvisomant at a fixed dose of 10, 15, or 20 mg/d for 12 wk. The most important finding was that a serum IGF-I value within the ageadjusted reference range was achieved in 54, 81, and 89% of patients receiving 10, 15, and 20 mg/d, respectively. Importantly, the fall in serum IGF-I was accompanied by significant improvement in the signs and symptoms of active acromegaly, in particular in soft tissue swelling, excessive perspiration, and fatigue. In longer-term experience with pegvisomant, normalization of serum IGF-I was observed in 97% of 90 patients treated for more than 12 months (mean 425 d) using doses of up to 40 mg/d. The improvement in signs and symptoms was maintained during longterm therapy.
Besides reducing the symptoms of acromegaly, longterm pegvisomant treatment corrects the metabolic defects of acromegaly, including insulin resistance and changes in cortisol and lipid metabolism.
Pegvisomant safety and tolerability
The determination of pegvisomant’s influence on pituitary tumor volume is fundamental to defining its place in the treatment of acromegaly. The influence of pegvisomant therapy is difficult to ascertain because it is not possible to predict which tumors will expand and which will remain the same size without intervention. Long-term surveillance of patients receiving pegvisomant therapy should answer this question. The major adverse effect of pegvisomant on commencing therapy is reversible abnormalities of liver function tests (LFTs). Disadvantages potentially associated with pegvisomant therapy include the cost of ongoing therapy and the need for a high level of patient compliance.
In summary, pegvisomant is the most effective medical therapy for normalizing serum IGF-I levels. Monitoring of LFT results and tumor volume changes is required.
Principles of monitoring therapy
- Symptoms and signs are an important measure of therapy, but they cannot be used in isolation as evidence of adequate control.
- The most helpful biochemical measurements to determine successful cure are GH values following glucose suppression using sensitive assays and random IGF-I levels. In patients treated with pegvisomant, IGF-I is the biological control marker of choice.
- Regardless of the treatment algorithm used, tumor size should be monitored. Magnetic resonance images should be repeated yearly for the first several years after start of therapy unless the tumor is known to be actively growing; in which case more frequent monitoring is required. Visual field assessment by perimetry once or twice per year is recommended in patients with visual problems before therapy and in patients with macroadenomas and residual extrasellar adenoma after surgery.