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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4759-4767
Copyright © 2003 by The Endocrine Society

Optimizing Control of Acromegaly: Integrating a Growth Hormone Receptor Antagonist into the Treatment Algorithm

David R. Clemmons, Kazuo Chihara, Pamela U. Freda, Ken K. Y. Ho, Anne Klibanski, Shlomo Melmed, Stephen M. Shalet, Christian J. Strasburger, Peter J. Trainer and Michael O. Thorner

University of North Carolina at Chapel Hill (D.R.C.), Chapel Hill, North Carolina 27599; Division of Endocrinology/Metabolism, Neurology, and Hematology/Oncology (K.C.), Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan; Department of Medicine (P.U.F.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Pituitary Research Unit (K.K.Y.H.), Garvan Institute of Medical Research, and Department of Endocrinology, St. Vincent’s Hospital, Darlinghurst 2010, Australia; Neuroendocrine Unit (A.K.), Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114; Cedars Sinai Medical Center (S.M.), University of California School of Medicine, Los Angeles, California 90048; Department of Endocrinology (S.M.S., P.J.T.), Christie Hospital, Manchester M20-4BX, United Kingdom; Division of Endocrinology (C.J.S.), Department of Medicine, Charite Campus Mitte, D-80336 Berlin, Germany; and Department of Medicine (M.O.T.), University of Virginia Health System, Charlottesville, Virginia 22908

Address correspondence and reprint requests to: David Clemmons, M.D., Professor of Medicine, University of North Carolina at Chapel Hill, 6111 Thurston-Bowles Building, CB #7170, Chapel Hill, North Carolina 27599. E-mail: endo{at}med.unc.edu.


   Abstract
Top
 Abstract
Introduction
 Mortality and Morbidity
 Diagnosis of Acromegaly and...
 Goals of Therapy
 Current Pharmacological...
 A New Therapy: Pegvisomant
 Conclusions
 References
 
Acromegaly is associated with significant morbidities and a 2- to 3-fold increase in mortality because of the excessive metabolic action of GH and IGF-I, a marker of GH output. Reductions in morbidity correspond with decreases in IGF-I, and mortality is lowered following normalization of IGF-I or GH levels. Therefore, this has become an important end point. Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy, in particular, the place of pegvisomant, a GH receptor antagonist. Treatment goals include normalizing biochemical markers, controlling tumor mass, preserving pituitary function, and relieving signs and symptoms. Surgery reduces tumor volume and is considered first-line therapy. Radiation reduces tumor volume and GH and IGF-I levels, but the onset of action is slow and hypopituitarism typically develops. Therefore, pharmacotherapy is often used following surgery or as first-line therapy for nonresectable tumors. Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH-prolactin-cosecreting tumors but will not achieve hormone normalization in most patients. Somatostatin analogs effectively suppress GH and IGF-I in most patients, but intolerance (e.g. diarrhea, cramping, gallstones) can occur. Pegvisomant, the newest therapeutic option, blocks GH action at peripheral receptors, normalizes IGF-I levels, reduces signs and symptoms, and corrects metabolic defects. Pegvisomant does not appear to affect tumor size and has few adverse effects. Pegvisomant is the most effective drug treatment for acromegaly in normalizing IGF-I and producing a clinical response; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs.


   Introduction
Top
 Abstract
 Introduction
Mortality and Morbidity
 Diagnosis of Acromegaly and...
 Goals of Therapy
 Current Pharmacological...
 A New Therapy: Pegvisomant
 Conclusions
 References
 
SINCE THE MOST recent acromegaly treatment algorithms were published, pegvisomant, a novel GH receptor antagonist (GHRA), has been approved in the United States and Europe, and new data regarding the long-term effects of this therapy have become available. For these reasons, reevaluation of the current treatment guidelines with an emphasis on the role of this new therapy is warranted.

Patients with acromegaly are referred to endocrinologists at several points in the natural history of their disease; therefore, a single algorithm for adequate management of every patient is not practical. However, certain guiding principles will govern decision making at each step in the process. Guiding principles that have been well articulated are based on long-term studies of the natural history of the disease.


   Mortality and Morbidity
Top
 Abstract
 Introduction
 Mortality and Morbidity
Diagnosis of Acromegaly and...
 Goals of Therapy
 Current Pharmacological...
 A New Therapy: Pegvisomant
 Conclusions
 References
 
Numerous epidemiological studies show that poor control of disease activity increases mortality by 2- to 3-fold (1, 2, 3, 4, 5, 6, 7). The greatest contributors to mortality are cardiac, vascular, and respiratory disease (2, 3, 5, 8, 9). Life expectancy in one cohort of 151 patients was reduced by 10 yr (6). Acromegaly also causes significant metabolic, cardiovascular, neurological, respiratory, and musculoskeletal morbidities. The frequencies of these complications are shown in Fig. 1Go. There is strong evidence that these complications are the consequences of GH and IGF-I excess.



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  		FIG. 1. Prevalence of clinical features of acromegaly at diagnosis, averaged from reported series. IGT, Impaired glucose tolerance.

 

   Diagnosis of Acromegaly and Evaluation of Treatment Outcome
Top
 Abstract
 Introduction
 Mortality and Morbidity
 Diagnosis of Acromegaly and...
Goals of Therapy
 Current Pharmacological...
 A New Therapy: Pegvisomant
 Conclusions
 References
 
Diagnosis of acromegaly can be accomplished using biochemical markers of GH action or dynamic tests that directly assess GH secretion. They have complementary roles in the diagnosis and evaluation of treatment outcomes.

IGF-I is a GH-regulated protein that circulates in blood as a ternary complex bound to IGF-binding protein-3 and an acid-labile subunit, both of which are also GH regulated (10, 11, 12). IGF-I is an accurate marker of GH output, with its level in blood defined by a logarithmic (GH) linear (IGF-I) relationship (13, 14, 15, 16). Thus, active acromegaly is characterized by persistent elevation of serum IGF-I levels. IGF-I is a highly sensitive and specific diagnostic tool, but it cannot be used during pregnancy (17, 18). It is equally valuable in assessing treatment efficacy. A normal IGF-I reflects normalization of GH action after treatment or adequate abrogation of GH action during therapy with the GHRA pegvisomant. Attainment of a normal IGF-I level does not necessarily indicate complete restoration of neurosecretory control of GH (14, 19). IGF-binding protein-3 and acid-labile subunit are also reliable markers of GH output (20, 21, 22) but offer no advantage over IGF-I.

Important considerations when evaluating IGF-I levels include age and gender as well as conditions that disrupt IGF-I regulation. Factors that increase IGF-I include pregnancy and adolescence. IGF-I levels are decreased in malnutrition, poorly controlled diabetes mellitus, and liver or end-stage renal disease (17, 23, 24). IGF-I levels should be measured with a reliable, well-characterized assay with age- and gender-matched normative ranges (25).

Dynamic tests may be of value when clinical suspicion is high, random GH levels are low, and IGF-I levels are equivocal (26). Dynamic tests most commonly involve assessment of the GH response to an oral glucose tolerance test (GTT). In general, the GTT is used in conjunction with IGF-I both to diagnose the disease and monitor treatment. The two tests give somewhat different information regarding tumor secretory capacity, with IGF-I providing a measure of net GH bioactivity in peripheral tissues. Both types of information are of value in the diagnosis and monitoring of patients. Because patients with diabetes do not demonstrate a suppression of GH in response to an oral glucose load, the GTT is not a useful diagnostic tool in these patients. Instead, serum IGF-I levels can be used, although in the absence of good control of diabetes, these levels may be lower than expected based on circulating GH levels.

The availability of new, highly sensitive GH assays has led to a careful evaluation of the criteria for normal GH suppression after GTT (27, 28, 29). Previous definitions using conventional RIAs were insufficiently sensitive because GH levels in normal subjects were usually below the limit of detectability. Recent evidence with sensitive assays has shown that normal glucose-suppressed GH levels are much less than 1 µg/liter (27, 28, 29). Data from one series has also shown that glucose-suppressed GH levels should fall less than 0.3 µg/liter in healthy individuals (28). However, not all patients with acromegaly whose postsurgery IGF-I levels are normalized show normal GH suppression after oral glucose (28). It is possible that these patients may be at higher risk for disease recurrence; therefore, these patients should be followed up more closely.

The epidemiological data noted previously were derived from GH measurements made by polyclonal RIAs (30). GH levels measured by newer assays are significantly lower than those determined by polyclonal RIA. Unfortunately, a direct extrapolation between RIA values and immunoradiometric assay or chemiluminescence assays is not possible (28). The availability of epidemiological data validating the GH criteria for disease control and their association with normalization of mortality will be crucial to our use of sensitive GH assays (25).


   Goals of Therapy
Top
 Abstract
 Introduction
 Mortality and Morbidity
 Diagnosis of Acromegaly and...
 Goals of Therapy
Current Pharmacological...
 A New Therapy: Pegvisomant
 Conclusions
 References
 
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.

Tight biochemical control

An important treatment goal is to restore GH hypersecretion or the response to excessive GH to normal, which is reliably gauged by the return of IGF-I levels to an age-adjusted normal range. As a marker of GH action, IGF-I concentrations are a good index of biochemical control. Morbidities such as excessive sweating, obstructive sleep apnea, carpal tunnel syndrome, cardiac dysfunction, and diabetes may improve markedly when IGF-I levels are lowered significantly (31). The strongest case for tight biochemical control comes from mortality data demonstrating that survival in acromegaly is restored to a level similar to that of the general population if random GH levels are less than 2.5 µg/liter or IGF-I levels are normalized (1, 30, 32, 33).

Tumor volume control

The clinical manifestations resulting from the mass effects of an enlarging tumor include headache, visual impairment, hypopituitarism, and rarely hypothalamic dysfunction. Reduction of the mass effect by tumor volume control is also a goal of treatment. Successful pituitary surgery improves visual field abnormalities in nearly 75% of patients with nonfunctioning tumors (34). This is most successfully achieved by surgical resection. Among available drug therapies, somatostatin receptor ligands (SRLs) are more effective than other agents, although the effect is modest (35). Radiation therapy is also effective but has a slow onset of action (36).

Preservation of pituitary function

The three principal modalities of therapy, pharmacotherapy, surgery, and radiation, differ in their efficacy and ability to preserve anterior pituitary function. Preservation of pituitary function is a definite advantage of medical therapy, but this must be balanced against efficacy, tolerability, and cost of treatment.

Theoretically, medical therapies that shrink GH-secreting adenomas may restore pituitary function, although this has not been systematically evaluated. Dopamine agonists have only a modest effect on pure GH-secreting adenomas but induce dramatic shrinkage of macroprolactinomas, which may result in recovery of anterior pituitary function (37, 38). Whereas SRLs inhibit GH secretion, reduction in tumor size is modest and not as great as that induced by dopamine agonists on prolactinomas.

Advances in surgical techniques aimed at selective adenectomy have had a positive impact on preserving pituitary function. Recovery of anterior pituitary hormone deficits that were present before surgery may occur (39, 40, 41, 42, 43).

The frequency and severity of hypopituitarism after radiotherapy is dose related and increases with time after treatment (33, 36, 39, 41, 44, 45, 46). Between 15 and 20% of patients have evidence of pituitary function impairment at the start of radiotherapy, and this increases to more than 50% after 5–10 yr (36, 41). It is not known whether the risk of hypopituitarism differs between conventional radiotherapy and stereotactic radiosurgery.

Reestablish endocrine homeostasis

Glucose intolerance, lipid abnormalities, and pituitary dysfunction are recognized metabolic perturbations of acromegaly that should be managed as part of the overall treatment paradigm. Carbohydrate intolerance or overt diabetes occurs in 25–50% of patients. They result from the direct anti-insulin effects of GH. Hyperglycemia and insulin sensitivity are improved by lowering GH or blocking its activity (9, 47, 48, 49). Hypertriglyceridemia because of decreased hepatic and lipoprotein lipase activities also resolves with treatment.


   Current Pharmacological Treatment Options
Top
 Abstract
 Introduction
 Mortality and Morbidity
 Diagnosis of Acromegaly and...
 Goals of Therapy
 Current Pharmacological...
A New Therapy: Pegvisomant
 Conclusions
 References
 
Current options for the pharmacological treatment of acromegaly include dopamine agonists, SRLs, and GHRA.

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 (38). 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 (37, 50).

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 (37). Large doses of bromocriptine (20 mg/d or more) may be required to obtain these responses.

Cabergoline, a newer dopamine agonist with 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 GH-secreting tumors and suppressed GH levels to less than 2 µg/liter in 44% (50). 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. Lower baseline GH or IGF-I levels were associated with somewhat greater efficacy. IGF-I levels normalized in 43% of patients with GH-secreting tumors with baseline levels less than 750 µg/liter and in 22% of patients with GH-secreting tumors with pretherapy levels more than 750 µg/liter. Most patients received cabergoline at a dose of 1 mg/wk to 1.75 mg/wk; higher doses (up to 3.5 mg/wk) were used in patients resistant to therapy.

Other data with cabergoline are less favorable (51). In combined data from four smaller studies, cabergoline normalized IGF-I levels in only 22% of patients (range 0–27%) (52, 53, 54, 55).

Dopamine agonists: safety and tolerability

Frequent adverse effects of dopamine agonist therapy are nausea, constipation, headache, mood disturbances, nasal stuffiness, and dizziness (37). In comparative studies in patients with prolactinomas, fewer adverse effects occur with cabergoline than with bromocriptine (56, 57). Therapy-limiting adverse effects with cabergoline are uncommon and lessened by slow dose escalation.

In summary, dopamine agonists are orally administered, are less expensive than other medical therapies, and do not disturb pituitary function. Their major disadvantage is that they are ineffective. In addition, side effects at higher doses may limit effectiveness.

Somatostatin analogs

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 (58).

Octreotide is 45 times more potent, has a long half-life (~120 min after sc injection), and lacks rebound hypersecretion, compared with endogenous somatostatin (59). The usual dose is 100–400 µg sc every 8 h (60). 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 (48, 60, 61, 62, 63). The im formulation of lanreotide (SR) is injected as a 30-mg dose every 7–14 d (64, 65, 66, 67), 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 (35). GH levels reach their nadir within 2 h of an sc octreotide injection. In a recent review of SRLs, Freda (35) 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. Importantly, the majority of these patients in the initial octreotide LAR open-label trials were preselected for octreotide responsiveness (35). In a group of newly diagnosed patients, the normalization of GH and IGF-I concentrations was observed among 38% (9 of 24) and 33% (8 of 24) of study patients, respectively, after 24 wk of sc octreotide therapy; tumors also shrank by 43–49% (median) (68). Among a subgroup of 15 patients who received an additional 24 wk of therapy with octreotide LAR, 79 and 53% of patients had normal GH and IGF-I levels, respectively, after 48 wk. Additionally, this subgroup of patients had an additional median tumor reduction of 24%.

Approximately 30% of patients receiving SRLs exhibit significant tumor shrinkage (35, 69, 70, 71, 72, 73, 74, 75, 76), with most SRL studies reporting tumor size reductions of 20–50% (35). Factors accounting for the variable results include postsurgical scarring, radiation effect, differences in imaging techniques, and differences in drug dosages and duration of therapy. Control of GH and IGF-I levels does not appear to correlate with tumor shrinkage, and the predominant mass response occurs within the first year of treatment. The clinical significance of the tumor shrinkage has yet to be fully established because large reductions in tumor size are not necessarily paralleled by biochemical control (68). This may be indicative of different mechanisms for these effects. It is unknown whether tumor shrinkage results in recovery of previously impaired pituitary function.

Headache, fatigue, perspiration, arthralgias, and carpal tunnel syndrome improve or resolve in up to 75% of patients within the first 6 months of SRL therapy (77). Cardiovascular function (blood pressure, cardiac failure, and ejection fraction) also improves, episodes of sleep apnea diminish, and hyperglycemia if present may improve as GH levels are lowered (73, 78, 79, 80). Glycated hemoglobin (A1c) may also improve with therapy (48).

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 octreotide treatment.

The development of gallbladder disease is reported with great variability. This variation may be related to regional and dietary differences; in addition, there are discrepancies in the frequency of related symptoms (48, 60). However, clinically symptomatic gallbladder disease is uncommon (81). Current recommendations are that gallstones be managed in the same manner as in patients without acromegaly (51). In asymptomatic patients, routine gallbladder ultrasonography during somatostatin therapy is not necessary.

Initially occurring symptoms such as cramps, diarrhea, and fatty stools disappear within 10–14 d of continuous administration, probably as a consequence of local adaptation within the gastrointestinal tract and exocrine pancreas (81). Only the effects on biliary composition and gallbladder contractility are of longer duration.

Other less frequent adverse effects of SRLs include bradycardia, transient hair loss, vitamin B12 deficiency, and pain at the injection site in a small percentage of patients receiving the depot formulation (48, 75).

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 (82).


   A New Therapy: Pegvisomant
Top
 Abstract
 Introduction
 Mortality and Morbidity
 Diagnosis of Acromegaly and...
 Goals of Therapy
 Current Pharmacological...
 A New Therapy: Pegvisomant
Conclusions
 References
 
Current treatment modalities for acromegaly endeavor to control pituitary GH secretion. The outcome of surgery depends on the expertise of the surgeon and on the anatomy and invasiveness of the tumor. The response to radiotherapy depends on the radiosensitivity of the tumor. In addition, the anatomy of the tumor may govern the type of radiation therapy that can be given. The effectiveness of conventional medical therapy is determined by the density and function of dopamine and/or somatostatin receptors. In contrast, 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 (83). 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 age-adjusted 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 only 12 wk, mean ring size decreased in a dose-dependent manner up to 2.5 sizes in patients receiving 20 mg/d.

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 (49). The improvement in signs and symptoms was maintained during long-term therapy.

Besides reducing the symptoms of acromegaly, long-term pegvisomant treatment corrects the metabolic defects of acromegaly, including insulin resistance and changes in cortisol and lipid metabolism (84, 85, 86).

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. Van Der Lely et al. (49) reported no significant alteration in mean tumor volume in 131 patients treated for a mean of 1 yr and followed up with semiannual magnetic resonance images. This was true regardless of whether patients had received radiotherapy. Tumors grew in two patients while receiving pegvisomant, but those tumors had grown before therapy (87). It is well known that the growth rate of pituitary tumors is variable. Therefore, 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). Two patients have shown reversible increases in alanine aminotransferase and aspartate aminotransferase within 12 wk of commencing pegvisomant. There were no significant changes in bilirubin. LFT monitoring is essential in all patients commencing pegvisomant. Except for mild, self-limiting injection site reactions reported by 11% of patients in placebo-controlled studies, no significant adverse reactions have been reported with this drug. Disadvantages potentially associated with pegvisomant therapy, as with other medical therapies, 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

1. Symptoms and signs are an important measure of therapy, but they cannot be used in isolation as evidence of adequate control. Although often greatly improved, biochemical indices of acromegaly may remain significantly abnormal. Because this observation has been demonstrated repeatedly, a combination of clinical and biochemical assessment is important for establishing the need for further therapeutic measures to be undertaken.

2. 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.

3. 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.

Treatment algorithms (Fig. 2Go)

For initial therapy of acromegaly, two treatment options, transsphenoidal surgery or primary medical therapy, have been used. Numerous reviews have expressed the importance of a highly skilled neurosurgeon in determining surgical cure (88, 89, 90). This is reinforced by the variability of surgical outcome, which varies from approximately 12–90%, depending on the type of tumor (macroadenoma, microadenoma), the experience and skill of the neurosurgeon, and the definition of a cure (88, 90). In patients with microadenomas, surgical cure rates by skilled surgeons are as high as 90%; therefore, surgery should be the first line of therapy in these patients when such surgical expertise is available. Transsphenoidal surgery is almost always chosen as the first therapeutic option. The reasons supporting this conclusion are potential for cure, thus avoiding the need for lifelong medical therapy, and decompression of the tumor mass, thus avoiding potential complications secondary to mass effect, such as optic chiasm compression, cavernous sinus invasion, and panhypopituitarism. In addition, results of some studies suggest that tumor debulking allows easier control of GH secretion from the residual tumor with medical therapy.



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  		FIG. 2. Treatment algorithm. MRI, Magnetic resonance imaging; DA, dopamine.

 
Although primary medical therapy is a desirable goal, no long-term data exist regarding its effects on morbidity and mortality. Some retrospective and prospective studies indicate that primary treatment with an SRL may provide long-term biochemical control equivalent to that of surgery or surgery plus subsequent medical treatment (74, 91). However, no controlled data support preoperative use of primary medical therapy as a means of improving surgical outcome. For these reasons, transsphenoidal surgery should be a first option in patients with resectable adenomas or symptoms requiring decompression until adequate data regarding the long-term efficacy and safety of primary medical therapy are available.

The issue of whether postsurgical radiotherapy should be offered often arises. In past years it had been used routinely in patients in whom surgery had failed. With the advent of new medical therapies and the known disadvantages of radiotherapy, more conservative use of radiotherapy should be practiced. Thus, the role of radiotherapy in controlling disease activity is less well defined. Clearly, if followed long enough, many patients will benefit from radiotherapy with an improvement in symptoms and signs and lowering of GH and IGF-I. However, the time interval required to obtain improvement in these parameters, compared with that obtained with pharmacotherapy, can be long (in excess of 10 yr). IGF-I levels normalize in more than 80% of patients after 10 yr, but medical therapy is required in the interim to maintain normal IGF-I levels, and vigilance is needed to monitor for development of pituitary deficiency (36, 92). Therefore, at this time, the factors that need to be considered before deciding if radiotherapy should be given include the size and location of residual tumor, the degree of biochemical abnormality, the ability of the patient to sustain the cost of long-term medical therapy, and the prior existence of hypopituitarism. In general, postoperative radiation therapy should be reserved for those patients whose hormone levels fail to normalize with medical therapy. Likewise, although uncommon, radiotherapy may be followed by structural central nervous system and/or optic pathway damage and extremely rarely, secondary malignancies, including sarcoma development. These issues should be discussed with the patient before undertaking this therapy.

Because the surgical cure rate and number of patients considered candidates for supplemental radiotherapy are low, the most common scenario following transsphenoidal surgery is likely to be a decision to proceed with medical therapy. A therapeutic trial of dopamine agonists can be attempted in patients who have mild elevations of GH and IGF-I and, in particular, those with GH-PRL-cosecreting tumors. Follow-up evaluation can be conducted relatively rapidly, and a final decision about efficacy should be made at approximately 3 months to determine whether adequate improvement in signs and symptoms and GH and IGF-I values has been achieved. If adequate improvement is shown, long-term therapy with these agents is reasonable, and data indicate that this degree of suppression can be maintained if adequate patient compliance is present. For this small group of patients with acromegaly, this represents a reasonable treatment option and should be strongly considered.

Consensus among experts is that the majority of patients will require long-term maintenance therapy with SRLs or pegvisomant. The major advantage of SRLs is low frequency of administration and sustained suppression of GH and IGF-I in patients in whom adequate suppression occurs. The disadvantages can include the need for health care professionals to administer long-acting analogs as well as acute and chronic adverse effects, such as gastrointestinal symptoms (i.e. diarrhea and abdominal pain), biliary sludging, or, rarely, gallstones. The incidence of these adverse effects appears to vary widely geographically, and, therefore, it is not possible to predict whether they will occur in a given patient. Somatostatin analog therapy should be initiated with an empiric trial with a short-acting agent. If tolerated, a long-acting SRL can be administered. If gallstones develop and do not require an emergency cholecystectomy, consideration should be given to stopping the drug and starting a GHRA. Chronic maintenance of normal GH and IGF-I levels is possible with SRLs and, if achieved early in therapy, is likely to be maintained. If headaches are the predominant symptom and they are relieved with short-acting SRLs, preferential consideration should be given to chronic therapy with those agents.

There is less long-term experience with pegvisomant in treating acromegaly, compared with dopamine agonists and SRLs. Experience with this drug has been limited to 3 yr; however, safety data during this time indicate that pegvisomant is safe and has a very low adverse event profile. Pegvisomant may be considered as first-line medical therapy in patients who have never been exposed to other medical therapies. There has been a concern that use of this drug would result in further tumor enlargement. However, current experience suggests that pegvisomant is not likely to stimulate tumor enlargement. Because tumor size has not been shown to increase and because this drug is highly efficacious, it represents a very reasonable choice for medical therapy. This is the preferred drug for patients who are resistant to or intolerant of SRLs, and these patients should be strongly considered for monotherapy with pegvisomant. Although combination therapy with the GHRA and an SRL is feasible, there is very little experience with this combination, and no published safety data are available. The cost of overall therapy would increase significantly using the combination. Additionally, because of the high rate of IGF-I normalization associated with GHRA therapy, there is no compelling need for combined therapy except in very rare instances in which IGF-I cannot be normalized or intense headaches remain a prominent complaint.


   Conclusions
Top
 Abstract
 Introduction
 Mortality and Morbidity
 Diagnosis of Acromegaly and...
 Goals of Therapy
 Current Pharmacological...
 A New Therapy: Pegvisomant
 Conclusions
References
 
In summary, the management of acromegaly is complex because of the chronic, insidious progression of signs and symptoms of the disease and the varied presentations of patients who are referred to pituitary disease specialists. With the addition of pegvisomant to the current therapeutic armamentarium, we are now in an era in which biochemical control of acromegaly can be attained in almost every patient. The algorithm selected will be determined by the endocrine state and the tumor anatomy. Choosing the appropriate treatment algorithm involves selecting an individualized treatment program for each patient based on clinical and biochemical parameters as well as issues of efficacy, safety, cost, and availability of treatment options. A rational decision can be made in almost all cases, but it requires empiric follow-up to verify that the best option has been selected. Future clinical research studies and drug development are likely to alter this paradigm, but at present, this is the optimum series of steps among the treatment options available.


   Acknowledgments
 
The content of this article was developed at a meeting held October 3–5, 2002, in Chatham, Massechusetts, with Drs. Clemmons and Thorner acting as the conference coordinators and hosts. All listed authors attended this meeting and participated in the rigorous review of data, writing, and preparation of this article.


   Footnotes
 
This meeting was supported by an unrestricted educational grant from Pharmacia Corporation.

Abbreviations: GHRA, GH receptor antagonist; GTT, glucose tolerance test; LFT, liver function test; PRL, prolactin; SRL, somatostatin receptor ligand.

Received March 25, 2003.

Accepted July 1, 2003.


   References
Top
 Abstract
 Introduction
 Mortality and Morbidity
 Diagnosis of Acromegaly and...
 Goals of Therapy
 Current Pharmacological...
 A New Therapy: Pegvisomant
 Conclusions
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals