Acromegaly: A Rational Approach to Medical Management of Patients with Residual and Recurrent Disease

Educational Objectives

The goal of this program is to improve management of residual and recurrent disease in acromegaly using medical therapy. After hearing and assimilating this program, the clinician will be better able to:

1. Summarize pitfalls of currently available clinical practice guidelines and algorithms for treatment of acromegaly.
2. Identify factors that increase risk for recurrent or residual disease.
3. Describe the mechanism of action, efficacy, and side effects of medical therapies used for acromegaly.
4. Select optimal treatment strategies for patients with acromegaly based on disease characteristics.
5. Develop strategies for management of patients with acromegaly based on treatment setting and disease characteristics.

Summary

Incidence and prevalence: incidence — 3 to 4 million cases are diagnosed per year worldwide; prevalence — 40 to 90 cases per million individuals; time to diagnosis — often delayed by 4 to 10 yr

Causes: pituitary adenoma is the primary cause, but acromegaly is occasionally caused by genetic syndromes (eg, McCune-Albright syndrome and Carney complex) and growth hormone-releasing hormone-secreting tumors; of pituitary adenomas, ≈75% are macroadenomas and ≈25% are microadenomas

Characteristics: micromegaly refers to a condition with clinical and biochemical features of acromegaly without classic findings on magnetic resonance imaging (MRI), with tumors ≈2 mm in size; giant adenomas measure >4 cm in greatest dimension; co-secretion of prolactin and thyroid-stimulating hormone is common; double adenomas may be present and produce different types of hormones

Outcomes

Definition of remission after surgery: in the past, surgery was considered successful if patients achieved random growth hormone (GH) levels of <5 ng/mL and GH of <2 ng/mL on a glucose suppression test, but long-term outcomes were shown to be poor; currently, success is now defined as achieving normal insulin-like growth factor-1 (IGF-1) levels (ideally in the lower half of the normal range) and random GH level of <1 ng/mL on a sensitive assay; GH of <0.4 ng/mL on a glucose suppression tests is associated with lower likelihood of recurrence; however, cutoff values used in studies vary

Survival: study showed that patients who achieved a normal IGF-1 after transsphenoidal surgery had better survival than those who had an elevated IGF-1, independent of additional treatment; Holdaway et al (2004) found that survival was similar to that of the healthy population in patients with normal IGF-1 level after transsphenoidal surgery but was poorer for patients with IGF-1 levels above the upper limit of normal; survival was similar to that of the healthy population in patients with GH <1 ng/mL, although higher levels of GH were associated with increasingly poor outcomes; comorbidities, eg, diabetes, hypertension, and sleep apnea, are also associated with poorer survival

Remission following surgery: rates reported in surgical series are 75% to 95% of patients with intrasellar microadenomas and 45% to 68% for noninvasive macroadenomas; for invasive macroadenomas, rate depends on the degree and location of invasion

Predictors of recurrence: rates vary because of length of follow-up and definition of recurrence but are generally higher for invasive and noninvasive macroadenomas than for microadenomas; remission rates are lower with acromegaly than with prolactinomas and Cushing disease but are higher than with nonfunctioning tumors because surgeons often decompress the visual pathways rather than completely remove the tumors (which can be aggressive); size and invasiveness of the tumor, regardless of type, are predictive of residual or recurrent disease; Meji et al (2002) studied biopsies of postoperative tumor cavities and found microscopic invasion in many cases, but recurrence rates were lower than in cases with residual disease, likely because the areas were devascularized; recurrence from microscopic disease may occur in different areas along the periphery of the evacuated space where the tumor was located; residual or recurrent disease is more likely to occur in patients with a high GH level at baseline; cure rates are higher in patients who receive surgery from an experienced surgeon

Management of residual or recurrent disease: the first priority is to improve symptoms and signs of the disease and treat comorbidities that affect outcomes, with the goal of improving overall survival; IGF-1 and GH levels should be normalized; the secondary goal involves control of residual tumors by resolving mass effects, preventing progression, and preserving or improving pituitary function with surgery; most patients need at least one therapeutic modality (eg, repeat surgery, radiotherapy with repeat surgery, radiotherapy with medical therapy, or medical therapy alone), and optimal treatment is highly individual

Pitfalls of guidelines and algorithms: existing guidelines are based on data from large studies and do not consider patient factors (eg, tissue biology, neuropsychiatric and psychological factors, and family and work situations); bias from authors and sponsors may be present, and caveats of therapies and ramifications of third-party payer mandates are often overlooked; insurance companies may insist on use of medications that are not appropriate for the patient and do not consider medicolegal ramifications; the efficacy of drugs may not be the same as that described in the literature; there may not be a consensus about optimal management practices even after guidelines are published; some algorithms do not offer a choice between drugs; considerations about the age of the patient, overall health, or complications of acromegaly are often overlooked; therapies can be complex, and patients need to make informed choices, implement and monitor treatment, and accept side effects; therapy may need to be altered based on tumor size, invasiveness, or secretory status; patient response to prior intervention and comorbidities that alter treatment are often overlooked; radiotherapy is not strongly recommended in many guidelines but often allows patients to stop medical therapy sooner and controls local tumor growth; financial constraints (insurance covers and copays) are also overlooked

Medical Therapies

Indications: generally reserved for patients who do not achieve control with surgery or radiotherapy; can also be used preoperatively in patients with severe respiratory or cardiac compromise; used either alone or in addition to radiotherapy

Dopamine agonists

Mechanism of action: bind to dopamine receptors on tumor cells and inhibit production and release of GH and prolactin; expression of dopamine receptors on tumor cells and proper functioning of the enzymatic machinery are needed for the drug to be effective

Indications: good option for tumors with prolactin co-secretion, mammosomatotroph adenomas, or acidophil stem cell adenomas; patients with mildly elevated IGF-1 levels and older patients (especially women) tend to respond well; may be considered prior to surgery in patients with invasive tumors, normal pituitary function, and no visual compromise

Efficacy: study found that ≈15% of patients achieved normal IGF-1 levels with bromocriptine (high doses are often needed); patients with acromegaly tend to tolerate higher doses than those with prolactinomas; studies show that 20% to 40% of patients achieve normal IGF-1 levels with cabergoline, but caution is warranted when prescribing high doses for patients with acromegalic cardiomyopathy or hypertensive heart disease because dopamine agonists activate serotonin receptors on the endocardium and cause structural changes (eg, endocardial fibroelastosis, enlarged annuli, and thickened chordae tendineae); patients may have a complete or partial response, and agents can also be combined with other classes of drugs

Somatostatin analogues (SSAs)

Mechanism of action: bind to somatostatin receptors (SSTRs) on pituitary adenomas and block production of GH; SSTR2 and SSTR5 may be present in GH-secreting tumors; mechanisms of signal transduction and expression of receptors are necessary for efficacy; some patients who have positive SSTR2 immunostaining do not respond to SSAs because signal transduction pathways may not work in dedifferentiated tumors

Benefits and indications: normalizing the GH and IGF-1 levels improves comorbidities; patients with significant residual tumor and those with high SSTR2 immunostaining may benefit from SSAs, but patients with no MRI findings and active acromegaly are unlikely to benefit

Types: devices, routes of administration, and pharmacokinetics (eg, gels or microspheres) differ among products, and it is important to know characteristics of individual products and when to check IGF-1 levels or change doses

Efficacy: one study found that 38% to 68% of patients achieved normal IGF-1 levels and a GH level <2.5 ng/mL; another study found that 54% to ≈75% of patients achieved normalization of IGF-1 alone; other studies suggest that both criteria are achieved in ≈55% of patients; in unselected populations, ≈44% and ≈34% of patients achieved a GH level of <2.5 ng/mL and normal IGF-1, respectively

Tumor regression: has been described when used for primary or residual and recurrent disease; occurs in ≈43% of patients on octreotide long-acting release (LAR), ≈17% of patients on lanreotide LAR, and 48% of patients treated before surgery; patients with sleep apnea may benefit from SSA therapy given preoperatively

Side effects: include cholelithiasis, gastrointestinal symptoms due to maldigestion and malabsorption, hypothyroidism, glucose intolerance and diabetes mellitus, and delayed atrioventricular conduction (rare)

Considerations: patients should be educated about each drug and given a choice; LAR products take ≈3 mo to determine efficacy, whereas gel and oral products take 6 to 8 wk; efficacy of oral SSAs is ≈80% among patients who respond to injectable SSAs

Pegvisomant

Mechanism of action: growth hormone receptor antagonist (GHRA) that incapacitates GH receptors on cells and decrease hepatic production of IGF-1

Side effects: abnormal liver function tests, skin changes, or injection site reactions (in patients with latex allergy) may occur

Indications: can be given to patients with glucose intolerance or diabetes mellitus, as well as patients with biochemical evidence of disease but unidentifiable or small residual tumors; patients who have severe side effects with SSAs can be switched to GHRAs unless tumor control is needed

Efficacy: a study found that most patients across age groups achieve normal or low IGF-1 levels (although low IGF-1 levels may cause symptoms of GH deficiency, and treatment should be discontinued if this occurs); ≈97% of patients achieved normal IGF-1 levels with doses of ≤40 mg

ACROSTUDY trial: assessed efficacy of pegvisomant in the real-world setting; tumor enlargement was observed in ≈3.2% of patients (although this rate is similar to that observed without the drug); abnormal liver function tests were observed in 2.5%, which is thought to be due to pegylation of the drug (although the change was reversible); other liver conditions (eg, cholelithiasis, Gilbert syndrome, hepatitis, and fatty infiltration of the liver unrelated to the drug) and injection site reactions were also observed; ≈63% of patients had normal IGF-1 levels after 5 yr, although the low dose used in the study (mean of 18 mg) suggests that the drug may be underutilized or not escalated properly

Considerations for selection of therapy: histopathologic evaluation is recommended for residual or recurrent acromegaly with no residual tumor identified on MRI; positive staining for SSTR2 — pegvisomant can be given; dopamine agonists can be considered if the tumor is co-secreting prolactin; residual tumor on MRI and plans for radiotherapy — pegvisomant may be beneficial because it does not suppress tumor cells, which allows for increased cell turnover, mitosis, and apoptosis from radiation damage; positive or unknown SSTR2 immunostaining and no need for radiotherapy — SSA, dopamine agonist (if prolactin is positive), or pegvisomant can be given; negative SSTR2 and positive prolactin immunostaining — dopamine agonist is the first choice; pegvisomant may be considered; negative prolactin and SSTR2 immunostaining — pegvisomant can be used

Combination therapy: treatment with one drug should be optimized to the maximum recommended dose before adding another drug; if one drug does not work, it should be discontinued (rather than adding a second drug); patients on SSA therapy can try switching to another SSA; if a patient has a partial response to one drug, it is better to switch to a drug that may be more effective, unless there is a reason to continue the first drug (eg, tumor regression is seen); if needed, a low dose of a second drug can be started and titrated upward as needed; studies showed that adding cabergoline to an SSA is beneficial for patients with a partial response to the SSA; an SSA with pegvisomant given twice weekly is effective for many patients

Considerations in pregnancy: IGF-1 levels improve or remain stable in most pregnant patients because estrogens induce hepatic resistance to GH; diethylstilbestrol therapy reduces symptoms of acromegaly but was abandoned due to abnormal menstrual bleeding in women and breast growth in men; a study found that tumor size increases in ≈9% of pregnant women with acromegaly; the incidence of gestational diabetes mellitus or hypertension is slightly higher than in the normal population; patients can be treated medically during pregnancy and undergo surgery after delivery, and medication can be discontinued during pregnancy in some patients; dopamine agonists, SSAs, and GHRAs are not associated with adverse maternal or fetal outcomes, but SSAs can increase risk for gestational diabetes mellitus; dopamine agonists and SSAs cross the placenta and may increase risk for mild microsomia, but GHRAs do not and can be tried first; patients with severe headaches associated with acromegaly may respond to subcutaneous octreotide

Questions and answers

Duration between starting therapy and dose adjustment or discontinuation: IGF-1 levels reach their nadir ≈6 wk after surgery, but ≤12 wk may be needed to determine if medical therapy is needed; for patients taking SSA therapy, IGF-1 levels should be checked ≈2 wk after the third dose; for patients taking lanreotide (eg, Somatuline Depot), IGF-1 levels should be checked ≈6 wk after starting therapy or adjusting the dose to assess response

Selection of optimal dose of cabergoline: can be started at a dose of 0.25 mg once or twice per week for patients (particularly women) with hyperprolactinemia and microadenoma; for patients with acromegaly, starting dose of 0.5 mg 2 to 3 times per week is typical (particularly if a large tumor is present) and increased to ≤1 mg/day as tolerated

Monitoring of patients with acromegaly: routine testing of prolactin and IGF-1 levels at the outset can identify co-secretion or a stalk effect; for co-secreting tumors, prolactin levels are checked regularly with IGF-1 and GH levels because an increase in prolactin can identify recurrence before IGF-1 levels rise

Assessment of need for lifelong medical therapy: patients undergoing radiotherapy often do not need lifelong medical therapy because they often go into remission; responses may be observed after 1 to 2 yr of stereotactic radiosurgery and 3 to 5 yr of conventional radiotherapy; radiotherapy can be withdrawn if a decrease in IGF-1 is observed, and IGF-1 level can be monitored for 6 to 8 wk; if IGF-1 increases, treatment should be resumed for another year, at which point IGF-1 is rechecked; ≈75% of patients are in remission 7 yr after stereotactic radiosurgery and 15 yr after conventional radiotherapy

Treatment for GH deficiency in patients with nonfunctioning tumors: the goal of GH replacement is to restore IGF-1 levels to the normal range (determined based on resolution of signs and symptoms) and eliminate side effects; for residual tumors, risk for progression in response to GH is not increased; surgery is not needed if pituitary function is normal, and restoring GH and IGF-1 levels does not cause tumor growth; in patients with craniopharyngioma, meningioma, and chordoma, GH replacement can be considered ≥1 yr after surgery if no growth of the residual tumor is observed; ≈50% of patients with severe GH deficiency have normal IGF-1 levels, and poor quality of life after surgical resection and optimization of other hormone levels may indicate GH deficiency

Testing for GH deficiency: unnecessary for patients with hypopituitarism and normal IGF-1 levels because they are deficient in GH in ≈99% of cases; an IGF-1 Z score between 0 and 1 is ideal; most patients tolerate GH replacement without elevation in IGF-1

Readings

Brzana JA, Yedinak CG, Delashaw JB, et al. Discordant growth hormone and IGF-1 levels post pituitary surgery in patients with acromegaly naïve to medical therapy and radiation: what to follow, GH or IGF-1 values? Pituitary. 2012; 15(4):562-570. doi:10.1007/s11102-011-0369-1; Butz LB, Sullivan SE, Chandler WF, et al. “Micromegaly": an update on the prevalence of acromegaly with apparently normal GH secretion in the modern era. Pituitary. 2016; 19(6):547-551. doi:10.1007/s11102-016-0735-0; Chen L, White WL, Spetzler RF, et al. A prospective study of nonfunctioning pituitary adenomas: presentation, management, and clinical outcome. J Neurooncol. 2011; 102(1):129-138. doi:10.1007/s11060-010-0302-x; Clemmons DR, Chihara K, Freda PU, et al. Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm. J Clin Endocrinol Metab. 2003; 88(10):4759-4767. doi:10.1210/jc.2003-03051; de Vries F, Lobatto DJ, Verstegen MJT, et al. Outcome squares integrating efficacy and safety, as applied to functioning pituitary adenoma surgery. J Clin Endocrinol Metab. 2021; 106(9):e3300-e3311. doi:10.1210/clinem/dgab138; Gittoes NJ, Sheppard MC, Johnson AP, et al. Outcome of surgery for acromegaly--the experience of a dedicated pituitary surgeon. QJM. 1999; 92(12):741-745. doi:10.1093/qjmed/92.12.741; Hannon AM, O'Shea T, Thompson CA, et al. Pregnancy in acromegaly is safe and is associated with improvements in IGF-1 concentrations. Eur J Endocrinol. 2019; 180(4):K21-K29. doi:10.1530/EJE-18-0688; Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004; 89(2):667-674. doi:10.1210/jc.2003-031199; Manjila S, Wu OC, Khan FR, et al. Pharmacological management of acromegaly: a current perspective. Neurosurg Focus. 2010; 29(4):E14. doi:10.3171/2010.7.FOCUS10168; Meij BP, Lopes MB, Ellegala DB, et al. The long-term significance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. J Neurosurg. 2002; 96(2):195-208. doi:10.3171/jns.2002.February 96, 0195; Melmed S, Bronstein MD, Chanson P, et al. A Consensus Statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018; 14(9):552-561. doi:10.1038/s41574-018-0058-5; Ramos-Leví AM, Marazuela M. Cardiovascular comorbidities in acromegaly: an update on their diagnosis and management. Endocrine. 2017; 55(2):346-359. doi:10.1007/s12020-016-1191-3; van der Lely AJ, Biller BM, Brue T, et al. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab. 2012; 97(5):1589-1597. doi:10.1210/jc.2011-2508; Verhelst J, Abs R, Maiter D, et al. Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab. 1999; 84(7):2518-2522. doi:10.1210/jcem.July 84, 5810.

Disclosures

Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Blevins was recorded at Pituitary Disorders: Advances in Diagnosis and Management, held virtually on August 14-15, 2021, and presented by the University of California, San Francisco School of Medicine. For information on future CME activities from this presenter, please visit meded.ucsf.edu/continuing-education. Audio Digest thanks the speaker and the University of California, San Francisco School of Medicine for their cooperation in the production of this program.

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