Recent advances in the management of acromegaly

Somatostatin analogues

Somatostatin downregulates GH secretion and induces cell cycle arrest and apoptosis through binding to five subtypes (somatostatin receptors 1–5 [SSTR1-SSTR5]) of G-protein-coupled receptors expressed on the somatotroph cells. Somatotroph adenomas express somatostatin receptor subtype 2 (SSTR2) and SSTR5 at high levels, and somatostatin analogues (SSAs) with greater specificity for these receptors and a longer half-life (than the 2–3 minutes of the natural somatostatin molecule) have been developed (octreotide and lanreotide).

Somatostatin analogues as pre-operative medical therapy. Acromegalic patients present a challenge peri-operatively, as their airway anatomy and cardiovascular co-morbidities increase the risk of anesthetic complications^12,13. Pre-operative treatment with SSAs is not recommended routinely⁴, but in selected cases it may rapidly reduce soft tissue swelling, improve sleep apnea and cardiac function, and reduce intubation-related complications^13–16. A recent meta-analysis of five retrospective controlled, two prospective non-randomized, and three prospective randomized controlled studies explored the role of pre-operative use of SSAs in improving biochemical cure rate after surgery; the results were consistent with a borderline significant effect (pooled odds ratio [OR] 1.62; 95% confidence interval [CI] 0.93–2.82). When only the three randomized prospective controlled trials were analyzed, a significant benefit was found with a pooled OR of 3.62 (95% CI 1.88–6.96)¹⁷.

In a group of 30 newly diagnosed acromegalics, pre-surgical treatment with lanreotide autogel for 24 weeks induced tumor shrinkage ≥20% in 79% (23/29) and resulted in mean GH <1 μg/L and IGF-1 normalization in 33.3% (10/33) of the patients. Metabolic profile including fasting blood glucose, HbA1c, lipids, and blood pressure did not change significantly, but amelioration of arterial stiffness and endothelial function were documented. Notably, the apnea/hypopnea index improved in 61%, remained unchanged in 8.7%, and deteriorated significantly in 30.4% of the patients¹⁸.

Fougner et al. evaluated the impact of pre-operative octreotide treatment on long-term remission. When both remission criteria of IGF-1 levels ≤ upper limit of normal (ULN) and nadir GH ≤2 mU/L on the oral glucose tolerance test were applied, no beneficial effect was confirmed 1 and 5 years post-operatively for both microadenoma and macroadenoma subgroups¹⁹.

Somatostatin analogues as primary therapy. The 2014 Endocrine Society Clinical Practice Guideline recommends that primary therapy with SSAs is principally used for a subgroup of patients with larger tumors when surgical cure is unlikely and, additionally, if surgery is refused or contraindicated⁴.

Primary therapy with lanreotide autogel was evaluated in a prospective 48-week multicenter study which recruited 90 naive acromegalics with macroadenomas. Tumor shrinkage ≥20% was observed in 54.1%, 56.3%, and 62.9% of patients at 12, 24, and 48 weeks, respectively, and mean GH ≤1.0 μg/L and IGF-1 normalization was reported in 21.4%, 23.4%, and 30.6% of patients at the same time intervals²⁰.

Furthermore, a meta-analysis of 35 studies on treatment-naive acromegalics showed that in comparison with medical treatment, surgery was associated with higher remission rates at longer follow-up periods (≥24 months) but not at shorter follow-up intervals (≤6 months)²¹.

The effect of different treatment modalities on mortality rates was evaluated in 438 acromegalic patients for the period 1966–2009 by Bogazzi et al.²². Interestingly, after correction for several covariates, the risk of death in patients receiving primary SSA therapy was five times higher than the risk in all patients submitted to adenomectomy (hazard ratio [HR]: 5.52, 95% CI 1.06–28.77, p=0.043). Stratification of patients by the presence of diabetes mellitus revealed that diabetic patients receiving primary SSA therapy had a significantly elevated HR of 21.94 (95% CI 1.56–309.04, p=0.022), whereas in non-diabetic ones the HR was only 1.30 (95% CI 0.04–38.09, p=0.881)²².

Somatostatin analogues as adjuvant medical therapy. SSAs are a treatment option for patients with significant persistent disease after surgery⁴. Adenoma GH granularity and SSTR2A-positive immunohistochemistry may predict the response with the densely granulated and those expressing SSTR2A being more responsive^23–27. Sparsely granulated adenomas exhibit lower SSTR2 expression and respond less to somatostatin receptor ligands (SRLs)^25,27; it is presumed that, if SSTR5 expression is present, response to novel SSAs may be the case²⁸. It has also been reported that Ki-67 is higher in non-SSA responders^29,30.

T2 intensity on magnetic resonance imaging (MRI) has also been proposed as a marker of responsiveness. Hypointense T2-weighted MRI signal is associated with a better responsiveness to octreotide than an isointense or hyperintense one in patients not cured after surgery³¹. Notably, it has been suggested that hyperintense tumors have lower baseline GH and IGF-1 levels and tend to be larger than the hypointense ones. T2 intensity and granulation pattern correlate and sparsely granulated adenomas tend to be hyperintense^32,33.

Effectiveness of somatostatin analogues. A recent meta-analysis on the biochemical response rates to SSAs as primary or adjuvant therapy – including retrospective and prospective studies with both short- and long-acting octreotide and lanreotide formulations (sustained-release and depot/autogel) – between 1987 and 2012 (total of 3787 patients) showed that the average GH control rate was 56% and the IGF-1 normalization rate was 55% with no significant difference in the effectiveness between the different SSA agents³⁴.

Furthermore, a meta-analysis of 41 studies on the effects of octreotide (as first-line or adjuvant therapy) on tumor shrinkage revealed that overall 57% of patients achieved >20% volume decrease. Tumor shrinkage was greater in patients treated with octreotide long-acting release (LAR) rather than subcutaneous octreotide and in those achieving mean GH levels below 2.0–2.5 ng/ml or normal IGF-1³⁵.

The option of discontinuing octreotide in patients well-controlled on low doses offered at long intervals was studied in 12 responders fulfilling the following criteria: single basal GH <1.5 ng/ml and IGF-1 <1.2*ULN, no history of irradiation or recent dopamine agonist use, and tumor remnant <8 mm after discontinuation of octreotide. Five patients (41.7%) remained in remission after 12 months of follow-up and seven (58.3%) relapsed within 1 year of discontinuation. Interestingly, three out of five subjects who remained in remission were on octreotide LAR injections every 12 weeks but none of the seven who recurred³⁶.

Finally, a number of studies have shown that surgical debulking of the adenoma improves the subsequent response to SSAs^37–39.

Oral octreotide

Recently, oral octreotide capsules (OOCs) have become available. The capsule contains 20 mg non-modified octreotide acetate formulated with a novel transient permeability enhancer, which enables transient and reversible paracellular tight junction passage of molecules <70 kDa. This new formulation facilitates intestinal octreotide absorption.

OOC effectiveness in maintaining biochemical response to injectable SSAs has been assessed in a phase III multicenter, open-label, dose-titration, baseline-controlled study. A total of 155 complete or partially controlled patients (IGF-1 <1.3*ULN, and 2-h integrated GH <2.5 ng/mL) receiving injectable SSAs for ≥3 months were switched to 40 mg daily OOCs; the dose was escalated to 60 mg and then up to 80 mg daily. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. A total of 65% of the participants maintained response and achieved the primary endpoint of IGF-1 <1.3*ULN and mean GH <2.5 ng/mL at the end of the core treatment period; this rate was 62% after 13 months’ treatment⁴⁰. Further studies on the efficacy, safety, and convenience of this formulation are needed.

Pasireotide

Pasireotide is a novel multi-ligand SRL with high affinity for SSTR1, SSTR2, SSTR3, and particularly SSTR5. In a head-to-head comparison prospective study of pasireotide vs. octreotide in 358 medical treatment-naive patients, biochemical control (defined as mean GH <2.5 μg/L and normal for age IGF-1) at 12 months was achieved in a higher percentage of patients on pasireotide in both the de novo and the post-surgical groups (31.3% vs. 19.2%; p=0.007). Interestingly, the two drugs had the same effect on GH inhibition, but pasireotide was more effective in reducing IGF-1⁴¹.

The PAOLA study randomly assigned 198 inadequately controlled patients (previously treated with 30 mg octreotide long-acting or 120 mg lanreotide autogel as monotherapy for 6 months or longer) to pasireotide 40 mg, pasireotide 60 mg, or continued treatment with octreotide or lanreotide. At 24 weeks, 15% of the patients of the pasireotide 40 mg group and 20% of the pasireotide 60 mg group achieved biochemical control; no patient in the sustained octreotide or lanreotide group achieved this goal (absolute difference from control group 15.4%, 95% CI 7.6–26.5, p=0.0006 for pasireotide 40 mg group, 20.0%, 95% CI 11.1–31.8, p<0.0001 for pasireotide 60 mg group)⁴².

It should be noted that the impact of pasireotide on blood glucose control remains a concern^41,42 and careful monitoring of glycemic status is required. Pasireotide-associated hyperglycemia is related to reduced insulin secretion and incretin hormone responses, without changes in hepatic/peripheral insulin sensitivity⁴³. Pasireotide has the highest affinity for SSTR5, which is known to play an important role in mediating insulin secretion. Dipeptidyl peptidase (DPP)-4 inhibitors (e.g. sitagliptin, vildagliptin, saxagliptin, and linagliptin) and glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. liraglutide and exenatide) may be the most effective agents for controlling pasireotide-associated hyperglycemia⁴⁴.

Pegvisomant

Pegvisomant is a human GH receptor antagonist which blocks the production of IGF-1. The latest analysis from the ACROSTUDY included 1288 patients and reported IGF-1 control in 63% of them after 5 years on pegvisomant⁴⁵. Increase in adenoma size was found in 3.2% of the patients and increase in the hepatic enzymes >3 times the ULN in 2.5%; no case of liver failure was described. The current recommendations suggest monitoring liver function tests monthly for the first 6 months and 6-monthly thereafter with consideration of discontinuation of pegvisomant in case of >3-fold elevation of transaminases. As pegvisomant does not have a tumor-suppressive effect, it is proposed that imaging is performed at 6 and 12 months initially and if there is no size change at 1 year, then yearly imaging⁴.

Other medical treatments

Dopamine agonists are useful in patients with modest elevations of GH and IGF-1 levels with or without concomitant hyperprolactinemia. A meta-analysis (including 160 patients) estimated that cabergoline as single-agent therapy normalizes IGF-1 levels in 34% of acromegalics and as an add-on therapy to SSAs in 52% of them. This effect may occur even in patients with normoprolactinemia and it is dose independent⁴⁶.

Clomiphene citrate – a selective estrogen receptor modulator with organ-specific estrogenic and antiestrogenic properties – has been tried as an “add on” therapy together with octreotide LAR and/or cabergoline in a group of 16 male acromegalics with IGF-1 above the ULN for at least 1 year despite the use of available medical therapies. At the end of the study, serum IGF-1 decreased by 41%, leading to normal values in 44% (7/16) of them⁴⁷.

Combination of medical treatments

The combination of pegvisomant with cabergoline or SSAs has been reported in two small studies as a potential effective treatment option in patients with acromegaly not responsive to monotherapy. The addition of pegvisomant (10 mg daily for 12 weeks) to cabergoline (offered in a maximum dose of 0.5 mg once daily) reduced significantly the IGF-1 levels in comparison with either cabergoline alone (on a maximum dose of 0.5 mg once daily) or low-dose (10 mg daily) pegvisomant monotherapy; 68% of the patients achieved normal IGF-1⁴⁸. Furthermore, the addition of pegvisomant (median dose 60 mg weekly) in partially controlled acromegalics on high-dose SSAs normalized IGF-1 in 57.9% of them⁴⁹.