Medical Treatment of Acromegaly: What's New?

Medical treatment of acromegaly – When the tumor size matters: A narrative review

Chapter 14 - Medical treatment in acromegaly

In this issue of Endocrine, van der Lely et al. [1] provided a well-written, extensive review of all reported cases of pegvisomant use in pregnancy, (mother and father) from a large safety database. Acromegaly is a relatively rare disease, caused by a growth hormone (GH) secreting pituitary adenoma [2]; however, reports now suggest disease incidence might be higher than previously reported, with women and men equally affected [2–4]. Hypogonadism is reported in approximately 70 % of patients with acromegaly [2]. The decreased rate of fertility in women with acromegaly is multifactorial. Gonadotrope reserve can be lower due to mass tumor effect, stalk effect or subsequent to surgery or radiation [5]. The hyperprolactinemia in mixed tumors also plays a role, while GH/insulin-like growth factor 1 (IGF-1) excess per se has been noted to have direct effect on the ovaries. Nevertheless, over the last two decades, more women with acromegaly achieve successful pregnancy [5]. This is due to improved outcomes after transsphenoidal surgery, use of medical therapy as a first line treatment in many patients, and delegation of pituitary radiation to a third line treatment, and of course advances in fertilization techniques. How to better care for women with acromegaly is complex and not well studied [5]. Management of acromegaly in patients desiring pregnancy should include optimizing biochemical control and maximizing tumor shrinkage before becoming pregnant [5–8]. After becoming pregnant, most reports recommend stopping all medical treatment for acromegaly [5, 9, 10] and restarting only if severe symptoms (headache for example), visual changes, or tumor growth are present. Interestingly, acromegaly symptoms usually improve during pregnancy. A diagnosis of new onset acromegaly while pregnant is problematic due to the complex issue of measuring GH, which includes placental GH and GH resistance in the presence of high estrogen [5]. The focus of this editorial will be medical treatment of acromegaly during pregnancy, with a review of new data regarding pegvisomant use during pregnancy, published in this issue [1]. Rather than summarizing study-related findings, comments will focus on current, if somewhat limited data on outcomes after acromegaly treatment in pregnancy. For example, do physicians need to treat and if yes, which approach should be pursued? Pregnancy has not been found to change the course of acromegaly, other than, in rare cases of asymptomatic tumor enlargement, which may or may not be related to physiologic pituitary hyperplasia [5, 9]. Tumor enlargement may also be theoretically triggered by somatostatin receptor ligand (SRL) discontinuation at pregnancy onset. The literature indicates an increased risk of gestational diabetes and gravid hypertension in women with noncontrolled GH/IGF-1 hypersecretion before gestation, which must be appropriately and aggressively treated, but in most patients, specific acromegaly therapy can be delayed until after delivery. Based on experience with dopamine agonists (DAs) in prolactinomas, bromocriptine and cabergoline have constituted the initial treatment of choice for acromegaly in pregnancy; however, efficacy is limited outside of mild cases. & Maria Fleseriu fleseriu@ohsu.edu

We studied the effects of acute and chronic sc administration of SMS 201-995 (SMS), a long-acting somatostatin analog, in acromegalic patients. The results were compared with those obtained in the same patients treated with oral bromocriptine (Brc). A single dose of 50 micrograms SMS administered to 28 patients induced a more rapid, greater, and more prolonged reduction in plasma GH levels than did 2.5 mg Brc. Chronic treatment [60-330 days; mean 208 +/- 23 (+/- SEM)] with SMS (100-300 micrograms/day) induced in 16 patients a significantly greater decrease in mean plasma GH and somatomedin-C levels than did 20 mg Brc. Combined treatment with the 2 agents had an additional effect. The clinical and metabolic parameters of acromegaly dramatically improved in all patients whose plasma GH and somatomedin-C levels decreased even if they were not normalized by SMS. Reduction in tumor size occurred in 3 of the 10 patients examined by computed tomography before and during SMS treatment. We conclude that SMS is more effective than Brc and that the 2 drugs may be complementary in the medical treatment of acromegaly.

Acromegaly is a chronic systemic disease associated with significant morbidity due to its many complications, which lead to increased mortality rates. Adequate treatment is essential to reduce the development of long-term complications and to restore mortality rates to those of the general population. Three modalities of treatment are currently available (surgery, medical therapy and radiotherapy). Surgery is considered the first-line treatment and achieves disease cure in approximately 50% of patients in reference centers. Three drug classes are currently available (somatostatin receptor ligands, dopamine agonists and growth hormone receptor antagonists); however, disease control is not achieved in a considerable proportion of patients (approximately 40%). Despite significant advances in medical therapy over the last few decades, the treatment burden is still high, and quality of life is not fully restored in many patients, even when biochemical control is achieved. Therefore, the development of medications with greater efficacy and/or easier and more convenient administration is an unmet need in the treatment of acromegaly. In addition, shifting from the current trial-and-error approach to a more precise treatment strategy guided by biomarkers predictive of the response to different medical therapies will optimize and improve patient outcomes. In this review, current treatments as well as new drugs in different phases of development are detailed, and the role of precision medicine in the treatment of acromegaly is discussed.

First-generation somatostatin receptors ligands (SRL) are the mainstay in the medical treatment of acromegaly, however the percentage of patients controlled with these drugs significantly varies in the different studies. Many factors are involved in the resistance to SRL. In this review, we update the physiology of somatostatin and its receptors (sst), the use of SRL in the treatment of acromegaly and the factors involved in the response to these drugs. The SRL act through interaction with the sst, which up to now have been characterized as five subtypes. The first-generation SRL, octreotide and lanreotide, are considered sst2 specific and have biochemical response rates varying from 20 to 70%. Tumor volume reduction can be found in 36-75% of patients. Several factors may determine the response to these drugs, such as sst, AIP, E-cadherin, ZAC1, filamin A and β-arrestin expression in the somatotropinomas. In patients resistant to first-generation SRL, alternative medical treatment options include: SRL high dose regimens, SRL in combination with cabergoline or pegvisomant, or the use of pasireotide. Pasireotide is a next-generation SRL with a broader pattern of interaction with sst. In the light of the recent increase of treatment options in acromegaly and the deeper knowledge of the determinants of response to the current first-line therapy, a shift from a trial-and-error treatment to a personalized one could be possible.

Central adrenal insufficiency (CAI) in acromegaly may be related to pituitary adenoma or induced by various medical treatments, transsphenoidal neurosurgery (TNS) or radiotherapy (RT), alone or combined. We assessed the role of all available treatments for acromegaly in inducing CAI. We retrospectively studied 97 patients. CAI was diagnosed if morning serum cortisol was <138 nmol/l, or if its response was inadequate in the low-dose short synacthen test. Seventy-four subjects underwent TNS (and 17 of whom also underwent RT), and 23 were on primary medical therapy: overall we diagnosed 21 cases of CAI. Duration of acromegaly, invasion of cavernous sinus, disease control, and type of medical treatment were much the same for patients with and without CAI, which was identified in 18% of patients (10/57) after one TNS, and in 53% (9/17) after RT (p=0.01); repeat surgery increased the risk of CAI (p=0.02). The risk of CAI onset during the follow-up was lower among patients treated with TNS or medical therapy than after RT (p=0.035). Medical treatment did not raise the risk of CAI, whereas a 5- and 4-fold higher risk of CAI was associated with repeat TNS and RT, respectively. Basal or stimulated cortisol levels were similar among acromegalic patients without CAI and matched controls with nonsecreting pituitary lesions. A significant proportion of patients with acromegaly developed CAI over time. While primary or secondary medical treatment did not contribute to the risk of CAI, repeat TNS and RT correlated with pituitary-adrenal axis impairment.

Historically, medical treatment of acromegaly has mainly been used as an adjuvant therapy after surgery. In the last decades, an increased range of medical therapy options has been available. Somatostatin analogues have become the cornerstones of medical treatment in acromegaly and are even seen as a primary treatment in a selected group of acromegaly patients. The most recent medical treatment available for acromegaly patients is pegvisomant, a growth hormone receptor antagonist. To date, it is the most effective medical treatment, but it is costly. Pegvisomant is used as monotherapy and combined with somatostatin analogues. In this article, we review clinical studies and cohorts that have documented the efficacy of pegvisomant monotherapy and combined therapy and give a concise overview of associated side effects.

Resistance to first-generation somatostatin receptor ligand (fgSRL) treatment in acromegaly is common, making the identification of biomarkers that predict fgSRL response a desired goal. We conducted a retrospective analysis on 21 patients with acromegaly who underwent surgery and subsequent pharmacological treatment. Through immunohistochemistry (IHC), we assessed the expression of the somatostatin receptor subtypes SSTR2 and SSTR5, E-Cadherin, and cytokeratin granulation pattern (sparsely or densely). Patients were divided into responders and non-responders based on their biochemical response to fgSRL and/or the newer agent, Pasireotide, or the GH-blocker, Pegvisomant. Patients resistant to fgSRL (n = 12) exhibited lower SSTR2 and E-Cadherin expressions. Sparsely granulated tumors were more frequent in the non-responder group. SSTR2 (p = 0.024, r = 0.49) and E-Cadherin (p = 0.009, r = 0.64) positively correlated with the Insulin-like Growth Factor 1 (IGF-1) decrease after fgSRL, while SSTR5 (p = 0.107, r = -0.37) showed a trend towards negative correlation. SSTR5 positivity seemed to be associated with Pasireotide response, albeit the number of treated patients was too low (n = 4). No IHC markers correlated with Pegvisomant response. Our findings suggest that densely granulated tumors, with positive SSTR2 and E-Cadherin seem to be associated with favorable fgSRL responses. The strongest predictive value of the studied markers was found for E-Cadherin, which seems to surpass even SSTR2.

New depot somatostatin analogs such as lanreotide-slow release (LAN) represent a significant improvement in the medical treatment of acromegaly. Seventy-three consecutive acromegalic patients, treated by LAN, were evaluated in a retrospective monocentric study. Sixteen were excluded from further evaluation due to combined treatment with dopamine agonist drugs, early LAN withdrawal for persistence of headache, or gastrointestinal side-effects. Fifty-seven patients (aged 20-82 years, 16 males) were thus evaluated. Thirty-two patients had been previously treated by neurosurgery (Tx) and/or radiotherapy (Rx). After washout, LAN (30 mg) was administered im at 10-14-day intervals. Time intervals between injections were then individually tailored to normalize IGF-I levels. LAN was administered for 12 (6-36) [median (range)] months. GH and IGF-I levels decreased from 13 (7-20) [median (interquartile)] microg/l to 3.2 (1.7-6.2) microg/l (p<0.0001) and from 780 (596-1000) microg/l to 264 (180-530) microg/l (p<0.000001), respectively. Seven patients were resistant to treatment. Among the 50 sensitive patients, GH levels fell below 2.5 microg/l in 52% (and below 1 microg/l in 18%), IGF-I levels normalized in 72% and both results were obtained in 46%. IGF-I values normalized in 87% of patients treated every 14 days, in 100% every 21-28 days, in 69% every 10 days and in 22% every 7 days. No different control of GH/IGF-I hypersecretion was evidenced between patients previously treated or not by Tx and/or Rx. Patients with the lowest basal hormonal levels and those over 55 years showed greater responsiveness (both p<0.05). The maintenance of LAN schedule up to 18 months determined a further suppression (p=0.04 for IGF-I). A reduction of tumor size was shown in 60% of evaluated patients (6/10). HbA1c slightly increased in 42% of patients and gallstones were observed in 16%. LAN is a very effective tool in the treatment of acromegaly: its chronic administration normalizes GH/IGF-I levels in most patients, shrinks the tumor in a high percentage of patients and seems to control hormonal hypersecretion as primary treatment as well as neurosurgery.

Introduction Acromegaly is a disease characterized by elevated growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels. Surgery is the only curative treatment, while medical therapies are administered life-long. To date, almost 30% of patients treated with the currently available medical therapies do not achieve biochemical control. Areas covered This review focuses on new drugs in development for acromegaly. In detail, we provide an overview of the new molecules designed to improve disease control rate (such as novel somotostatin receptor ligands and antisense oligonucleotides), as well as the new formulations of existing medications aiming to improve patients’ compliance (e.g. oral or long-acting subcutaneous octreotide). Expert opinion The constant progresses in the medical treatment of acromegaly could lead to an individualized therapy based on tumor, as well as patient’s characteristics. Besides disease control, patient’s need represents a major target of medical treatment in chronic diseases such as acromegaly, in order to improve compliance to therapy and patients’ quality of life.

Long-acting somatostatin analogs are frequently used as adjuvant treatment of acromegaly patients after noncurative surgery. This sudy aims to compare the efficacy of octreotide long-acting release (OCT) and lanreotide Autogel (LAN) in acromegaly patients. Sixty-eight patients not cured by transsphenoidal endoscopic or microscopic pituitary surgery between 2003 and 2009 were retrospectively analyzed (25 men; 43 women; mean age 41.1 ± 10.9 years [range 18–65 years]). The patients were assigned randomly to OCT (n = 36) and LAN (n = 32) groups. Evaluations included insulin-like growth factor I (IGF-I) and growth hormone (GH) after oral glucose tolerance test (OGTT) 3, 6, 12 and 18 months after starting medical treatment; pituitary magnetic resonance imaging was performed before treatment and after 3 and 12 months. Patients achieving IGF-I levels within the age and gender normal range and GH level <1 μg/l following OGTT were considered a ‘biochemical cure’. Mean IGF-I and GH values and tumor volumes (cm3) in the LAN and OCT groups were similar in the post-operative period before initiation of medical treatment. A statistically significant decrease in GH and IGF-I levels was obtained for both treatment groups at each follow-up visit compared to the previous value. Tumor shrinkage after 12 months of treatment was statistically significant in both groups but the percentage tumor shrinkage (28.5% vs. 34.9%, P = 0.166) and rate of patients achieving biochemical cure (63.9 and 78.1%, P = 0.454) were similar between OCT and LAN groups, respectively. OCT and LAN treatment options have similar efficacy for ensuring biochemical cure and tumor shrinkage in acromegaly patients who had noncurative surgery.

Acromegaly is a severe disabling neuroendocrine disease caused by hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). The problem of resistance to drug therapy in patients with acromegaly is quite common in clinical practice and requires a personalized approach, considering various predictors of sensitivity to the choice of the treatment method. To date, first-generation somatostatin analogues are first-line drugs in the medical treatment of acromegaly, but up to 50% of patients do not achieve biochemical remission of the disease. The prognosis of sensitivity to somatostatin analogues is of great importance and the selection of patients in whom this therapy will be not successful provides invaluable assistance in choosing the optimal treatment approach. This review summarizes potential predictors of sensitivity and resistance to existing drug treatment of acromegaly, discusses possible ways to overcome the resulting resistance to therapy, suggests options for a personalized approach to choosing a treatment strategy in the absence of disease control against the background of monotherapy with somatostatin analogues, including «off-label» combinations. Timely addition of growth hormone receptor antagonist (pegvisomant) avoids repeated neurosurgical intervention, radiation therapy or prescribing excessively high doses of somatostatin analogues. Optimal use of mono- or combination therapy contributes to the achievement of biochemical remission in most resistant patients.

Medical treatment in acromegaly.

Hormone secretion by functioning pituitary tumors is characterized by increased basal (nonpulsatile) secretion, enhanced pulse frequency, amplified pulse mass, and increased disorderliness. The objective of the study was to quantify (subtle) abnormalities of hormone secretion by pituitary adenomas and the influence of selective pituitary surgery and suppressive medications on these parameters. Approximate entropy (ApEn) was quantified with a refined algorithm, spikiness by a new method to evaluate sudden short-lived increases in hormone levels, and pulsing regularity, determined with a fully automated deconvolution program. These 3 distinct measures of secretory disruption were compared in untreated and treated patients with acromegaly, prolactinoma, and Cushing's disease together with matching profiles in healthy controls. ApEn and spikiness were markedly increased in all untreated patient groups and normalized after pituitary surgery in acromegaly and hypercortisolism. In contrast, hormone-suppressive medical treatment in acromegaly and prolactinoma did not normalize ApEn. Spikiness normalized in acromegalic patients but not in prolactinoma. GH and cortisol pulsing regularity was elevated in acromegaly and Cushing's disease, respectively, and normalized after surgery. Medical treatment caused normalization of pulsing regularity in acromegaly but not in prolactinoma patients. This study extends the understanding of disorganized hormone secretion by hyperfunctioning pituitary adenomas. The new findings are increased spikiness in all 3 tumor groups and increased pulsing regularity in GH- and ACTH-secreting adenomas. The mechanisms behind the marked pattern irregularity and the selective normalization by surgical and medical therapies are not established yet but may include diminished feedback signaling in addition to the anatomical and functional disorganization of intrapituitary cell networks.