THE PLACE OF MEDICAL TREATMENT OF ACROMEGALY IN SERBIA: CURRENT STATUS

The past two decades have brought significant advancement in treatment of acromegaly, primarily due to discovery of new medications and broadening of their availability. Accordingly, mortality rate of patients with acromegaly has decreased significantly and in adequately treated patients it approximates the general population. Treatment of acromegaly requires a combination of several modalities: neurosurgical operation, medical treatment and radiotherapy. Treatment of acromegaly in Serbia is conducted in accordance to international guidelines and recommendations. Recent availability of novel medical therapies for acromegaly in Serbia, demanded a need for creation of recommendations for optimal application of these new treatment options. Medical treatment of acromegaly encompasses three groups of drugs: 1) somatostatin receptor ligands, 2) dopamine agonists, 3) GH receptor antagonists. Every patient requires individual approach in treatment selection, usually involving a combination of multiple treatment modalities. Considerable cost of some medications, even in the economically developed countries, poses an additional challenge for the endocrinologist responsible for selection of treatment. Individualized approach to treatment ensures better disease control, reduction or elimination of comorbidities and reduction in cost of treatment of this chronic disease.


Introduction
Acromegaly is a chronic, multisystemic disease, caused in 98% of cases by a somatotroph pituitary adenoma. 1,2 Secretory hyperactivity of somatotroph adenoma results in the abnormal serum concentration of growth hormone (GH) which either directly, or more often through its physiological mediatorinsulin like growth factor-I (IGF-1) causes the spectrum of complications of this disease. The prevalence of acromegaly in Europe is estimated to 28-137 cases per million, and the estimation of annual incidence varies from 2 to 11 patients per million. 3,4 Due to its slow onset and insidious progression, acromegaly often remains long unrecognized in spite of presence of signs and symptoms. Time from first symptoms to diagnosis is estimated as 5-10 years. 2,5 Acromegaly caused by diseases other than somatotropinoma is exceptional. These rare cases include ectopic GH or GHRH secretion from lung, pancreas, adrenal or mediastinal tumors. 6 Over the past 20 years, genetic background has been elucidated for some forms of acromegaly, occurring syndromicaly within MEN 1, MEN 4, McCune Albright or Carney complex or as part of isolated familial pituitary adenoma (FIPA). 7,8 Along the hallmark signs and symptoms of acromegaly, such as enlargement of hands, feet, nose and ears, facial soft tissue swelling or mandible protrusion, the most frequent complications of the disease are: diabetes mellitus, arterial hypertension, cardiovascular diseases (heart failure, arrhythmias, atherosclerosis, endothelial dysfunction), articular deformities in large joints, vertebral fractures (with or without osteoporosis), respiratory disfunction (obstructive sleep apnea syndrome) and thyroid, colon or prostate neoplasia. 1, 9-5 14 Patients with active acromegaly are attributed with a 2 to 3-fold increase in mortality rate compared to general population. The average life expectancy in these patients is reduced by an average of 10 years compared to healthy controls. The leading causes of death in this group are malignancies, cardiovascular and respiratory diseases. 15 An adequate control of acromegaly enables prevention or attenuation of the disease complications and converging of the mortality rate of these patients to the one in general population. 4,16 The goals in acromegaly treatment are: normalization of serum IGF-1 (for the age specific reference range), achieving serum GH < 1 µg/l, reduction of pituitary tumor mass or its GHsecreting remnant, elimination or reduction of disease symptoms and comorbidities. 17,18 The treatment of acromegaly includes a combination of several modalities: neurosurgical operation, medical treatment and radiotherapy. Over the last two decades a significant advancement was made in the field of acromegaly medications development, promoting a dramatical improvement in the treatment outcomes in acromegaly. Along with the contemporary internationally accepted guidelines for acromegaly treatment, all of the aforesaid treatment modalities are in use in the Republic of Serbia. 19,20 The emerging availability of novel medical options in Serbia, raises the need for generating recommendations for the place and role of each specific treatment option. Treating acromegaly is a multidisciplinary task. The key decisions should be made by an interdisciplinary team including a neuroendocrinologist, neurosurgeon, pathologist, radiologist and geneticist as needed.

Surgical treatment
Operation of GH secreting pituitary tumor represents the first line of treatment of acromegaly both worldwide and in Serbia. Somatotropinomas are operated by transsphenoidal approach in more than 90% of cases. Operative outcome is primarily dependent on the experience and skill of neurosurgeon, and on size and propagation of the tumor. A neurosurgeon is recognized as an expert in pituitary surgery if performing more than 200 transsphenoidal pituitary surgeries annually. 21 The surgical remission of acromegaly is usually defined by age-related normal IGF-1 and a random serum GH, or OGTT-nadir GH of <1 µg/lassessed 3 months post operatively. In specialized pituitary neurosurgery units, remission is achieved in 75-90% of microadenomas and 45-70% of macroadenomas. 22  Lanreotide Autogel is available in 90mg and 120mg doses, applied also once in 28 days but in the form of subcutaneous injection. The latest recommendation, also observed in Serbia, advises a maximal initial dose of these medications (octreotide LAR 30mg or lanreotide LAR 120mg) over the first 6 months of treatment, followed by optional dose reduction or an increase in dosing intervals (e.g. lanreotide autogel once in 56 days, instead of 28 days) after the achievement of biochemical disease control. 24 The first control of GH and IGF-1 is scheduled for 3 months after the SRL-fg treatment initiation. In the case of inefficiency of one of the drugs from this group, the switch to the other SRL-fg should be tried. 25 Overall, no superiority in efficacy was established for one of SRL-fg over the other. 26 These drugs effectively inhibit GH synthesis and somatotroph cells proliferation, thus inducing reduction in tumor size. A complete biochemical response to SRL-fg is defined by serum GH of < 1µg/l and IGF1 normalization, and it is achieved in 30% of treated patients. A partial response is defined by a reduction in GH and/or IGF-1 for ≥ 50% from baseline, and it is achieved in 50% of patients. Resistance to SRL-fg is characterized by a decrease in serum GH and IGF1 for < 50% from baseline, and it is observed in 20% of patients. 27 Decrease in tumor remnant size for > 20% is observed in 65% of patients treated with SRL-fg. Reduction of tumor size is expected after 6 months of treatment. 28 SRL-fg treatment is generally well tolerated and these drugs are believed to have a good safety profile. Side effects of these drugs are mostly associated with gastrointestinal impairment (nausea, abdominal pain, diarrhea, gall bladder stones or sludge, constipation, malabsorption, liver function derangements). 29 Cholelithiasis occurs in about 30% of patients treated with SRL-fg, usually in the first two years of treatment, rarely demanding cholecystectomy. Glucose tolerance impairment is observed in about 30% of patients, while in less than 5% either bradycardia, hypertension or anemia are reported. 30 Dose reduction usually leads to resolution of side effects.
Indications for SRL-fg treatment include conditions when: Administration). 7 Pasireotide LAR is a multi-receptor somatostatin ligand with the highest affinity for somatostatin receptor subtype SSTR-5, followed by the SSTR-1, and with a lesser affinity for SSTR-2 in comparison to the SRL-fg (octreotide and lanreotide). Owing to the greater number of the receptors to which it binds, pasireotide LAR assures a better clinical effect compared to SRL-fg. Results of clinical studies involving this drug demonstrate IGF-8 1 normalization in 20% of patients resistant to SRL-fg treatment. 31 Pasireotide LAR also exhibits a better antitumor effect compared to SRL-fg, reducing the tumor size by 40% in about 80% of treated patients. All these characteristics make pasireotide LAR the drug of choice for acromegaly patients with a tumor remnant in proximity to optic chiasm. 32 Pasireotide LAR is available world wide in doses of 10mg, 20mg, 30mg, 40mg and 60mg, applied as an intramuscular injection once in 4 weeks. In Serbia, pasireotide LAR is currently available in the 40mg dose, which is the initial dose for treatment, while 60mg is the maximal monthly dose of this drug.
The treatment with pasireotide LAR is considered in the following cases: pasireotide LAR is similar to the one of SRL-fg, except for glycemic impairment, which is observed in around 70% of treated patients. 33 In about 10% of patients pasireotide LAR treatment needs to be discontinued due to hyperglycemia. In the first 3 months after treatment initiation, fasting glucose evaluation is advised once weekly, and afterwards once in 6 weeks.
In the treatment of diabetes mellitus induced by pasireotide LAR treatment, metformin is usually in combination with SRL-fg, pasireotide LAR or pegvisomant. 20 Cabergoline is attributed with a greater efficacy in remission achievement in acromegaly (estimated as 34%) compared to bromocriptine (10%). 35 Mechanism of action of DA in acromegaly relies on the fact that most somatotroph adenomas exhibit type 2 dopamine receptor (D2R), and about 20% of these tumors, in addition to GH co-secrete prolactin (mixed somatotroph/lactotroph tumors). The efficacy of DA is limited to milder forms of disease, but oral application and low cost make them nevertheless attractive for treatment in acromegaly. 36 The average dose of cabergoline is 2.5mg weekly (ranging from 1 to 7mg) which is 2 to 5-fold greater than the doses used in hyperprolactinemia.
Dopamine agonists are used in treatment of acromegaly in following cases ( Figure 1): -mild biochemical activity of acromegaly (IGF-1< 2.5 ULNupper limit of normal for age) with mild disease symptoms. The optimal effect of DA is achieved in cases with IGF-1< Pegvisomant is recommended in following cases: -acromegalic patients treated with SLR-fg with persistent disease but small or undetectable tumor remnant.
-acromegalic patients uncontrolled on SRL-fg, who also suffer from diabetes mellitus

Impairment of liver function tests is reversible upon dose reduction or drug discontinuation.
Drug discontinuation is advised if the level of liver enzymes is 5-fold above upper limit of normal (0.5%). Due to the known possible elevation of liver enzymes, follow up of ALT and AST is advised every 4-6 weeks in the first 6 months of treatment. To avoid potential local skin reactions to drug application, sites of administration should regularly be altered. Pegvisomant has no effect on pituitary tumor remnant size reduction, and is even attributed with a small potential risk of its increase (in 1-3%). 44 Treatment with pegvisomant is thus not recommended if the tumor remnant is larger or if its distance from the optic chiasm is less than 3mm. 19 Follow up sellar region MRI is advised during pegvisomant treatment.

Preoperative medical treatment
Medical treatment in acromegaly could also be considered preoperatively, as the first line of treatment (mainly involving SRL-fg), resulting in an increased rate of biochemical disease control, compared to patients operated without prior medical treatment. However, current literature does not provide sufficient evidence to justify a benefit of preoperative treatment with SRL-fg. 45 Conditions in which medical therapy is the first line of treatment in acromegaly include: -contraindications for surgery -need for preoperative reduction in surgical and anesthetic risk in acromegaly complicated by: high output cardiac failure, severe pharyngeal thickness and swelling of soft tissue, or severe sleep apnea syndrome

Combined medical treatment
Combined medical treatment is advised when monotherapy with SRL-fg is insufficiently effective (Figure 1). Addition of cabergoline to SRL-fg treatment enables IGF-1 normalization in over 50% of patients uncontrolled by SRL-fg monotherapy. 46 Combination of cabergoline and pegvisomant may be an effective alternative in patients not responding to SRL-fg treatment. 47  years from SRT application. 51 Major side effect of radiotherapy is hypopituitarism, observed in 70% of treated patients, while optic nerve lesions, cerebrovascular impairment or secondary tumorigenesis are much less frequent. 52 SRT is not recommended when tumor is in high proximity to optic chiasm. SRT modalities available in Serbia include "gamma knife" and "X knife". Prior medical treatment of acromegaly (with SRL or DA) is believed to be associated with a possible reduction in radio-sensitivity. A temporary cessation of medical treatment, although not an universally recommended practice, was observed to improve both initial and long-term effect of SRT. SRL are advised to be discontinued 6 to 8 weeks prior of SRT and restarted 4 to 8 weeks after, while DA can be discontinued only 2 weeks before SRT.
Pegvisomant, as a drug not targeting the pituitary tumor, should not influence radio-sensitivity and does not need to be discontinued. 52 Radiotherapy should be considered in following cases:  tumor remnant and active acromegaly are persistent after somatotroph adenoma surgery followed by multimodal medical treatment (SRL-fg, DA, SRL-sg,

pegvisomant)
 medical treatment is ineffective, unavailable, or needs to be discontinued due to side effects.

Personalized approach to patient and prognostic factors of outcome
In the course of treatment of acromegaly, in addition to follow up of GH and IGF-1 levels, and tumor remnant size, evaluation of patient`s quality of life is recommended, through the use of AcroQoL questionnaire, as well as disease activity clinical assessment with the use of ACRODAT (Acromegaly Disease Activity) or SAGIT (Signs and symptoms, Associated comorbidities, GH levels, IGF1 level, Tumor profile) questionnaires. [53][54][55] In more than 50% of acromegaly patients, application of all treatment modalities is necessary. Every patient demands individual approach in selection of optimal treatment modalities or their combinations. 3  However, judging by the international registries data, one third of acromegaly patients are undertreated and lack disease control. 3 Considerable cost of some medications used in treatment of acromegaly (pasireotide LAR, pegvisomant), result in their unavailability, particularly in the countries of eastern and central Europe. 59