The place of medical treatment of acromegaly: current status and perspectives

Introduction: Acromegaly is characterized by elevated growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels and by progressive somatic disfigurement and systemic manifestations, which lead to a mortality rate higher than the general population. Therefore, diagnosis and properly treatment should be performed as soon as possible.

Areas covered: This article focuses on the state of the art of acromegaly medical treatment. Somatostatin analogs, dopamine agonists and GH receptor antagonist were reviewed. Somatostatin analogs, the first-choice pharmacotherapy, can be used as primary or pre-operative treatment or as secondary therapy after failed surgery. Dopamine agonists have been used in patients with slightly elevated hormone levels and/or mixed GH/prolactin adenomas. Pegvisomant is indicated for resistant to somatostatin analogs/dopamine agonists. Combined treatment is also an option for resistant cases. Other non-conventional therapies and perspectives of treatment were also been discussed.

Expert opinion: The control of disease activity in acromegaly is of paramount importance. Medical treatment is an important option for cases in which surgery was unsuccessful or not indicated. Despite the achievements in medical treatment, somatotropic tumor aggressiveness and/or resistance to the drugs currently available remain a concern. Therefore, novel therapy targets based on molecular pathogenesis of GH-secreting tumors are currently in development, aiming at fulfilling this important gap.     

Lanreotide autogel in acromegaly – a decade on

Introduction: The novel formulation of lanreotide, lanreotide (LAN) autogel (ATG), has been available in Europe since 2001 and USA from 2006 for the treatment of acromegaly. It is one of only two clinically available somatostatin analogs available for use in acromegaly. Data relating to the use of ATG in acromegaly, specifically relating to comparison to octreotide (OCT) LAR and patient acceptability and preference, have been slow to accumulate.

Areas covered: We performed a comprehensive review of the original literature relating to development, pharmacokinetics, acceptability and clinical efficacy of ATG.

Expert opinion: LAN ATG is a novel formulation of LAN consequent on self-assembly of nanotubules in water. Diffusion between molecules within the nanotubules and surrounding tissue fluid in vivo leads to pseudo first-order pharmacokinetics. Efficacy is equivalent to the alternate long-acting somatostatin analog, OCT LAR, normalizing growth hormone and IGF-I levels in around 60 and 50% respectively. Control of tumor growth is observed in over 95% of patients, with 64% seeing a clinically significant reduction in tumor size. ATG is provided in a prefilled syringe for deep subcutaneous injection, allowing self-injection, and may be administered up to 8 weeks greatly improving convenience for the patient. The data strongly support consideration of ATG as the medical therapy of choice for patients with acromegaly.     

Investigational drugs targeting somatostatin receptors for treatment of acromegaly and neuroendocrine tumors

Introduction: Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2. However, this peculiarity may become a weakness in some patients with tumors harboring somatostatin receptors different from the subtype 2. Another clinically relevant aspect related to the use of octreotide LAR and lanreotide ATG is the burden of injectable drug regimen that may adversely impact the quality of life of patients with acromegaly and NETs.

Areas covered: The authors review the recently published evidence on novel drugs targeting somatostatin receptors developed for treating acromegaly and NETs. Within this article, the authors discuss: i) the pharmacology of somatostatin and traditional somatostatin analogs; ii) the efficacy and safety of multireceptor-targeted somatostatin analogs in acromegaly and NETs; iii) the efficacy of chimeric molecules in acromegaly and NETs; iv) the preliminary data on the use of new injectable, oral and transdermal formulations of octreotide in acromegaly.

Expert opinion: The development of new somatostatin analogs and new formulations has opened a new scenario for treatment of acromegaly and NETs. That being said, even though there have been big steps taken in the development of new therapies for acromegaly, there are still a number of unresolved issues, while more trials are necessary for the use of somatostatin anaologs in the treatment of NETs.     

Current and future medical treatments for patients with acromegaly

Introduction: Acromegaly is a relatively rare condition of growth hormone (GH) excess associated with significant morbidity and, when left untreated, high mortality. Therapy for acromegaly is targeted at decreasing GH and insulin-like growth hormone 1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant) and radiotherapy. However, despite all these treatments option, approximately 50% of patients are not adequately controlled.

Areas covered: In this paper, the authors discuss: 1) efficacy and safety of current medical therapy 2) the efficacy and safety of the new multireceptor-targeted somatostatin ligand pasireotide 3) medical treatments currently under clinical investigation (oral octreotide, ITF2984, ATL1103), and 4) preliminary data on the use of new injectable and transdermal/transmucosal formulations of octreotide.

Expert opinion: This expert opinion supports the need for new therapeutic agents and modalities for patients with acromegaly.     

Investigational therapies for acromegaly

Introduction: The treatment of acromegaly aims at normalizing growth hormone (GH) and insulin-like growth factor (IGF-I) levels and controlling tumor growth. The approaches to therapy are essentially three: surgery and pharmacotherapy, alone or in combination, and radiotherapy, generally used in more aggressive tumors.

Areas covered: This review focuses on the novel drug formulations being developed for medical therapy of acromegaly. Even though many efficient treatments have been made available to manage acromegaly in the last two decades, a significant number of patients remain still uncontrolled. Medical therapy represents an important therapeutic option and can be used as the first-line treatment in many patients. However, roughly 25% of patients might be considered as poor responsive or resistant to conventional long-acting somatostatin analogs (SSA) treatment. Therefore, new longer-acting SSA, oral SSA formulations, new combined therapies with weekly doses of pegvisomant, combination therapy with pegvisomant (PEG) and cabergoline (CAB) or SSA and new approaches have been proposed. New molecules are currently under investigation in clinical trials, such as the SSA multi-receptor ligand, pasireotide, which represents a promising option therapy, especially in patients not adequately controlled with currently available SSA. Further, temozolomide has been suggested as an efficient drug for treating GH-aggressive pituitary tumors resistant to conventional therapy.

Expert opinion: All these novel SSA formulations and new molecules implement the available options in therapies of acromegaly to improve disease control. However, further studies are needed to define the exact role of these newer agents. The predicting factors for response to these new therapies should also be determined.     

Pasireotide for the treatment of Cushing's disease

Importance of the field: It is important to treat patients with Cushing's disease as rapidly as possible to limit both the mortality and morbidity of the disease. Pituitary surgery remains the treatment of choice, but the rate of cure at long-term follow-up is suboptimal and recurrence rates are high. If surgery fails or relapse occurs, no treatment has proven to be fully satisfactory. Currently available medical therapies are considered a transient and palliative treatment. However, recently there has been renewed interest in medical therapy due to new insights in pathogenetic mechanisms of corticotroph pituitary tumors.

Areas covered in this review: We summarize the pharmacodynamics and possible mechanism of action of pasireotide (SOM230), a novel multireceptor-targeted somatostatin analogue. Pasireotide has a unique binding profile, with high affinity for four of the five somatostatin receptors, especially SSTR₅, the receptor most prevalent in corticotroph tumors.

What the reader will gain: The reader should gain an understanding of preclinical and clinical data supporting the potential use of pasireotide in patients with Cushing's disease.

Take home message: Preliminary data suggest that pasireotide shows promise as a tumor-targeted medical therapy in patients with Cushing's disease. If the efficacy of pasireotide is confirmed by larger studies, this compound may be a useful treatment option not only in patients with severe Cushing's disease, but also in patients with mild hypercortisolism where its efficacy might be more evident.     

Current management of acromegaly

Acromegaly, a chronic disease of growth hormone (GH) hypersecretion, is most typically caused by a pituitary adenoma. Early diagnosis is critical for prompt intervention to prevent deleterious effects of prolonged exposure to elevated GH and insulin-like growth factor Type I (IGF-I) levels. Current therapy for acromegaly includes several options: surgery, radiotherapy and pharmacotherapy. Transsphenoidal adenomectomy remains a mainstay of therapy for acromegaly. Cure rates are high in microadenomas, but << 50% in macroadenomas. Conventional and stereotactic procedures for radiation therapy are also effective in decreasing GH levels in acromegalic patients, but they need years to normalise GH hypersecretion and carry with them the risk of hypopituitarism. The major classes of drugs currently used to treat acromegaly are dopamine agonists and analogues of somatostatin. Dopamine agonists bind to the D₂ receptor and suppress GH hypersecretion in some patients with acromegaly. Their clinical effectiveness is modest, although promising results have been obtained with two novel compounds, quinagolide and cabergoline, that possess long duration of action. Somatostatin analogues have been shown to improve clinical symptoms of acromegaly, decrease hypersecretion of GH and IGF-I and reduce tumour volume in a clinically significant number of patients. Octreotide is administered by sc. route several times a day, but the recently developed sustained release formulations (octreotide LAR and SR lanreotide) are administered only every 7 - 28 days by im. injections. The complications associated with somatostatin analogues are small, relative to the benefits. Lastly, compounds with a novel mechanism of action, the GH receptor antagonists, are presently under investigation.     

Current pharmacotherapy of central precocious puberty by GnRH analogs: certainties and uncertainties

Introduction: GnRH analogs represent the drug of choice for medical treatment of central precocious puberty (CPP). They provided prompt and reversible suppression of reproductive axis and several reports have shown that adult height is preserved in treated children.

Areas covered: This review updates GnRH analog treatment in CPP by a search of the literature published on the topic since 1980.

Expert opinion: Monthly GnRH analogs are currently considered the ‘gold standard' for the medical treatment of CPP, since a lot of experience is accumulated on their use in children. Differences in long-term outcome (in terms of adult height) are reported and they may be due to differences in selection criteria, treatment monitoring, criteria to stop of therapy, different biological activity of the various drugs and different genetic background of treated patients; altogether, these items remain poorly evaluated. Psychological indications for treatment and long-term psychological outcome of treated children should be better addressed. Comparative trials among the various GnRH analogs are very scarce. New very long-acting GnRH analogs (quarterly or yearly formulations) may improve compliance with therapy, but longer follow-up studies are needed. Medical treatment of CPP should be close to pediatric endocrinologists or tertiary pediatric endocrinology centers with documented experience in this field.     

Pituitary-targeted medical therapy of Cushing's disease

Background: The goals of ideal medical therapy for Cushing's disease should be to target the aetiology of the disorder, as is the case for surgery, which is the current ‘gold standard’ treatment. However, no effective drug that directly and reliably targets the adrenocorticotropin-secreting pituitary adenoma has yet been found. Objective: To summarise pituitary-targeted medical treatment of Cushing's disease. Methods: Compounds with neuromodulatory properties and ligands of different nuclear hormone receptors involved in hypothalamo–pituitary regulation have been investigated. Results: The somatostatin analogue pasireotide and the dopamine agonist cabergoline, as well as their combination, show some therapeutic promise in the medical therapy of Cushing's disease. Other treatments such as retinoic acid analogues look promising and may be a possible option for further investigation. No other medical therapies seem to be reliably effective currently. Conclusion: Since a percentage of patients treated with surgery are not cured, or improve and subsequently relapse, there is an urgent need for effective medical therapies for this disorder. At present, only cabergoline and pasireotide are under active investigation.     

Synthesis and characterization of multiply-tyrosinated,multiply-iodinated somatostatin analogs

Radio-labeled somatostatin analogs have recently gained popularity as agents useful in intraoperative tumor localization, external scintigraphy and in situ radiotherapy. We have synthesized and characterized a series of novel N-terminally extended multiply-tyrosinated somatostatin analogs that possess high binding affinity for somatostatin receptors, exhibit biological activity comparable to the native peptide and retain these characteristics after iodination. These analogs can be radio-iodinated to high specific activities. Following radio-iodination, these analogs exhibit minimal radiolysis and may be clinically useful for tumor localization, scanning and therapy.     

Chronic rhinosinusitis: an update on current pharmacotherapy

Introduction: Chronic rhinosinusitis (CRS) is an inflammatory disease of the nasal and paranasal mucosa with great impact on quality of life and a large financial burden on society. This article provides an overview of its current and future pharmacotherapy, the mainstay of CRS treatment.

Areas covered: This article reviews the etiology, antibiotic and corticosteroid treatment, nasal irrigation therapy, bacterial lysates, anti-immunoglobulin E and anti-interleukin-5 therapy of CRS. This review highlights articles of interest on these topics in the PubMed database. Studies not in English language were excluded.

Expert opinion: CRS is a spectrum of disease characterized by mucosal inflammation. Defining its various subtypes will change its medical treatment from general anti-inflammatory medicine towards tailor-made pharmacotherapy. The optimal timing of endoscopic sinus surgery in this treatment process remains to be defined.     

Emerging therapeutic options for advanced enteropancreatic neuroendocrine tumors

Introduction: Several chemotherapy agents and combinations have proven effective in the therapy of advanced enteropancreatic neuroendocrine tumors (EP-NETs). However, their toxicity can be significant. Recent understanding of the molecular mechanisms of these tumors, especially the central role of tumor angiogenesis, has led to the identification of new therapeutic targets and agents directed at the molecular level.

Areas covered: This paper gives a comprehensive evaluation of the existing therapeutic armamentarium for EP-NETs. Narrated in a historical perspective, this review analyzes the available information on traditional chemotherapy agents, interferon-α and somatostatin analogs, as well as newer therapies and experimental agents.

Expert opinion: Despite recent advances, a curative approach for metastatic EP-NETs is yet to be discovered. To date, sunitinib and everolimus have been shown to impact progression-free survival only in pancreatic NETs, and the duration of this benefit has not yet been established. Further research is necessary to determine whether a combination of these drugs, either together or with other therapies, may yield superior outcomes. Moreover, sequential use of these agents should be explored in an attempt to improve survival. Efficacy of a variety of experimental agents is also being tested in clinical trials.     

Improvement of drug-like properties of peptides: the somatostatin paradigm

Importance of the field: Peptides are promising candidates as therapeutic agents due to their wide involvement in physiological processes. However, their often non-selective activity and their poor drug-like properties, mainly their inherent low stability to enzymatic degradation and poor oral bioavailability, limit their clinical potential. Somatostatin is a peptide hormone involved in many different biological functions. The role of its five different receptor subtypes and their interplay in medicinal processes is only partially understood. In addition, it suffers from poor drug-like properties.

Areas covered in this review: We review several promising chemical modifications, including head-to-tail and backbone cyclization as well as N-methylation, which were applied throughout the years in the development of various somatostatin analogs.

What the reader will gain: These modifications led to enhanced metabolic stability and intestinal permeability. In addition, several analogs exhibited specific receptor subtype activation.

Take home message: The results presented in this review suggest a potential use of these chemical modifications in order to achieve required characteristics for a bioactive peptide, mainly for clinical usage.     

Pharmacologic therapy in growth hormone disorders and the heart

Growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is not only involved in the regulation of somatic growth but also has important physiological functions in adults. Several studies have shown that GH deficiency in adults is associated with abnormalities in body composition, metabolic derangements, and suboptimal physical performance. Furthermore, GH/IGF-I axis plays an important role in the maintenance of heart structure and function. Until recently, GH therapy was only used to treat short stature children, with or without established GH deficiency, and it remains common practice to discontinue GH replacement therapy when final height is achieved. Acromegaly, entity characterized by GH hypersecretion, is associated with an increased risk of premature death. Cardiac complications are known to be major determinants of the shortened life expectancy. Treatment of acromegaly accounts for a substantial decrease in morbidity and mortality. Surgery, radiation therapy and bromocriptine have only been able to reduce GH levels to normal levels in 10-30% of patients. The synthesis of somatostatin analogs has provided a new approach to acromegaly treatment. These drugs reduce GH and IGF-I levels in 80% of cases and normalize them in 40-60% of cases. Finally, GH/IGF-I system improves left ventricular systolic function and has also indirect effects on the cardiovascular system, mainly as a consequence of the peripheral vasodilatation. These effects are important in the understanding of the potential role of GH on improving ventricular systolic dysfunction and point to the use of GH as a potential therapy for chronic heart failure. The aim of the present review is to provide an update overview describing the role of GH on acromegaly, adult GH deficiency and heart failure, as well as the influence of GH-based therapy on heart structure and function.     

Current management of acromegaly

Acromegaly, a chronic disease of growth hormone (GH) hypersecretion, is most typically caused by a pituitary adenoma. Early diagnosis is critical for prompt intervention to prevent deleterious effects of prolonged exposure to elevated GH and insulin-like growth factor Type I (IGF-I) levels. Current therapy for acromegaly includes several options: surgery, radiotherapy and pharmacotherapy. Transsphenoidal adenomectomy remains a mainstay of therapy for acromegaly. Cure rates are high in microadenomas, but < 50% in macroadenomas. Conventional and stereotactic procedures for radiation therapy are also effective in decreasing GH levels in acromegalic patients, but they need years to normalise GH hypersecretion and carry with them the risk of hypopituitarism. The major classes of drugs currently used to treat acromegaly are dopamine agonists and analogues of somatostatin. Dopamine agonists bind to the D2 receptor and suppress GH hypersecretion in some patients with acromegaly. Their clinical effectiveness is modest, although promising results have been obtained with two novel compounds, quinagolide and cabergoline, that possess long duration of action. Somatostatin analogues have been shown to improve clinical symptoms of acromegaly, decrease hypersecretion of GH and IGF-I and reduce tumour volume in a clinically significant number of patients. Octreotide is administered by s.c. route several times a day, but the recently developed sustained release formulations (octreotide LAR and SR lanreotide) are administered only every 7-28 days by i.m. injections. The complications associated with somatostatin analogues are small, relative to the benefits. Lastly, compounds with a novel mechanism of action, the GH receptor antagonists, are presently under investigation.     

Receptor-mediated tumor targeting based on peptide hormones

Importance of the field: Tumor targeting with peptides is based on the discovery that receptors for many regulatory peptides are overexpressed in tumor cells, compared with their expression in normal tissues. Consequently, these peptides and their analogues can be used as carriers/targeting moieties for the preparation of diagnostic and therapeutic agents that have increased selectivity and decreased peripheral toxicity.

Areas covered in this review: Here an overview is given of the most relevant gonadotropin-releasing hormone (GnRH) and somatostatin derivatives, as well as of their applications in cancer diagnosis and therapy. For this purpose, recently published data in these areas (mostly articles published from 2000 to 2009) were reviewed.

What the reader will gain: In contrast to other regulatory peptides that stimulate the tumor growth, GnRH and somatostatin derivatives have inhibitory effect; therefore, they were used primarily for the preparation of various conjugates to be used in targeted chemotherapy, targeted radiotherapy, photodynamic therapy, boron neutron capture therapy and cancer diagnosis. Some of these conjugates have already found clinical applications, whereas others are now in preclinical and clinical trials.

Take home message: Tumor targeting with hormone peptides provides a basis for the development of new diagnostic and therapeutic approaches for cancer.     

Emerging drugs in endometrial cancers

Importance of the field: Endometrial cancer remains the most common gynecologic malignancy. The treatment of endometrial cancer is rapidly evolving.

Areas covered in this review: In this article, we aim to review current and future treatment options in the medical treatment of endometrial cancers.

What the reader will gain: The cornerstone of curative therapy for patients with endometrial cancer is surgical treatment. Cytotoxic chemotherapy is the mainstay of therapy for metastatic and advanced endometrial cancer. The most active chemotherapy agents are anthracyclines, platinum compounds and taxanes. Combination chemotherapy has produced higher response rates than single agent therapy. Cisplatin and doxorubicin combination chemotherapy has served as the control arm in many trials. Three-drug combination regimen has shown the highest response rate but with increased toxicity. Despite the lack of published data supporting the superiority of the paclitaxel plus carboplatin combination over doxorubicin and cisplatin, many centers prefer this regimen as a standard of care. Hormonal therapy should be considered in patients with low grade tumors and in those with a poor performance status. Recent advances in the understanding of the molecular biology of endometrial cancer have led to development of targeted therapies. Among these the more promising ones are mTOR inhibitors and antiangiogenic agents.

Take home message: Clinical trials are planned to further explore how to best incorporate novel agents into the current treatment algorithm with the aim to improve outcome for women with endometrial adenocarcinomas.     

Somatostatin analogs for idiopathic pulmonary fibrosis therapy

Background: Idiopathic pulmonary fibrosis (IPF) is a potentially lethal disease characterized by diffuse multifocal fibrosis. SOM230 (also known as pasireotide), a somatostatin analog, is a potential antifibrotic therapy in early evaluative phase. Objective: Evaluation of data on the role of somatostatin receptors in pulmonary fibrosis and of in vivo and in vitro SOM230 antifibrotic activities. Methods/results: This study assessed somatostatin receptor expression in human normal and IPF lungs, and in animal lungs with bleomycin-induced fibrosis, as well as the effects of SOM230. The overall overexpression of somatostatin receptor subtype 2 and the anti-inflammatory/antifibrotic activities of SOM230 were demonstrated. Conclusion: These results are promising for further preclinical and clinical testing of SOM230 as an antifibrotic therapy.     

Somatostatin analogs in the treatment of neuroendocrine tumors: current and emerging aspects

Introduction: Neuroendocrine tumors (NETs) harbor somatostatin receptors and there is a strong rationale for using somatostatin analogs (SSAs) for treatment of NETs.

Areas covered: This article discusses i) pharmacology of somatostatin and its analogs; ii) antisecretory and anti-proliferative effects of SSAs in NETs; iii) efficacy and safety of emerging therapeutic regimens with first generation SSAs administered at either high doses or in combination with antineoplastic drugs; iv) efficacy and safety of pasireotide and chimeric molecules; v) efficacy of radionuclide therapy of NETs using SSAs.

Expert opinion: SSAs are the first-line medical therapy for functioning and non-functioning well-differentiated NETs. In patients not responder to first generation SSAs, the increase of drug dose over the conventional regimens, the combination of SSAs with other biotherapies or molecular targeted therapies, the switch to pasireotide or the use of SSAs in radionuclide therapy may improve the therapeutic success.