Therapy For Acromegaly Research Articles

Octreotide-LAR vs lanreotide-SR as first-line therapy for acromegaly: A retrospective, comparative, head- to- head study

No head-to-head comparisons are available to analyze the efficacy of octreotide (LAR) and lanreotide (LAN) as first-line treatment of acromegaly.We compared the efficacy of these two drugs in 54 newly diagnosed patients (21 women, 33 men), 27 treated with LAR (10-30 mg every 28 days) and 27 with LAN (60-90 mg/28 days), for 12 months. Each LAR-treated patient was matched with one LAN-treated patient as for GH levels, sex, and age (+/-5 yr). Outcome measures were GH and IGF-I levels and tumor shrinkage and secondarily classical cardiovascular risk factors (total/HDL-cholesterol ratio, glucose tolerance), blood pressure and drug tolerability. In LAR- and in LAN-treated patients, respectively: GH and IGF-I were controlled in 21 (77.7%) and in 16 patients (59.3%; p=0.26); tumor shrinkage was absent (<25%) in 4 and 5 patients (p=1), mild (25.1-50%) in 9 and 12 (p=0.57), moderate (50.1-75%) in 10 and 6 (p=0.37) and notable (>75%) in 4 and 4 patients (p=1). The total/HDL-cholesterol ratio and insulin levels significantly decreased while glucose levels significantly increased in both groups. None of the patients with normal glucose tolerance at diagnosis developed diabetes mellitus. Side effects were mostly at the gastrointestinal level and were similar with both drugs. In conclusion, newly diagnosed patients with acromegaly treated with LAR and LAN have no significantly different prevalence of disease control, tumor shrinkage, improvement of cardiovascular risk markers and side effects. Therefore, both drugs can be safely employed as first-line therapy of acromegaly.

Clinical use of cabergoline as primary and adjunctive treatment for acromegaly

Cabergoline is a dopamine agonist that may be used as primary or adjunctive therapy for acromegaly. Although one study suggested biochemical control may be achieved in a substantial proportion of patients, it is still commonly perceived to be a relatively ineffective treatment. A prospective audit was performed of 15 consecutive acromegalic patients (eight males, seven females, median age 55, range 31-92 at presentation) treated with cabergoline to determine the effective dose and tolerability. All had normal anterior pituitary function; two patients had hyperprolactinaemia. Magnetic resonance imaging revealed nine adenomata, two partially empty sellae and four structurally normal pituitary glands. Nine patients had undergone transsphenoidal surgery 1-12 months, and one patient had received pituitary radiotherapy 18 years, prior to commencement of cabergoline. All patients had biochemical GH excess; median serum IGF1 471 ng/ml, range 239-746 ng/ml. The calculated mean of a series of GH measurements ranged from 2.7-45.8 mIU/l, median 9.7 mIU/l. On a median weekly dose of cabergoline of 1.75 mg (range 0.5-7 mg) normalisation of both IGF1 and GH occurred in 4 out of the 15 patients (27%). Out of the 15 patients (33%), 5 achieved a serum IGF1 within the reference range with notable reductions seen in a further five patients. Nine patients (60%) achieved a mean serum GH level of less than 5 mIU/l. Duration of treatment was 2-52 months and was well tolerated in 14 patients. Cabergoline can be an effective and well tolerated primary or adjunctive therapy for acromegaly and useful clinical responses are noted even with modest doses.

Acromegaly and gigantism in the medical literature. Case descriptions in the era before and the early years after the initial publication of Pierre Marie (1886).

In 1886 Pierre Marie used the term “acromegaly” for the first time and gave a full description of the characteristic clinical picture. However several others had already given clear clinical descriptions before him and sometimes had given the disease other names. After 1886, it gradually became clear that pituitary enlargement (caused by a pituitary adenoma) was the cause and not the consequence of acromegaly, as initially thought. Pituitary adenomas could be found in the great majority of cases. It also became clear that acromegaly and gigantism were the same disease but occurring at different stages of life and not different diseases as initially thought. At the end of the 19th and beginning of the 20th century most information was derived from case descriptions and post-mortem examinations of patients with acromegaly or (famous) patients with gigantism. The stage was set for further research into the pathogenesis, diagnosis and therapy of acromegaly and gigantism.

Octreotide LAR for the treatment of acromegaly

Background: Somatostatin analogs previously considered as adjuvant therapy in acromegaly are increasingly used as a first-line therapy in selected cases. Objective: To review the octreotide LAR pharmacological and clinical data, and discuss the impact of this agent on current treatment regimens. Methods: We reviewed PubMed publications since the first use of octreotide LAR in acromegaly, and historical articles related to the discovery and development of this molecule. We chose, for efficacy and safety data, reviews, clinical and randomized controlled trials that included ≥ 10 patients. Results/conclusion: Octreotide LAR controls acromegaly in approximately 50 – 60% of patients by inhibiting GH and IGF-I secretion, and by reducing tumor size. This drug is well tolerated in most patients.

A Critical Analysis of Clinically Available Somatostatin Analog Formulations for Therapy of Acromegaly

Short and long-acting somatostatin (SRIF) analogs are approved for clinical use in acromegaly. Recent analysis of the relative efficacy of octreotide LAR and lanreotide SR on the GH-IGF-I axis in acromegaly favored octreotide LAR in the secondary treatment of patients not preselected by SRIF responsiveness. A novel aqueous formulation of lanreotide, lanreotide Autogel (ATG), has recently been approved and is the predominant (and only in the United States) formulation of lanreotide used clinically. We performed a critical review of SRIF analog treatment to establish the relative efficacy of three clinically available SRIF analog preparations, octreotide LAR, lanreotide SR, and lanreotide ATG (Somatuline depot in the United States) in control of the GH-IGF-I axis in acromegaly. Data were drawn from MEDLINE and the bibliography of analyses of long-acting SRIF analogs. We reviewed the largest studies of sc octreotide, octreotide LAR, and lanreotide SR, all that included biochemical end-point data for lanreotide ATG, and studies that directly compared the efficacy of octreotide LAR and lanreotide SR. Caveats considered included differences in baseline GH and IGF-I values, patient selection, and interassay and intraassay variability, confounding the analysis. Studies comparing patients treated contiguously with lanreotide SR and octreotide LAR are fraught with methodological problems, however, are suggestive of marginally greater efficacy in control of the GH-IGF-I axis for octreotide LAR. Lanreotide ATG shows noninferiority to lanreotide SR. Five small studies directly comparing octreotide LAR and lanreotide ATG suggest no significant differences between these preparations in control of biochemical end-points. Lanreotide ATG and octreotide LAR are equivalent in the control of symptoms and biochemical markers in patients with acromegaly.

Extensive Clinical Experience:Changing Patterns in Diagnosis and Therapy of Acromegaly over Two Decades

The increased morbidity and mortality of acromegaly makes early diagnosis and therapy critical. However, whether the type of medical professional who first diagnoses acromegaly, the major complaint prompting medical attention, or the management paradigms used in the setting of novel medical therapies have changed over time has not been well explored. Our objective was to identify the medical professional who first suspected acromegaly and the complaint prompting the diagnosis, and if these have changed. Additional goals were to assess the interval from symptom onset to diagnosis of acromegaly and to compare treatment trends over consecutive decades. This was a case-record retrospective study. The study was performed in a neuroendocrine clinical center at a tertiary care center. A total of 100 patients (45 men and 55 women) with acromegaly referred from 1985-2005 was included in the study. Acral changes (24%) and headaches (20%) were most prevalent presenting symptoms prompting diagnosis. Eighteen percent reported no symptoms of acromegaly at diagnosis. The primary care physician most often initiated the evaluation (44%). Comorbidities were more prevalent in older patients (P = 0.001). The interval between symptom onset and diagnosis decreased, compared with previous reports. Radiation therapy was used less frequently in the decade after 1994 than in the prior (16 vs. 33%; P < 0.05). The primary care doctor plays the major role in diagnosis of acromegaly. The increased use of brain magnetic resonance imaging may contribute to the many incidentally discovered cases and to the shortened time interval to diagnosis. Presumably due to the availability of new medical therapies, the use of radiation therapy has decreased.

Clinical and biochemical improvement in acromegaly during pregnancy

Numerous case reports of pregnancy in acromegaly exist, however detailed descriptions of changes in placental and pituitary GH and IGF-I throughout gestation are rare. A 19-yr-old female presented to this institution with signs and symptoms of a GH-secreting pituitary adenoma. Following transphenoidal hypophysectomy, she had 3 unplanned pregnancies, despite ongoing active disease. No pregnancy was complicated by glucose intolerance or hypertension and 3 healthy newborns were delivered near or at term. Clinical improvement was observed during each pregnancy, accompanied by IGF-I levels lower than in the non-pregnant state, the majority lying within the normal range. This was despite increasing placental GH levels, and was not consistent with previous reports in the literature. Further surgical and medical therapies for acromegaly failed to normalize nonpregnant GH or IGF-I levels in this woman. Estrogen is known to alter GH signaling via its interaction with Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways. We hypothesize that increasing concentrations of estrogen or other pregnancy-related hormones resulted in her clinical and biochemical improvement during pregnancy. This may be used for future therapeutic benefit.

Radiation therapy in acromegaly

Radiation therapy is generally not a primary treatment modality for growth hormone-secreting pituitary adenomas. However, in patients with acromegaly refractory to medical and/or surgical interventions, radiation can offer durable tumor control and often biochemical remission. Technique of radiation therapy delivery and dose vary by adenoma size and extrasellar extension. Radiation can be delivered in a single sitting by stereotactic radiosurgery or in fractionated form of smaller doses delivered over typically 5-6 weeks in 25-30 treatments. A brief overview of forms of radiation modalities is reviewed followed by discussion of the role for radiation therapy, rationale of delivery method, and potential adverse effects.

Optimalization and cost management of lanreotide-Autogel therapy in acromegaly

Lanreotide-Autogel is a depot formulation of the somatostatin analog lanreotide used in the treatment of acromegaly. We investigated whether prolonging or shortening the interval between injections would offer any benefit. The interval was prolonged from once every 4 weeks to once every 6 weeks when patients (n=9) had normal IGF-I and GH concentrations. When patients (n=12) had still elevated IGF-I or GH on the maximal dose of 120 mg every 4 weeks, the interval was shortened to once every 3 weeks. Serum IGF-I and GH were measured after 12 and 24 weeks to allow for dose adaptation. Symptoms and tumor volume were evaluated at baseline and after 36 weeks. In seven of the nine subjects with normal IGF-I and GH, the interval could be extended to 6 weeks without loosing efficacy on IGF-I (195 vs 213 microg/l; not significant, NS) and GH concentrations (1.4 vs 1.3 microg/l; NS). The weekly dose could significantly be reduced (from 23.3 to 17.8 mg; P=0.002). In only 1 of the 12 not-controlled patients, reducing the interval to once every 3 weeks induced normalization of IGF-I and GH. In subjects whose acromegaly is well controlled using lanreotide-Autogel, prolonging the time interval between injections can often be increased 4 to 6 weeks without loss of efficacy, thereby improving the subject's comfort and reducing the cost of treatment. On the other hand, in subjects whose acromegaly is not controlled on a dose of 120 mg every 4 weeks, reducing the interval to every 3 weeks is rarely beneficial.

A CENTURY OF PITUITARY SURGERY

Although pituitary tumors were well recognized by the end of the 20th century, very few surgeons had attempted to remove such tumors. In 1906, Hermann Schloffer at the Innsbruck University Clinic of Surgery reviewed the subject of pituitary surgery. Very little was known about the function of the pituitary, and no reports had yet been published on attempts to surgically remove pituitary neoplasms. Schloffer pointed out that ophthalmological symptoms evidently reflected mass effect of the tumor and, hence, resection of the tumor would be beneficial. He also proposed a transsphenoidal approach to the sella, although he was well aware of the risk of meningitis associated with this procedure. On March 16, 1907, Schloffer performed the first transsphenoidal operation for a pituitary adenoma. Unfortunately, the patient died 2 months later from a large residual tumor. Within a few years, several patients had undergone operation with procedures similar to the one described by Schloffer, several of whom experienced acromegaly, thus introducing neurosurgery as routine therapy for acromegaly and settling the long debate on the etiology of acromegaly.

Current thinking on the management of the acromegalic patient

Although the concept that acromegaly is associated with heightened cardiovascular risk is not new, it has become apparent that there are a number of risk factors associated with this disease and that specific therapeutic modalities may have variable effects on these risk factors. In addition, it is important to understand the medical therapies available for acromegaly and their role in acromegaly management. Acromegaly is associated with heightened cardiovascular risk, including derangements in glucose homeostasis and lipids, but also in markers of vascular function. Recent studies have demonstrated treatment-specific effects on these markers. In addition, recent studies have detailed further the efficacy and safety of various therapeutic options, in particular that of pegvisomant, the growth hormone receptor antagonist. A role for medical therapy as primary, de-novo therapy has been considered and recent studies support such use. The goals of acromegaly therapy are to control excess growth hormone secretion and limit, if not reverse, the long-term medical consequences and risk of premature mortality associated with acromegaly. It is critical to control both the growth hormone hypersecretion and associated cardiovascular risk factors to prevent the associated risks of cardiovascular disease and enhanced mortality. Medical therapy has an important adjuvant role in the management of acromegaly and use of somatostatin analogs as first-line therapy for specific groups of patients should be considered.

Pituitary tumor enlargement in two patients with acromegaly during pegvisomant therapy

Several classes of pharmacological agents are approved for the medical therapy of acromegaly, including dopamine agonists, somatostatin analogs and a growth hormone receptor antagonist. Pegvisomant, a growth hormone receptor antagonist, suppresses IGF-1 levels into the normal range in over ninety percent of patients. However, increased tumor volume was reported in patients receiving pegvisomant who had not received prior radiotherapy. To describe two patients with acromegaly who developed significant tumor enlargement on pegvisomant and discuss the potential mechanisms involved. Both patients received long-acting somatostatin analog (octreotide) therapy subsequent to incomplete transsphenoidal tumor resection. Octreotide did not normalize GH/IGF-1 levels in either patient but did control tumor mass size. Pegvisomant therapy was initiated after discontinuing octreotide. Both patients exhibited suppression of IGF-1 into the normal range during pegvisomant therapy. However, significant tumor enlargement occurred in both. Potential mechanisms for tumor enlargement include the natural tendency of the tumor to grow with time, discontinuation of tumor suppressive effects of the somatostatin analog, or a direct effect of pegvisomant. The presumed mechanism of tumor enlargement is by loss of the inhibitory effect on tumor growth when IGF-1 levels are reduced. This could also explain the increase in circulating GH levels in patients with acromegaly receiving pegvisomant; patient 1 demonstrated an 18-fold increase in circulating GH levels while receiving the drug. The mechanisms of tumor enlargement in patients with acromegaly on pegvisomant are likely multifactorial. Patients, especially those who have not received prior radiotherapy, should be closely monitored for tumor enlargement.

Efficacy of a slow‐release formulation of lanreotide (Autogel® 120 mg) in patients with acromegaly previously treated with octreotide long acting release (LAR): an open, multicentre longitudinal study

Lanreotide Autogel 120 mg (ATG120; Ipsen S.p.A, Milan, Italy) is a high-dose, sustained-release aqueous gel formulation, supplied in a prefilled syringe and given by deep subcutaneous injection. The aim of this study was to compare efficacy and tolerability of ATG120 given every 4-8 weeks with those of octreotide LAR (o-LAR) given every 4 weeks. DESIGN PATIENTS AND INTERVENTION: A phase III multicentre Italian open clinical study of 23 acromegalic patients (15 female, 8 male). All patients had received o-LAR for 6-18 months and, after 3 months wash out, ATG120 was given every 6 weeks for a total of four injections (Period 1). Then the interval between ATG120 injections was adjusted according to three different schemes: every 4, 6 or 8 weeks depending on GH levels (GH > 2.5 microg/l; 1 < GH <or= 2.5 microg/l; GH <or= 1 microg/l, respectively). ATG120 was given for a further two to three doses, with a final assessment (Period 2) at Week 34, 36 or 42. Hormonal (GH and IGF-I) and clinical efficacy and tolerability. ATG120 induced a significant GH decrease from 9.9 +/- 11.3 at baseline (Visit 1) to 3.5 +/- 5.7 at the end of Period 1 (P < 0.01) and to 3.8 +/- 5.7 microg/l at the final visit (P < 0.01). IGF-I also decreased from 544 +/- 312 at baseline (Visit 1) to 318 +/- 181 at Period 1 and to 356 +/- 187 microg/l at the final visit (both P < 0.05 vs. baseline). The frequency of ATG120 administrations was adjusted to every 4 weeks in 12 patients, every 6 weeks in 4 patients and every 8 weeks in 6 patients; 1 patient withdrew before the dose adjustment. Serum GH and IGF-I achieved at the end of Period 1 and Period 2 were similar to those reached with o-LAR. The number of patients who achieved GH < 2.5 microg/l was comparable between o-LAR (43%) and ATG120 at Period 1 (48%) and at Period 2 (62%). Normal IGF-I levels were recorded in 8 patients during o-LAR (35%), 11 during ATG Period 1 (48%) and 10 at the final visit (43%). Last, 4 patients showed a better response to ATG120 and 2 to o-LAR. Lanreotide Autogel 120 mg is an effective and well-tolerated therapy for acromegaly. In approximately half of patients ATG120 may be administered every 6-8 weeks, instead of every 4 weeks, without lost of efficacy.

Approach to the evaluation of the GH/IGF-axis in patients with pituitary disease: which test to order

The diagnosis of adult growth hormone deficiency (AGHD) and acromegaly involves assessment of serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations. The diagnosis of AGHD typically requires a provocative test of GH reserve, but is supported by demonstration of low-serum IGF-1 levels. Therapeutic monitoring of rhGH replacement is performed utilizing measurement of serum IGF-1 concentrations. In patients with suspected acromegaly, the diagnosis is confirmed by elevated serum IGF-1 levels and further validated by the presence of elevated GH levels both before and following an oral glucose load. A goal of acromegaly therapy is to normalize IGF-1 concentrations, and, depending on the therapeutic modality, GH levels as well. Using case based clinical scenarios, we have presented a standard approach to the biochemical diagnosis and therapeutic monitoring of these disorders.

Primary surgical therapy of acromegaly – results and prognostic parameters from the German acromegaly register

Surgery is used as a first-line therapy in many patients with acromegaly. We analyzed the German Acromegaly Register to investigate its efficacy and search for predictive factors. At the time of data lock, 1485 patients had been enrolled into the register.

先端巨人症の内科的治療 : 最近の進歩(GH産生下垂体腺腫のupdate)

先端巨人症の内科的治療 : 最近の進歩(<特集>GH産生下垂体腺腫のupdate)

Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: Safety and efficacy evaluation from the German Pegvisomant Observational Study

The GH receptor antagonist pegvisomant is a highly effective new treatment option in acromegaly. The German Pegvisomant Observational Study (GPOS) was started to monitor long-term safety and efficacy of pegvisomant as prescribed in clinical practice. GPOS is an observational, multi-center, surveillance study, which comprises non-interventional data collection. Of the 229 patients included in the study, 90.4% had previous pituitary surgery, 43.2% were treated by radiation therapy, and 94.3% had previous medical therapy for acromegaly that had been discontinued mainly due to persistent IGF-I elevation or side effects. The intention-to-treat population included 177 patients with at least one post-baseline efficacy measurement. IGF-I levels decreased from 1.75+/-0.91-fold the upper limit of normal at baseline to 1.05+/- 0.62 at the 6-month visit, 0.96+/-0.60 at the 12-month visit, and to 0.89+/-0.41-fold after 24 months (P<0.0001). Mean duration of pegvisomant therapy was 51.8+/-35.8 weeks (median=51.9 weeks). IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0 mg/day, in 70.9% at 12 months, and in 76.3% at 24 months. Fasting glucose levels improved from 114.4+/-45.9 to 101.5+/- 42.8 mg/dl after 6 months (P<0.01) and to 100.6+/-33.2 mg/ml after 12 months (P<0.01). General physical condition measured by specific signs and symptoms score improved significantly. Adverse events occurring in >1% were injection site reactions in 7.4%, elevated liver enzymes (>3 times of normal) in 5.2% (3.1% spontaneously normalized during continued treatment), reported increase of pituitary tumor volume in 5.2% (which was verified in 3.1%), and headache in 1.7%. Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials and can effectively reduce IGF-I in patients with acromegaly refractory to conventional therapy.

First-line therapy of acromegaly: A statement of the A.L.I.C.E. (Acromegaly primary medical treatment Learning and Improvement with Continuous Medical Education) Study Group

First-line therapy of acromegaly: A statement of the A.L.I.C.E. (Acromegaly primary medical treatment Learning and Improvement with Continuous Medical Education) Study Group

Dopamine agonist therapy in combination with somatostatin analogue treatment in patients with acromegaly: analysis of the German Acromegaly Registry

Somatostatin analogues (SA) are recommended as the standard medical therapy in acromegaly, but only a part of the treated patients can be effectively controlled under continuous administration. According to the guidelines for acromegaly management, the combination of long-acting somatostatin analogues with dopamine agonists has been proposed, but the combined therapy has not yet been sufficiently evaluated. Retrospectively, we assessed patients with dopamine agonist addition to somatostatin analogue treatment in 35 out of the 1434 patients that have been entered into the German Acromegaly Registry. Only patients with somatostatin analogues treatment for at least 3 months before dopamine agonist addition and without radiotherapy during the monotherapy were considered. Methods: Thirty-five patients fulfilled these criteria with 21 patients having received primary surgical therapy and 14 patients who were treated medically as primary treatment. Six patients received radiotherapy after primary treatment and before somatostatin analogue therapy was started (mean duration 28,8+/-28,6 months before combined therapy). Eleven patients received dopamine agonists as monotherapy before the combined treatment.

Recent advances in medical therapy for acromegaly

For a considerable time, somatostatin analogues (SA) have been the medical therapy of choice for the treatment of acromegaly. In addition to their well-established use as an adjunctive therapy, primary therapy with SA has been investigated in recent years, demonstrating biochemical and proliferative control in a relevant percentage of patients.