First-generation Somatostatin Analogs Research Articles

The Role of the GH Receptor Polymorphisms as a Prognostic Factor of Vertebral Fractures in Acromegalic Patients Resistant to First-generation SSAs and Treated with Pegvisomant or Pasireotide LAR.

Acromegaly is associated with skeletal fragility and increased prevalence of vertebral fractures (VF). Two isoforms of GH receptor (GHR) have been described, which differ in the presence or absence of a transcript of exon 3 of the GHR gene. Both isoforms produce a functional receptor, but the exon 3-deleted isoforms (d3-GHR) have greater sensitivity to endogenous and recombinant GH than the full-length isoform (fl-GHR). We conducted a longitudinal, retrospective, observational, single-center study to investigate the role of GHR polymorphism as a prognostic factor of incidental VF (I-VF) in firstgeneration somatostatin analogs (fg-SSAs)-resistant acromegalic patients and treated with Pegvisomant or Pasireotide LAR. Seventy-two patients with active acromegaly were included: 28 patients carried the d3-GHR isoform, and 44 patients carried the fl-GHR isoform. Forty-six patients were treated with Pegvisomant in combination with fg-SSAs, and 26 were treated with Pasireotide LAR. At the last follow-up, 58 patients achieved biochemical control of acromegaly. Eighteen patients carried prevalent VF (P-VFs), while 14 patients experienced the occurrence of I-VFs. From the group treated with Pegvisomant in combination with fg-SSAs, 32 patients carried the fl-GHR isoform, and 14 carried the d3-GHR isoform. From the group treated with Pasireotide LAR, 12 patients had the fl-GHR isoform, and 14 patients carried the d3-GHR isoform. I-VF occurred more frequently in patients with the fl-GHR isoform compared to d3-GHR (p =0.04); otherwise, I-VF occurred more frequently in patients with the d3-GHR isoform than fl-GHR (p =0.01). The GHR polymorphisms could improve the therapeutic approach in acromegaly, tailored to the individual patient, in the context of personalized medicine.

Emerging therapies for advanced insulinomas and glucagonomas.

Pancreatic neuroendocrine neoplasms (panNENs) are rare relatively malignancies that, despite their frequently slow-growing pattern, have the ability to metastasize. Metastatic and/or advanced insulinomas and glucagonomas are functioning panNENs emerging from the pancreas displaying unique peculiarities, depending on their hormonal syndromes and increased malignant potential. Advanced insulinomas management follows usually the panNENs therapeutic algorithm, but some distinctions are well advised together with aiming to control hypoglycemias that occasionally can be severe and refractory to treatment. When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect. There is evidence that everolimus is still effective after rechallenge retaining its hypoglycemic effect independently of its antitumor effect that seems to be mediated by different molecular pathways. Peptide receptor radionuclide therapy (PRRT) constitutes a promising therapeutic option for both its antisecretory and antitumoral action. Similarly, advanced and/or metastatic glucagonomas management also follows the panNENs therapeutic algorithm, but the clinical syndrome has to be addressed by aminoacid infusion and by first-generation SSAs to improve the patient performance status. PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging the overall survival of patients suffering from these malignancies.

Association between Biomarkers (VEGF-R2, VEGF-R3, VCAM-1) and Treatment Duration in Patients with Neuroendocrine Tumors Receiving Therapy with First-Generation Somatostatin Analogues

Angiogenic factors (AF) promote vascular formation and may thus support neuroendocrine tumour (NET) development. This study aimed to assess AF serum level changes in NET patients treated with prolonged-acting somatostatin analogues (SSAs). The study enrolled 49 healthy volunteers (Group A) and 56 NET patients: treatment naïve (Group B) and after-SSA treatment in various periods (months): under 12 (Group C), 13-24 (Group D), 25-36 (Group E), 37-60 (Group F), and over 60 months (Group G). The serum vascular endothelial growth factor receptors 2, 3 (VEGF-R2, VEGF-R3), and vascular cell adhesion molecule-1 (VCAM-1) concentrations were tested using the ELISA. We noted significant differences in the concentrations of VEGF-R2, VEGF-R3, and VCAM-1 depending on the SSA treatment duration (p < 0.001). In the studied AFs, the highest decreasing levels of VEGF-R2 were observed after two years of therapy. However, monitoring VEGF-R2, VEGF-R3, and VCAM-1 during SSA treatment did not allow for the identification of good responders for this kind of therapy. Therefore, these biomarker measurements were not helpful in assessing SSA treatment effectiveness in NET patients.

Assessment of VEGF and VEGF R1 serum levels in patients with neuroendocrine neoplasms before and after treatment with first-generation somatostatin analogues.

Vascular endothelial growth factor (VEGF) is a known promoter of angiogenesis that can support neuroendocrine neoplasm (NEN) development. The aim of the study was to evaluate the serum VEGF and vascular endothelial growth factor receptor 1 (VEGF R1) concentration changes in patients with NEN treated with first-generation long-acting somatostatin analogues (SSA). The study comprised 55 controls and 56 NEN patients before and after SSA treatment in various periods of time (months): 1-12 (n = 54), 13-24 (n = 46), 25-36 (n = 35), 37-60 (n = 26), and over 60 months (n = 22). An analysis of medical records and serum VEGF and VEGF R1 concentration measurements of NEN patients, by enzyme-linked immunosorbent assay (ELISA) were made. During SSA treatment time, a decrease of the VEGF and an increase of VEGF R1 concentrations was observed. We confirmed significant VEGF differences between 2 pairs of SSA-treated NEN patient subgroups: Group 1-12 vs. Group 37-60 (p = 0.039) and Group 1-12 vs. Group > 60 (p = 0.026). We did not note significant differences of VEGF R1 levels between SSA-treated NEN patient subgroups. Among the studied biomarkers, VEGF R1 exhibited the best performance in distinguishing between NEN patients with controls; area under the curve (AUC) = 1 (p < 0.001). The examined angiogenesis factors (VEGF and VEGF R1) seem to have limited usage in the assessment of SSA treatment effectiveness in NEN. However, the assessment of serum levels of these factors may help in the differentiation of NEN patients and healthy controls; in particular, VEGF R1 seems to be a good diagnostic biomarker for NEN patients.

Efficacy of lanreotide 120 mg primary therapy on tumour shrinkage and ophthalmologic symptoms in acromegaly after 1 month.

Few studies have attempted to evaluate the early efficacy of first-generation somatostatin analogues in somatotroph macroadenomas. To investigate the short-term efficacy of primary therapy with lanreotide 120 mg at 1 and 3 months on tumour shrinkage and ophthalmologic symptoms in newly diagnosed patients with acromegaly. This single-centre retrospective study included 21 patients with de novo acromegaly resulting from pituitary macroadenoma, with optic chiasm compression (Grade ≤ 2) and/or cavernous sinus invasion, treated with a monthly injection of lanreotide 120 mg. Clinical, hormonal, ophthalmologic and magnetic resonance imaging scan evaluations were conducted after the first and the third months of treatment. Tumour volume reduction was more pronounced at 1 month; mean volume change: -31.4 ± 19.5%, p < .0001than between the first and third month of treatment; mean volume reduction: -20.6 ± 13.4%, p = .0009. The mean volume change between baseline and the third month was - 46.4 ± 21.6, (p < .0001). A significant volume reduction (≥25%) was observed in 61.9% of individuals (13/21) at the first month. Among 14 individuals with optic chiasm compression and visual field defects, visual field normalization or improvement were observed in seven cases (50%), stabilization in four cases (28.5%), and mild worsening in three cases (21.4%) at 1 month. The decrease in growth hormone and IGF-1 serum values was significant at 1 month. Primary treatment with lanreotide 120 mg in patients with somatotroph macroadenomas provides early significant tumour shrinkage with rapid improvement of visual symptoms at the end of the first month in 50% of patients.

Cost-Utility of Acromegaly Pharmacological Treatments in a French Context.

ObjectiveEfficacy of pharmacological treatments for acromegaly has been assessed in many clinical or real-world studies but no study was interested in economics evaluation of these treatments in France. Therefore, the objective of this study was to estimate the cost-utility of second-line pharmacological treatments in acromegaly patients.MethodsA Markov model was developed to follow a cohort of 1,000 patients for a lifetime horizon. First-generation somatostatin analogues (FGSA), pegvisomant, pasireotide and pegvisomant combined with FGSA (off label) were compared. Efficacy was defined as the normalization of insulin-like growth factor-1 (IGF-1) concentration and was obtained from pivotal trials and adjusted by a network meta-analysis. Costs data were obtained from French databases and literature. Utilities from the literature were used to estimate quality-adjusted life year (QALY).ResultsThe incremental cost-utility ratios (ICUR) of treatments compared to FGSA were estimated to be 562,463 € per QALY gained for pasireotide, 171,332 € per QALY gained for pegvisomant, and 186,242 € per QALY gained for pegvisomant + FGSA. Pasireotide seems to be the least cost-efficient treatment. Sensitivity analyses showed the robustness of the results.ConclusionFGSA, pegvisomant and pegvisomant + FGSA were on the cost-effective frontier, therefore, depending on the willingness-to-pay for an additional QALY, they are the most cost-effective treatments. This medico-economic analysis highlighted the consistency of the efficiency results with the efficacy results assessed in the pivotal trials. However, most recent treatment guidelines recommend an individualized treatment strategy based on the patient and disease profile.

Resistance to drug treatment of acromegaly and ways to overcome it

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.

Gender-Specific Efficacy Revealed by Head-to-Head Comparison of Pasireotide and Octreotide in a Representative In Vivo Model of Nonfunctioning Pituitary Tumors.

Simple SummaryNo effective medical therapy exists for residual/recurrent nonfunctioning pituitary tumors (NFPTs). First-generation somatostatin analogs (SSAs) like octreotide targeting somatostatin receptor type 2 (SSTR2) are the mainstay therapy for functioning PTs, but have shown little effect in NFPTs. This is in agreement with an SSTR profile characterized by low SSTR2, and high SSTR3 levels in the latter. Pasireotide a multi-SSTR-preferring SSA, should be effective against NFPTs. To test this hypothesis, we conducted a head-to-head comparison of octreotide and pasireotide in the only spontaneous in vivo model of NFPTs (MENX rats), which recapitulates the human disease. Pasireotide showed a superior anti-tumor effect vs. octreotide, especially in females. Interestingly, Sstr3 levels were higher in female vs. male NFPTs. A sex-related SSTR3 expression may extend to human NFPTs, thereby representing a tool for patient stratification. Our results have translational relevance for the medical treatment of patients with residual/recurrent NFPTs currently lacking efficacious therapeutic options.Invasive nonfunctioning pituitary tumors (NFPTs) are non-resectable neoplasms associated with frequent relapse and significant comorbidities. Current treatments, including somatostatin receptor 2 (SSTR2)-directed somatostatin analogs (SSAs), often fail against NFPTs. Thus, identifying effective therapies is clinically relevant. As NFPTs express SSTR3 at high levels, pasireotide, a multireceptor-targeted SSA, might be beneficial. Here we evaluated pasireotide in the only representative model of spontaneous NFPTs (MENX rats) in vivo. Octreotide long-acting release (LAR), pasireotide LAR, or placebo, were administered to age-matched, tumor-bearing MENX rats of both sexes for 28 d or 56 d. Longitudinal high-resolution magnetic resonance imaging monitored tumor growth. While tumors in placebo-treated rats increased in volume over time, PTs in drug-treated rats displayed significant growth suppression, and occasional tumor shrinkage. Pasireotide elicited stronger growth inhibition. Radiological responses correlated with tumors’ proliferation rates. Both SSAs, but especially pasireotide, were more effective in female vs. male rats. Basal Sstr3 expression was significantly higher in the former group. It is noteworthy that female human NFPTs patients also have a trend towards higher SSTR3 expression. Altogether, our studies provide the rationale for testing pasireotide in patients with residual/recurrent NFPTs. If confirmed, the sex-related SSTR3 expression might be used as criteria to stratify NFPTs patients for treatment with pasireotide.

Акромегалия: подходы к оптимизации медикаментозного лечения

Acromegaly is a chronic disease that often requires long-term medical treatment. The main group of drugs for acromegaly consists of the first-generation somatostatin analogues such as octreotide and lanreotide. It is also possible to use the dopamine receptor agonist cabergoline. Since 2018, one more growth hormone antagonist, pegvisomant, has been registered in Russia. The goal of drug therapy is to normalize the level of insulin-like growth factor 1, so it is fundamentally important to monitor this indicator. If the level of insulin-like growth factor 1 does not normalize during the use of octreotide or lanreotide in maximum doses for 3–12 months, it is necessary to optimize therapy. In the case of complete resistance to somatostatin analogues, it is possible to switch to pegvisomant, as well as active neurosurgical and/or radio surgical intervention. In case of partial resistance, the use of combination therapy with somatostatin analogues and cabergoline/pegvisomant is justified. The article discusses and justifies various options for optimizing the drug treatment of acromegaly.

Real-World Experience With Pasireotide Lar in Acromegaly Resistant to First-Generation Somatostatin Analogs: A Single Center 1-Year Observation

Introduction: First generation somatostatin analogs (SSAs) are the treatment of choice in persistent acromegaly after transsphenoidal surgery. However, they are effective in 25% to 45 % of patients and a second generation SSA - pasireotide LAR may be a more effective alternative. Aim Our aim was to evaluate the impact of 1-year treatment with pasireotide LAR on disease control and on glucose metabolism in patients with acromegaly after debulking surgery resistant to first-generation SSAs. Material and methods In this single-center prospective study 29 consecutive patients with resistant acromegaly were treated with pasireotide LAR. The initial drug dose was 40 mg i.m. every 28 days. If patient did not achieve biochemical control (GH <2.5 ng/mL and IGF-1 ≤ULN for age and sex) at month 3, the dose was increased to 60 mg i.m. every 28 days. Assessment (GH, IGF-1, glucose, HbA1c) was performed at month 3, 6, 9 and 12. Results: In total, 22 patients (10 females, 12 males) completed a 1-year treatment. Mean age was 41.8±13.8 years. Twelve patients (54.5%) were ≤ 40 years old (including 6 (27.3%) patients of age ≤30 years). At baseline, mean IGF-1 level was 2.3 (SD 0.7) x ULN (age- and sex-specific) (583.9 ng/mL; SD 182.2) and mean GH concentration was 3.9 (SD 2.8) ng/mL. Both values decreased significantly after 1 year of treatment (P<0.001). Pasireotide LAR dose was increased to 60 mg in 16 (72.7%) patients and decreased to 20 mg in one patient patient due to worsening of diabetes control. The magnitude of mean GH level decrease was the largest within first 6 months (mean change from baseline: -1.75 ng/mL, 95% CI: -2.64, -0.85, P=0.0006). Mean IGF-1 level decreased rapidly within the first 3 months (mean change from baseline: -153.20 ng/mL, 95% CI: -203.20, -103.19, P<0.0001) and remained low during 12-month follow-up. GH level ≤ 1 ng/mL and ≤2.5 ng/mL was achieved by 7 (31.8%) and 17 (77.3%) patients, respectively. Six patients (27.3%) achieved normal IGF-1 level (IGF-1 ≤1 x ULN) (P=0.0275). IGF-1 ≤1.3 x ULN was observed in 11 (50.0%) of patients. Full biochemical control (GH ≤1 ng/mL and IGF-1 ≤1 x ULN) was achieved in 3 (13.6%) patients. Pasireotide LAR treatment resulted in significant increase of mean fasting glucose level: 119.2 (SD 17.3) vs. 107.5 (SD 13.9) mg/dL, P<0.001. The largest change was observed in first 3 months, and it remained stable until month 12. HbA1c level also increased significantly during first 3 months and stayed on similar level during follow-up (mean for month 12: 6.3 (SD 0.6) vs. 5.9 (SD 0.5) % at baseline, P<0.001). Conclusions: Pasireotide LAR is an effective treatment in most patients with persistent acromegaly after surgical debulking resistant to first generation SSAs. The largest increase of glycemia occurs during first 3 months of treatment and it remains stable afterwards.

Patient and Healthcare Provider Perspectives of First-Generation Somatostatin Analogs in the Management of Neuroendocrine Tumors and Acromegaly: A Systematic Literature Review.

IntroductionSomatostatin analogs (SSAs) are used to treat neuroendocrine tumors (NETs) and acromegaly. Two first-generation SSAs, octreotide long-acting release (OCT LAR) and lanreotide autogel/depot (LAN), are available. A systematic literature review (SLR) was conducted to investigate which characteristics beyond efficacy are most important in patient and healthcare practitioner (HCP) experience of LAN and OCT when used to treat acromegaly and NETs.MethodsMEDLINE, Embase, the Cochrane Library, and Database of s of Reviews of Effect were searched from database inception to January 2019 with terms for first-generation SSAs, NETs, acromegaly, preferences, decision-making, and human factors. Key congresses in 2016–2018 and SLR bibliographies were hand-searched. Two independent reviewers screened articles at title/abstract and full-text stage. Publications fulfilling pre-specified inclusion criteria reported patient or HCP perspectives of LAN or OCT, or any factors affecting treatment perspectives for NETs or acromegaly.ResultsA total of 1110 unique records were screened, of which 21 studies were included, reporting from the perspectives of patients (n = 18) and/or HCPs (n = 9). Perspectives were collected using shared decision-making frameworks, questionnaires, informal patient opinion, and a Delphi panel. Where patient preference was specifically reported, LAN was preferred in 4/5 studies and OCT LAR in 1/5. Common factors underlying treatment experience included technical problems with injections and associated pain, emotional quality/anxiety of injections, time and convenience of treatment administration, and independence. Immediate aspects of injections appeared most important to patients, though the possibilities of extended dosing intervals and self-/partner-injection with LAN were also notable factors.ConclusionsStudy outcomes favored LAN in this SLR, with factors surrounding injection administration most influential in treatment experience. The findings of this SLR provide a basis that could inform development of decision-making criteria, with patient and HCP treatment perspectives considered. Future studies should utilize a common method to report preference and associated drivers.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-020-01600-x.

The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas

Most pituitary adenomas (PAs) are considered benign tumors, but approximately 0.2% can present metastasis and are classified as pituitary carcinomas (PCs). Refractory PAs lie between benign adenomas and true malignant PC and are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments, including temozolomide. It is notoriously difficult to manage refractory PAs and PC because of the limited therapeutic options. As a promising therapeutic approach, cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The purpose of this review is to report the progress of immunotherapy in pituitary tumors, including refractory PAs and PCs. The tumor immune microenvironment has been recognized as a key contributor to tumorigenesis, progression, and prognosis. One study indicated that the number of CD68+ macrophages was positively correlated with tumor size and Knosp classification grade for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but pituitary growth hormone (GH) adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in pituitary tumor size and invasiveness. Another study suggested that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogs in acromegaly patients, highlighting a potential role of the tumor immune microenvironment in determining the prognosis of somatotroph pituitary tumors. Preclinical studies have indicated that widely varying degrees of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) are found among different subtypes. Functional PAs and aggressive PAs express significantly higher levels of PD-L1 and TILs than other subtypes, indicating that PD-1 blockade might be a promising alternative therapy for patients with aggressive PAs. PD-L1 transcript and protein levels were found to be significantly increased in functioning (GH and prolactin-expressing) pituitary tumors compared to nonfunctioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary tumors harbored higher levels of PD-L1 mRNA than recurrent tumors. These findings suggest the possibility of considering checkpoint blockade immunotherapy for functioning pituitary tumors refractory to conventional management. Animal models of Cushing’s disease also demonstrated PD-L1 and TIL expression in cultured tumors and murine models, as well as the effectiveness of checkpoint blockade therapy in reducing the tumor mass, decreasing hormone secretion, and increasing the survival rate. Clinical studies show that immunotherapy may be an effective treatment in patients with pituitary tumors. One corticotroph carcinoma patient showed a significant reduction in hormone levels and shrinkage of the tumor size of primary and metastatic lesions immediately after investigational treatment with ipilimumab and nivolumab. However, another patient with corticotroph adenoma progressed rapidly after four cycles of anti-PD-1 (pembrolizumab) treatment. To date, there are two registered clinical trials of immunotherapy for pituitary tumors. One of them is the phase II clinical trial of nivolumab combined with ipilimumab for patients with aggressive pituitary tumors (NCT04042753). The other one is also a phase II clinical trial of the combination of nivolumab and ipilimumab for rare tumors, including pituitary tumors (NCT02834013). Both clinical trials are in the stage of recruiting patients and have not been completed. In summary, the results from preclinical research and clinical studies indicated that immunotherapy might be a promising alternative therapy for PCs and refractory PAs resistant to conventional treatments. The combination of immunotherapy and radiotherapy or temozolomide may have synergistic effects compared to a single treatment. More preclinical and clinical studies are needed to further indicate the exact efficacy of immunotherapy in pituitary tumors.

Risk factors and management of pasireotide-associated hyperglycemia in acromegaly.

Pasireotide, a multireceptor-targeted somatostatin analog with highest affinity for somatostatin receptor subtype (SST) 5, has demonstrated superior efficacy over the SST2-preferential somatostatin analogs octreotide and lanreotide. The safety profile is similar to those of octreotide and lanreotide, except for a higher frequency and degree of hyperglycemia. This analysis investigated baseline characteristics and occurrence and management of hyperglycemia during pasireotide treatment in patients with acromegaly treated in two prospective clinical studies, SOM230C2305 (C2305) and SOM230C2402 (C2402; PAOLA). One hundred and seventy-eight patients naïve to medical therapy at baseline (C2305) and 125 uncontrolled on first-generation somatostatin analogs at baseline (C2402) received long-acting pasireotide in these studies. Of patients treated with pasireotide in studies C2305 and C2402, respectively, 75.3 (134/178) and 65.6% (82/125) developed hyperglycemia or experienced worsening of existing hyperglycemia. Occurrence of hyperglycemia during pasireotide treatment was less frequent in patients with lower age (<40 years, C2402; <30 years, C2305), normal glucose tolerance, and no history of hypertension or dyslipidemia at baseline. Thirteen (4%) patients discontinued pasireotide because of hyperglycemia-related adverse events. Metformin alone or in combination with other oral antidiabetic medications controlled elevations in glucose levels in most pasireotide-treated patients; 78% of C2305 patients and 73 (pasireotide 40 mg) and 60% (pasireotide 60 mg) of C2402 patients achieved the ADA/EASD goal of HbA1c <7% (<53 mmol/mol) at the end of the core phase. Not all patients develop hyperglycemia, and it is reversible upon pasireotide withdrawal. Close monitoring, patient education and prompt action remain key elements in addressing hyperglycemia during pasireotide treatment.

Surgical and Pharmacological Outcomes in Acromegaly: Real-Life Data From the Mexican Acromegaly Registry.

Acromegaly registries constitute a valuable source of therapeutic outcome information in real-life. The objective of this work is to analyze surgical and pharmacological outcomes in the Mexican Acromegaly Registry (MAR). Data were extracted from the MAR informatic platform. Surgical remission was defined by a postoperative postglucose (GH) of less than 1 ng/mL and an insulin-like growth factor 1 (IGF-1) of less than 1.2 × upper limit of normal (ULN). Pharmacological remission was defined by a basal GH of less than 1 ng/mL and an IGF-1 of less than 1.2 × ULN. A total of 650 surgical outcomes were analyzed (94.6% transsphenoidal). Surgical remission was achieved in 40.15%, whereas 44.15% remained biochemically active. Persistently active disease after surgery was significantly associated with harboring an invasive macroadenoma, a basal GH of greater than 10 ng/mL, and/or an IGF-1 of greater than 2 × ULN at diagnosis on bivariate and multivariate analysis. The outcome of monotherapy with first-generation somatostatin analogs (SSAs) was evaluated in 267 patients (adjunctive in 65%), of whom 28.4% achieved remission. Persistently active disease was significantly associated with harboring an invasive macroadenoma as well as with pretreatment basal GH and IGF-1 levels of greater than 10 ng/mL and greater than 2 × ULN, respectively, on bivariate and multivariate analysis. Combined therapy with SSA and cabergoline was analyzed in 100 patients, of whom 19% achieved remission and 44% remained active; in this subset of patients, only a pretreatment IGF-1 of greater than 2 × ULN was significantly associated with persistent disease activity. Surgical and pharmacological outcomes in acromegaly are highly dependent on tumor size/invasiveness as well as on the degree of hypersomatotropinemia.

MRI follow-up of patients with acromegaly treated with first-generation somatostatin analogues (SMSa): Is there a difference during primary or post-operative treatment?

MRI follow-up of patients with acromegaly treated with first-generation somatostatin analogues (SMSa): Is there a difference during primary or post-operative treatment?

Evaluation of the Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Inadequately Controlled With First-Generation Somatostatin Analogs.

Introduction: Acromegaly is a rare, serious endocrine disorder characterized by excess growth hormone (GH) secretion by a pituitary adenoma and overproduction of insulin-like growth factor I (IGF-I). Transsphenoidal surgery is the treatment of choice, although many patients require additional interventions. First-generation somatostatin analogs (SSAs) are the current standard of medical therapy; however, not all patients achieve control of GH and IGF-I. Outcomes from a Phase IIIb open-label study of patients with uncontrolled acromegaly on first-generation SSAs switching to pasireotide are reported.Methods: Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 μg/L from a five-point profile over 2 h, and IGF-I >1.3× upper limit of normal [ULN]) despite ≥3 months' treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be increased (maximum: 60 mg/28 days) after week 12 if biochemical control was not achieved, or decreased (minimum: 10 mg/28 days) for tolerability. Patients who completed 36 weeks' treatment could continue receiving pasireotide during an extension (weeks 36–72) when concomitant medication for acromegaly was permitted. Primary endpoint was proportion of patients with mGH <1 μg/L and IGF-I <ULN at week 36. Biochemical control was also assessed during the extension. Safety was assessed throughout.Results: One hundred and twenty-three patients were enrolled and received pasireotide; 88 patients continued into the extension. Overall, 18 [14.6% (95% CI: 8.9–22.1)] patients achieved mGH <1 μg/L and IGF-I <ULN at week 36; biochemical control was achieved in 42.9% with screening mGH 1.0–2.5 μg/L and 6.4% with screening mGH >2.5 μg/L. For patients who entered the extension, 14.8% (95% CI: 8.1–23.9), 12.5% (95% CI: 6.4–21.3), 14.8% (95% CI: 8.1–23.9) and 11.4% (95% CI: 5.6–19.9) had mGH <1 μg/L and IGF-I <ULN at weeks 36, 48, 60, and 72, respectively. During the overall study period, most frequent investigator-reported drug-related adverse events were hyperglycemia (41.5%), diabetes mellitus (23.6%), and diarrhea (11.4%).Conclusions: Switching to long-acting pasireotide provided biochemical control in some patients, which was sustained with continued treatment. Long-term safety and tolerability of long-acting pasireotide was consistent with the known safety profile. These data support long-acting pasireotide for some patients with acromegaly who are uncontrolled on first generation SSAs.Clinical Trial Registration: clinicaltrials.gov, identifier: NCT02354508.

Tumour-infiltrating cytotoxic T lymphocytes in somatotroph pituitary neuroendocrine tumours

IntroductionSomatotroph pituitary tumours are often resistant to first-generation somatostatin analogues and can invade the surrounding structures, limiting the chances of curative surgery. Recent studies suggested that the immune microenvironment and pro-angiogenic factors can influence neuroendocrine tumour prognosis. In this study, we aimed to investigate the prognostic role of immune cell-specific markers and endocan, a proteoglycan involved in neoangiogenesis and cell adhesion, in a cohort of acromegaly patients who underwent pituitary surgery as first-line treatment.Subjects and methodsSixty four eligible subjects were identified. CD4+, CD8+ and CD68+ cells and endocan expression were evaluated by immunohistochemistry and results correlated with clinical and neuroradiological findings. Responsiveness to somatostatin analogues was assessed in patients with persistent disease following surgery.ResultsThe number of CD8+ lymphocytes was significantly lower in tumours with cavernous sinus invasion (median 0.2/HPF, IQR: 2.2) compared with those without cavernous sinus invasion (median 2.4/HPF, IQR: 2.3; P = 0.04). Tumours resistant to first-generation somatostatin analogues had lower CD8+ lymphocytes (median 1/HPF, IQR: 2.4) compared with responders (median 2.4/HPF, IQR: 2.9; P = 0.005). CD4+ lymphocytes were observed sporadically. The number of CD68+ macrophages and the endothelial or tumour cell endocan expression did not differ based on tumour size, cavernous sinus invasion or treatment responsiveness.ConclusionsOur study suggests that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogues in acromegaly patients. These results highlight a potential role of the tumour immune microenvironment in determining the prognosis of somatotroph pituitary tumours.

T2-signal intensity, SST receptor expression and first-generation somatostatin analogs efficacy predict hormone and tumor responses to pasireotide in acromegaly

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial.

Ann Oncol 2017; 28(6): 1309–1315 (doi: 10.1093/annonc/mdx078) The following funding information has been added: “This work was supported in part by The University of Texas MD Anderson Cancer Center Support Grant P30 CA016672.” A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trialAnnals of OncologyVol. 28Issue 6PreviewSeveral studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET. Full-Text PDF Open Archive

Cost-effectiveness analysis of second-line pharmacological treatment of acromegaly in Spain

ABSTRACT Objective To estimate the cost-effectiveness of second-line pharmacological treatments in patients with acromegaly resistant to first-generation somatostatin analogues (FG SSA) from the Spanish National Health System (NHS) perspective. Methods A Markov model was developed to analyze the cost-effectiveness of pegvisomant and pasireotide in FG SSA-resistant acromegaly, simulating a cohort of patients from the treatment beginning to death. Treatment with pegvisomant or pasireotide was compared to FG SSA retreatment. Efficacy data were obtained from clinical trials and utilities from the literature. Direct health costs were obtained from Spanish sources (€2018). Results The Incremental Cost Effectiveness Ratio (ICER) of pegvisomant vs. FG SSA was €85,869/Quality-adjusted life years (QALY). The ICER of pasireotide vs. FG SSA was €551,405/QALY. The ICER was mainly driven by the incremental efficacy (4.41 QALY for pegvisomant vs. FG SSA and 0.71 QALY for pasireotide vs. FG SSA), with a slightly lower increase in costs with pegvisomant (€378,597 vs. FG SSA) than with pasireotide (€393,151 vs. FG SSA). Conclusion The ICER of pasireotide compared to FG SSA was six times higher than the ICER of pegvisomant vs. FG SSA. Pegvisomant is a more cost-effective alternative for the treatment of acromegaly in FG SSA-resistant patients in the Spanish NHS.