Search the Community

Introduction: Pasireotide (PAS) is a novel somatostatin receptor ligands (SRL), used in controlling hormonal hypersecretion in both acromegaly and Cushing’s Disease (CD). In previous studies and meta-analysis, first-generation SRLs were reported to be able to induce significant tumor shrinkage only in somatotroph adenomas. This systematic review and meta-analysis aim to summarize the effect of PAS on the shrinkage of the pituitary adenomas in patients with acromegaly or CD. Materials and methods: We searched the Medline database for original studies in patients with acromegaly or CD receiving PAS as monotherapy, that assessed the proportion of significant tumor shrinkage in their series. After data extraction and analysis, a random-effect model was used to estimate pooled effects. Quality assessment was performed with a modified Joanna Briggs’s Institute tool and the risk of publication bias was addressed through Egger’s regression and the three-parameter selection model. Results: The electronic search identified 179 and 122 articles respectively for acromegaly and CD. After study selection, six studies considering patients with acromegaly and three with CD fulfilled the eligibility criteria. Overall, 37.7% (95%CI: [18.7%; 61.5%]) of acromegalic patients and 41.2% (95%CI: [22.9%; 62.3%]) of CD patients achieved significant tumor shrinkage. We identified high heterogeneity, especially in acromegaly (I2 of 90% for acromegaly and 47% for CD), according to the low number of studies included. Discussion: PAS treatment is effective in reducing tumor size, especially in acromegalic patients. This result strengthens the role of PAS treatment in pituitary adenomas, particularly in those with an invasive behavior, with progressive growth and/or extrasellar extension, with a low likelihood of surgical gross-total removal, or with large postoperative residual tissue. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022328152, identifier CRD42022328152 Introduction Pasireotide (PAS) is a novel somatostatin receptor ligand (SRL) with a high affinity for the somatostatin receptor (SSR) type 5 (1, 2). Somatotroph adenomas are usually responsive to first-generation SRLs (octreotide and lanreotide), as they are able to reduce growth hormone (GH) secretion through SSR type 2 (3). In the flow-chart of acromegaly treatment, PAS is suggested in case of resistance to first-generation SRLs, as SSR type 5 is also abundantly expressed in GH-secreting adenomas (3). A phase III study with PAS long-acting release (LAR) proved its efficacy in first-generation SRLs-resistant acromegalic patients after 6 months (4). In the extension study (Colao A et al.), 37% of patients achieved normalization of insulin-like growth factor 1 (IGF-1) and/or GH levels <1 µg/L, considering both those performing the extension treatment and those crossing over from the first-generation SRL-control group to the PAS LAR group. Nearly two-thirds of responses were achieved after at least 6 months of treatment. Up-titration of the dose from 40 to 60 mg monthly enriched the number of responders, suggesting that the PAS LAR effect may be both time- and dose-dependent (5). Concomitant improvement in signs and symptoms has also been confirmed in other series (6–9). SSR type 5 is the predominant isoform in human corticotroph adenomas, since it is not down-regulated by high cortisol levels, as SSR type 2 does. Therefore, PAS is the only SRL available in patients with Cushing’s Disease (CD) (2). In a phase III study, subcutaneous (s.c.) PAS proved to be effective in normalizing urinary free cortisol (respectively in 13% and 25% of patients taking 600 µg or 900 µg bis-in-die for 12 months) (10), achieving significant clinical improvement (11). In the same clinical setting, PAS LAR showed similar efficacy and safety profiles (12). These benefits could be maintained for up to 5 years in an extension study (13, 14). In a recent meta-analysis, PAS treatment provided disease control in 44% of 522 patients with CD (15). Patients harbouring USP-8 mutations demonstrated an increased SSR type 5 expression in the corticotroph adenoma, increasing the likelihood of a positive response to PAS therapy (16). The safety profile of PAS is similar to that of first-generation SRLs, except for a significant worsening in glucose homeostasis (17). Despite the normalization of hormonal excess, another goal of the medical treatment in GH-secreting pituitary adenomas is the reduction of the size of the adenoma (18). First-generation SRLs proved to be effective in achieving tumor shrinkage in acromegaly: Endocrine Society clinical practice guidelines suggested their role as primary therapy in poor surgical candidates and in those with extrasellar extension without chiasmal compression (18). Cozzi et al. reported in a large prospective cohort of acromegalic patients a significant Octreotide-induced tumor shrinkage in 82% of those receiving SRL as first-line treatment; most of them exhibited an early shrinkage with a progressive trend in reduction later on (19). A meta-analysis of 41 studies reported a significant tumor shrinkage in 50% of included patients (20). Data from the primary treatment with once-monthly lanreotide in surgical naïve patients demonstrated its efficacy in reducing tumor volume, achieving significant tumor shrinkage in 63% of them (21). Hypo-intensity on T2-weighted sequences at baseline magnetic resonance imaging (MRI) seems to predict tumor volume reduction during first-generation SRLs treatment (22). Regarding patients with CD, most patients presented a microadenoma, usually not aggressive or invasive: only in selected cases tumor shrinkage is an aim to achieve in patients with corticotropinoma. As available data are scarce (or limited to selected studies), and the issue of pituitary adenoma shrinkage is of primary importance in the management of tumors that cannot be addressed through surgery, the aim of this systematic review and meta-analysis is to summarize available data regarding the effect of PAS on tumor size. Materials and Methods We used the Population-Intervention-Comparison-Outcome (PICO) model to formulate the research questions for the systematic review (23), as summarised in Figure 1. The systematic review and meta-analysis were conducted and are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) statement (24). We registered the protocol on the International Prospective Register of Systematic Reviews database (PROSPERO, https://www.crd.york.ac.uk/PROSPERO, number CRD42022328152). Figure 1 FIGURE 1 PICO (Population-Intervention-Comparison-Outcome) model design to our study. Search Strategy An extensive Medline search was performed for the research question by two of the authors (F.C. and A.M.) independently, discrepancies were resolved by discussion. The literature search was performed up to January 2022, no language restriction was applied. Research included the following keywords: 1) (“acromegalies” [All Fields] OR “acromegaly”[MeSH Terms] OR “acromegaly”[All Fields]) AND (“pasireotide”[Supplementary Concept] OR “pasireotide”[All Fields]); 2) (“pituitary ACTH hypersecretion”[MeSH Terms] OR (“pituitary”[All Fields] AND “ACTH”[All Fields] AND “hypersecretion”[All Fields]) OR “pituitary ACTH hypersecretion”[All Fields]) AND (“pasireotide”[Supplementary Concept] OR “pasireotide”[All Fields]). Inclusion and exclusion criteria were specified in advance and protocol-defined, in order to avoid methodological bias for post-hoc analysis. The searches were designed to select all types of studies (retrospective, observational, controlled, randomized, and non-randomized) conducted in patients with acromegaly or CD treated with PAS as monotherapy; the assessment of the proportion of significant tumor shrinkage was an inclusion criterion. Search terms were linked to Medical Subject Headings when possible. Keywords and free words were used simultaneously. Additional articles were identified with manual searches and included a thorough review of other meta-analyses, review articles, and relevant references. Consolidation of studies was performed with Mendeley Desktop 1.19.8. Study Selection We included all original research studies conducted in adult patients that underwent PAS treatment used as monotherapy (s.c. bis-in-die and intramuscular once/monthly), that provided sufficient information about tumor size reduction during treatment. In case of overlapping cohorts of patients (as clinical trials with core and extension phases), we included only the extension study, in order to select those patients with measurable tumor shrinkage after long-term treatment. Local reports regarding patients involved in multicenter trials were excluded from the analysis, as they had been already considered in the larger series. Reviewers were not blinded to the authors or journals when screening articles. Data Extraction and Quality Assessment Two authors (F.C. and A.M.) read the included papers and extracted independently relevant data, any disagreements were resolved by discussion. If data were not clear from the original manuscript, the authors of the primary study were contacted to clarify the doubts. Contents of data extraction in the selected paper included: name of the first author, year of publication, setting (referral centre, academic hospital, mono- or multi-centric collection), type of treatment, its dose schedule and duration, pituitary imaging method during follow- up, the endpoint type regarding adenoma size analysis (i.e. primary vs exploratory). When data were reported for each patient or for subgroups, a global percentage of significant tumor shrinkage was calculated considering all subjects involved in the study. To assess the risk of bias in the included studies, the critical appraisal tool from Joanna Briggs’s Institute (JBI) was adapted to evaluate those considered in our metanalysis (25). Among the items proposed, we selected the most appropriate to our setting: 1. Were the inclusion criteria clearly identified? 2. Were diagnostic criteria for acromegaly or CD well defined? 3. Were valid methods applied to evaluate tumor shrinkage? 4. Was the inclusion of participants consecutive and complete? 5. Was the reporting of baseline participants’ features (demographic and clinical) complete? 6. Was the report of the outcomes clear? 7. Was the report of demographics of the involved sites complete? 8. Was statistical analysis appropriate? For each aspect we assigned as possible choices of answer: yes, no or unclear. Data Synthesis and Analysis A qualitative synthesis was performed summarizing the study design and population characteristics (age, male to female ratio, macro- to micro-adenoma ratio, prior treatments). A random-effect model was used to estimate pooled effects. Forest plots for percentages of significant tumor size reduction were generated to visualize heterogeneity among the studies. In order to assess publication bias, despite the low number of articles considered, we performed funnel plot and asymmetry analysis adjusted for the low number of studies (an Egger’s regression test and a three-parameter selection model where two tailed p < 0.05 was considered statistically significant). The I2 test was conducted to analyze the heterogeneity between studies: an I2 >50% indicated a between-study heterogeneity. Statistical analyses were performed with R: R-4.1.2 for Windows 10 (32/64 bit) released 2021-11-01 and R studio desktop RStudio Desktop 1.4.1717 for Windows 10 64 bit (R Foundation for Statistical Computing, Vienna, Austria, URL https://www.R-project.org/). Results Study Selection The study selection process for acromegaly is depicted in Figure 2. The electronic search revealed 179 articles, with one duplicate (N = 178). After the first screening, 141 articles did not meet the eligibility criteria and were discarded. The full-text examination of the remaining studies excluded additional 31 articles: 27 did not provide adequate data about tumor size, two represented the core phase of an extension study, another one referred to a subset of patients from a larger study, and the last one did not provide sufficient data about the percentage of tumor size reduction. Thus, six studies fulfilling eligibility criteria (reported in Tables 1, 2), were selected for data extraction and analysis. Figure 2 FIGURE 2 Search strategy for acromegaly. * Petersenn S, 2010 (PAS sc, phase II) and Colao A, 2014 (PAS LAR). ** Shimon I, 2015 (PAS LAR). *** Tahara S, 2019 (PAS LAR, phase II). PAS, pasireotide, sc, subcutaneous, LAR, long-acting release. Table 1 TABLE 1 Studies considered for the metanalysis in acromegaly. Table 2 TABLE 2 Studies considered for the metanalysis in acromegaly. The study selection process for CD is depicted in Figure 3. The electronic search revealed 122 articles; an additional one had been included post-hoc, through reference analysis of selected articles (N = 123). After the first screening, 91 articles did not meet the eligibility criteria and were discarded. The full-text examination of the remaining studies excluded 29 more articles: 23 did not provide sufficient data on tumor shrinkage, two of them represented the core phase of extension studies, two referred to subsets of patients included in a larger study and two did not provide sufficient data regarding the percentage of tumor size reduction. Thus, three studies fulfilling eligibility criteria (reported in Tables 3, 4) were selected for data extraction and analysis. Figure 3 FIGURE 3 Search strategy for Cushing’s Disease. * Lacroix A, 2018 (PAS LAR, phase III) and Lacroix A, 2020 (PAS sc, phase III post-hoc analysis). ** Simeoli C, 2014 (PAS sc) and Colao A 2012 (PAS sc, phase III). *** Daniel E, 2018 (PAS sc and LAR) and Trementino L, 2016 (PAS sc). PAS, pasireotide, sc, subcutaneous, LAR, long acting release. Table 3 TABLE 3 Studies considered for the metanalysis in Cushing’s Disease. Table 4 TABLE 4 Studies considered for the metanalysis in Cushing’s Disease. Study Characteristics Four multi- and two mono-centric studies in patients with acromegaly were considered and analyzed, all presenting a prospective design. Tumor size analysis was not one of the primary endpoints in any of the considered studies; from an initial overall recruitment of 358 patients, only 265 were included for tumor size reduction analysis. Most patients had previously undergone different treatments (Table 1). All studies, except one, used PAS LAR, dose titration was allowed in all trials. Median follow-up ranged from 6 to 25 months; MRI was performed to evaluate tumor size reduction and the criteria for considering it significant was mainly based on tumor volume analysis, except for Lasolle H et al. which considered median height reduction (26). Data from the PAOLA study provided separate percentages of significant tumor shrinkage for PAS at 40 mg or 60 mg once monthly; considering that respectively 12 and 7 patients showed a reduction >25%, a significant shrinkage was reported in 19 out of 79 considered cases (24%) (4). Stelmachowska-Banás et al. described one patient with McCune-Albright’s syndrome presenting with pituitary hyperplasia, without a visible adenoma at MRI; as its pituitary volume decreased during treatment, the patient was included in the group with significant tumor shrinkage (27). No study provided information about macro- to micro-adenoma ratio. Data regarding age and male to female ratio are also reported in Table 2. Three studies including patients with CD met the eligibility criteria (Tables 3, 4); all of them presented a multicentre prospective design, recruiting 139 patients, most of them assuming PAS as a second-line treatment, after a surgical failure. For tumor shrinkage analysis, a subgroup of 34 patients was considered, taking s.c. PAS bis-in-die in two studies and PAS LAR in the third; in all cases titration was admitted. Tumor size analysis was a secondary endpoint in all three studies. Follow-up ranged from 6 to 60 months; tumor size assessment was performed with pituitary MRI. Only Pivonello et al. evaluated maximum diameter, instead of tumor volume changes (28). The population analyzed for tumor shrinkage mainly presented with a microadenoma. Data regarding age and gender are reported in Table 4. In the trial reported by Petersenn S et al., we arbitrarily fixed the criterion to define a significant tumor volume reduction (at least 25% of the baseline size of the pituitary adenoma), and the proportion of responders was calculated from the supplementary materials accordingly (3/6 = 50%) (13). Pivonello et al. separated patients exhibiting mild-moderate from those with severe hypercortisolism; we considered them together for tumor size analysis obtaining an overall proportion of significant size reduction of 21.4% (3 out of 14 subjects) (28). Risk of Bias The evaluation of the risk of bias performed with the adapted JBI tool is reported in Table 5. All studies presented clear diagnostic and inclusion criteria, except that of Lasolle H et al. (26). Although all papers reported a valid tool for tumor shrinkage analysis (MRI), two of them did not analyse tumor volume and did not provide a clear definition of significant size reduction (26, 28). Regarding other items, the majority of the considered studies did not appear to present a clear source of bias. Table 5 TABLE 5 Evaluation of the risk of bias performed with the adapted Joanna Briggs’s Institute (JBI) tool. Meta-Analysis In the six studies considered for acromegaly, 37.7% (95%CI: [18.7%; 61.5%]) of patients demonstrated a significant tumor size reduction (Figure 4). As expected, heterogeneity in tumor reduction between studies was high (I2 = 90%). We attempted to address publication bias despite the low-number of studies (Figure 6A😞 Egger’s regression test did not indicate the presence of funnel plot asymmetry (intercept = -3.15 with 95%CI: [-10.17; 3.85], t = -0.883, p = 0.427) and the three-parameter selection model performed for p < 0.05 (and p < 0.1 as a sensitivity analysis) suggested absence of publication bias (28). Figure 4 FIGURE 4 Pooled effect for the proportion of responders (i.e. presenting significant tumor shrinkage) in acromegaly. CI, confidence interval. In the three studies considered for CD, 41,2% (95%CI: [22.9%; 62.3%]) of patients overall demonstrated a significant tumor size reduction (Figure 5). The heterogeneity in tumor reduction between the studies represented by I2 amounted to 47%. Publication bias analysis (Figure 6B) was performed using Egger’s regression test (intercept = -1.828 with 95%CI: [-14.53; 10.88], t = -0.282, p = 0.825) without evidence of asymmetry. The three-parameter selection model on the contrary could not be performed due to the small number of studies. Figure 5 FIGURE 5 Pooled effect for the proportion of responders (i.e. presenting significant tumor shrinkage) in Cushing’s Disease. CI, confidence interval. Figure 6 FIGURE 6 (A) Funnel plot assessing publication bias for Acromegaly. (B) Funnel plot assessing publication bias for Cushing’s Disease. Discussion The biochemical efficacy of medical treatment with PAS in GH- or ACTH-secreting pituitary adenomas has been described in previous metanalyses for acromegaly (29, 30) and CD (15), the latter also exploring the clinical benefit. In addition to these reports, this meta-analysis shows that PAS treatment can induce an additional clinically significant tumor shrinkage in approximately 40% of patients. Acromegaly Overall, PAS treatment provided tumor shrinkage in 37.7% of the considered patients. A previous metanalysis on octreotide in acromegaly provided a higher percentage of tumor size reduction (over 50%) (20). Nevertheless, since PAS treatment is usually considered as a second- or third-line treatment in the therapeutic flow-chart of acromegaly, the population recruited is mainly composed of patients with first-generation SRL-resistant somatotroph adenomas. This bias in recruited populations of acromegalic patients may explain this difference in the outcome. In a direct comparison, although PAS LAR seemed more effective in achieving biochemical control, both the SRLs, the first- and the second-generation types, achieved similar percentages of tumor shrinkage (6, 7). Moreover, in the crossover extension, the switch from octreotide to PAS was more effective than the reverse schedule, achieving a slightly higher percentage of further significant tumor shrinkage (8). Lasolle et al. reported that the expression of SSR type 5 and the granulation pattern are of limited value for the prediction of PAS responsiveness: 5 out of 9 somatotropinomas in their series were densely granulated (two did not respond to PAS), and the expression of SSR type 5 was modest in one controlled patient (26). Other than SRLs, a further therapeutic option targeting the somatotroph adenoma is cabergoline, either as monotherapy in mild cases or as an add-on treatment for resistant adenomas (18). In a previous metanalysis, cabergoline in monotherapy resulted less effective than SRLs, achieving tumor shrinkage in about one third of the enrolled patients (31). It should also be mentioned that some studies reported an escape phenomenon from its treatment efficacy (32). Data coming from the combination of PAS LAR and pegvisomant in acromegaly were not considered in our metanalysis, due to inclusion criteria and variable combination therapy of the two drugs (33). Since some cases of adenoma growth had been reported during pegvisomant use (34, 35), this combination therapy represents a rational approach, but tumor volume analysis is less reliable, given the purpose of our study. Despite concerns regarding tumor growth, pegvisomant effectiveness in acromegaly is well documented (18, 29), although the cost of this combination treatment can limit its applicability in real-life practice. Moreover, it is worth mentioning Coopmans and collaborators’ follow-up analysis, suggesting a PAS mediated anti-tumoral effect in acromegaly. During treatment, patients exhibited a significant increase in T2-weighted sequences signal at MRI; moreover, patients exhibiting this MRI characteristic in their adenomas showed a more evident decrease in IGF-1 levels, but not a similar pattern in reduction of pituitary adenoma size (36). This finding may be related to cell degeneration or tumor cell necrosis, without necessarily determining significant tumor size reduction. Further studies, probably with more data coming from histological reports, may be necessary to better understand these findings. Cushing’s Disease Overall, PAS treatment provided significant tumor shrinkage in 41.2% of CD patients. Regarding pituitary-directed drugs, at this moment available for CD treatment, the efficacy of cabergoline has been proven in vitro studies, but its efficacy in clinical trials is still debated (15, 37). In a previous prospective study, cabergoline induced significant tumor shrinkage (defined as tumor volume reduction >20%) in 4 out of 20 (20%) of the patients recruited after 24 months (38). PAS is the only pituitary-directed treatment for this condition approved by Drug Agencies. Although few studies have been considered in this metanalysis, due to the strict inclusion criteria, PAS appears more effective in tumor size reduction versus cabergoline, resulting in a better choice in CD therapy when aiming to control the pituitary adenoma. In contrast to acromegaly, the majority of CD patients present a microadenoma, suggesting that tumor size might be a less relevant issue during medical treatment, even if the “cure” of the disease may forecast the resolution of the adenoma. Besides, up to 30% of CD patients, depending also on MRI accuracy and neuro-radiologist’s expertise, may present with negative imaging that prevents any evaluation of tumor shrinkage (39). In spite of that, endocrinologists, not so infrequently, deal with aggressive corticotroph adenomas, characterized by invasive local growth and/or resistance to conventional therapies. This challenging entity often requires multidisciplinary expertise to suggest different approaches, including PAS treatment (40). It should be mentioned that some non-pituitary targeting drugs, as inhibitors of cortisol synthesis, have been associated with tumor growth, due to cortisol-ACTH negative feedback. In particular, during osilodrostat treatment in a phase III study, four recruited patients discontinued osilodrostat after a significant increase in tumor volume (two with micro- and two with macro-adenomas 41), and this growth had also been described during ketoconazole and mitotane treatments (42). Thus, it may be speculated that PAS could provide a rational approach as an combination treatment with steroidogenesis inhibitors. Moreover, after bilateral adrenalectomy, pituitary adenoma tumor size is of the utmost importance, as patients may be at risk of developing a progression of the adenoma, the so-called Nelson’s syndrome. In a prospective study from Daniel E et al., PAS proved to be also effective in this setting, reducing ACTH levels and stabilizing the residual tumor over a treatment period of 7 months (43). Further studies, with longer treatment observation, may reveal whether PAS may achieve significant tumor shrinkage in these patients, as suggested by previous case reports in literature (44, 45). Conclusion The main limitation of our study resides in the scarce literature provided up to now (260 patients with acromegaly and 34 with CD), in the different therapy schedules and different criteria for tumor shrinkage in the selected study (largest tumor diameter vs a selected percentage of reduction). Moreover, in none of the study tumor reduction was one of the primary endpoints, and surgery was performed before PAS in most patients (78-88% of CD and 43-96% of acromegaly). PAS is a novel compound, with a rising role in the treatment of secreting pituitary adenomas. Thus, this topic might be amplified with more data coming from further clinical studies, as real-life studies, possibly also addressing markers predictive of response to this treatment (e.g., expression of SSR type 2 and type 5 or somatic mutations in USP8 at tissue level of ACTH-secreting adenomas). Nevertheless, we can already state that PAS treatment is effective in reducing tumor size, especially in acromegaly. Our results strengthen the role of PAS treatment in somatotroph and corticotroph adenomas, especially when tumor volume is a relevant issue (i.e. tumor progression, extrasellar invasion) (18, 39), as a neoadjuvant treatment before surgery or as tailored treatment, alone or in combination, in persistent disease or when surgery is not feasible. Future research aiming to characterize markers predictive of response could help to identify optimal candidates for this treatment. Data Availability Statement The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author. Ethics Statement Informed consent was obtained from all subjects participating in the studies analyzed. Author Contributions Authors involved contributed to research as reported: literature search (FC, AM), preparation of original draft (FC, AM, MB, LD), literature review (CS, FC, AM, MF), manuscript editing (CS, FC, AM, MB, LD, MF) and supervision (RM, CS). All authors approved the final version of the paper. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher’s Note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1. Chinezu L, Vasiljevic A, Jouanneau E, François P, Borda A, Trouillas J, et al. Expression of Somatostatin Receptors, SSTR2A and SSTR5, in 108 Endocrine Pituitary Tumors Using Immunohistochemical Detection With New Specific Monoclonal Antibodies. Hum Pathol (2014) 45(1):71–7. doi: 10.1016/j.humpath.2013.08.007 PubMed Abstract | CrossRef Full Text | Google Scholar 2. Ceccato F, Scaroni C, Boscaro M. Clinical Use of Pasireotide for Cushing's Disease in Adults. Ther Clin Risk Manage (2015) 11:425–34. doi: 10.2147/TCRM.S37314 CrossRef Full Text | Google Scholar 3. Melmed S, Colao A, Barkan A, Molitch M, Grossman AB, Kleinberg D, et al. Guidelines for Acromegaly Management: An Update. J Clin Endocrinol Metab (2009) 94(5):1509–17. doi: 10.1210/jc.2008-2421 PubMed Abstract | CrossRef Full Text | Google Scholar 4. Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, et al. Pasireotide Versus Continued Treatment With Octreotide or Lanreotide in Patients With Inadequately Controlled Acromegaly (PAOLA): A Randomised, Phase 3 Trial. Lancet Diabetes Endocrinol (2014) 2(11):875–84. doi: 10.1016/S2213-8587(14)70169-X PubMed Abstract | CrossRef Full Text | Google Scholar 5. Colao A, Bronstein MD, Brue T, De Marinis L, Fleseriu M, Guitelman M, et al. Pasireotide for Acromegaly: Long-Term Outcomes From an Extension to the Phase III PAOLA Study. Eur J Endocrinol (2020) 182(6):583. doi: 10.1530/EJE-19-0762 PubMed Abstract | CrossRef Full Text | Google Scholar 6. Colao A, Bronstein MD, Freda P, Gu F, Shen CC, Gadelha M, et al. Pasireotide Versus Octreotide in Acromegaly: A Head-to-Head Superiority Study. J Clin Endocrinol Metab (2014) 99(3):791–9. doi: 10.1210/jc.2013-2480 PubMed Abstract | CrossRef Full Text | Google Scholar 7. Sheppard M, Bronstein MD, Freda P, Serri O, De Marinis L, Naves L, et al. Pasireotide LAR Maintains Inhibition of GH and IGF-1 in Patients With Acromegaly for Up to 25 Months: Results From the Blinded Extension Phase of a Randomized, Double-Blind, Multicenter, Phase III Study. [Published Correction Appears in Pituitary]. (2015) 18(3):385–94. doi: 10.1007/s11102-014-0585-6 CrossRef Full Text | Google Scholar 8. Bronstein MD, Fleseriu M, Neggers S, Colao A, Sheppard M, Gu F, et al. Switching Patients With Acromegaly From Octreotide to Pasireotide Improves Biochemical Control: Crossover Extension to a Randomized, Double-Blind, Phase III Study. BMC Endocr Disord (2016) 16:16. doi: 10.1186/s12902-016-0096-8 PubMed Abstract | CrossRef Full Text | Google Scholar 9. Gadelha M, Bex M, Colao A, Pedroza García EM, Poiana C, Jimenez-Sanchez M, et al. Evaluation of the Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Inadequately Controlled With First-Generation Somatostatin Analogs. Front Endocrinol (Lausanne). (2020) 10:931. doi: 10.3389/fendo.2019.00931 PubMed Abstract | CrossRef Full Text | Google Scholar 10. Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. A 12-Month Phase 3 Study of Pasireotide in Cushing's Disease. N Engl J Med (2012) 366(10):914–24. doi: 10.1056/NEJMoa1105743 PubMed Abstract | CrossRef Full Text | Google Scholar 11. Pivonello R, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. Pasireotide Treatment Significantly Improves Clinical Signs and Symptoms in Patients With Cushing's Disease: Results From a Phase III Study. Clin Endocrinol (Oxf). (2014) 81(3):408–17. doi: 10.1111/cen.12431 PubMed Abstract | CrossRef Full Text | Google Scholar 12. Lacroix A, Gu F, Gallardo W, Pivonello R, Yu Y, Witek P, et al. Efficacy and Safety of Once-Monthly Pasireotide in Cushing's Disease: A 12 Month Clinical Trial. Lancet Diabetes Endocrinol (2018) 6(1):17–26. doi: 10.1016/S2213-8587(17)30326-1 PubMed Abstract | CrossRef Full Text | Google Scholar 13. Petersenn S, Salgado LR, Schopohl J, Portocarrero-Ortiz L, Arnaldi G, Lacroix A, et al. Long-Term Treatment of Cushing's Disease With Pasireotide: 5-Year Results From an Open-Label Extension Study of a Phase III Trial. Endocrine. (2017) 57(1):156–65. doi: 10.1007/s12020-017-1316-3 PubMed Abstract | CrossRef Full Text | Google Scholar 14. Fleseriu M, Petersenn S, Biller BMK, Kadioglu P, De Block C, T'Sjoen G, et al. Long-Term Efficacy and Safety of Once-Monthly Pasireotide in Cushing's Disease: A Phase III Extension Study. Clin Endocrinol (Oxf). (2019) 91(6):776–85. doi: 10.1111/cen.14081 PubMed Abstract | CrossRef Full Text | Google Scholar 15. Simões Corrêa Galendi J, Correa Neto ANS, Demetres M, Boguszewski CL, Nogueira VDSN. Effectiveness of Medical Treatment of Cushing's Disease: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). (2021) 12:732240. doi: 10.3389/fendo.2021.732240 PubMed Abstract | CrossRef Full Text | Google Scholar 16. Hayashi K, Inoshita N, Kawaguchi K, Ibrahim Ardisasmita A, Suzuki H, Fukuhara N, et al. The USP8 Mutational Status may Predict Drug Susceptibility in Corticotroph Adenomas of Cushing's Disease. Eur J Endocrinol (2016) 174(2):213–26. doi: 10.1530/EJE-15-0689 PubMed Abstract | CrossRef Full Text | Google Scholar 17. Samson SL, Gu F, Feldt-Rasmussen U, Zhang S, Yu Y, Witek P, et al. Managing Pasireotide-Associated Hyperglycemia: A Randomized, Open-Label, Phase IV Study. Pituitary. (2021) 24(6):887–903. doi: 10.1007/s11102-021-01161-4 PubMed Abstract | CrossRef Full Text | Google Scholar 18. Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, et al. Acromegaly: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab (2014) 99(11):3933–51. doi: 10.1210/jc.2014-2700 PubMed Abstract | CrossRef Full Text | Google Scholar 19. Cozzi R, Montini M, Attanasio R, Albizzi M, Lasio G, Lodrini S, et al. Primary Treatment of Acromegaly With Octreotide LAR: A Long-Term (Up to Nine Years) Prospective Study of its Efficacy in the Control of Disease Activity and Tumor Shrinkage. J Clin Endocrinol Metab (2006) 91(4):1397–403. doi: 10.1210/jc.2005-2347 PubMed Abstract | CrossRef Full Text | Google Scholar 20. Giustina A, Mazziotti G, Torri V, Spinello M, Floriani I, Melmed S. Meta-Analysis on the Effects of Octreotide on Tumor Mass in Acromegaly. PloS One (2012) 7(5):e36411. doi: 10.1371/journal.pone.0036411 PubMed Abstract | CrossRef Full Text | Google Scholar 21. Caron PJ, Bevan JS, Petersenn S, Flanagan D, Tabarin A, Prévost G, et al. Tumor Shrinkage With Lanreotide Autogel 120 Mg as Primary Therapy in Acromegaly: Results of a Prospective Multicenter Clinical Trial. J Clin Endocrinol Metab (2014) 99(4):1282–90. doi: 10.1210/jc.2013-3318 PubMed Abstract | CrossRef Full Text | Google Scholar 22. Potorac I, Petrossians P, Daly AF, Alexopoulou O, Borot S, Sahnoun-Fathallah M, et al. T2-Weighted MRI Signal Predicts Hormone and Tumor Responses to Somatostatin Analogs in Acromegaly. Endocr Relat Cancer. (2016) 23(11):871–81. doi: 10.1530/ERC-16-0356 PubMed Abstract | CrossRef Full Text | Google Scholar 23. Schardt C, Adams MB, Owens T, Keitz S, Fontelo P. Utilization of the PICO Framework to Improve Searching PubMed for Clinical Questions. BMC Med Inform Decis Mak. (2007) 7:16. doi: 10.1186/1472-6947-7-16 PubMed Abstract | CrossRef Full Text | Google Scholar 24. McInnes MDF, Moher D, Thombs BD, McGrath TA, Bossuyt PM. Preferred Reporting Items for a Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement [Published Correction Appears in JAMA. 2019 Nov 26;322(20):2026]. JAMA. (2018) 319(4):388–96. doi: 10.1001/jama.2017.19163 CrossRef Full Text | Google Scholar 25. Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, et al. Methodological Quality of Case Series Studies: An Introduction to the JBI Critical Appraisal Tool. JBI Evid Synth. (2020) 18(10):2127–33. doi: 10.11124/JBISRIR-D-19-00099 PubMed Abstract | CrossRef Full Text | Google Scholar 26. Lasolle H, Ferriere A, Vasiljevic A, Eimer S, Nunes ML, Tabarin A. Pasireotide-LAR in Acromegaly Patients Treated With a Combination Therapy: A Real-Life Study. Endocr Connect. (2019) 8(10):1383–94. doi: 10.1530/EC-19-0332 PubMed Abstract | CrossRef Full Text | Google Scholar 27. Stelmachowska-Banaś M, Czajka-Oraniec I, Tomasik A, Zgliczyński W. Real-World Experience With Pasireotide-LAR in Resistant Acromegaly: A Single Center 1-Year Observation. Pituitary. (2022) 25(1):180–90. doi: 10.1007/s11102-021-01185-w PubMed Abstract | CrossRef Full Text | Google Scholar 28. Pivonello R, Arnaldi G, Scaroni C, Giordano C, Cannavò S, Iacuaniello D, et al. The Medical Treatment With Pasireotide in Cushing's Disease: An Italian Multicentre Experience Based on "Real-World Evidence". Endocrine. (2019) 64(3):657–72. doi: 10.1007/s12020-018-1818-7 PubMed Abstract | CrossRef Full Text | Google Scholar 29. Leonart LP, Ferreira VL, Tonin FS, Fernandez-Llimos F, Pontarolo R. Medical Treatments for Acromegaly: A Systematic Review and Network Meta-Analysis. Value Health (2018) 21(7):874–80. doi: 10.1016/j.jval.2017.12.014” PubMed Abstract | CrossRef Full Text | Google Scholar 30. Qiao N, He M, Shen M, Zhang Q, Zhang Z, Shou X, et al. Comparative Efficacy Of Medical Treatment For Acromegaly: A Systematic Review And Network Meta-Analysis Of Integrated Randomized Trials And Observational Studies. Endocr Pract (2020) 26(4):454–62. doi: 10.4158/EP-2019-0528 PubMed Abstract | CrossRef Full Text | Google Scholar 31. Sandret L, Maison P, Chanson P. Place of Cabergoline in Acromegaly: A Meta-Analysis. J Clin Endocrinol Metab (2011) 96(5):1327–35. doi: 10.1210/jc.2010-2443 PubMed Abstract | CrossRef Full Text | Google Scholar 32. Giraldi EA, Ioachimescu AG. The Role of Dopamine Agonists in Pituitary Adenomas. Endocrinol Metab Clin North Am (2020) 49(3):453–74. doi: 10.1016/j.ecl.2020.05.006 PubMed Abstract | CrossRef Full Text | Google Scholar 33. Muhammad A, van der Lely AJ, Delhanty PJD, Dallenga AHG, Haitsma IK, Janssen JAMJL, et al. Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Controlled With Pegvisomant and First-Generation Somatostatin Analogues (PAPE Study). J Clin Endocrinol Metab (2018) 103(2):586–95. doi: 10.1210/jc.2017-02017 PubMed Abstract | CrossRef Full Text | Google Scholar 34. uhk JH, Jung S, Psychogios MN, Göricke S, Hartz S, Schulz-Heise S, et al. Tumor Volume of Growth Hormone-Secreting Pituitary Adenomas During Treatment With Pegvisomant: A Prospective Multicenter Study. J Clin Endocrinol Metab (2010) 95(2):552–8. doi: 10.1210/jc.2009-1239 PubMed Abstract | CrossRef Full Text | Google Scholar 35. Marazuela M, Paniagua AE, Gahete MD, Lucas T, Alvarez-Escolá C, Manzanares R, et al. Somatotroph Tumor Progression During Pegvisomant Therapy: A Clinical and Molecular Study. J Clin Endocrinol Metab (2011) 96(2):E251–9. doi: 10.1210/jc.2010-1742 PubMed Abstract | CrossRef Full Text | Google Scholar 36. Coopmans EC, van der Lely AJ, Schneiders JJ, Neggers SJCMM. Potential Antitumour Activity of Pasireotide on Pituitary Tumours in Acromegaly. Lancet Diabetes Endocrinol (2019) 7(6):425–6. doi: 10.1016/S2213-8587(19)30113-5 PubMed Abstract | CrossRef Full Text | Google Scholar 37. Ferriere A, Cortet C, Chanson P, Delemer B, Caron P, Chabre O, et al. Cabergoline for Cushing's Disease: A Large Retrospective Multicenter Study. Eur J Endocrinol (2017) 176(3):305–14. doi: 10.1530/EJE-16-0662 PubMed Abstract | CrossRef Full Text | Google Scholar 38. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, et al. The Medical Treatment of Cushing's Disease: Effectiveness of Chronic Treatment With the Dopamine Agonist Cabergoline in Patients Unsuccessfully Treated by Surgery. J Clin Endocrinol Metab (2009) 94(1):223–30. doi: 10.1210/jc.2008-1533 PubMed Abstract | CrossRef Full Text | Google Scholar 39. Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al. Consensus on Diagnosis and Management of Cushing's Disease: A Guideline Update. Lancet Diabetes Endocrinol (2021) 9(12):847–75. doi: 10.1016/S2213-8587(21)00235-7 PubMed Abstract | CrossRef Full Text | Google Scholar 40. Ceccato F, Lombardi G, Manara R, Emanuelli E, Denaro L, Milanese L, et al. Temozolomide and Pasireotide Treatment for Aggressive Pituitary Adenoma: Expertise at a Tertiary Care Center. J Neurooncol. (2015) 122(1):189–96. doi: 10.1007/s11060-014-1702-0 PubMed Abstract | CrossRef Full Text | Google Scholar 41. Pivonello R, Fleseriu M, Newell-Price J, Bertagna X, Findling J, Shimatsu A, et al. Efficacy and Safety of Osilodrostat in Patients With Cushing's Disease (LINC 3): A Multicentre Phase III Study With a Double-Blind, Randomised Withdrawal Phase. Lancet Diabetes Endocrinol (2020) 8(9):748–61. doi: 10.1016/S2213-8587(20)30240-0 PubMed Abstract | CrossRef Full Text | Google Scholar 42. Varlamov EV, Han AJ, Fleseriu M. Updates in Adrenal Steroidogenesis Inhibitors for Cushing's Syndrome - A Practical Guide. Best Pract Res Clin Endocrinol Metab (2021) 35(1):101490. doi: 10.1016/j.beem.2021.101490 PubMed Abstract | CrossRef Full Text | Google Scholar 43. Daniel E, Debono M, Caunt S, Girio-Fragkoulakis C, Walters SJ, Akker SA, et al. A Prospective Longitudinal Study of Pasireotide in Nelson's Syndrome. Pituitary. (2018) 21(3):247–55. doi: 10.1007/s11102-017-0853-3 PubMed Abstract | CrossRef Full Text | Google Scholar 44. Katznelson L. Sustained Improvements in Plasma ACTH and Clinical Status in a Patient With Nelson's Syndrome Treated With Pasireotide LAR, a Multireceptor Somatostatin Analog. J Clin Endocrinol Metab (2013) 98(5):1803–7. doi: 10.1210/jc.2013-1497 PubMed Abstract | CrossRef Full Text | Google Scholar 45. He X, Spencer-Segal JL. Rapid Response of Nelson's Syndrome to Pasireotide in Radiotherapy-Naive Patient. Clin Diabetes Endocrinol (2020) 6(1):22. doi: 10.1186/s40842-020-00110-7 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: pasireotide, cushing, acromegaly, tumor volume, tumor size Citation: Mondin A, Manara R, Voltan G, Tizianel I, Denaro L, Ferrari M, Barbot M, Scaroni C and Ceccato F (2022) Pasireotide-Induced Shrinkage in GH and ACTH Secreting Pituitary Adenoma: A Systematic Review and Meta-Analysis. Front. Endocrinol. 13:935759. doi: 10.3389/fendo.2022.935759 Received: 04 May 2022; Accepted: 06 June 2022; Published: 01 July 2022. Edited by: Mohammad E. Khamseh, Iran University of Medical Sciences, Iran Reviewed by: Rosa Paragliola, Catholic University of the Sacred Heart, Rome, Italy Marek Bolanowski, Wroclaw Medical University, Poland Adriana G Ioachimescu, Emory University, United States Copyright © 2022 Mondin, Manara, Voltan, Tizianel, Denaro, Ferrari, Barbot, Scaroni and Ceccato. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Filippo Ceccato, filippo.ceccato@unipd.it †ORCID: Alessandro Mondin, orcid.org/0000-0002-6046-5198 Renzo Manara, orcid.org/0000-0002-5130-3971 Giacomo Voltan, orcid.org/0000-0002-3628-0492 Irene Tizianel, orcid.org/0000-0003-4092-5107 Luca Denaro, orcid.org/0000-0002-2529-6149 Marco Ferrari, orcid.org/0000-0002-4023-0121 Mattia Barbot, orcid.org/0000-0002-1081-5727 Carla Scaroni, orcid.org/0000-0001-9396-3815 Filippo Ceccato, orcid.org/0000-0003-1456-8716 Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. From https://www.frontiersin.org/articles/10.3389/fendo.2022.935759/full

Lacroix A, et al. Pituitary. 2019;doi:10.1007/s11102-019-01021-2. January 7, 2020 Andre Lacroix Most adults with persistent or recurrent Cushing’s disease treated with the somatostatin analogue pasireotide experienced a measurable decrease in MRI-detectable pituitary tumor volume at 12 months, according to findings from a post hoc analysis of a randomized controlled trial. “Pasireotide injected twice daily during up to 12 months to control cortisol excess in patients with residual or persistent Cushing's disease was found to reduce the size of pituitary tumors in a high proportion of the 53 patients in which residual tumor was still visible at initiation of this medical therapy,” Andre Lacroix, MD, FCAHS, professor of medicine at the University of Montreal Teaching Hospital in Montreal, Canada, told Healio. “Pituitary tumors causing Cushing's syndrome which cannot be removed completely by surgery have the capacity to grow in time, and a medical therapy that can reduce tumor growth in addition to control excess cortisol production should be advantageous for the patients.” Lacroix and colleagues analyzed data from 53 adults with persistent or recurrent Cushing’s disease, or those with newly diagnosed Cushing’s disease who were not surgical candidates, who had measurable tumor volume data (78% women). Researchers randomly assigned participants to 600 g or 900 g subcutaneous pasireotide (Signifor LAR, Novartis) twice daily. Tumor volume was assessed independently at 6 and 12 months by two masked radiologists and compared with baseline value and urinary free cortisol response. Most adults with persistent or recurrent Cushing’s disease treated with the somatostatin analogue pasireotide experienced a measurable decrease in MRI-detectable pituitary tumor volume at 12 months. Source: Shutterstock Researchers found that reductions in tumor volume were both dose and time dependent. Tumor volume reduction was more frequently observed at month 6 in the 900 g group (75%) than in the 600 g group (44%). Similarly, at month 12 (n = 32), tumor volume reduction was observed more frequently in the 900 g group (89%) than in the 600 g group (50%). Results were independent of urinary free cortisol levels. The researchers did not observe a relationship between baseline tumor size and change in tumor size. “Taken together, the results of the current analysis demonstrate that treatment with pasireotide, a pituitary-directed medical therapy that targets somatostatin receptors, can frequently lead to radiologically measurable reductions in pituitary tumor volume in patients with Cushing’s disease,” the researchers wrote. “Tumor volume reduction is especially relevant in patients with larger microadenomas, suggesting that pasireotide is an attractive option for these patients, especially in cases in which patients cannot undergo transsphenoidal surgery or do not respond to surgical management of disease.” – by Regina Schaffer For more information: Andre Lacroix, MD, FCAHS, can be reached at the University of Montreal Teaching Hospital, Endocrine Division, 3840 Saint-Urbain, Montreal, H2W 1T8, Canada; email: andre.lacroix@umontrael.ca. Disclosures: Novartis supported this study and provided writing support. Lacroix reports he has received funding from Novartis Pharmaceuticals to conduct clinical studies with pasireotide and osilodrostat in Cushing’s disease and served as a consultant, advisory board member or speaker for EMD Serono, Ipsen and Novartis. Please see the study for all other authors’ relevant financial disclosures. From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B8e4d31fb-d61a-4cf8-b4c4-7d0bdf012fbd%7D/pasireotide-reduces-pituitary-tumor-volume-in-cushings-disease

Written by Kathleen Doheny with Maria Fleseriu, MD, FACE, and Vivien Herman-Bonert, MD Cushing's disease, an uncommon but hard to treat endocrine disorder, occurs when a tumor on the pituitary gland, called an adenoma—that is almost always benign—leads to an overproduction of ACTH (adrenocorticotropic hormone), which is responsible for stimulating the release of cortisol, also known as the stress hormone. Until now, surgery to remove the non-cancerous but problematic tumor has been the only effective treatment. Still, many patients will require medication to help control their serum cortisol levels, and others cannot have surgery or would prefer to avoid it. Finally, a drug proves effective as added on or alternative to surgery in managing Cushing's disease. Photo; 123rf New Drug Offers Alternative to Surgery for Cushing's Disease Now, there is good news about long-term positive results achieved with pasireotide (Signifor)—the first medication to demonstrate effectiveness in both normalizing serum cortisol levels and either shrinking or slowing growth of tumors over the long term.1,2 These findings appear in the journal, Clinical Endocrinology, showing that patients followed for 36 months as part of an ongoing study had improved patient outcomes for Cushing’s disease.2 "What we knew before this extension study was—the drug will work in approximately half of the patients with mild Cushing's disease," says study author Maria Fleseriu, MD, FACE, director of the Northwest Pituitary Center and professor of neurological surgery and medicine in the division of endocrinology, diabetes and clinical nutrition at the Oregon Health and Sciences University School of Medicine. “Pasireotide also offers good clinical benefits," says Dr. Fleseriu who is also the president of the Pituitary Society, “which includes improvements in blood pressure, other signs and symptoms of Cushing’s symptom], and quality of life.”2 What Symptoms Are Helped by Drug for Cushing's Disease? Among the signs and symptoms of Cushing’s disease that are lessened with treatment are:3 Changes in physical appearance such as wide, purple stretch marks on the skin (eg, chest, armpits, abdomen, thighs) Rapid and unexplained weight gain A more full, rounder face Protruding abdomen from fat deposits Increased fat deposits around the neck area The accumulation of adipose tissue raises the risk of heart disease, which adds to the urgency of effective treatment. In addition, many individuals who have Cushing’s disease also complain of quality of life issues such as fatigue, depression, mood and behavioral problems, as well as poor memory.2 As good as the results appear following the longer term use of pasireotide,2 Dr. Fleseriu admits that in any extension study in which patients are asked to continue on, there are some built-in limitations, which may influence the findings. For example, patients who agree to stay on do so because they are good responders, meaning they feel better, so they’re happy to stick with the study. “Fortunately, for the patients who have responded to pasireotide initially, this is a drug that can be continued as there are no new safety signals with longer use," Dr. Fleseriu tells EndocrineWeb, "and when the response at the start is good, very few patients will lose control of their urinary free cortisol over time. That's a frequent marker used to monitor patient's status. For those patients with large tumors, almost half of them had a significant shrinkage, and all the others had a stable tumor size." What Are the Reasons to Consider Drug Treatment to Manage Cushing’s Symptoms The extension study ''was important because we didn't have any long-term data regarding patient response to this once-a-month treatment to manage Cushing's disease," she says. While selective surgical removal of the tumor is the preferred treatment choice, the success rate in patients varies, and Cushing's symptoms persist in up to 35% of patients after surgery. In addition, recurrent rates (ie, return of disease) range from 13% to 66% after individuals experience different durations remaining in remission.1 Therefore, the availability of an effective, long-lasting drug will change the course of therapy for many patients with Cushing’s disease going forward. Not only will pasireotide benefit patients who have persistent and recurrent disease after undergoing surgery, but also this medication will be beneficial for those who are not candidates for surgery or just wish to avoid having this procedure, he said. Examining the Safety and Tolerability of Pasireotide This long-acting therapy, pasireotide, which is given by injection, was approved in the US after reviewing results of a 12-month Phase 3 trial.1 In the initial study, participants had a confirmed pituitary cause of the Cushing's disease. After that, the researchers added the optional 12-month open-label, extension study, and now patients can continue on in a separate long-term safety study. Those eligible for the 12-month extension had to have mean urinary free cortisol not exceeding the upper limit of normal (166.5 nanomoles per 24 hour) and/or be considered by the investigator to be getting substantial clinical benefit from treatment with long-action pasireotide, and to demonstrate tolerability of pasireotide during the core study.1 Of the 150 in the initial trial, 81 participants, or 54% of the patients, entered the extension study. Of those, 39 completed the next phase, and most also enrolled in another long-term safety study—these results not yet available).2 During the core study, 1 participants were randomly assigned to 10 or 30 mg of the drug every 28 days, with doses based on effectiveness and tolerability. When they entered the extension, patients were given the same dose they received at month.1,2 Study Outcomes Offer Advantages in Cushing’s Disease Of those who received 36 months of treatment with pasireotide, nearly three in four (72.2%) had controlled levels of urinary free cortisol at this time point.2 Equally good news for this drug was that tumors either shrank or did not grow. Of those individuals who started the trial with a measurable tumor (adenoma) as well as those with an adenoma at the two year mark (35 people), 85.7% of them experienced a reduction of 20% or more or less than a 20% change in tumor volume. No macroadenomas present at the start of the study showed a change of more than 20% at either month 24 or 36.2 Improvements in blood pressure, body mass index (BMI) and waist circumference continued throughout the extension study.1 Those factors influence CVD risk, the leading cause of death in those with Cushing's.4 As for adverse events, most of the study participants, 91.4%, did report one or more complaint during the extension study—most commonly, it was high blood sugar, which was reported by nearly 40% of participants.2. This is not surprising when you consider that most (81.5%) of the individuals participating in the extension trial entered with a diagnosis of diabetes or use of antidiabetic medication, and even more of them (88.9%) had diabetes at the last evaluation.1 This complication indicates the need for people with Cushing’s disease to check their blood glucose, as appropriate. Do You Have Cushing’s Disese? Here's What You Need to Know Women typically develop Cushing’s disease more often than men. What else should you be aware of if you and your doctor decide this medication will help you? Monitoring is crucial, says Dr. Fleseriu, as you will need to have your cortisol levels checked, and you should be on alert for any diabetes signals, which will require close monitoring and regular follow-up for disease management. Another understanding gained from the results of this drug study: "This medication works on the tumor level," she says. "If the patient has a macroadenoma (large tumor), this would be the preferred treatment." However, it should be used with caution in those with diabetes given the increased risk of experiencing high blood sugar. The researchers conclude that "the long-term safety profile of pasireotide was very favorable and consistent with that reported during the first 12 months of treatment. These data support the use of long-acting pasireotide as an effective long-term treatment option for some patients with Cushing's Disease."1 Understanding Benefits of New Drug to Treat Cushing's Diseease Vivien S. Herman-Bonert, MD, an endocrinologist and clinical director of the Pituitary Center at Cedars-Sinai Medical Center in Los Angeles, agreed to discuss the study findings, after agreeing to review the research for EndocrineWeb. As to who might benefit most from monthly pasireotide injections? Dr. Herman-Bonert says, "any patient with Cushing's disease that requires long-term medical therapy, which includes patients with persistent or recurrent disease after surgery." Certainly, anyone who has had poor response to any other medical therapies for Cushing's disease either because they didn't work well enough or because the side effects were too much, will likely benefit a well, she adds. Among the pluses that came out of the study, she says, is that nearly half of the patients had controlled average urinary free cortisol levels after two full years, and 72% of the participants who continued on with the drug for 36 months were able to remain in good urinary cortisol control .1 As the authors stated, tumor shrinkage was another clear benefit of taking long-term pasireotide. That makes the drug a potentially good choice for those even with large tumors or with progressive tumor growth, she says. It’s always good for anyone with Cushing’s disease to have an alterative to surgery, or a back-up option when surgery isn’t quite enough, says Dr. Herman-Bonert. The best news for patients is that quality of life scores improved,1 she adds. Dr Herman-Bonert did add a note of caution: Although the treatment in this study is described as ''long-term, patients will need to be on this for far longer than 2 to 3 years," she says. So, the data reported in this study may or may not persist, and we don’t yet know what the impact will be 10 or 25 years out. Also, the issue of hyperglycemia-related adverse events raises a concern, given the vast majority (81%) of patients who have both Cushing’s disease and diabetes. Most of those taking this drug had a dual diagnosis—having diabetes, a history of diabetes, or taking antidiabetic medicine. If you are under care for diabetes and you require treatment for Cushing’s disease, you must be ver mindful that taking pasireotide will likely lead to high blood sugar spikes, so you should plan to address this with your healthcare provider. Dr. Fleseriu reports research support paid to Oregon Health & Science University from Novartis and other 0companies and consultancy fees from Novartis and Strongbridge Biopharma. Dr. Herman-Bonert has no relevant disclosures. The study was underwritten by Novartis Pharma AG, the drug maker. From https://www.endocrineweb.com/news/pituitary-disorders/62449-cushings-disease-monthly-injection-good-alternative-surgery

The chemotherapy temozolomide partially improved a case of an aggressive pituitary tumor that caused symptoms of Cushing’s disease (CD), according to a new study in Poland. However, after tumor mass and cortisol levels were stabilized for a few months, the patient experienced rapid progression, suggesting that new methods for extending the effects of temozolomide are needed. The study, “Temozolomide therapy for aggressive pituitary Crooke’s cells corticotropinoma causing Cushing’s Disease: A case report with literature review,” appeared in the journal Endokrynologia Polska. Aggressive pituitary tumors are usually invasive macroadenomas, or benign tumors larger than 10 mm. A very rare subset of pituitary adenoma — particularly corticotropinoma, or tumors with excessive secretion of corticotropin (ACTH) — exhibit Crooke’s cells. These tumors are highly invasive, have a high recurrence rate, and are often resistant to treatment. Information is not widely available about the effectiveness of treating aggressive pituitary tumors, particularly those that cause Cushing’s disease. The management of these tumors usually requires neurosurgery, followed by radiotherapy, and pharmacotherapy. However, the chemotherapy medication temozolomide has been increasingly used as a first-line treatment after initial evidence of its effectiveness in treating glioblastoma, the most common form of brain cancer. In this study, researchers at the Jagiellonian University, in Poland, discussed the case of a 61-year-old man with ACTH-dependent Cushing’s syndrome caused by Crooke’s cell corticotropinoma. The patient first presented with symptoms of severe hypercorticoidism — the excessive secretion of steroid hormones from the adrenal cortex — in December 2011. He also showed advanced heart failure, severe headaches, and impaired vision, which had started two or three years before diagnosis. Examinations revealed osteoporosis and a fracture in the Th5 vertebra. His morning ACTH levels were high. The same was observed for mean cortisol levels even after dexamethasone treatment, which was suggestive of a pituitary tumor secreting ACTH. MRIs showed the existence of a tumor mass, later identified as a macroadenoma with high cell polymorphism, the presence of Crooke’s cells, and ACTH secretion. The patient was referred for transsphenoidal nonradical neurosurgery, performed through the nose and the sphenoid sinus, and bilateral adrenalectomy, or the surgical removal of the adrenal glands, in 2012-2013. However, he developed fast, postoperative recurrence of hypercorticoidism and tumor regrowth. This led to three additional transsphenoidal neurosurgeries and radiotherapy. The patient’s clinical status worsened as he developed severe cardiac insufficiency. Doctors began temozolomide treatment in April 2015, which did not result in adverse effects throughout treatment. The initial standard dose (150–200 mg/m2) was given once daily in the morning for five consecutive days, in a 28-day cycle. The patient also received 600 mg of ketoconazole, an antifungal medication. Ondansetron was administered to prevent nausea and vomiting. Subsequent examinations revealed clinical and biochemical improvements, including a reduction in ACTH and cortisol levels. In addition, the patient also showed reduced cardiac insufficiency, less frequent and less severe headaches, visual field improvements, and better physical fitness and mood. However, clinical symptoms worsened after the eighth temozolomide cycle. The tumor size also suddenly increased after the ninth cycle, reaching the inner ear. Temozolomide was then discontinued and ACTH levels increased by 28 percent one month later. The patient also demonstrated deteriorated vision, hearing loss, and strong headaches. Clinicians then decided to start treatment with the Cushing’s disease therapy Signifor (pasireotide), but a worsening of diabetes was observed, and the patient died in February 2016. “The most probable reason for death was compression of the brainstem, which had been observed in the last MRI of the pituitary,” the researchers wrote, adding that “due to the very short duration of treatment, any conclusions on the treatment with Signifor cannot be drawn.” Overall, “the results of the presented case suggest that [temozolomide] treatment monotherapy could have only partial response in aggressive corticotroph adenoma causing Cushing’s disease, followed by sudden progression,” the investigators wrote. This contrasts with mostly responsive cases reported in research literature, they noted. “Therefore, further research on the factors of responsiveness and on novel methods to extend the duration of the effect of [temozolomide] should be carried out,” they wrote. From https://cushieblog.com/2018/02/10/temozolomide-may-partially-improve-aggressive-pituitary-tumors-causing-cushings-disease/

From Kathy's bio at http://cushingsbios.com/2014/04/25/kathy-c-pituitary-bio/ Kathy will be interviewed May 7, 2014 in BlogTalkRadio. You can listen live and ask questions or download the podcast later.

November 7, 2012 The US Food and Drug Administration's (FDA) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted unanimously in support of the use of Signifor® (pasireotide) for the treatment of patients with Cushing's disease who require medical therapeutic intervention. The recommendation was based on data from clinical trials of pasireotide, including PASPORT-CUSHINGS (PASireotide clinical trial PORTfolio - CUSHING'S disease), the largest randomized Phase III study to evaluate a medical therapy in patients with Cushing's disease. Patient Assistance for SIGNIFOR support for patients includes: - Therapy-specific support programs for out-of-pocket costs - Alternative assistance searches and referrals to Federal and State assistance programs - Referrals to Independent Charitable Foundations for assistance with co-pay costs - Patient assistance for low-income and uninsured patients For more information, or to speak to a Patient Assistance NOW Endocrinology representative, please call 1-877-503-3377 (select option #3 for SIGNIFOR) Monday to Friday 8 am - 8 pm ET.

Basel Monday, December 17, 2012, 16:00 Hrs [iST] The US Food and Drug Administration (FDA) has approved Novartis' Signifor (pasireotide) injection for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative. Signifor is the first medicine to be approved in the US that addresses the underlying mechanism of Cushing's disease, a serious, debilitating endocrine disorder caused by the presence of a non-cancerous pituitary tumour which ultimately leads to excess cortisol in the body. This approval follows a unanimous recommendation from the FDA Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) in support of the use of Signifor. "The FDA approval of Signifor for Cushing's disease brings a novel pituitary-directed therapy to patients with limited treatment options," said Hervé Hoppenot, president, Novartis Oncology. "Today's milestone reinforces Novartis' commitment to addressing unmet needs and advancing treatments for rare pituitary-related disorders." Cushing's disease most commonly affects adults as young as 20 to 50 years and affects women three times more often than men. It may present with weight gain, central obesity, a round, red full face, severe fatigue and weakness, striae (purple stretch marks), high blood pressure, depression and anxiety. Cushing's disease can cause severe illness and death with mortality up to four times higher than in the healthy population. The approval is based on data from PASPORT-CUSHINGS (PASireotide clinical trial PORTfolio - CUSHING'S disease), the largest randomized Phase III study to evaluate a medical therapy in patients with Cushing's disease. Results from the PASPORT-CUSHINGS study found that a decrease in mean urinary-free cortisol (UFC), the key measure of biochemical control of the disease, was sustained during the treatment period in most patients with a subset of patients reaching normal levels. The study also showed that certain clinical manifestations of Cushing's disease tended to improve. "Patients with Cushing's disease may suffer from debilitating manifestations, and there are many serious health complications associated with the disease," said Mary Andrews, CEO and Co-Founder of the US non-profit, The MAGIC Foundation. "The FDA approval of Signifor offers the option of a medical therapy that may help certain patients with Cushing's disease." In April 2012, the European Commission approved Signiforfor the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed. Other worldwide regulatory filings for pasireotide for this use are also underway. Signifor (pasireotide) is approved in the US for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative, and in the European Union for the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed. For the treatment of Cushing's disease, Signifor has been studied as a twice-daily subcutaneous (sc) injection and is currently being evaluated as a long-acting release (LAR), once-monthly intramuscular (IM) injection as part of a global Phase III program in Cushing's disease and acromegaly. Signifor is a multireceptor targeting somatostatin analog that binds with high affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3 and 5). From http://pharmabiz.com/NewsDetails.aspx?aid=72752&sid=2

Committee votes unanimously in favor of Signifor (pasireotide) as the first medication to treat US patients with Cushing's disease Pasireotide represents the first targeted approach for this potentially debilitating endocrine disorder caused by a pituitary tumor that triggers excess cortisol[1],[2] Majority of patients in the Phase III clinical trial experienced a rapid and sustained decrease in mean cortisol levels with subset of patients achieving normalization[3] Basel, November 7, 2012 - The US Food and Drug Administration's (FDA) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) has voted unanimously in support of the use of Signifor®(pasireotide) for the treatment of patients with Cushing's disease who require medical therapeutic intervention. "We are encouraged by today's favorable advisory committee recommendation for pasireotide in Cushing's disease and will work closely with the FDA as it completes its review of our application," said Hervé Hoppenot, President, Novartis Oncology. "There is a significant unmet medical need for Cushing's disease patients and Novartis is committed to providing the endocrinology community with a novel therapeutic approach for this rare and debilitating endocrine disorder." The recommendation was based on data from clinical trials of pasireotide, including PASPORT-CUSHINGS (PASireotide clinical trialPORTfolio - CUSHING'S disease), the largest randomized Phase III study to evaluate a medical therapy in patients with Cushing's disease. Although not obliged to follow the recommendation, the FDA can seek the advice of its advisory committees as it reviews and decides whether to approve treatments[1],[4]. Results from the PASPORT-CUSHINGS study found that mean urinary-free cortisol (UFC), the key measure of biochemical control of the disease, was rapidly decreased and sustained in a majority of patients, with a subset of patients reaching normalized levels. The study also showed that, on average, as UFC levels were reduced, clinical manifestations of Cushing's disease improved. The most frequently reported adverse events (AEs) (>10%) by investigators for pasireotide were diarrhea, nausea, hyperglycemia, cholelithiasis, abdominal pain, diabetes mellitus, injection site reactions, fatigue and increased glycosylated hemoglobin (HbA1c), with most events being Grade 1-2. The safety profile of pasireotide was similar to that of other somatostatin analogs (SSA) with the exception of the greater degree of hyperglycemia[3]. Cushing's syndrome is an endocrine disorder caused by excessive cortisol, a vital hormone that regulates metabolism, maintains cardiovascular function and helps the body respond to stress. Cushing's disease is a form of Cushing's syndrome, in which excess cortisol production is triggered by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. It is a rare but serious disease that affects approximately one to two patients per million per year. Cushing's disease most commonly affects adults as young as 20 to 50 years and affects women three times more often than men. It may present with weight gain, central obesity, a round, red full face, severe fatigue and weakness, striae (purple stretch marks), high blood pressure, depression and anxiety. The first line and most common treatment approach for Cushing's disease is surgical removal of the tumor[1],[2],[5],[6],[7]. About pasireotide Pasireotide is a multireceptor targeting somatostatin analog (SSA) that binds with high affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3 and 5)[2]. In April 2012, the European Commission approved pasireotide under the brand name Signiforfor the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed. Other worldwide regulatory filings for pasireotide for this use are also underway. For the treatment of Cushing's disease, pasireotide has been studied as a twice-daily subcutaneous (sc) injection and is currently being evaluated as a long-acting release (LAR), once-monthly intramuscular (IM) injection as part of a global Phase III program in Cushing's disease and acromegaly[8],[9]. There is no guarantee that pasireotide will become commercially available anywhere else in the world. As an investigational compound, the safety and efficacy profile of pasireotide has not yet been established in all countries for the treatment of Cushing's disease or any other indications. Access to pasireotide outside of the approved indications has been carefully controlled and monitored in clinical trials designed to better understand the potential benefits and risks of the compound. Information about Novartis clinical trials for pasireotide can be obtained by healthcare professionals at www.pasporttrials.com. Disclaimer The foregoing release contains forward-looking statements that can be identified by terminology such as "recommended," "potentially," "encouraged," "will," "committed," "recommendation," "underway," "potential," or similar expressions, or by express or implied discussions regarding potential marketing approvals for Signifor or regarding potential future revenues from Signifor. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Signifor to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Signifor will be approved for sale in any market, or at any particular time. Nor can there be any guarantee that Signifor will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Signifor could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; government, industry and general public pricing pressures; competition in general; unexpected manufacturing issues; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.