Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

[Management of prolactinoma prior to, during, and after pregnancy]. / Management des Prolaktinoms vor, während und nach der Schwangerschaft.

Hyperprolactinemia should actively be investigated as a potential reason of infertility. Underlying prolactinomas may successfully be treated with dopamine agonists. However, patients with micro- or well-circumscribed macroprolactinomas (Knosp 0 or 1) should also be informed about transsphenoidal surgery offering cure in contrast to long-lasting medical therapy. Management prior to and during pregnancy is usually unremarkable but may pose some specific challenges.

Aggressive pituitary tumours and carcinomas, characteristics and management of 171 patients.

Objective: To describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC). Design: Electronic survey August 2020-May 2021. Results: 96% of 171 (121 APT, 50 PC), initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated aggressive behaviour after 5.5 years (IQR: 2.8-12). Of the patients, 63% were men. Adrenocorticotrophic hormone (ACTH)-secreting tumours constituted 30% of the APT/PC, and the gonadotroph subtypes were under-represented. Five out of 13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7-12.1) from diagnosis. At the first surgery, the Ki67 index was ≥3% in 74/93 (80%) and ≥10% in 38/93 (41%) tumours. An absolute increase of Ki67 ≥ 10% after median of 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67 ≥ 10% and ACTH-secretion were associated with worse prognosis. Conclusion: APT/PCs exhibit a wide and challenging spectrum of behaviour. Temozolomide is the first-line chemotherapy, and other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers.

Prevalence of comorbidities and concomitant medication use in acromegaly: analysis of real-world data from the United States.

PURPOSE: Patients receiving treatment for acromegaly often experience significant associated comorbidities for which they are prescribed additional medications. We aimed to determine the real-world prevalence of comorbidities and concomitant medications in patients with acromegaly, and to investigate the association between frequency of comorbidities and number of concomitantly prescribed medications. METHODS: Administrative claims data were obtained from the IBM® MarketScan® database for a cohort of patients with acromegaly, identified by relevant diagnosis codes and acromegaly treatments, and a matched control cohort of patients without acromegaly from January 2010 through April 2020. Comorbidities were identified based on relevant claims and assessed for both cohorts. RESULTS: Overall, 1175 patients with acromegaly and 5875 matched patients without acromegaly were included. Patients with acromegaly had significantly more comorbidities and were prescribed concomitant medications more so than patients without acromegaly. In the acromegaly and control cohorts, respectively, 67.6% and 48.4% of patients had cardiovascular disorders, the most prevalent comorbidities, and 89.0% and 68.3% were prescribed > 3 concomitant medications (p < 0.0001). Hypopituitarism and hypothalamic disorders, sleep apnea, malignant neoplasms and cancer, and arthritis and musculoskeletal disorders were also highly prevalent in the acromegaly cohort. A moderate, positive correlation (Spearman correlation coefficient 0.60) was found between number of comorbidities and number of concomitant medications in the acromegaly cohort. CONCLUSION: Compared with patients without acromegaly, patients with acromegaly have significantly more comorbidities and are prescribed significantly more concomitant medications. Physicians should consider the number and type of ongoing medications for individual patients before prescribing additional acromegaly treatments.

Consensus on diagnosis and management of Cushing's disease: a guideline update.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Neuroendocrine Tumors in Routine Clinical Practice in Germany and Austria.

BACKGROUND: The long-acting somatostatin analog lanreotide autogel is effective in the treatment of patients with neuroendocrine tumors. OBJECTIVE: To evaluate the long-term treatment response in patients with neuroendocrine tumors receiving lanreotide autogel in routine clinical practice. METHODS: Non-interventional, 24-month study in patients with neuroendocrine tumors treated with lanreotide autogel (NCT01840449). RESULTS: Patients (n=80) from 26 centers in Germany and Austria were enrolled. Neuroendocrine tumors were mainly grade 1/2, metastasized, intestinal, and associated with carcinoid syndrome; 88.9% had received previous neuroendocrine tumor treatment. Of those, 84.4% had previous surgery, 18.7% had received octreotide. The primary endpoint, defined by a <50% chromogranin A increase at month 12 compared with the lowest value between baseline and month 3 was achieved by 89.5% patients. Stable disease according to Response Evaluation Criteria in Solid Tumors 1.1 was observed in 76.9 and 75.0% patients at months 12 and 24 of lanreotide treatment, respectively. Mean change of chromogranin A levels from baseline to month 24 was -0.12 × upper limit of normal (95% CI, -0.22; -0.45). In a post hoc analysis, 38.5% of the subgroup of patients with carcinoid syndrome had daily diarrhea at baseline vs. 21.4% at month 24. At baseline, 27.8% of patients received lanreotide 120 mg every 4 weeks vs. 56.7% at month 24. Quality of life data were heterogeneous. No new safety issues arose and/or required further investigation. CONCLUSIONS: Our study reflects routine lanreotide autogel use in patients with advanced/metastatic neuroendocrine tumors. This analysis shows effectiveness with stabilization of disease-related symptoms and good tolerability of lanreotide autogel in clinical practice.

International Multicenter Validation Study of the SAGIT® Instrument in Acromegaly.

CONTEXT: The SAGIT® instrument (SAGIT) has been developed to enable accurate characterization of acromegaly disease activity. OBJECTIVE: We evaluated the ability of SAGIT to discriminate acromegaly disease control status. METHODS: This multicenter, noninterventional, prospective and retrospective, longitudinal study, conducted at academic and private clinical practice sites, included patients aged ≥ 18 years with a diagnosis of controlled (n = 109) or non-controlled (n = 105) acromegaly, assessed by clinical global evaluation of disease control (CGE-DC) questionnaire, investigator therapeutic decision, and international guidelines. Control status was not determined at baseline for 13 patients. Since 9 patients were enrolled retrospectively, all presented analyses are based on the prospective population (N = 227). Patients were assessed over a 2-year follow-up period. Classification and regression tree (CART) analyses were performed to investigate how SAGIT components at baseline (signs/symptoms [S], associated comorbidities [A], growth hormone levels [G], insulin-like growth factor 1 levels [I], tumor features [T]) discriminate between controlled and non-controlled acromegaly. RESULTS: Baseline mean subscores S, G, I, and T were significantly lower in patients with CGE-DC controlled vs CGE-DC non-controlled acromegaly. SAGIT components I and G for CGE-DC and S, A, G, I, and T for the clinician's therapeutic decision were retained by CART analyses. For international guidelines, only SAGIT component I was retained. The risk for undergoing ≥ 1 treatment change during the study was 3.44 times greater for CGE-DC non-controlled acromegaly relative to CGE-DC controlled acromegaly. CONCLUSION: The SAGIT instrument is a valid and sensitive tool to comprehensively and accurately assess acromegaly severity.

Biochemical diagnosis of Cushing's disease: Screening and confirmatory testing.

Due to the variable clinical features and its rarity diagnosis of Cushing's disease (CD) is often delayed. Clearly, awareness for CD needs to be raised, accompanied by the availability of simple and accurate screening tests. Late-night salivary cortisol (LNSC), 1 mg dexamethasone suppression test (DST), and urinary free cortisol (UFC) have all been extensively studied, demonstrating high sensitivity and specificity for the diagnosis of Cushing's syndrome. However, each of those well-established tests has its own distinctive features, making it preferable in specific clinical conditions and patient groups. To choose the most appropriate test in individual patients, an expert endocrinologist should be consulted. This review will discuss the pitfalls for each of those tests.

Medical Therapy of Aggressive Pituitary Tumors.

The rare aggressive pituitary adenoma presents a special challenge, due to the heterogenous presentation of the disease. The prognosis of aggressive pituitary adenomas has been improved due to recent studies demonstrating clinically-relevant efficacy of temozolomide, which is now considered first-line chemotherapy. However, there is limited data on second-line therapies in patients with treatment failure. This review presents a summary on the potential of medical therapies in aggressive pituitary tumors.

Bevacizumab in Aggressive Pituitary Adenomas - Experience with 3 Patients.

OBJECTIVE: To investigate bevacizumab as alternative treatment of aggressive pituitary adenomas after exhaustion of standard therapies. DESIGN AND METHODS: Retrospectively, 3 patients undergoing microscopic transsphenoidal surgery of aggressive pituitary adenomas from 2008 till 2018 that were treated with bevacizumab were identified. Development of disease and treatment were evaluated. RESULTS: Two patients suffered from ACTH-secreting adenomas, one from a non-functioning adenoma. All patients underwent multiple surgical, chemo- and radiotherapeutical approaches including temozolomide, showing favorable results in one patient. Deterioration of clinical condition in all patients led to an individual, palliative attempt of bevacizumab. Patients 1 and 2 showed a decrease of ACTH after first administrations, but therapy had to be ended shortly after due to a further deterioration of their condition. Patient 3 showed a stabilization of the disease for 18 months. Patients died 8, 15 and 7 years after initial diagnosis, respectively, and 2, 4, and 24 months after initiation of bevacizumab therapy, respectively. CONCLUSION: The demonstrated results suggest a considerable effect of bevacizumab in aggressive pituitary adenomas. The advanced stage of disease in all three patients, the overall short period of administration and just one patient showing a clinical benefit do not allow a general statement on the effectiveness. At the current stage of clinical experience, an approach with bevacizumab can be considered as an individual palliative attempt of treatment, when standard treatments are exhausted. Our results underline the need for further studies to evaluate this drug as potential player in therapy resistant aggressive pituitary tumors.

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Acromegaly in Routine Clinical Practice in Germany, Austria and Switzerland.

BACKGROUND: Evidence from controlled trials has shown that lanreotide autogel is effective in achieving biochemical and symptom control in patients with acromegaly. However, it is important to better understand the real-world patient population receiving lanreotide autogel treatment. METHODS: In this non-interventional study the long-term treatment response to lanreotide autogel in adult patients with acromegaly from office-based centers or clinics in Germany, Austria and Switzerland was studied. Assessments included growth hormone and insulin-like growth factor-I levels, symptoms, quality of life, lanreotide plasma levels and tumor somatostatin receptor subtype expression. The primary endpoint was achievement of full biochemical control, defined as growth hormone ≤2.5 µg/L and insulin-like growth factor I normalization at month 12. RESULTS: 76 patients were enrolled from 21 sites. 7/51 (13.7%) patients of the efficacy population had full biochemical control at baseline, 15/33 (45.5%) at month 12 and 10/26 (38.5%) at month 24 of treatment. At 12 months of treatment higher rates of biochemical control were observed in the following subgroups: older patients (>53 years [median]), females, treatment-naïve patients, and patients with a time since diagnosis of longer than 1.4 years (median). No clinically relevant differences in acromegaly symptoms or quality of life scores were observed. Median fasting blood glucose and glycated hemoglobin levels remained unchanged throughout the study. No new safety signals were observed. Overall tolerability of treatment with lanreotide autogel was judged by 80.8% of the enrolled patients at month 12 as 'very good' or 'good'. CONCLUSION: Treatment with lanreotide autogel in a real-world setting showed long-term effectiveness and good tolerability in patients with acromegaly.

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Are aggressive pituitary tumors and carcinomas two sides of the same coin? Pathologists reply to clinician's questions.

Pituitary adenohypophyseal tumors are considered as benign and termed "adenomas". However, many tumors are invasive and a proportion of these exhibit an "aggressive behavior" with premature death due to progressive growth. Only very rare (0.2%) tumors with metastases are considered malignant and termed "carcinomas". Taking into account this variability in behavior and the oncological definition, pathologists have proposed changing the term adenoma to tumor. Here we explain why use the term tumor instead of adenoma and identify tumor characteristics, associated with a high risk for poor prognosis. In a cohort of 125 tumors with aggressive behavior (APT) and 40 carcinomas with metastases (PC), clinical and pathological features were very similar. The comparison of this cohort (APT+PC) with a reference surgical cohort of 374 unselected patients clearly shows that the two cohorts differ greatly, especially the percentage of tumors with Ki67 ≥ 10% (35%vs3%; p < 0.001). A five-tiered prognostic classification, associating invasion and proliferation, identified grade 2b tumors (invasive and proliferative), with a high risk of recurrence/progression. Because half of the APT+ PC tumors have a Ki67 index ≥10%, and 80% of them show 2 or 3 positive markers of proliferation, we suggest that tumors that are clinically aggressive, invasive and highly proliferative with a Ki67 ≥ 10%, represent tumors with malignant potential. The percentage of grade 2b tumors, suspected of malignancy, which will become aggressive tumors or carcinomas is unknown. It is probably very low, but higher than 0.2% in surgical series. Early identification and active treatment of these aggressive tumors is needed to decrease morbidity and prolong survival.

Targeted systemic and peptide radio-ligand therapy for aggressive pituitary tumors and carcinomas.

Aggressive pituitary tumors comprise a rare but challenging subset of pituitary tumors. A major issue currently is the absence of a holistic definition that reliably identifies these tumors in a prospective manner. Although comprehensive evaluation of patient gender, age, local invasiveness, treatment responses, radiological and histopathological features may be informative to assess the potential for aggressiveness, a definitive diagnosis of this entity cannot be confidently made until disease progression is actually observed despite standard medical and surgical therapy. Failure to diagnose these aggressive pituitary tumors early may impede initiation of suitable intensive stepwise multimodal treatments, and lessen their ultimate therapeutic success. Even though current therapeutic options for aggressive pituitary tumors are suboptimal in many cases, large-scale randomized prospective clinic trials are impractical and will likely never be conducted due to the rarity of this disease entity. Therefore, the majority of novel therapies in this subset of tumors derive from case reports or small case series, which greatly reduces their validity to make strong recommendations. This chapter, as part of this series on aggressive pituitary tumors, focuses on the role of systemic targeted medical and peptide radio-receptor therapy in treatment of aggressive pituitary tumors and carcinomas, and discusses future directions in these fields.

Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the PRIMARYS study.

PURPOSE: PRIMARYS (NCT00690898) was a 48-week, open-label, phase 3b study, evaluating treatment with the somatostatin receptor ligand lanreotide autogel (stable dose: 120 mg/28 days) in treatment-naïve patients with growth hormone (GH)-secreting pituitary macroadenoma. This post hoc analysis aimed to evaluate factors predictive of long-term responses. METHODS: Potential predictive factors evaluated were: sex, age, and body mass index at baseline; and GH, insulin-like growth factor-1 (IGF-1), and tumor volume (TV) at baseline and week 12, using univariate regression analyses. Treatment responses were defined as hormonal control (GH ≤ 2.5 µg/L and age- and sex-normalized IGF-1), tight hormonal control (GH < 1.0 µg/L and normalized IGF-1), or ≥ 20% TV reduction (TVR). Receiver-operating-characteristic (ROC) curves were constructed using predictive factors significant in univariate analyses. Cut-off values for predicting treatment responses at 12 months were derived by maximizing the Youden index (J). RESULTS: At baseline, older age, female sex, and lower IGF-1 levels were associated with an increased probability of achieving long-term hormonal control. ROC area-under-the curve (AUC) values for hormonal control were high for week-12 GH and IGF-1 levels (0.87 and 0.93, respectively); associated cut-off values were 1.19 µg/L and 110% of the upper limit of normal (ULN), respectively. Results were similar for tight hormonal control (AUC values: 0.92 [GH] and 0.87 [IGF-1]; cut-off values: 1.11 µg/L and 125% ULN, respectively). AUC and J values associated with TVR were low. CONCLUSIONS: The use of predictive factors at baseline and week 12 of treatment could inform clinical expectations of the long-term efficacy of lanreotide autogel.