In contrast to the clear indication for surgical treatment in symptomatic patients with clinically nonfunctioning pituitary adenomas (NFPA), there are no randomized controlled studies comparing therapeutic strategies such as watchful waiting, irradiation or medical therapy for the management of NFPA after surgery. Further, no medical therapy is currently approved for the treatment of NFPA. In this review, we summarize accumulating data on medications currently approved for secreting pituitary adenomas, used off-label in patients with NFPA. Perspectives on overall treatment optimization and potential future therapies are also detailed.
Ilan Shimon, Raquel S Jallad, Maria Fleseriu, Chris G Yedinak, Yona Greenman and Marcello D Bronstein
Patients with acromegaly usually harbor macroadenomas measuring between 10 and 30 mm in maximal diameter. Giant (adenoma size ≥40 mm) GH-secreting pituitary tumors are rarely encountered and the aim of this study is to analyze different methods for managing them.
Design and methods
We have identified 34 patients (15 men and 19 females) with giant adenomas among 762 subjects (4.5%) with acromegaly in our records, and characterized their clinical characteristics and response to treatment.
Mean age at diagnosis was 34.9±12.5 years (range, 16–67 years). Mean adenoma size was 49.4±9.4 mm (range, 40–80 mm); 30 adenomas showed cavernous sinus invasion and 32 had suprasellar extension. Twenty-nine (85%) patients had visual field defects. Mean baseline IGF1 was 3.4±1.8×ULN. All patients except one underwent pituitary surgery (one to three procedures), but none achieved hormonal remission following first surgery. Among the 28 subjects with visual disturbances, 14 recovered post-operatively and 13 improved. Treatment with somatostatin analogs was given to all patients after surgical failure. Six achieved remission, nine others were partially controlled (IGF1<1.5×ULN; 3/9 when combined with cabergoline), and 17 did not respond (two were lost). Nine patients were treated with pegvisomant, alone (n=4) or in combination with somatostatin analogs (n=5); five are in remission and two are partially controlled. Pasireotide-LAR achieved hormonal remission in one of the six patients. Currently, after a mean follow-up period of 8.9 years, 17 patients are in biochemical remission, eight are partially controlled, and seven are uncontrolled (two were lost to follow-up).
Giant GH-secreting adenomas are invasive, uncontrolled by surgery, and respond poorly to medical treatment. Aggressive multimodal therapy is critical for their management, enhancing control rate and biochemical remission.
Marianna Yaron, Yona Greenman, Joseph B Rosenfeld, Elena Izkhakov, Rona Limor, Etty Osher, Galina Shenkerman, Karen Tordjman and Naftali Stern
To assess arterial stiffness in a cohort of hypogonadal males and to investigate the effect of testosterone replacement therapy on arterial properties in this specific group.
Eighteen male patients with untreated acquired hypogonadism due to either adult-onset idiopathic hypogonadotropic hypogonadism (n=9) or pituitary tumor (n=9) and 12 age-, sex, and weight-matched eugonadal healthy controls were recruited for the study. Arterial properties, plasma glucose, lipid profile, total, and bioavailable testosterone (BT) levels were measured in fasting state. In the hypogonadal subjects, the effect of transdermal testosterone replacement therapy on arterial properties was studied by repeat noninvasive measurements at baseline, as well as 48 h and 90 days following the initiation of treatment.
Arterial stiffness was evaluated using applanation tonometry and pulse wave analysis by three different standard devices that assess various measures of arterial stiffness: pulse wave velocity (PWV), augmentation index (AIx), and large/small artery compliance (C1 and C2).
Age- and blood pressure-adjusted PWV was significantly higher in hypogonadal men (8.90±2.29 vs 6.78±1.16 m/s in the control group; P=0.025). Testosterone therapy increased BT level from 2.01±1.04 to 4.68±2.43 and 7.83±6.2 nmol/l after 48 h and 3 months respectively (P=0.001). PWV decreased from 8.9±2.29 to 8.24±1.39 and 8.25±1.82 m/s after 48 h and 3 months of treatment respectively (P=0.03).
Male hypogonadism is associated with increased PWV, which is rapidly but incompletely ameliorated by normalization of circulating testosterone levels.
Ann McCormack, Olaf M Dekkers, Stephan Petersenn, Vera Popovic, Jacqueline Trouillas, Gerald Raverot, Pia Burman and ESE survey collaborators
To collect outcome data in a large cohort of patients with aggressive pituitary tumours (APT)/carcinomas (PC) and specifically report effects of temozolomide (TMZ) treatment.
Electronic survey to ESE members Dec 2015–Nov 2016.
Reports on 166 patients (40 PC, 125 APT, 1 unclassified) were obtained. Median age at diagnosis was 43 (range 4–79) years. 69% of the tumours were clinically functioning, and the most frequent immunohistochemical subtype were corticotroph tumours (45%). Ki-67 index did not distinguish APT from PC, median 7% and 10% respectively. TMZ was first-line chemotherapy in 157 patients. At the end of the treatment (median 9 cycles), radiological evaluation showed complete response (CR) in 6%, partial response (PR) in 31%, stable disease (SD) in 33% and progressive disease in 30%. Response was more frequent in patients receiving concomitant radiotherapy and TMZ. CR was seen only in patients with low MGMT expression. Clinically functioning tumours were more likely to respond than non-functioning tumours, independent of MGMT status. Of patients with CR, PR and SD, 25, 40 and 48% respectively progressed after a median of 12-month follow-up. Other oncological drugs given as primary treatment and to TMZ failures resulted in PR in 20%.
This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.