RESUMO
Background: No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled trials are lacking. In vivo somatostatin receptor assessment with 68Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68Ga-DOTATATE PET-positive NFPMA. Methods: The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10 mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120 mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22. Findings: Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 [50%]) or placebo (22 [50%]). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was +1·2 (2·5) mm with lanreotide and +1·3 (1·5) mm with placebo; adjusted mean difference versus placebo -0·1 mm (95% CI -1·3 to 1·2, p = 0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events. Interpretation: Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68Ga-DOTATATE PET-positive NFPMA. Funding: Ipsen Farmaceutica BV.
RESUMO
PURPOSE: Clinically non-functioning pituitary macroadenomas (NFMA) have been reported to express somatostatin receptors (SSTR), but results are inconsistent across different studies. This may be related to limited sensitivity and specificity of techniques used to date, i.e. immunohistochemistry in surgical specimens and 111In-DTPA-octreotide scintigraphy in vivo. The aim of this study was to assess SSTR expression in NFMA in vivo using 68Ga-DOTATATE PET, which offers superior sensitivity and spatial resolution as compared with planar scintigraphy or SPECT. METHODS: Thirty-seven patients diagnosed with NFMA underwent 68Ga-DOTATATE PET/CT of the head in the framework of a randomised controlled trial assessing the effect of the somatostatin analogue lanreotide on NFMA size. Individual co-registered T1-weighted pituitary MRIs were used to assess 68Ga-DOTATATE uptake (SUVmean) in the adenoma. An SUVmean of > 2 was considered positive. RESULTS: 68Ga-DOTATATE uptake was positive in 34/37 patients (92%), with SUVmean of positive adenomas ranging from 2.1 to 12.4 (mean ± SD 5.8 ± 2.6). CONCLUSIONS: This is the first report of 68Ga-DOTATATE PET performed in NFMA patients, demonstrating in vivo SSTR expression in the vast majority of cases. The high positivity rate when compared with results obtained with 111In-DTPA-octreotide scintigraphy probably reflects the superior sensitivity of PET imaging. TRIAL REGISTRATION: Netherlands Trial Register, NL5136, registered on 18 August 2015; EudraCT, 2015-001234-22, registered on 10 March 2015, https://eudract.ema.europa.eu/.
RESUMO
CONTEXT: Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). OBJECTIVE: To determine which type of α-adrenergic receptor blocker provides the best efficacy. DESIGN: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898). SETTING: Multicenter study including 9 centers in The Netherlands. PATIENTS: 134 patients with nonmetastatic PPGL. INTERVENTION: Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. RESULTS: Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% (5.3-20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days. CONCLUSIONS: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.