Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity 131 I-meta-iodobenzylguanidine (HSA 131 I-MIBG) in patients with advanced PPGL. Methods: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA 131 I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA 131 I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 mo. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0, biochemical tumor marker response, overall survival, and safety. Results: Of the 68 patients who received at least 1 therapeutic dose of HSA 131 I-MIBG, 17 (25%; 95% confidence interval, 16%–37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 mo. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed, with confirmed complete and partial responses 12 mo after treatment in 19 of 28 patients (68%). The median overall survival was 36.7 mo (95% confidence interval, 29.9–49.1 mo). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA 131 I-MIBG. Conclusion: HSA 131 I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.
Purpose: Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR). 18F-DCFPyL is a highly selective, small-molecule prostate-specific membrane antigen–targeted PET radiotracer. CONDOR was a prospective study designed to determine the performance of 18F-DCFPyL-PET/CT in patients with BCR and uninformative standard imaging. Experimental Design: Men with rising PSA ≥0.2 ng/mL after prostatectomy or ≥2 ng/mL above nadir after radiotherapy were eligible. The primary endpoint was correct localization rate (CLR), defined as positive predictive value with an additional requirement of anatomic lesion colocalization between 18F-DCFPyL-PET/CT and a composite standard of truth (SOT). The SOT consisted of, in descending priority (i) histopathology, (ii) subsequent correlative imaging findings, or (iii) post-radiation PSA response. The trial was considered a success if the lower bound of the 95% confidence interval (CI) for CLR exceeded 20% for two of three 18F-DCFPyL-PET/CT readers. Secondary endpoints included change in intended management and safety. Results: A total of 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2–98.4 ng/mL) underwent 18F-DCFPyL-PET/CT. The CLR was 84.8%–87.0% (lower bound of 95% CI: 77.8–80.4). A total of 63.9% of evaluable patients had a change in intended management after 18F-DCFPyL-PET/CT. The disease detection rate was 59% to 66% (at least one lesion detected per patient by 18F-DCFPyL-PET/CT by central readers). Conclusions: Performance of 18F-DCFPyL-PET/CT achieved the study’s primary endpoint, demonstrating disease localization in the setting of negative standard imaging and providing clinically meaningful and actionable information. These data further support the utility of 18F-DCFPyL-PET/CT to localize disease in men with recurrent prostate cancer. See related commentary by True and Chen, p. 3512
Prostate specific membrane antigen-targeted positron emission tomography/computerized tomography has the potential to improve the detection and localization of prostate cancer. OSPREY was a prospective trial designed to determine the diagnostic performance of 18 F-DCFPyL-positron emission tomography/ computerized tomography for detecting sites of metastatic prostate cancer. Materials and Methods: Two patient populations underwent 18 F-DCFPyLpositron emission tomography/computerized tomography. Cohort A enrolled men with high-risk prostate cancer undergoing radical prostatectomy with pelvic lymphadenectomy. Cohort B enrolled patients with suspected recurrent/ metastatic prostate cancer on conventional imaging. Three blinded central readers evaluated the 18 F-DCFPyL-positron emission tomography/computerized tomography. Diagnostic performance of 18 F-DCFPyL-positron emission tomography/computerized tomography was based on imaging results compared to histopathology. In cohort A, detection of pelvic nodal disease (with specificity and sensitivity as co-primary end points) and of extrapelvic metastases were evaluated. In cohort B, sensitivity and positive predictive value for prostate cancer within biopsied lesions were evaluated.
These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg.
Tolvaptan is an arginine vasopressin (AVP) antagonist that acts to increase excretion of free water (aquaresis) in patients without introducing electrolyte abnormalities or worsening renal function. It works via blockade of vasopressin-2 receptors at the renal collecting duct. Since the approval of tolvaptan for the treatment of hypervolemic and euvolemic hyponatremia in 2009, new studies have been reported to better characterize its pharmacokinetic and pharmacodynamic profile of tolvaptan. This paper is a review of both these clinical studies, as well as previous literature, in order to help guide appropriate clinical use of tolvaptan in patients. With appropriate monitoring of serum sodium, tolvaptan may be safely dose escalated from 15 mg once daily to a maximum effective dose of 60 mg once daily for multiple days, to achieve optimal aqauretic effects. In terms of drug interactions, co-administration of moderate to potent CYP3A4 inhibitors and inducers should be avoided. Tolvaptan should also be co-administered with caution and proper monitoring in the presence of P-glycoprotein substrate and strong inhibitors. Co-administration of tolvaptan with diuretic therapy did not appear to alter the aquaretic effect of tolvaptan; and was shown to be safe and well tolerated.
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