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
F-DCFPyL-positron emission tomography/computerized tomography for detecting sites of metastatic prostate cancer.
Two patient populations underwent
F-DCFPyL-positron 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
F-DCFPyL-positron emission tomography/computerized tomography. Diagnostic performance of
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.
A total of 385 patients were enrolled. In cohort A (252 evaluable patients),
F-DCFPyL-positron emission tomography/computerized tomography had median specificity of 97.9% (95% CI: 94.5%-99.4%) and median sensitivity of 40.3% (28.1%-52.5%, not meeting prespecified end point) among 3 readers for pelvic nodal involvement; median positive predictive value and negative predictive value were 86.7% (69.7%-95.3%) and 83.2% (78.2%-88.1%), respectively. In cohort B (93 evaluable patients, median prostate specific antigen 11.3 ng/ml), median sensitivity and positive predictive value for extraprostatic lesions were 95.8% (87.8%-99.0%) and 81.9% (73.7%-90.2%), respectively.
The primary end point for specificity was met while the primary end point for sensitivity was not. The high positive predictive value observed in both cohorts indicates that
F-DCFPyL-positive lesions are likely to represent disease, supporting the potential utility of
F-DCFPyL-positron emission tomography/computerized tomography to stage men with high-risk prostate cancer for nodal or distant metastases, and reliably detect sites of disease in men with suspected metastatic prostate cancer.
Tc-trofolastat (
Tc-MIP-1404), a small-molecule inhibitor of prostate-specific membrane antigen, shows high potential to detect prostate cancer (PCa) noninvasively using SPECT. We therefore wanted to ...assess the performance of
Tc-trofolastat SPECT/CT in a phase 2 multicenter, multireader prospective study in patients with intermediate- and high-grade PCa, before radical prostatectomy and extended pelvic lymph node (LN) dissection, with histopathology as the gold standard.
PCa patients (
= 105) with an increased risk of LN involvement (LNI) underwent pelvic
Tc-trofolastat SPECT/CT before radical prostatectomy with extended pelvic LN dissection. The sensitivity of
Tc-trofolastat for detection of PCa on a patient and lobe basis, using visual and semiquantitative (tumor-to-background ratio TBR) scores, and of LNI was evaluated as well as the correlation of uptake within the gland to Gleason scores (GS) and assessment of the predictive potential of
Tc-trofolastat uptake for LNI.
PCa was detected in 98 patients (94%) with acceptable variability between readers. There was a significantly higher visual score and TBR in positive lobes compared with tumor-negative lobes. Receiver-operating characteristic analysis showed that visual scores more accurately discriminated lobes with GS ≤ 3 + 3 from ≥ 3 + 4, whereas TBRs discriminated high-grade disease from normal lobes better. Visual scores and TBRs correlated significantly with GS.
Tc-trofolastat SPECT/CT detected LNI with a sensitivity of 50% and specificity of 87%, and TBR values significantly predicted LNI with a sensitivity of 90%.
Tc-trofolastat SPECT/CT detects PCa with high sensitivity in patients with intermediate- and high-risk PCa compared with histology. It has the potential to be used as a surrogate marker for GS and predict LNI.
Oral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides ...a detailed safety analysis from that study.
Adults (n=803) with chronic noncancer pain for ≥2 months and confirmed OIC while receiving opioid doses ≥50 mg morphine equivalent per day for ≥14 days were randomized 1:1:1:1 to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily for 4 weeks, followed by as-needed use for 8 weeks. Safety was evaluated by examining treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, electrocardiography, rescue-laxative and opioid use, Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS), and pain-intensity scores.
TEAEs occurred at a similar incidence in the methylnaltrexone groups (59.0%) and placebo group (63.0%). The most common TEAEs with methylnaltrexone were abdominal pain (8.0% vs 8.5% with placebo), nausea (6.8% vs 9.0%), and diarrhea (6.0% vs 3.5%). Cardiac-related TEAEs occurred in 1.8% and 1.0% of patients, respectively, and no major adverse cardiovascular events were reported. No patient had a cluster of TEAEs associated with opioid withdrawal after excluding gastrointestinal TEAEs. Changes in laboratory parameters, vital signs, and electrocardiography were generally small and similar across treatment groups. Rescue-laxative use was more common with placebo than methylnaltrexone 450 mg (6.20% vs 4.27% of study days,
=0.024). Changes in opioid dose, OOWS and SOWS scores, and pain-intensity scores during treatment were minimal.
Oral methylnaltrexone had a safety profile comparable with placebo in the treatment of OIC in patients with chronic noncancer pain, with no evidence of cardiac toxicity or opioid withdrawal.
Methylnaltrexone, a peripheral mu-opioid receptor antagonist with restricted ability to cross the blood-brain barrier, may relieve opioid-induced constipation (OIC) without reversing analgesia. A ...total of 154 patients with advanced illness and OIC enrolled in a double-blind, randomized, placebo-controlled trial, with optional open-label phases (up to 4 months) in hospice and palliative care centers during 2003-2005. They received a single subcutaneous injection of methylnaltrexone (0.15 mg/kg or 0.3 mg/kg) or placebo. Laxation response within 4 hours was 62% and 58% for methylnaltrexone 0.15 mg/kg and 0.3 mg/kg, respectively, compared with 14% for placebo (P < 0.0001; each dose vs placebo). Approximately half of the methylnaltrexone responders defecated within 30 minutes of dosing. Open-label phase response rates mirrored those for methylnaltrexone during the double-blind phase.There was no change in pain scores or evidence of central opioid withdrawal.The most common adverse events (AEs) were abdominal pain and flatulence.Three patients had serious AEs attributed to methylnaltrexone. Subcutaneous methylnaltrexone was efficacious in rapidly inducing laxation and was generally well tolerated in patients with advanced illness and OIC.
Postoperative ileus contributes to surgical morbidity and is associated with prolonged hospitalization and increased health care costs. The efficacy and safety of the peripherally acting μ-opioid ...receptor antagonist methylnaltrexone in shortening the duration of postoperative ileus following segmental colectomy was evaluated.
Two identically designed, multicenter, double-blind, parallel-group, placebo-controlled studies randomly assigned patients undergoing segmental colectomy (study 1, N = 515; study 2, N = 533) to receive 12 or 24 mg of methylnaltrexone intravenously or placebo every 6 hours starting within 90 minutes of surgery completion, continuing for up to 10 days or up to 24 hours after gastrointestinal recovery. The primary efficacy end point was the time from the end of surgery to the first bowel movement. Safety was evaluated via standard assessments (ie, adverse events and related withdrawals, physical examinations, laboratory tests, vital signs, electrocardiograms) and assessment of surgical complications.
The primary and secondary efficacy outcomes (time to discharge eligibility, time to hospital discharge, and clinically meaningful events of nausea and vomiting following segmental colectomy) did not differ significantly between patients treated with either a dose of methylnaltrexone or with placebo. Rates of adverse events and serious adverse events were comparable across all treatment groups in both studies. The most commonly observed adverse events were nausea, pyrexia, and vomiting.
Although the efficacy of methylnaltrexone in reducing the duration of postoperative ileus was not demonstrated in these studies, intravenous methylnaltrexone at doses of 12 mg and 24 mg was safe, in general, and well tolerated in postcolectomy patients. The utility of intravenous methylnaltrexone in treating postoperative ileus remains unproven.
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
I-meta-iodobenzylguanidine (HSA
I-MIBG) in patients with advanced PPGL.
In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA
I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA
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.
Of the 68 patients who received at least 1 therapeutic dose of HSA
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
I-MIBG.
HSA
I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.
Abstract
Background: Metaiodobenzylguanidine (MIBG; iobenguane), a guanethidine derivative, is a substrate for norepinephrine reuptake transporter which is highly expressed on the surface of ...neuroblastoma cells. AZEDRA® (HSA I-131 MIBG) has been approved by the FDA for the treatment of pheochromocytoma and paraganglioma, in pts 12 years and older with MIBG avid, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. The aim of this study was to establish the maximum tolerated dose in children with neuroblastoma, with secondary aims of assessing overall response and tumor and organ dosimetry. Here we report current long-term survival and toxicity data. Methods: Eligible pts were 1-30 years old with resistant neuroblastoma. A diagnostic dose of HSA I-131 MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. To prevent prolonged myelosuppression, autologous hematopoietic stem cells were infused 14 days after therapy. Response and toxicity were evaluated on day 60. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/µL within 28 days, or platelets to greater than 20,000/µL within 56 days, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: First pt was enrolled in June 2008. 15 pts total were evaluable at 12 (n=5), 15 (n=3), and 18 (n=7) mCi/kg. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight pts had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. MYC-N amplification was present in two of 11 pts with available results. Of the 15 treated pts, 1 had a complete response, 3 had a partial response, 1 had a mixed response and 6 had stable disease. The remaining 4 had progressive disease. Twelve of the 15 evaluable pts received non-protocol therapy after HSA I-131 MIBG, the remaining 3 died due to tumor without further therapy. At 3.6 years of follow-up the overall survival was 26.7% (95% CI, 8.3%-49.6%). As of March 2018, one remaining pt is in long term follow up with an overall survival of 8.4 years. This pt was previously reported to have a secondary malignancy of myelodysplastic syndrome which has been in remission since receiving an allogenic bone marrow transplant in March 2014. Conclusions: HSA I-131 MIBG contributed to long term median survival of two years and was well tolerated. Treatment showed promising activity in the absence of significant nonhematologic toxicity.
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