Iopromide for Contrast-Enhanced Mammography: A Systemic Review and Meta-Analysis of Pertinent Literature.

Background: Contrast-enhanced mammography (CEM) is an emerging breast imaging modality. Clinical data is scarce. Objectives: To summarize clinical evidence on the use of iopromide in CEM for the detection or by systematically analyzing the available literature on efficacy and safety. Design: Systematic review and meta-analysis. Data sources and methods: Iopromide-specific publications reporting its use in CEM were identified by a systematic search within Bayer's Product Literature Information (PLI) database and by levering a recent review publication. The literature search in PLI was performed up to January 2023. The confirmatory-supporting review publication was based on a MEDLINE/EMBASE + full text search for publications issued between September 2003 and January 2019. Relevant literature was selected based on pre-defined criteria by 2 reviewers. The comparison of CEM vs traditional mammography (XRM) was performed on published results of sensitivity and specificity. Differences in diagnostic parameters were assessed within a meta-analysis. Results: Literature search: A total of 31 studies were identified reporting data on 5194 patients. Thereof, 19 studies on efficacy and 3 studies on safety. Efficacy: in 11 studies comparing iopromide CEM vs XRM, sensitivity was up to 43% higher (range 1%-43%) for CEM. Differences in specificity were found to be in a range of -4% to 46% for CEM compared with XRM. The overall gain in sensitivity for CEM vs XRM was 7% (95% CI [4%, 11%]) with no statistically significant loss in specificity in any study assessed. In most studies, accuracy, positive predictive value, and negative predictive value were found to be in favor of CEM. In 2 studies comparing CEM with breast magnetic resonance imaging (bMRI), both imaging modalities performed either equally well or CEM tended to show better results with respect to sensitivity and specificity. Safety: eight cases of iopromide-related adverse drug reactions were reported in 1022 patients (0.8%). Conclusions: Pertinent literature provides evidence for clinical utility of iopromide in CEM for the detection or confirmation of breast cancer. The overall gain in sensitivity for iopromide CEM vs XRM was 7% with no statistically significant loss in specificity.

Sensitivity of Contrast-Enhanced Breast MRI vs X-ray Mammography Based on Cancer Histology, Tumor Grading, Receptor Status, and Molecular Subtype: A Supplemental Analysis of 2 Large Phase III Studies.

Background: The impact of certain tumor parameters on the sensitivity of imaging tools is unknown. The purpose was to study the impact of breast cancer histology, tumor grading, single receptor status, and molecular subtype on the sensitivity of contrast-enhanced breast magnetic resonance imaging (CE-BMRI) vs X-ray mammography (XRM) to detect breast cancer. Materials and Methods: We ran a supplemental analysis of 2 global Phase III studies which recruited patients with histologically proven breast cancers. The sensitivity of CE-BMRI vs XRM to detect cancer lesions with different histologies, tumor grading, single receptor status, and molecular subtype was compared. Six blinded readers for each study evaluated the images. Results were summarized as the "Mean Reader." For each reader, sensitivity was defined as the proportion of detected lesions vs the total number of lesions identified by the standard of reference. Two-sided 95% confidence intervals were calculated for within-group proportions, and for the difference between CE-BMRI and XRM, using a normal approximation to the binomial distribution. Results: In 778 patients, 1273 cancer lesions were detected. A total of 435 patients had 1 lesion, 254 had 2 lesions, and 77 had 3 or more lesions. The sensitivity of CE-BMRI was significantly higher compared with XRM irrespective of the histology. The largest difference was seen for invasive lobular carcinoma (22.3%) and ductal carcinoma in situ (19%). Across all 3 tumor grades, the sensitivity advantage of CE-BMRI over XRM ranged from 15.7% to 18.5%. Contrast-enhanced breast magnetic resonance imaging showed higher sensitivity compared with XRM irrespective of single receptor expressions (15.3%-19.4%). The sensitivities for both imaging methods were numerically higher for the more aggressive ER- (estrogen receptor), PR- (progesterone receptor), and HER2+ (human epidermal growth factor receptor 2) tumors. Irrespective of molecular subtype, sensitivity of CE-BMRI was 14.8% to 18.9% higher compared with XRM. Conclusions: Contrast-enhanced breast magnetic resonance imaging showed significantly higher sensitivity compared with XRM independent of tumor histology, tumor grading, single receptor status, and molecular subtype.Trial Registration: ClinicalTrials.gov: NCT01067976 and NCT01104584.

Phase 1, open-label, dose-escalation study of sorafenib in combination with eribulin in patients with advanced, metastatic, or refractory solid tumors.

Combining sorafenib and eribulin mesylate may provide synergistic antitumor activities with limited overlapping toxicities. This phase 1b, open-label, dose-escalation study evaluated safety, pharmacokinetics, maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), and preliminary efficacy of sorafenib plus standard-dose eribulin mesylate in patients with advanced, metastatic, or refractory tumors. Patients received sorafenib 200 mg twice daily (BID; n = 5), 600 mg/day (n = 8), and 400 mg BID (MTD; n = 27). Dose-limiting toxicities were increased alanine aminotransferase and acute coronary syndrome (both grade 3) in the 400-mg BID dose-escalation and expansion cohorts, respectively. No significant increase in mean QTcF duration was observed with eribulin plus sorafenib versus eribulin alone; there were no drug-drug interactions. Five patients achieved partial response; 16 achieved stable disease. The combination of sorafenib and eribulin mesylate presented no unexpected safety concerns and no significant impact on QT/QTc intervals or drug-drug interactions. Sorafenib 400 mg BID plus standard-dose eribulin is the RP2D.

Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancers.

UNLABELLED: Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity. In this phase I trial we evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Nine patients enrolled before premature termination of the study. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Regorafenib had acceptable tolerability and minor pharmacokinetic interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. BACKGROUND: The combination of bevacizumab, an antiangiogenesis agent, with cytotoxic chemotherapy improves survival in patients with advanced nonsquamous non-small-cell lung cancers (nsNSCLCs). Regorafenib is an oral multitargeted kinase inhibitor with potent antiangiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. In this phase I trial we evaluated the safety, pharmacokinetics (PK), and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. PATIENTS AND METHODS: Chemotherapy-naive patients with advanced nsNSCLCs were treated with regorafenib 60 mg/d continuously and cisplatin 75 mg/m(2) with pemetrexed 500 mg/m(2) once every 21 days for up to 6 cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. RESULTS: Nine patients enrolled before premature termination of the study because of slow recruitment and a change in the development strategy of regorafenib by the study sponsor. Five patients experienced at least 1 treatment-related Grade 3 adverse event. No Grade 4 or 5 toxicity occurred. Five of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range, 1.5-15.1 months). Minor PK interactions between regorafenib and chemotherapy were observed. CONCLUSION: Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naive patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results.

Pharmacokinetics and safety of gadobutrol-enhanced magnetic resonance imaging in pediatric patients.

OBJECTIVES: This clinical study investigated the pharmacokinetics and safety of gadobutrol, a magnetic resonance (MR) imaging extracellular contrast agent, in pediatric patients aged 2 to 17 years. MATERIALS AND METHODS: In this open-label, multicenter study, patients scheduled for routine contrast-enhanced MR imaging of the brain, spine, liver or kidney, or MR angiography received a single intravenous injection of gadobutrol (0.1 mmol/kg/0.1 mL/kg). Patients were stratified by age groups (2-6, 7-11, and 12-17 years). Blood and urine samples were collected at prespecified time points and analyzed for gadolinium concentrations. Plasma data were evaluated by means of a nonlinear mixed effects model, and urine data were analyzed using descriptive statistics. In addition, the safety of gadobutrol was evaluated. RESULTS: A total of 130 patients (2-6 years, n = 45; 7-11 years, n = 39; 12-17 years, n = 46) were included in the final population pharmacokinetic analysis. Gadobutrol pharmacokinetics in children aged 2 to 17 years were adequately described by an open 2-compartment model with elimination from the central compartment. The median estimates (2.5th percentile, 97.5th percentile) of body weight-normalized total body clearance (L/h/kg) per age group were 0.10 (0.05, 0.17) for all ages, 0.13 (0.09, 0.17) in the 2 to 6 year age group, 0.10 (0.05, 0.17) in the 7 to 11 year age group and 0.09 (0.05, 0.10) in the 12 to 17 year age group. The body weight-normalized median estimates of total volume of distribution (L/kg) were 0.20 (0.12, 0.28) for all ages, 0.24 (0.20, 0.28) in the 2 to 6 year age group, 0.19 (0.14, 0.23) in the 7 to 11 year age group and 0.18 (0.092, 0.23) in the 12 to 17 year age group. Median gadolinium plasma concentrations at 20 minutes postinjection were simulated using the population pharmacokinetic model and ranged from 414 (13 kg subject) to 518 micromol/L (65 kg subject). Body weight was identified as the major covariate influencing the pharmacokinetic parameters of total body clearance and central volume of distribution. Age was not found to be an additional independent parameter. The median amount of renally excreted gadolinium was 77.0% of the administered dose within 6 hours postinjection, indicating that gadobutrol was renally excreted in this pediatric population aged 2 to 17 years. Gadobutrol was well tolerated, with drug-related adverse events of mild intensity reported for 8 (5.8%) of 138 patients. CONCLUSIONS: Observed differences in pharmacokinetics were attributed to body weight, with no additional independent effect of age. Thus, no dose adjustment from the standard dose of gadobutrol in adults based on body weight (0.1 mmol/kg) is necessary in pediatric patients aged 2 to 17 years. Gadobutrol was safe and well tolerated in the pediatric population in this study.