Combinations of cytotoxic chemotherapy with estramustine phosphate (EMP), a nornitrogen mustard-estrogen conjugate, are used to treat patients with hormone-refractory prostate carcinoma (HRPC). ...However, thromboembolic events (TE), including deep venous thrombosis (DVT), pulmonary embolism, stroke, myocardial infarction, and arterial thrombosis, are significant toxicities of these regimens. The current study sought to establish the rate of TE and to determine risk factors for TE.
A MEDLINE-based search identified EMP-based clinical trials published in the English-language peer-reviewed literature after 1990 in which > or = 20 patients with HRPC were enrolled and TE were clearly documented. Patient characteristics and the dose of EMP given were analyzed to determine their association with the rate of TE.
Twenty-three studies, enrolling a total of 896 patients, were included in the analysis. The overall risk of TE was 0.07 (95% confidence interval 95% CI, 0.05-0.11). The risk of DVT was 0.06 (95% CI, 0.04-0.09). The risks of all other types of TE were <0.01. Using univariate logistic regression analysis, the dose of EMP administered, baseline patient age, and baseline prostate-specific antigen level were not found to be associated with the total risk of TE. The rates of total TE and DVT may be inflated because one of the analyzed studies initially had a very high rate of DVT (25%) when compared with the others.
The rate of TE in men with HRPC who are treated with EMP-based regimens is significant, but it does not appear to be related to the dose of EMP. Whether TE can be prevented with anticoagulant prophylaxis remains to be determined.
Purpose: DMP 840, a novel bisnaphthalimide, has demonstrated promising schedule dependent anti-tumor activity in vitro and in vivo against several tumor cell lines. A phase I study was conducted to ...evaluate the effect of a 24-hour infusion schedule repeated every three weeks, on the therapeutic efficacy of DMP 840. Patients and methods: Fourteen patients with refractory solid tumor malignancies were treated with DMP 840 at doses of 20, 40, 50 and 60 mg/m2. Results:A combination of neutropenia, thrombocytopenia and stomatitis were dose-limiting at doses of 50 and 60 mg/m2in both minimally- and extensively-pretreated patients. In contrast, all courses at lower dose levels were well tolerated. Pharmacokinetic analysis demonstrated that DMP 840 had a prolonged terminal half life (median 39 hours; range 25-86) and that dose-limiting events were significantly related to several indices of systemic DMP 840 exposure (P 0.01, Wilcoxon Rank Sum test). Conclusion:The recommended dose of DMP 840 for further disease oriented evaluations is 40 mg/m2 administered over 24 hours every three weeks. The infusion duration evaluated in this study did not result in a substantial increase in the tolerable dose compared to shorter, less cumbersome schedules.
In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified ...exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data.
PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m
Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis.
At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 95% confidence interval (CI): 0.57, 0.77. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival 0.63 (95% CI: 0.45, 0.89) and newly collected samples 0.53 (95% CI: 0.38, 0.72). In patients with TPS ≥1%, PFS HRs were similar across archival 0.82 (95% CI: 0.66, 1.02) and newly collected samples 0.83 (95% CI: 0.68, 1.02).
Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples.
ClinicalTrials.gov: NCT01905657.
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