A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin)

Prolonged exposure to topotecan in in vitro and in vivo experiments has yielded the highest antitumor efficacy. An oral formulation of topotecan with a bioavailability of 32-44% in humans enables convenient prolonged administration. Pharmacokinetic/pharmacodynamic relationships from four Phase I studies with different schedules of administration of oral topotecan in 99 adult patients with malignant solid tumors refractory to standard forms of chemotherapy were compared. Topotecan was administered as follows: (a) once daily (o.d.) for 5 days every 21 days (29 patients); (b) o.d. for 10 days every 21 days (19 patients); (c) twice daily (b.i.d.) for 10 days every 21 days (20 patients); and (d) b.i.d. for 21 days every 28 days (31 patients). Pharmacokinetic analysis was performed in 55 patients using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic me

The evaluation of cytotoxic drugs

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The cardiotoxicity of anticancer agents

It is clear from this review that a number of the antineoplastics cause or are associated with cardiotoxicity. Cardiotoxicity is not uncommon with the anthracyclines, but is rare for most of the other antineoplastics. With the use of anthracyclines earlier in patients' illnesses and in particular in adjuvant situations the clinical investigator must be constantly aware of the possible cardiotoxicity of those agents. Improved methods to detect cardiotoxicity before it is clinically apparent are sorely needed, particularly for this adjuvant group. The possibility of a chemotherapy induced cardiac disorder should always be entertained in the patient with cancer who develops a cardiac problem. © 1982.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The delta and epsilon errors in the assessment of cancer clinical trials

The error probabilities α and β are widely used to compute sample sizes and to analyze results of clinical trials. These errors are, however, not the only probablities to consider when assessing results of clinical studies. The rate of false positive (δ) and false negative (ε) results allows one to determine if an experimental finding is likely to reflect the true situation in the population of interest. The δ error is generally high in randomized phase III and in early phase II clinical trials in cancer patients, whereas the ε error is relatively low in these settings. This is essentially due to the small probability of detecting a more effective treatment or a new chemotherapeutic agent active in cancer. The δ error could be considerably reduced by increasing the sample sizes and by restricting the allowance made for the α error, which should be set at a 1% level as a minimum requirement.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: Long-term survival from a phase III trial

Background: Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up. Methods: Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided. Results: The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P 5). Conclusions: These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer.SCOPUS: ar.jinfo:eu-repo/semantics/publishe