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

Incorporating Toxicity Grade Information in the Continual Reassessment Method

The Continual Reassessment Method (CRM) is a Bayesian method for estimating the Maximum Tolerated Dose (MTD) in Phase I cancer clinical trials. In the standard CRM a parametric model is assumed for the dose-toxicity relationship and prior distributions are chosen for the model parameter(s). Parameter estimates are updated sequentially after each patient using the dichotomized toxicity information obtained at that patient's treatment dose. Subsequent patients are then treated at the estimated MTD from the updated model. This approach to dose escalation has been shown to have significant advantages over standard dose-escalation procedures in that fewer patients are required and fewer patients are given doses that are likely to be ineffective. However, this procedure has been recently criticized because doses that are too toxic may also be recommended. We present a modification to the standard CRM in which ordinal toxicity grade information is incorporated into the estimation of the MTD u..