Preclinical trials from the standpoint of clinical trials]

The establishment of reliable preclinical test is essential for the reasonable clinical trial. As a methodology for the screening of new active anticancer agents, disease oriented strategy using human tumor cell lines has been proposed in USA. The important questions in DOS are to determine the representative cell lines of specific cancer and it is also extremely important to decide the numbers of cell lines used for the screening. CPT-11, topoisomerase I inhibitor, developed in my country has been demonstrated to be active against lung cancer cell lines compared with mice tumors such as S-180 and P-388. However, no compound is demonstrated to be clinically active so far by this methodology. The criteria for the application of clinical trial are obscure and each drug company decides empirically by themselves. We have proposed to use PEI (predictive efficacy index) for the prediction of antitumor activity of new compounds. The clinical effect of new platinum analogue well correlated with this value. We have conducted phase II trial of 5-FU + LV against NSCLC without no prior chemotherapy. No responder was observed in the trial. Augmentive effect of leucovorin on the cytotoxicity of 5-FU and FdUrd was examined in vitro against NSCLC and colon cancer cell lines. Leucovorin stimulated the cytotoxicity of both drugs only against colon cancer cell lines. We tried to predict the response rate of new platinum derivative based on the data of bioassay of patient's serum administrated with platinum compounds. The predicted response rates of 254-S were 57-67% and 16-27% against SCLC and NSCLC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative clinical trials

The therapeutic advantages of a newly developed cancer chemotherapy should be evaluated in comparison with the standard (or control) treatment. Therefore the comparative clinical trials should be designed so that the only differences observed among treatment groups are directly made by treatment program. This requires comparability of patients throughout the trial. The preferred method of evaluation is randomized controlled trials which can eliminate conscious or unconscious bias in assigning treatment. Before patients are randomized into the treatments of the trial, it is advisable to stratify patients according to known prognostic factors (stratified randomization) in an attempt to achieve equal distribution of these factors within each stratum. There are many difficulties with historical control study in the conduct of the comparative clinical trials, and its use may be acceptable only when randomized controlled trials are not feasible. The method of administration of anticancer drugs, patient eligibility, response parameters, toxicity of anticancer drugs, size and duration of the study, and advantages and disadvantages of multi-institution trials were also discussed within the framework of the comparative clinical trials.