Faculty Bibliography

Advanced cancer, because of its accompanying tumor burden, complex adverse host effects, and cellular heterogeneity, will prove much more difficult to control successfully than grave infectious diseases such as tuberculosis. This will likely be so, even when moderately successful chemotherapy is or will be available. Nevertheless, prospects for improving current results are present through application of chemotherapy alone or in combination with other modalities. Important developments include not only the availability of an increasing number of effective drugs, but also a better understanding of drug pharmacology, prediction of tumor cell cytotoxicity, locoregional drug delivery, exploitation of interactions with other forms of local therapy, and delineation of immunologic factors in tumor control. The single, most likely contribution to a curative approach to cancer, however, is likely to emerge from the application of aggressive systemic treatment in the circumstances of minimal residual disease. This topic is covered elsewhere.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA; NSC-249992) is a new anticancer agent that has undergone extensive experimental investigation. Clinical trials have recently been initiated and current data suggest a wide spectrum of antitumor activity in human cancer.

This paper considers two-stage patient-accrual plans for phase II trials of anticancer drugs. The purpose is to identify the therapeutic level of drugs as either above or below a reference response rate. Using such a plan, decisions concerning the future disposition of drugs can be made more formally and objectively. The tables used to implement the plan are prepared for a 20% reference response rate, due to its wide acceptance in the design of phase II clinical trials.

Potential risk factors responsible for development of doxorubicin-induced congestive heart failure were examined through retrospective analysis of 4018 patient records. The overall incidence of drug-induced congestive heart failure was 2.2% (88 cases). The probability of incurring doxorubicin-induced congestive heart failure was related to the total dose of doxorubicin administered. There was a continuum of increasing risk as the cumulative amount of administered drug increased. A weekly dose schedule of doxorubicin was associated with a significantly lower incidence of congestive heart failure than was the usually employed every 3-week schedule. An increase in drug-related congestive heart failure was also seen with advancing patient age. Performance status, sex, race, and tumor type were not risk factors. These data will enable clinicians to better estimate the risk/benefit ratio in individual patients receiving prolonged administration of doxorubicin. They also provide a basis for the investigation of less cardiotoxic anthracycline analogues or for designing measures to prevent doxorubicin-induced cardiomyopathy.

The error probabilities alpha and beta are widely used to compute sample sizes and to analyze results of clinical trials. These errors are, however, not the only probabilities to consider when assessing results of clinical studies. The rate of false positive (delta) and false negative (epsilon) results allows one to determine if an experimental finding is likely to reflect the true situation in the population of interest. The delta error is generally high in randomized phase III and in early phase II clinical trials in cancer patients, whereas the epsilon 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 delta error could be considerably reduced by increasing the sample sizes and by restricting the allowance made for the alpha error, which should be set at a 1% level as a minimum requirement.

A statistical method for interpreting data on the efficacy of anticancer agents is proposed. Tables were prepared for the retrospective analysis of studies evaluating the activity of anticancer agents against individual tumor types. The number of responding patients and the number of patients entered in the study were used to more objectively and formally determine the future disposition of the drug. Several examples of clinical studies show that use of our tables allows a more satisfactory and reliable classification than is often currently reported.