Evidence for Ethnic Differences in Cancer Drug Metabolism and Deposition: Potential Relevance for Clinical Trials and Practice

Asian vs. European Caucasian) may result in clinically relevant differences in the metabolism (activation or inactivation) of cytotoxic agents, increasing or decreasing the relative biological activity of a drug. In theory, such alterations in activity of an agent could lead to greater or reduced therapeutic efficacy or toxicity. Important evidence for the potential impact of such differences has been provided by the reported experience with combination chemotherapy in the management of extensive stage small cell lung cancer. A phase 3 randomized trial conducted in Japan that compared cisplatin plus either etoposide or irinotecan revealed an improvement in survival associated with the irinotecan-containing regimen [1] . However, a very similar study conducted in the United States failed to confirm the superiority of this regimen [2] . In fact, in the United States cooperative group study, the irinotecan program was revealed to cause substantially more gastrointestinal toxicity than observed with the etoposide-containing regimen. It was speculated that the striking differences in the outcome of these two studies (efficacy and toxicity) may have been related to genetic differences in the metabolism of irinotecan. Another study directly compared differences in the distribution of alleles of genes known to influence DNA For several reasons, there has been increasing interest by the pharmaceutical industry in the conduct of cancer trials across international borders and in multiple countries. First, the rapidly growing global economy has resulted in an ever-expanding market for anti-neoplastic agents. Second, the increase in the number of products requiring evaluation, including phase 3 randomized trials, necessitates larger patient populations willing to participate in such studies. And third, it is recognized that the costs of conducting clinical trials in developing countries may be substantially less than that associated with trials run exclusively in North America and Western Europe. While a number of benefits of this basic approach to oncologic drug development can be cited, including the ability to rapidly evaluate the potential clinical utility of an increasing number of anti-neoplastic agents in the pharmaceutical industry pipeline, an important assumption of this strategy has been called into question. In the conduct of clinical trials, there has been limited appreciation or concern for possible unique differences between populations (genetic and environmental) within the regions of the world participating in such studies that might influence outcomes. For example, well or poorly characterized genetic variations among relatively homogeneous ethnic groups (e.g. Received: July 29, 2011 Accepted: July 29, 2011 Published online: September 30, 2011 Oncology