This year, more than 550,000 Americans will die from cancer, and this number is expected to increase as the population ages, according to background information in the article. Efforts to develop new therapies have never been greater. There are more than 550 phase 1 trials open to cancer patients in the United States at any given time, and the numbers are steadily increasing as more products of the biotech industry reach the clinic. Phase 1 clinical trials represent the first testing of an investigational agent in humans. The major objectives during phase 1 are to characterize the agent's toxicity profile and to determine a dose and schedule appropriate for phase 2 testing. Patients who chose to participate may experience significant risks with limited chance to benefit.
Over the last decade, cancer drugs under development have become more targeted, and the clinical research environment has become more scrutinized. The impact of these changes on the risks and benefits to patients who participate in phase 1 cancer trials has been unknown.
Thomas G. Roberts, Jr., M.D., M.Soc.Sci., of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues conducted a study to determine if trends in the rates of objective response, treatment-related death, and serious toxicity in phase 1 cancer trials have changed over time. The authors searched abstracts and journal articles reporting the results of phase 1 cancer treatment trials originally submitted to annual meetings of the American Society of Clinical Oncology (ASCO) from 1991 through 2002.
The researchers found that the overall toxic death rate for 213 studies (involving 6,474 cancer patients) published in peer-reviewed journals was 0.54 percent, while the overall objective response rate was 3.8 percent. Toxic death rates decreased over the study period, from 1.1 percent over the first 4 years of the study (1991-1994) to 0.06 percent over the most recent 4-year period (1999-2002). Response rates also decreased, but by proportionally much less. After adjusting for characteristics of the experimental trials and the investigational agents, the odds of a patient dying from an experimental treatment while participating in a trial submitted during the most recent 4-year period were less than one-tenth those of a patient participating in a trial submitted during the first 4-year period. In comparison, the adjusted odds of a patient experiencing an objective response over the same time periods decreased by approximately half.
"There are several potential explanations for the sharp decline in treatment-related deaths. First, almost half (47 percent) of the trials in our detailed analysis involved the testing of targeted/biologic agents, which tend to have more favorable toxicity profiles compared with the [toxic to cells] drugs that have dominated cancer drug development in the past," the authors write. "The introduction of better supportive care over the study period ... are likely to have played a positive role."
(JAMA. 2004; 292:2130-2140. Available post-embargo at www.jama.com)
Editor's Note: For funding and disclosure information, please see the JAMA article.
Editorial: Risks and Benefits of Phase 1 Clinical Trials Evaluating New Anti-Cancer Agents - A Case for More Innovation
In an accompanying editorial, Eric X. Chen, M.D., Ph.D., and Ian F. Tannock, M.D., Ph.D., of Princess Margaret Hospital and the University of Toronto, Ontario, Canada, emphasize the need for more innovation in the design of phase 1 clinical trials.
"With an ever-increasing number of molecular targeted agents entering clinical trials, end points based on changes in target expression, pharmacokinetics, and functional imaging should be incorporated into phase 1 studies," the authors write. "The appropriate dose for a molecular targeted agent is not necessarily the highest tolerated; it is the dose that effectively inhibits the molecular target in tumor cells. Unfortunately, recent reviews indicate that the majority of phase 1 studies continue to use traditional study designs, and toxicity remains the primary outcome measure for determining the recommended phase 2 dose."
"The study by Roberts et al is a timely reminder that investigators should be innovative in designing phase 1 studies. Only through these efforts will patient benefit be maximized, accrual increased, and effective new anti-cancer agents brought to clinical practice in a timely fashion," the editorialists conclude.
(JAMA. 2004; 292: 2150-2151. Available post-embargo at www.jama.com)