Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials.

Context: In the past, cancer patients entering phase 1 studies confronted the prospects of high risk and unlikely 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 is unknown.

Objective: To determine trends in the rates of treatment-related (toxic) death, objective response, and serious toxicity and to identify factors associated with these outcomes.

Data Sources: We 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.

Study Selection: We focused on published single-agent trials that enrolled patients with advanced solid tumors and excluded studies testing agents already approved by the US Food and Drug Administration at the time of the ASCO presentation.

Data Extraction: Multiple observers independently extracted information on trial design, location, sponsorship, types of tumors treated, drug class, route of administration, and clinical outcomes.

Data Synthesis: The overall toxic death rate for 213 studies (involving 6474 cancer patients) published in peer-reviewed journals was 0.54%, while the overall objective response rate was 3.8%. Toxic death rates decreased over the study period, from 1.1% over the first 4 years of the study (1991-1994) to 0.06% over the most recent 4-year period (1999-2002) (P<.01). 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 (odds ratio, 0.09; 95% confidence interval, 0.01-0.67; P = .009). In comparison, the adjusted odds of a patient experiencing an objective response over the same time periods decreased by approximately half (odds ratio, 0.46; 95% confidence interval, 0.32-0.66; P<.001).

Conclusions: The level of risk experienced by cancer patients who participate in phase 1 treatment trials appears to have improved over the 12-year period from 1991 through 2002. Because toxic death rates have decreased more quickly than have objective response rates, the ratio of risk to benefit may have also improved. These changes relate in part to the targeted and less-toxic nature of newer cancer drugs and are coincident with the increased attention that has been paid to the safety of clinical research over the time period we analyzed.