Author Affiliations: Division of Hematology/Oncology,
Massachusetts General Hospital, Harvard Medical School, Boston, Mass (Drs
Roberts, Goulart, Chabner, and Clark); Program on the Pharmaceutical Industry,
Massachusetts Institute of Technology, Cambridge (Drs Roberts, Stallings,
and Finkelstein and Ms Squitieri); Institute for Technology Assessment, Massachusetts
General Hospital (Drs Roberts, Halpern, and Gazelle); Dana-Farber/Harvard
Cancer Center, Harvard Medical School (Drs Roberts, Chabner, and Clark).
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
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
Roberts TG, Goulart BH, Squitieri L, et al. Trends in the Risks and Benefits to Patients With Cancer Participating in Phase 1 Clinical Trials. JAMA. 2004;292(17):2130–2140. doi:10.1001/jama.292.17.2130
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