NCI Cancer Bulletin: A Trusted Source for Cancer Research NewsNCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 2, 2004 • Volume 1 / Number 42 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Mortality Risks Decline for Patients in Phase I Cancer Drug Trials

The risk of death related to treatment for cancer patients participating in phase I clinical trials has decreased over the past 12 years, according to a study published in the November 3 Journal of the American Medical Association (JAMA). Dr. Thomas G. Roberts, Jr., of Massachusetts General Hospital and Harvard Medical School and his colleagues analyzed data from abstracts and journal articles reporting early trial results originally submitted to annual meetings of the American Society of Clinical Oncology (ASCO) from 1991-2002.

The researchers reviewed data from 213 studies involving 6,474 cancer patients. The overall toxic (treatment-related) death rate was 0.54 percent; treatment-related death rates decreased over the study period from 1.1 percent over the first 4 years to 0.06 percent over the last 4 years. After adjusting for the characteristics of the experimental trials and investigational agents, the chances of a patient dying from an experimental treatment while participating in a trial in the last 4 years of the study period were less than one-tenth those of a patient participating in a trial during the first 4 years.

"This is an encouraging finding," said Dr. James Doroshow, director of NCI's Division of Cancer Treatment and Diagnosis and chair of the National Cancer Institute (NCI) Clinical Trials Working Group. "Almost half of the trials involved molecular targeted agents - another indicator of the potential of targeted therapies to improve outcomes while reducing the often debilitating toxicities of cancer treatment."

Phase I clinical trials represent the first tests of new investigational agents in humans. They are designed to evaluate an agent's safety, tolerability, and toxicity and determine doses and schedules appropriate for testing in phase II trials. A second goal of phase I trials is often to assess any therapeutic value gained from the agents being tested. This can be difficult in cancer trials because, unlike phase I trials in other areas of medicine that recruit healthy patients, phase I cancer trials generally enroll patients who have exhausted standard treatment options. The article notes the possibility that "patients with advanced cancer would accept higher risk if it were accompanied by higher likelihood of response." In this study, researchers found that the response rate declined during the 12-year study period - from 6.2 percent in the first 4-year period to 2.6 percent in the second 4-year period to 2.5 percent in the third 4-year period.

"Our principal finding - that phase I cancer trials appear to be safer, coincident with declining response rates - has important policy implications. A patient with cancer who is considering enrollment in the types of trials we analyzed may expect an improved level of safety compared with that expected by a patient enrolling just 10 years ago," the authors wrote. "Future work should focus on applying new phase I designs that would treat fewer patients at subtherapeutic drug levels, especially for trials testing targeted agents with little expectation of toxicity," they concluded.

"The study by Roberts et al., is a timely reminder that investigators should be innovative in designing phase 1 studies," wrote Drs. Eric X. Chen and Ian F. Tannock of Princess Margaret Hospital and the University of Toronto in an editorial in JAMA. Phase I studies, they continued, especially those involving targeted agents, should incorporate end-points based on target expression, pharmacokinetics, and functional imaging.

"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," they wrote. "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 II dose."