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Razelle Kurzrock, M.D., Professor, Division of Cancer Medicine Phase I Program |
Robert S. Benjamin, M.D., Professor, Department of Sarcoma Medical Oncology |
Phase I trials are closely scrutinized and their ethics debated because of the many unknown factors participants face.
An often-repeated misconception is that the sole function of phase I trials is to find the right dose and to assess toxicity—that evaluation of clinical responses is not an objective. It is true that the design of phase I trials generally precludes the statistical assessment of response rates, but we think that describing responses is important. Indeed, almost all new anticancer agents approved in recent years by the FDA brought about objective clinical responses among patients in phase I trials. Even so, the ethics associated with phase I trials have been questioned, in part because the prospect for improvement is perceived as low.
A recent article by Horstmann et al.,1 however, shows that the chance of benefit is higher than previously reported. Indeed, 10.6% of patients with advanced cancer, for whom conventional options offered no hope, achieved a complete or partial remission; an additional 34.1% had either stable disease or a “less-than-partial” response. From this perspective, then, 44.7% of participants derived a benefit, since all patients had to have progressive cancer to qualify for a phase I trial. In addition, these trials have an impressive safety record, with less than 0.5% of the close to 12,000 participants dying of what could be drug-related toxicity.
Our clinical experience with patients with metastatic cancer who seek out clinical trials suggests that they want highly experimental therapy, even if the chances of a response are small, because their quality of life is improved by “not giving up.” Lobbying efforts for earlier access to experimental therapies for AIDS and breast cancer are further evidence that patients facing inevitable death may be less risk-averse than is the regulatory community. Indeed, in one trial that allowed fully informed patients to choose among doses of a therapeutic agent, 28% of patients chose the highest available dose.
Phase I trials are crucial for the development of new cancer therapies. Several phase I trials have proved so pivotal that they have changed the landscape of cancer therapy. Perhaps the most striking example is the phase I trial of imatinib mesylate for the treatment of chronic myelogenous leukemia, which yielded a 93% response rate. For most phase I studies, the response rate is considerably lower, but the benefit-versus-risk ratio is, nevertheless, favorable.
Reprinted from The New England Journal of Medicine 2005;352:930-932. Adapted with permission 2005. Copyright 2005 Massachusetts Medical Society. All rights reserved. 1Horstmann E, McCabe MS, Grochow L, et al. Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med 2005;352:895-904For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call the M. D. Anderson Information Line at (800) 392-1611 (in the United States) or (713) 792-3245 (in Houston and outside the United States).
Other articles in OncoLog, September 2005 issue:
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