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Earliest Cancer Trials May Offer Lower Risk But Lower Benefit
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Earliest Cancer Trials May Offer Lower Risk But Lower Benefit
Phase I clinical trials of new cancer drugs seem to have become safer in the last decade for the people with incurable cancer who participate in them. Unfortunately, the already low chance that participants will benefit from an experimental drug in the first phase of testing also has dropped, at least by traditional measures of effectiveness.
The risk-benefit ratio has improved for oncology patients in the earliest clinical tests of experimental drugs, according to the first systematic review of the risks and benefits of phase I trials in more than a decade. The study authors are (from left) Lee Squitieri, Elkan Halpern, Thomas Roberts, Bernardo Goulart, Jeffrey Clark, and their colleagues at Massachusetts General Hospital, MIT, and the Dana-Farber/Harvard Cancer Center. (Photo by Steve Gilbert)
The mixed news comes from the first systematic review in more than a decade of the risks and benefits of phase I oncology trials, which have been considered some of the riskiest medical research. The paper is published in the Nov. 3 Journal of the American Medical Association.
"One of my patients who is enrolled in a phase I clinical trial said these findings took his homeland security warning level down from red to yellow, which is a nice way of describing it," said first author Thomas G. Roberts, HMS instructor in medicine at Massachusetts General Hospital.
| "The question before researchers is how to improve patient benefits without a substantial increase in risk." |
In contrast, "the classic oncology patient who participates in phase I trials has incurable cancer and has exhausted standard therapy, but has preserved organ function and performance status, such as spending more than 50 percent of time out of bed, doing light housework, or going to work," Roberts said. On average, phase I participants have had three prior cancer treatment regimens fail.
In their review of 213 published trials with 6,474 patients, Roberts and his colleagues found the average 12-year fatality and response rates had not changed much from the previous two decades. But a closer look at the data showed treatment-related deaths decreased from 11 in 1,000 participants in the first three years of the study to fewer than 1 in 1,000 most recently. Over the same time, people whose tumors responded to the drugs fell from 62 in 1,000 enrolled patients to 25 in 1,000.
By drug classes, 80 percent of the treatment-related deaths occurred in the trials testing cytotoxic chemotherapy aimed at dividing cells, which kill normal cells along with cancer cells, while 20 percent occurred in trials of new biologic and selectively targeted agents. This indicator of lower toxicity bodes well for the new targeted drugs, which people will likely be taking every day for the rest of their lives, said Joseph Eder, HMS assistant professor of medicine and clinical director of experimental therapeutics at Dana- Farber Cancer Institute.
Adjusting Benefits and Risks
The study period--1991 to 2002--spans a time of major changes in cancer clinical trials, such as beefed up enforcement of laws protecting participants. In fact, Roberts can trace the origins of this study back 10 years, when he was a second-year HMS student interested in clinical research, and the first of several highly publicized deaths of people in clinical trials raised concern about the safety of subjects. The deaths felt personal. "The last thing you'd want is someone harmed in a clinical trial you designed," he said.While the new report seems to show progress on one front, it also shows a low chance for therapeutic benefit, which has long been the basis of ethical concerns.
"The question before researchers is how to improve patient benefits without a substantial increase in risk," write Eric Chen and Ian Tannock of Toronto's Princess Margaret Hospital in an accompanying editorial. Chen and Tannock describe the need for an updated design of phase I trials, which would determine whether the molecule is inhibiting its putative target and might allow each patient to receive a potentially effective dose.
Although most patients who participate in early-stage clinical trials of new cancer drugs do not receive a measurable benefit, physicians often enroll patients with some hope of fighting the cancer. About 5 percent of the time, the drugs will work to shrink tumors, at least temporarily.
"All new anticancer agents approved in recent years by the Food and Drug Administration demonstrated antitumor activity in phase I studies," write Chen and Tannock. In their study, Roberts and his colleagues report that 11 of the 136 tested drugs were approved by the FDA.
Roberts and colleagues controlled for publication bias, in which researchers are more likely to publish positive findings, but it would only take a small number of unpublished studies with a relatively higher rate of toxic death to affect their conclusion, Chen and Tannock point out.
Measures of Success
The authors of both pieces agree that investigators need to apply new phase I trial designs that better suit the different tumor-fighting mechanisms of the targeted biological agents. In the new drugs, the optimal dose may be well below the maximum tolerated dose, Roberts said.The traditional measure of whether a cancer drug is working or not--a tumor that has shrunk by 50 percent, for example--may not apply to the newer drugs that may work instead to prevent the tumor from growing larger, said Eder, whose group specializes in discovering other meaningful biomarkers to measure antitumor drug activity. In another design improvement, Roberts noted that the trials that allowed investigators to escalate doses in patients had a better response rate in his study.
--Carol Cruzan Morton