Research Leaders Comment on Breast Cancer Clinical Trials

Arguably one of the most important advances during the last 50 years has been the introduction of prospectively randomized controlled trials to clinical medicine. Such trials provide information about the natural history of a disease and evaluate the worth of a particular therapy.

Moreover, they allow for testing of biological hypotheses and, thus, provide a mechanism whereby the scientific method can be applied to clinical problem-solving....By replacing anecdotal information (which has influenced therapeutic decision-making in the past) with more credible and substantive data, clinical trials play a major role in transforming the practice of medicine from an art to a science.

...As a vital component of the “research chain” clinical trials are an essential link between the laboratory and the clinic, providing means for determining whether the use of laboratory findings in the treatment of patients is justified....Without trials, much of the scientific information currently being reported could not be evaluated for its therapeutic worth. When properly employed, clinical trials supply definitive information about the value of therapies before their widespread use.

Appropriately conducted trials require participation by investigators, clinicians and statisticians who adhere to standards that are just as exact as those used in laboratory experiments or in complex surgical procedures....Unfortunately, every study contains unknown factors that can also affect the findings, and to minimize their effect, every effort must be made to ensure that these putative factors are equally distributed among the groups of patients being compared.In clinical trials, this goal is accomplished through the process of randomizing large numbers of patients to eliminate any biases, overt or covert, that might influence the study findings.

—Bernard Fisher, MD
News from the Commission on Cancer
of the American College of Surgeons 1991;2(2).

The randomised controlled trial has become the gold standard for evidence-based medicine; through the unbiased comparison of competing treatments it is possible to accurately quantify the cost-benefits and harm of individual treatments. This allows clinicians to offer patients an informed choice and provides the data on which purchasing authorities can make financial decisions.

We, of course, subscribe to this view but also recognize this as a gross oversimplification of the power of the randomised controlled trial. The randomised controlled trial is the expression of deductive science in clinical medicine.

Not only is it the most powerful tool we have for subjecting therapeutic hypotheses to the hazard of refutation but also the biological fallout from such trials should allow clinical scientists to refine biological hypotheses.

Trials of treatments for breast cancer have, at least twice, contributed substantially to a paradigm shift in our understanding of the disease.

—Michael Baum, ChM, FRCS; Joan Houghton, BSc
Br Med J 1999;319:568-571.

There are thousands of randomized trials in the world, which will lead to “zigs and zags” in the data. And, the “zags” are probably the ones that are going to be the most noteworthy and the most emphasized in meetings, because they look odd. They look surprising. Why are you going to present your trial at a meeting? What, another tamoxifen trial? We’ve had about 50 or 60 of them already. Why present it? Because the results look unusual.

So if you take lots of trials and then pick out the ones where the results look out of line with the other ones, then you’re quite likely to have something that is misleading. And if you split the patients up in various ways and looked at each little subgroup of patients, you’re going to get something even more freaky in some subgroup or other. And then that will get picked up and emphasized, and everyone can write press releases and circulate them around, and you can finish up in the newspapers with your results. It’s not a good way to obtain reliable answers.

You’ve got to systematically bring together all the evidence in the world — look at it irrespective of what the individual study shows — see what the grand total looks like, and then you’ve got something reliable. We’ve seen too many trial results that are odd things, that prove to be evanescent. It happens again and again, and then the next trial that comes out points you in the opposite direction,and then you say, “Now what?” But if you put all of the trials together, then you get reliable knowledge. If you don’t,you don ’t.

—Richard Peto, FRS

OVERVIEW OF COOPERATIVE CLINICAL RESEARCH GROUPS

Through the Cooperative Group Program,the National Cancer Institute supports groups of researchers, cancer centers and community physicians across the country and in Canada and Europe. These groups conduct large, phase III clinical trials as well as smaller phase I and II clinical trials, cancer control and prevention trials. Each Cooperative Group within the NCI program is supported to continually generate new trials compatible with its particular areas of interest and expertise, as well as with national priorities for cancer treatment research. The development of large, multicenter trials for investigational agents allows the rapid accrual of patients while reducing the possible bias of studies carried out at a single or a few institutions.

The NCI currently lists 11 adult cancer cooperative groups, nine of which conduct breast cancer treatment trials. All the cooperative group trials are listed in NCI’s clinical trials database at http://cancernet.nci.nih.gov/trialsrch.shtml, which can be searched by research groups or specific trials. The Cancer Information Service (1-800-4-CANCER) also provides contact and eligibility information for all cooperative group clinical trials.

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