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Bernard Fisher Reflects on a Half-Century's Worth of Breast Cancer Research

Kate Travis

Bernard Fisher, M.D., past chairman and scientific director of the National Surgical Adjuvant Breast and Bowel Project (NSABP), is widely credited with bringing clinical trials and statistical methodology to breast cancer research. Those efforts led to the elimination of the Halsted radical mastectomy, a severely disfiguring procedure that had been the standard breast cancer treatment for decades.



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Bernard Fisher, M.D., is widely credited as the driving force that brought clinical trials and statistical methodology to breast cancer research.

 
Fisher's involvement in breast cancer research began with a telephone call in the fall of 1957 from I. S. Ravdin, M.D., Fisher's mentor at the University of Pennsylvania. Ravdin had recently been appointed chairman of the Clinical Studies Panel of the Cancer Chemotherapy National Service Center at the National Institutes of Health. In the spring of 1957, he invited Fisher and 22 other surgeons to meet at Stone House on the NIH campus to discuss the creation of the Surgical Adjuvant Chemotherapy Breast Project, which would later become the NSABP.

"I informed him that I was more interested in continuing my laboratory investigations related to liver regeneration than in conducting breast cancer studies," Fisher said. "However, when someone who had been a two-star general and chief of the China–Burma–India Theater of Operations during World War II and who had operated on President Eisenhower gives a command, you obey. I felt compelled to go to Stone House."

Fisher had spent the previous 15 years in the laboratory studying liver regeneration, hypothermia, and transplantation biology. The meeting at Stone House was his first exposure to clinical trials, a relatively recent innovation. (The first randomized clinical trial, conducted by Austin Bradford Hill on the use of streptomycin for tuberculosis, had taken place less than a decade earlier in 1948.) Although Fisher wasn't immediately interested in doing a clinical trial in women with breast cancer, he became interested in the subject of tumor metastasis as a result of the meeting at Stone House.

In the decades that followed, Fisher's research on metastasis provided the basis for many of the hypotheses later tested in NSABP trials. "My desire to relate science to clinical medicine changed my life," Fisher said. Likewise, some 600 published papers and book chapters later, Fisher's research has changed the course of breast cancer treatment.

In this issue of the Journal, Fisher and his colleagues (p. 1652) present the 7-year follow-up of the Breast Cancer Prevention Trial (P-1), one of NSABP's most prominent clinical trials. During an interview in October at his office at the University of Pittsburgh, Fisher discussed some of his laboratory research, his experiences with clinical trials, and other topics.

What was the standard treatment for breast cancer when the first clinical trials began?

For more than the first half of the 20th century, surgery was the only treatment for breast cancer. During that time, there was uniform agreement about breast cancer treatment. Disagreement related to whether or not surgery should be more radical. Improvements in anesthesia and blood transfusions made it possible for surgeons to perform more extensive operations. That was the state of affairs when I received my invitation to come to Stone House.

The first randomized clinical trial evaluating the use of systemic therapy for the treatment of breast cancer was begun in 1958. At that time, researchers theorized that women died of breast cancer despite radical surgery because tumor cells were dislodged during the operation. It was believed that the dissemination of those cells resulted in metastasis and subsequent death. In that study, more than 800 women were treated with radical mastectomy either with or without perioperative thiotepa, an alkylating agent.

Despite the fact that thiotepa was used in almost homeopathic doses, patients experienced some undesirable side effects that led surgeons to be reluctant about using such therapy. The study did, however, demonstrate for the first time that systemic therapy could perturb the natural history of women with breast cancer.

Why did you challenge the idea that more expansive surgery was better than less extensive surgery?

From 1959 to 1984, I conducted laboratory investigations related to tumor metastasis. For more than 10 years, we conducted a multitude of investigations regarding the biology of tumor metastasis. From those laboratory studies, we formulated an alternative hypothesis—that breast cancer was a systemic disease in that tumor cells were likely to have been disseminated throughout the body by the time of diagnosis and that more expansive locoregional therapy was unlikely to improve survival. As a consequence, less radical surgery was likely to result in similar outcomes to those obtained following radical mastectomy. In 1971, we received about $200,000 to conduct the NSABP B-04 clinical trial. In that study, patients were randomly assigned to receive a Halsted radical mastectomy, a total (simple) mastectomy, or a total mastectomy followed by radiation therapy. In the 25-year follow-up of that study which was published in 2002 in the New England Journal of Medicine, the results from B-04 continued to indicate that there was no difference in overall survival, disease-free survival, or survival among the three groups of women.

What led you to realize that a randomized clinical trial was needed to test that hypothesis?

As a consequence of my laboratory research, I became familiar with the scientific method—the need for proper controls, the use of statistics, and other elements that contributed to a scientific gestalt. I looked upon clinical trials as an extension of my laboratory, and I appreciated that they could be used as a methodology for testing hypotheses. Until their use, anecdotalism was the primary source of information for determining treatment strategies. Consequently, using clinical trials to evaluate our alternative hypothesis seemed appropriate not only for evaluating the worth of radical mastectomy versus total (simple) mastectomy but also for determining the worth of lumpectomy.

Was there resistance to the lumpectomy trial?

When the lumpectomy trial began, it certainly wasn't popular. For 50 years surgeons had been trained to do radical surgery. They felt that performing the lumpectomy was totally inappropriate. At that particular time, my peers were my antagonists. The public did not participate in those controversies. It was difficult to get doctors to put patients into the trials, and, as might have been anticipated, it was even more difficult to persuade women to be randomized to a study in which some of them would undergo mastectomy and others would have their breasts preserved.

Did many of the clinical trials you conducted originate from biological hypotheses?

Almost all of our trials were examples of translational research. Even those that failed to yield positive findings were testing hypotheses that were formulated from laboratory findings. For example, we conducted a trial to compare the use of chemotherapy with or without the immunomodulator Corynebacterium parvum in operable breast cancer. The findings from our laboratory studies were highly positive. The use of C. parvum dramatically decreased tumor growth in experimental animals. Although the trial failed to demonstrate a benefit in patients, it was based on laboratory studies and not upon an epiphany. Unfortunately, I think that today too much of the latter gives rise to many of the studies that are being done.

How did the Breast Cancer Prevention Trial get started, and was there any resistance to the study?

In 1985, we submitted a grant application for conducting a prevention study based on the observation that less contralateral breast cancer occurred in women who received tamoxifen. That application was rejected. In 1991, the National Cancer Institute decided that it was appropriate to carry out a prevention study. The NCI put out a request for proposals. That action resulted in intense competition. At the same time, such a study was being opposed for a variety of reasons.

Much of the resistance came from groups that were anxious to test other modalities. Others challenged our risk-assessment strategies, as well as other aspects of the trial. For example, some felt that it was inappropriate to include women under age 50. It seemed to me, however, that, should tamoxifen be proven to be an effective agent, the drug might be even more effective in younger than in older women. In the end, we did include younger women in the study. Still others opposed our proposal for different reasons. For example, supporters of using a low-fat diet for breast cancer prevention were against our trial.

Even after we received the grant in 1992, some women's-interest groups expressed considerable antagonism against the trial. Reports of many of the toxicities from tamoxifen were never proven; nevertheless, those reports created an aura of fear about the use of the drug for prevention.

What message has resulted from the P-1 update?

The current results support those from our original presentation and clearly emphasize that there are women at increased risk for breast cancer for whom the benefits from tamoxifen far outweigh the risks. We show that, as the risk of breast cancer increases, the greater the number of breast cancers that can be prevented.

Has evidence-based medicine created a paradox?

When I began my career, I was attracted to the concept that, by application of the scientific method, opinion-based medicine would be supplanted by evidence-based medicine. Much to my dismay, I have found that as evidence-based medicine increases there has been a concomitant increase in opinion-based medicine. The increasing number of consensus conferences and the reliance on patient choice for selecting treatment support that thesis. That is an unfortunate circumstance.

What are the misperceptions about clinical trials?

Clinical trials are not research. Like an electron microscope or a flow cytometer, they are mechanisms for conducting research. The ideal clinical trial is one that tests a hypothesis. The strength of the thesis to be tested relates to its origins. The better the experimental evidence giving rise to the hypothesis, the greater the likelihood that the hypothesis will be supported by the findings obtained from the trial.



             
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