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Clinical decision-making in the absence definitive research data

Dr Mark Soloway and I shared the same elevator for more than a decade, and on occasion, we would exchange updates on our respective fields of prostate and breast cancer. One such encounter last fall particularly piqued my interest. Mark mentioned the preliminary results from the massive Early Prostate Cancer trials that evaluated the immediate use of the antiandrogen, bicalutamide. He was curious about medical oncologists’ reactions in the 1980s to similar evolving data on the adjuvant use of the antiestrogen, tamoxifen, in breast cancer.

In a series of subsequent lunch discussions, I reviewed with Mark the fascinating history of this paradigm-breaking oncologic research. My interest in adjuvant tamoxifen began as a faculty member in the division of medical oncology at the University of Miami. However, I gained a much different and unique perspective on this subject matter through a series of in-depth interviews with breast cancer research leaders that were part of a nationally distributed, continuing education audio series that I initiated in 1988. The production of Breast Cancer Update allowed me to observe firsthand both investigators and community physicians struggle in their attempt to apply what were often ambiguous trial results to daily patient care.

One of my first interviews was with Dr Michael Baum, a self-described “iconoclastic Brit,” who conducted several of the original tamoxifen studies. In the early 1980s, a number of individual trials demonstrated that tamoxifen reduced the recurrence rate when given immediately after primary surgery in women without evidence of distant disease. But at that time, no survival benefit was evident for tamoxifen, and oncologists hesitated to prescribe this intervention. Baum and others argued that the delay in appearance of metastases alone was sufficient reason to use this relatively nontoxic therapy and that the lack of a survival advantage was the result of insufficient events (deaths) in the database.

In 1985, Dr Baum and Oxford statistician, Richard Peto, conducted an international meta-analysis of all the existing randomized adjuvant tamoxifen trials. Now with sufficient events (deaths) to analyze, this meta-analysis clearly demonstrated that adjuvant tamoxifen led to a significant reduction in mortality. In 2002, adjuvant tamoxifen is the standard of care for most women with invasive breast cancer. Peto — who later was knighted for this groundbreaking research — recently estimated that in the United States alone there are approximately 10,000 fewer breast cancer deaths each year, mainly as a result of the widespread use of this treatment approach.

Dr Soloway was surprised to learn that 5 years of adjuvant tamoxifen has now been demonstrated to reduce the risk of developing metastases by about 50% and has been associated with about a one-third reduction in mortality. One obvious critical question in prostate cancer is whether immediate endocrine therapy may eventually prove to have similar benefits. Clearly, breast and prostate cancer are different diseases with some similarities, and the role of early endocrine therapy is only one of numero u s prostate cancer management questions that urologists and radiation therapists struggle with every day.

Having lived through the challenges of conducting the classic randomized trials comparing lumpectomy to mastectomy, I admire and empathize with investigators launching the American College of Surgeons’ SPIRIT trial that will compare radical prostatectomy to interstitial radiation therapy. To answer another key question challenging the urology and radiation oncology community, large cooperative group trials are randomizing high-risk patients to adjuvant androgen deprivation with or without chemotherapy. Certainly, breast cancer research has established that large - scale, well-designed and conducted randomized clinical trials are critical elements to cancer control. Most oncologists attribute the recent 22% reduction in breast cancer mortality to the widespread implementation of the modest but humanly important benefits that have been defined by randomized studies.

In the interim, during this “period of uncertainty,” prostate cancer patients and their physicians must make decisions about both local and systemic therapy based on what a re often provocative but less than definitive clinical trial results. Through our conversations, Mark and I began to see the potential benefit of launching an audio series like Breast Cancer Update that would provide urologists and radiation oncologists access to the opinions and experiences of prostate cancer research leaders. The success of our breast cancer audio series — more than 75% of oncologists are regular listeners — is based on the interest we all have in hearing research “mavens” describe new frontiers in cancer treatment and provide insights into what these strategies mean to patient care. Through Prostate Cancer Update, it is our intent to p rovide balanced perspectives and insights from clinical investigators at the cutting edge of this exciting field.

This inaugural issue reflects our interest in addressing not only the science but also the art of prostate cancer decision-making. Dr Paul Schellhammer — a faculty member who was invited because of his many contributions to prostate cancer clinical research and patient care — shares with us his own personal experience with the disease. Dr Schellhammer’s comments reflect what we all know — that it is very challenging for a healthcare professional to understand the thoughts and feelings of a cancer patient. In future issues of this audio series, a research initiative on the perspectives of prostate cancer patients will be described. At that time, Mark and I will solicit your participation in this innovative project.

Looking back at the evolution of breast cancer clinical research, we can predict that in perhaps ten years there will be clear-cut answers to the current controversies in prostate cancer management such as the role of radical prostatectomy compared to interstitial radiation, the best time to use hormonal therapy and the role of chemotherapy. Until that time, clinicians and patients will struggle every day to arrive at optimal individualized decisions. Eventually, today’s difficult choices will be replaced with a new generation of controversies in the continuous cycle that defines contemporary cancer medicine.

— Neil Love, MD

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