Section 4
Special Feature:Third Annual Lynn Sage Breast Cancer Symposium

BREAST CANCER CLINICAL TRIALS: DETECTING MODEST BUT HUMANLY IMPORTANT ADVANCES IN TREATMENT

The recently reported decline in breast cancer mortality in the United States and United Kingdom (Figures 1 and 2) has been attributed to multiple factors, particularly the increased use of screening mammography, adjuvant chemotherapy and endocrine therapy with tamoxifen.

Sir Richard Peto has estimated that in the United States alone, 10,000 fewer women a year are dying from breast cancer because of these advances, and he has predicted that over the next decade mortality rates will continue to decline, as established improvements in adjuvant systemic therapy are implemented in clinical practice.

Peto first proposed the concept of large scale clinical trials to detect modest but humanly important advances at the 1985 NIH Consensus Conference on Early Breast Cancer. In an initial public presentation of what was to become an ongoing series of key findings from an international meta-analysis of randomized clinical trials, the first Breast Cancer Overview revealed a sentinel groundbreaking finding about adjuvant therapy that had a profound effect on the structure of breast cancer clinical research.

Prior individual randomized studies had demonstrated that adjuvant tamoxifen improved disease-free survival, but no statistically significant impact on mortality was evident. Many observers concluded that adjuvant systemic therapy — particularly “cytostatic” endocrine therapy — would only delay recurrence without affecting the long-term outcome.

Peto noted that there are two potential reasons that clinical trial data fail to demonstrate an effect, such as mortality reduction:

1.The intervention has no effect on the outcome, e.g., adjuvant tamoxifen does not reduce breast cancer mortality.

or

2.The intervention does have the effect, but the data are not statistically powered to detect the effect, e.g., adjuvant tamoxifen does reduce mortality, but there were not enough events — in this case, deaths — observed in the individual trials to detect that effect.

The statistical mantra for this concept is: “The lack of evidence of an effect is not necessarily evidence of a lack of that effect. ”Specifically, researchers realized that one of the most salient features of research planning was to focus on the expected number of measured events, as opposed to just the size and follow-up of trials.

In what could be viewed as a classic moment in breast cancer medicine, Peto’s 1985 presentation demonstrated that combining the existing randomized individual trial data on tamoxifen into a meta-analysis revealed a clear-cut impact on mortality that was obscured by smaller trials with relatively few deaths. Increasing recognition of the importance of adequate statistical power in clinical trials has led to the evolution of large cooperative clinical research groups with the infrastructure to conduct studies with a sufficient number of events to detect moderate but important improvements in outcome.

In adjuvant trials, recurrences and deaths are usually key measured events, and for example, it became clear that for lower-risk study populations, more patients and longer follow-up would be required to observe an adequate number of these events. A fascinating footnote on this concept is the soon-to-be-reported ATAC adjuvant trial — perhaps the largest individual randomized study ever conducted in breast cancer — which has about ten times as many patients as the largest trial in the original tamoxifen meta-analysis reported by Peto in 1985.(Figures 3A,3B,3C)

The importance of breast cancer in the spectrum of current clinical research in oncology is demonstrated in Figure 4. This report from one of the leading cancer cooperative research groups demonstrates that about a third of patients entered in SWOG trials are women with breast cancer, despite the fact that only about 15% of all new cancer cases are people with this disease. Published reports of clinical trials also reflect the importance of breast cancer in oncologic medicine (Figure 5), and for example, the last 2000 San Antonio Breast Cancer Symposium included 437 scientific abstracts.

Physicians, nurses and other healthcare professionals caring for breast cancer patients should understand the background, rationale and design of these and other current randomized trials for several reasons:

1.Current trial designs provide insight into how research leaders interpret available research data on evolving treatment strategies.

The control arms of these studies are a commentary on what is considered “standard,” and the experimental arms provide clues as to what might be expected in the future.

2.Understanding the research questions being addressed prepares clinicians for the next generation of clinical trial results.

The evolution of independent external data monitoring committees sometimes leads to the seemingly precipitous dissemination of early trial results, which can be challenging to implement into clinical care unless there is prior familiarity with trial designs and objectives.

A good example was the sudden release in 1998 of initial data from NSABP P-1, the “Tamoxifen Prevention Trial.” Clinicians and researchers who were unfamiliar with the entry criteria and objectives for this study suddenly had to integrate a somewhat complex data set into clinical practice, but physicians who had participated in this trial were already well-positioned to understand its clinical implications.

3.All cancer patients deserve the opportunity to participate in clinical research.

A disappointing three percent of breast cancer patients are enrolled in clinical trials, although about half are interested in participation when asked. As noted by SWOG, enrollment of elderly women is particularly problematic.

Participation in clinical trials offers patients and physicians many well-documented advantages, including assurance that treatment and follow-up are state-of-the-art, and the gratification that comes with helping move the field forward.

Peto’s estimate of 10,000 lives saved annually means that every day, in the United States alone, about 25 women will be alive and well, who would have died without the seemingly modest but humanly important advances that have been made in diagnosis and treatment of breast cancer in the last two decades.

A closer look at the core of this encouraging trend is the emergence of large-scale randomized clinical trials that demonstrated the benefits of screening mammography and adjuvant systemic therapy. In essence, thousands of patients and healthcare professionals have together woven a new set of lifesaving standards through clinical research.

A decade or two from now,oncologists will likely be reading about the results of the current trials listed in this book and hopefully a new generation of patients will be alive and well as a result.

—Neil Love, MD

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