By the late 1970s, based on the studies of the National Surgical Adjuvant Breast Project (NSABP), the modified radical mastectomy had become the standard of care for localized breast cancer. In and of itself, this was a significant triumph for Bernie Fisher and his colleagues. However, as we discussed in last week’s article, there was accumulating anecdotal evidence to suggest that one could go even further and possibly dispense with the mastectomy altogether, instead resorting to variations on breast-conserving surgery, such as lumpectomy, possibly with whole-breast radiation therapy. This approach would be consistent with the theoretical ideas that Fisher and his brother believed regarding how breast cancer spreads from the primary site.
As with the prior study, and perhaps even more so, this idea of abandoning the mastectomy altogether was met with even more opposition and opprobrium from the surgical community than the prior study had been. Resorting to lumpectomies was felt to be unethical and dangerous for patients so again, many surgeons and institutions refused to participate in any trial of this procedure.
Nonetheless, Fisher and the NSABP moved forward with Protocol B-06, which began in 1976 and recruited until 1978. This was a randomized trial with three arms. To be eligible, women had to have stage 1 or 2 breast cancer that was 4 cm or less in size (about 1.5 inches) and mobile. In addition, the breast had to be large enough so that the cosmetic effect after a lumpectomy would be acceptable. One arm of the trial received a total mastectomy. The second arm underwent resection of the tumor with enough normal tissue around it to ensure that the margins were disease-free. The third arm of the trial was the same as the second arm except that radiation therapy was administered to the breast within six weeks of the surgery. All three arms of the study underwent removal of the axillary lymph nodes as well.
When the study began, it initially used the conventional methodology for randomization. This consisted of explaining the study to eligible women, soliciting their informed consent, and then randomizing them to one of the three treatment arms after they had consented. This apparently proved to be unworkable; eligible women refused to sign consents and be randomized. Some women had strong feelings about wanting mastectomy, while others had strong feelings about wanting limited surgery, but none wished to be randomized to a procedure. While the investigators could have met their recruitment goals by allowing women to choose their treatment groups, this obviously would have resulted in so-called volunteer or selection bias (the factors behind a subject’s choice of treatment are likely to be associated with the outcome), which is the primary reason we do randomized trials—to eliminate this and related biases.
To deal with this problem, the statisticians came up with a unique methodologic approach, pre-randomization. Rather than obtain the informed consent first and then randomize, the study staff would identify an eligible woman and randomize her first. Then when they approached the woman to inform her about the study and solicit her consent, they would already know which arm of the study she had been assigned to. Thus, when they requested consent, they could tell the patient that she was to undergo mastectomy or lumpectomy as part of the study. By doing it this way, most of the women were willing to sign the informed consent and the study was thus able to go forward smoothly and complete its recruitment goals.
In the end, 2,163 women were randomized and assigned to one of the three arms of the trial. In the New England Journal of Medicine article published in 1985, it was reported that the five-year disease-free and overall survival was the same for those undergoing mastectomy as for those undergoing limited surgery. Radiation therapy did reduce the occurrence of local recurrence though the overall survival was the same as for the other two arms.
Later follow-up studies with longer follow-up confirmed these results. It is difficult to express what a milestone achievement this study was and how profound an effect it had on the treatment of breast cancer. This study and its results led to significant changes, of course, in how breast cancer is managed. There are certain circumstances clinically that require the use of mastectomy—large tumors, poor cosmesis, the presence of satellite lesions, extensive ductal carcinoma in-situ, etc. But otherwise, women most often have the option of choosing the surgical procedure they wish. And what do they choose? The majority do choose the more limited surgical procedure while a small fraction opt for mastectomy, perhaps out of traditional fears or just not wishing to have concerns.
In any event, this study was a groundbreaking contribution by Bernie Fisher and the NSABP and its impact and ramifications have reverberated to this day.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
