NSABP Protocols B-04 and B-06, Ushering in the Era of Breast Conservation

The radical mastectomy or Halsted mastectomy was the “standard of care” procedure for patients with operable breast cancer from the late 1800’s through the 1970’s. It consisted of an en-bloc resection of the breast, pectoralis muscles, as well as axillary contents. Despite being such a radical operation, it was clear that it was not curative of all patients. In fact, many patients with seemingly small tumors would go on to develop distant recurrences and breast cancer death.  Dissatisfaction from the radical and disfiguring nature of the operation began to grow by the mid to late 1960’s.

New insight into tumor biology and the nature of metastases, began to emerge.  The NSABP implemented protocol B-04. The aim of the study was to determine whether patients with either clinically positive or negative lymph nodes could achieve outcomes similar to radical mastectomy with less extensive surgery.

Clinically node negative patients (1079) were randomized to radical mastectomy, total mastectomy with radiation or total mastectomy alone. Node positive patients (586)were randomized to radical mastectomy or total mastectomy plus radiation. 

Five year results from the study were first reported in 1977 and 25 year follow-up was reported in 2002. There was no survival advantage to radical mastectomy in either the node negative or the node positive patients. And there was no survival advantage from the addition of radiation to simple mastectomy in node negative patients.

There was, however, a significant decrease in the cumulative incidence of local or regional recurrence in the node negative patients when radiation was added to total mastectomy. Whether or not radiation therapy leads to a survival advantage in patients undergoing mastectomy has been the subject of considerable debate and has called into question the validity of the Fisher hypothesis. The NSABP was vindicated, however, when in 2014 the EBCTCG meta-analysis (Oxford overview) with 20 year follow-up showed no survival advantage to the addition of radiation therapy to total mastectomy in node negative patients.

NSABP protocol B-06 enrolled 2163 patients from 1976 - 1984 and was designed to evaluate the efficacy of further minimal surgery. Total mastectomy was compared to lumpectomy with and without radiation in node negative or node positive patients.  All patients received low axillary sampling.

In B-06, no significant survival differences were found among the 3 groups at 20 year follow-up. The authors noted radiation was associated with a marginally significant decrease in breast cancer deaths, but this decrease was partially offset by an increase in deaths from other causes. Similar to the findings in protocol B-04, Radiation therapy was associated with a significant decrease in local or regional recurrence.

The authors pointed out that at the time B-04 was initiated, it was popularly believed that five years could be viewed as a milestone and that women who lived that long may have been considered cured.  Extended follow-up showed that 25% of first distant recurrences and 50% of contralateral cancers were detected after 5 years, indicating the need for more extensive long term follow-up, particularly in patients with an an apparent good prognosis. The authors also point out the need to distinguish between breast cancer related mortality and mortality from any cause, particularly at longer survival intervals.

References:

1. Fisher B, et. al.: Twenty five year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567-575, 2002
2. Fisher B, et. al.: Twenty year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347: 1233-1241, 2002
3. EBCTCG (Early Breast Cancer Trialists' Collaborative Group): Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383: 2126-2135, 2014