ABSTRACT
The NSABP B-06 study is the largest of the breast conservation trials and was initiated by Fisher in 1976 shortly after the Milan 1 trial had begun recruiting patients (18). Patients were randomized to wide local excision, wide local excision and radiotherapy, or modified radical mastectomy. An update of this trial with 20-year follow-up confirms that postoperative irradiation improves local recurrence-free survival and in particular rates of early local recurrence (19). Of note, distant disease-free and overall survival are similar in the three arms of the trial suggesting that residual cancer cells are a determinant of local failure but not distant disease. Though there was no effect of local recurrence on overall survival in node-positive patients, it was evident in node-negative patients that local recurrence was associated with a statistically significant reduction in disease-free and distant disease-free survival. This suggested that local recurrence might be a determinant of distant disease, but Fisher interpreted this in a different way:
“As far as survival is concerned there is no difference between local excision, local excision and radiotherapy and modified radical mastectomy; there is however a progressive decrease in local recurrence with more aggressive treatments. Local recurrence affects survival adversely, but because survival is the same with the various types of treatment, local recurrence is not the cause of, but simply an indicator of poor prognosis”
IPSILATERAL BREAST TUMOR RECURRENCE AS A MARKER OF POOR PROGNOSIS Despite great variation in rates of ipsilateral breast tumor recurrence (IBTR) within the NSABP B-06 trial, these did not translate into survival differences, and Fisher concluded that no causal relationship existed between IBTR and distant disease. Using a Cox regression model, IBTR was found to be the strongest predictor for distant disease and was considered to be a marker for increased risk but not a cause of distant metastases (3.41-fold increased risk; 95% CI 2.70-4.30). Thus according to this novel perspective, IBTR was an independent predictor of distant disease and marker of risk, but not an instigator of distant metastases. Though locoregional treatment in the form of surgery or radiotherapy may prevent or reduce the chance of expression of the marker, such therapy does not alter the intrinsic risk of developing distant disease. This interpretation of IBTR rather flew in the face of classical surgical dogma that emphasized the importance of careful technique and attention to surgical margins. Indeed, the development of local relapse tended to imply suboptimal and inadequate surgery. Fisher’s concept had potentially devastating consequences in terms of the surgical component of breast cancer management; according to Fisherian precepts, breast cancer could be managed by minimal surgical excision of the primary lesion in conjunction with systemic therapy. Though rates of local recurrence would be higher, overall survival would be unaffected. What is the purpose in “overtreating” patients with mutilating local excisions and radiotherapy to the breast to prevent local recurrence? Lesser forms of locoregional therapy at the outset would be less likely to eliminate a clinical marker of risk for development of distant disease. IBTR in these circumstances (if and when it occurred) would indicate the need for more aggressive treatment with systemic therapy to maximize survival.
