This trial demonstrates that overall survival, disease-free survival, and regional control were all statistically equivalent in sentinel node negative patients who had a completion axillary dissection or sentinel node surgery alone. The observed survival difference between the two groups was less than 2% and any variation observed under that threshold is not significant. Indeed, in a trial of this magnitude exact numerical duplication of events are not expected. There did appear to be a non-significant trend in favor of Group 1. In Group 1, 75 patients had at least one positive non-sentinel node and 95% of this subset was treated with systemic adjuvant therapy. The outcome of these patients was not inferior to the group as a whole (average annual mortality rate: 0.99% vs. 1.02% respectively) even though they were node-positive. In Group 2, a similar subset of non-sentinel node-positive patients was expected. Since their node-positive status was not known, their adjuvant therapy was likely to be similar to the remaining Group 2 patients (84%). This may have modestly contributed to the observed survival trend. Also, following a second non-breast cancer there were 37 deaths in Group 1 and 54 in Group 2. This apparently random event (as indicated by the inclusion of 1 in the HR confidence interval in ) in favor of Group 1 may have also contributed to the observed trend.
Disease-free survival was not different between the two treatment groups. Comparisons based on sites of first treatment failures also showed no significant differences across all sites. This data further confirms the similarity in outcomes between the two treatment arms.
Each treatment group had less than 1% regional recurrences as first events. Similar to several nonrandomized reports,16
the B-32 results confirm the low rate of regional node recurrences following sentinel node surgery. The B-32 trial also validates that when the sentinel nodes are negative there is no significant difference in regional node recurrence between axillary node dissection and sentinel node resection.
The results from Protocol B-32 confirm previous reports1
that patient-reported outcomes and morbidity related to range of motion, edema, pain, and sensory defects is lower in the sentinel node group compared with the axillary dissection group.5,6
Sentinel node surgery is not without complications and there is a small increase over baseline of extremity edema and functional and neurological deficits.
Randomized trials have been instrumental in effecting changes in the surgical management of breast cancer. One of the last major surgical trial that led to safe reduction of surgery, NSABP Protocol B-06, was initially reported in 1985.17
The long-standing importance of this trial is demonstrated by the current use of breast-conserving therapy as a major indicator of quality care.18
Sentinel node surgery represents the next major step in reducing the extent of surgical procedures to treat breast cancer.
The design of randomized trials for breast-conserving therapy and lymph node-sparing surgery are similar. The goals are to preserve tissue but still achieve the same cancer control. A reduction in morbidity is an obvious goal but the more challenging metric is demonstrating that survival is not adversely affected. The B-32 trial was designed so that even a 2% difference in survival would be detected. This narrow difference in survival was chosen to ensure that reduced morbidity would not occur at the expense of reduced survival. This required high total accrual and is why the B-32 trial is the largest randomized surgical trial in breast cancer yet performed.
One measure of quality in trial design is the clarity of the goals.19
The primary outcomes of B-32 were clearly stated and the trial was monitored regularly by an independent Data Monitoring Committee. Disclosure of trial results was allowed only when overall survival endpoints were met. Assessing narrow differences in the primary outcomes in such a large group of patients mandated careful control of the trial conditions. Patient factors in this trial were well controlled and balanced. This was further validated by the survival results which, when evaluated with all of the stratification variables combined, yielded no significant differences.
Potential imprecision was possible because of the complexity of surgical and pathological procedures. Variation was controlled by a careful preregistration training program that focused on protocol compliance.20
In addition, extensive auditing of enrolled cases evaluated 94 specific items per case. Of the 224 surgeons audited, the outcomes were excellent.4
The quality of the trial is further supported by the extent of follow-up information (99.9% of cases).
Other sentinel node trials include the American College of Surgeons Oncology Group trial Z0011 that randomized 891 patients with pathologically positive sentinel nodes to axillary dissection or sentinel node only.21
This study closed prior to meeting accrual goals. A trial from Milan has reported data with follow up to 10 years.22-24
The primary objective for the Milan trial was “the predictive power of the status of the sentinel node.” Explicit survival data comparing patients who were treated only with sentinel node resection do not appear to be present. The primary outcomes from the ALMANAC trial and the SNAC trials are morbidity, although these well-designed trials do not address survival.25,26
The AMAROS trial (EORTC 10981-22023) is another well-designed randomized trial comparing axillary surgery to sentinel node and radiation therapy with no further axillary surgery.27
The primary objectives for the AMAROS trial are local and regional control and morbidity.
Data combined from available randomized trials of axillary dissection versus no axillary surgery indicated a modest survival advantage to axillary dissection.28
Survival has also been significantly associated with the number of nodes removed.29
Sentinel node surgery is neither observation-only nor removal of suspicious nodes from a fixed anatomic location. It is a highly targeted removal of the lymph nodes receiving direct drainage from a solid tumor in the breast. The results from B-32 demonstrate that in the sentinel node-negative population, any survival advantage to full axillary dissection is fully mitigated by simply removing the sentinel nodes.
Surgeons should continue to strive to optimize the methods of sentinel node surgery. For example, removal of only a single sentinel node increases the risk for false-negative sentinel node resection. Improving methods to validate that the nodes removed are in fact on the immediate drainage pathway from the cancer is important.3
Life-threatening anaphylactic reactions related to dyes occur in approximately 0.25% to 0.5% of cases.30
Genotoxity of blue dyes in the form of DNA strand breaks and increased levels of oxidative DNA lesions have been reported after very brief exposure to cells in vitro.31
There are clearly unfinished areas of research in the field of sentinel node surgery.