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Manage the Axilla with Z11 Data
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Editors' Bios
Pamela Benitez, MD
Dr. Benitez is a general surgeon
focusing exclusively on diseases
of the breast and breast cancer
at William Beaumont Hospital in
Royal Oak, Michigan
Martin Keisch, MD
Dr. Keisch is a board-certified radiation oncologist at University of Miami Hospital and President of Cancer HealthCare Associates (CHCA)
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Manage the Axilla with Z11 Data Pat Whitworth MD, Director, Nashville Breast Center, Clinical Associate Professor of Surgery, Vanderbilt University
Findings from the American College of Surgeons Oncology Group Z1011 trial have led many leading institutions to stop performing completion axillary dissection in breast conservation patients who have only one or two sentinel nodes with micro- or macro-metastases. As has been the case with all major practice-changing breast cancer clinical trials, "Z11" has been welcomed by some leaders in the field and rejected by others. As with the moves away from radical mastectomy after the NSABP B-04 trial and toward breast conservation with the NSABP B-06 trial, time will ultimately allow incorporation of the important findings from ACOSOG Z11 into common clinical practice. Already, leading institutions like Memorial Sloan Kettering Cancer Center, M.D. Anderson Cancer Center and the University of California San Francisco, to name just a few, have
incorporated practice changes based on the findings from Z11.
ACOSOG Z11 showed that, for patients having breast conservation treatment, sentinel node biopsy alone was non-inferior (p<0.01) to completion axillary dissection for those with one or two positive nodes (grossly positive or micro-metastases). Because Z11 was a randomized clinical trial, the results meet the highest level of evidence, "level one" for outcomes-based clinical practice. But Z11 is not free of controversy. It was stopped early, before meeting the 1900 patient accrual originally planned to provide 80–90% power to detect statistically significant non-inferiority. It was stopped for two reasons: first, accrual was consistently a few patients less than budgeted; second the outcomes were too good. The local-regional failure rate and the over-all death rate were so low, a choice between extending the study to achieve the event rates anticipated by the original design or simply stopping at around 900 patients had to be made. Fortunately for women with breast cancer, Z11 had already detected clinical non-inferiority (p=0.008) even though the chance of detecting statistically significant non-inferiority was only about 55% with the 891 patients who had been randomized. So Z11 was indeed "underpowered" based on the standard goal of 80–90% power employed in the planning and approval of clinical trials. Only good fortune and outcomes far more favorable than anticipated in both groups provided actionable statistical proof of non-inferiority.
Controversy about Z11 arises because, to the non-statistician, interpretation of the findings from a statistically significant non-inferiority study seems similar to interpreting findings from trials with a "superiority design" (like NSABP B-04 and B-06) where no statistical significance is found. However, power, or the likelihood of detecting
statistically significant superiority, is critical when interpreting statistically insignificant findings; not so when statistical significance is proven.
Why did patients in Z11 do so well? Two factors are cited most often. First, unlike in historical surgical trials, 97% of patients had systemic adjuvant treatment, endocrine or chemotherapy or both. Second, depending on body habitus, whole breast radiation reaches the level one axilla in over 50% of patients and level two in about 20%. Most agree that systemic treatment has changed the impact of axillary treatment; whether whole breast radiation is required in patients with positive nodes is the subject of ongoing and future clinical trials.
These findings and consequent changes in clinical practice apply only to standard breast conservation patients with one or two grossly (or less) involved sentinel nodes (without gross extracapsular extension). Such patients can safely forego completion axillary dissection. Changes in management of node-positive patients having mastectomy or accelerated partial breast irradiation await further study.
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