Although axillary lymph node dissection (ALND) remains the gold standard for breast cancer patients with a tumor-involved sentinel node, its effect on survival remains controversial. Equally controversial are the results of the American College of Surgeons Oncology Group Z0011 trial (ACOSOG Z11), which showed statistically significant non-inferiority for sentinel node biopsy alone vs. ALND for patients with limited nodal disease.
While some institutions have already embraced the findings from Z11, others are hesitant to incorporate practice changes without additional evidence. Two of the study's lead authors, Pat Whitworth, Jr., MD, FACS, and Peter Beitsch, MD, FACS, discuss the significance of the trial, its surrounding controversy and what it could mean for the future of breast cancer management.
What do the results of the Z11 trial reveal about the need for axillary lymph node dissection (ALND) in breast cancer patients who have tumor-involved sentinel lymph nodes?
Dr. Pat Whitworth, Jr.:
ACOSOG Z11 showed that, for patients having breast conservation treatment, sentinel node biopsy alone was non-inferior (p<0.01) compared to completion axillary dissection for those with one or two positive nodes (grossly positive or micro-metastases). These patients do not need further specific axillary treatment (completion dissection or radiation) if they are having standard breast conservation therapy (partial mastectomy/lumpectomy and whole breast radiation). Currently node positive patients are not considered candidates for APBI unless they are on the NSABP/RTOG protocol.
What impact will the results have on how surgeons manage these patients?
Dr. Peter Beitsch:
Before the advent of sentinel node biopsy essentially all women with invasive cancer had to have a complete axillary lymph node dissection. Then David Krag published his landmark multicenter sentinel lymph node trial in the NEJM in October 1998. Almost overnight,sentinel lymph node biopsy replaced complete dissection for the approximately 70% of women who do not have spread of breast cancer in their sentinel nodes. Now with Z11, women with one or two positive nodes (approximately two-thirds of the node positive patients) can be spared a complete dissection. So in the course of less than 15 years, we have gone from 100% of women with invasive cancer having a complete dissection to around 10% - that is tremendous progress in lessening the morbidity of breast cancer surgical treatment.
Dr. Whitworth:
In addition to foregoing completion ALND, surgeons implementing changes supported by the conclusive findings from ACOSOG Z1011 will change practice in several practical ways. For example, I understand the group at Memorial Sloan Kettering has stopped doing preoperative ultrasound-guided FNA biopsy of lymph nodes unless more than two appear abnormal. They have stopped performing intra-operative frozen section unless more than two nodes appear grossly abnormal.
Can you explain some of the controversy surrounding the Z11 trial?
Dr. Beitsch:
One of the main problems critics cite is that the study did not reach its accrual goal. The accrual goal was, in fact, not met; however, the study was statistically significant for non-inferiority. This means that the study actually needed fewer patients to reach a statistical significance than we initially thought. Therefore the likelihood that adding even twice as many patients (the original accrual goal) was extremely unlikely to change the conclusion.
Dr. Whitworth:
Achieving planned statistical power, i.e., planned accrual numbers, is only critical if a study yields a non-statistically significant result (this was the case with NSABP B04 and B06). Otherwise the non-significant finding might be a result of too few observations and therefore might miss an important difference or equivalence.
There are also some other common misconceptions that need to be addressed. Some surgeons have begun a policy of trying to remove three sentinel nodes in all cases out of concern that the study suggests a critical difference between two nodes versus three nodes. In reality, the average number of sentinel nodes removed in the study was two - no effort was made to remove three. It seems best to follow the study design to achieve the equivalent outcomes seen in the study.
Will there always be a certain subset of patients who require ALND? If so, what characteristics define this group of patients?
Dr. Beitsch:
I believe that axillary dissection for breast cancer will be reserved for grossly positive lymph nodes that are not able to be controlled with targeted chemotherapy. This will be a diminishingly small group of patients.
Dr. Whitworth:
I agree. There may also be other small subsets defined by emerging molecular/biological assays or neoadjuvant regimens demonstrating resistance to systemic agents. Presently node positive mastectomy patients are still considered a subset where axillary dissection may be important for survival.
Although patients on the Z11 trial all received whole breast radiation, is it ever suitable to eliminate ALND for node-positive patients who receive partial breast radiation?
Dr. Beitsch:
Partial breast irradiation in women with positive lymph nodes is controversial. There are really two questions. First, does tangential field ('high tangents') whole breast irradiation 'control' the other non-sentinel lymph nodes in the axilla? There is no current data available to determine the effect of 'high tangents' on the control of axillary lymph nodes. We are currently going back to the treatment plans of the patients in Z11 to try to tease out the effect of 'high tangents'(if there is any effect at all).
Second, should we be doing partial breast irradiation in women with positive nodes (even if they have a complete dissection) due to the intramammary lymphatics potentially harboring cancer cells that would be left untreated? There is a small amount of data on APBI in patients with positive nodes. The American Society of Breast Surgeons' MammoSite Registry has 22 patients (out of 1449 cases) with positive nodes treated with single lumen balloon brachytherapy. There have been no breast or axillary recurrences in these patients. Clearly more data is needed - which we should get in NSABP B39 in the next 5-10 years - but it is at least a little reassuring that even in positive node patients that whole breast irradiation may not be necessary to 'treat the intramammary lymphatics'.
How comfortable are physicians with eliminating ALND for node-positive patients? Is this becoming an increasingly accepted standard, or do a majority of surgeons feel more research is required before they change the way they practice?
Dr. Beitsch:
As with many radical changes (mastectomy to lumpectomy, for example), there tends to be slow adoption despite the potential benefits of decreasing the morbidity of breast cancer treatment. The 'true believers' will adopt quickly but more studies and data is needed before the majority of surgeons feel comfortable eliminating complete axillary dissection for women with one or two positive lymph nodes.
Dr. Whitworth:
It is extremely difficult for surgeons/oncologists to change practice when this means less aggressive treatment and the possibility of a bad outcome because of non-resected disease. Leading centers like Memorial Sloan Kettering, M. D. Anderson and UCSF have fully implemented the practices supported by the conclusive Z11 results. Informed patients will seek enlightened, state-of-the-art surgeons who implement these changes supported by level one evidence. But much like we saw with breast conservation, adoption of this improved care for women with breast cancer will proceed at an uneven pace depending on demographics.
Dr. Pat Whitworth is a breast surgeon oncologist, Director of the Nashville Breast Center and Associate Clinical Professor at Vanderbilt University. He has served as Vice Chair of the Breast Committee for the ACS Oncology Group, Chair of the Board of Directors for the ASBS and Chair of the Research Committee for the ASBS. Co-author of numerous articles on diagnosis, staging and therapeutic options in breast cancer, his research interests include translational molecular diagnostic and therapeutic clinical research as well as image-guided, minimally invasive surgical techniques for the diagnosis and treatment of breast cancer.
Dr. Peter Beitsch is a surgical oncologist in Dallas, Texas, and is Director of The Dallas Breast Center.He is well published in numerous peer reviewed journals, including New England Journal of Medicine, JAMA, Proceedings of the National Academy of Science and Annals of Surgical Oncology. His research interests includes molecular diagnostics, neoadjuvant therapy,lymphedema, oncoplastics/minimally invasive surgical techniques, and accelerated partial breast irradiation.He was the highest accruing surgeon in the American College of Surgeons Oncology Group Z11 study. In addition, he is Co-Principle Investigator of the ASBS MammoSite Registry for APBI. He is on the National Ultrasound Faculty of the ACS. He recently served on both the ASBS Board of Directors and the Executive Council of the SSO.