The Z0011 trial has resulted in dramatic shifts in staging, as well as in decreased use of ALND, but are these changes too hasty?
Michael S. Sabel, MD, FACS
Over the past year, the field of breast cancer surgery has seen a dramatic shift with the results of the American College of Surgeons Oncology Group Z0011 trial.1 This study, which randomly assigned patients with sentinel lymph node (SLN)-positive breast cancer to SLN biopsy and axillary lymph node dissection (ALND) or to SLN alone, reported that ALND was not associated with any survival benefit and that both groups had an extremely low regional recurrence rate (0.9% for SLN alone and 0.5% for ALND). This was despite the fact that 27.3% of the patients who received ALND had additional positive nonsentinel lymph nodes.
This study confirmed what many surgical oncologists had suspected: ALND provided minimal benefit while exposing a substantial number of patients to long-term morbidity, specifically lymphedema.
Therefore, there was great interest in shifting away from routine ALND for patients with SLN-positive disease, instead reserving this operation for patients who did not meet the Z0011 criteria (i.e., patients undergoing neoadjuvant chemotherapy, patients with palpable nodes, patients having mastectomy, or patients with more than three involved nodes).
|Dr. Michael S. Sabel
However, one needs to question whether we too quickly abandoned ALND for the entire Z0011-eligible population. The problems with the Z0011 trial have been well documented and include the statistical design, statistical interpretation, failure to accrue adequate patients, and missing data.2
The surprisingly low rate of regional recurrence in patients who received only the SLN biopsy has led many to overlook these shortcomings.
There are two concerning unanswered questions, the first of which involves whether the axilla truly went untreated. Although the trial expressly prohibited direct regional irradiation, it is suspect that many radiation oncologists adjusted their tangential fields in order to cover a larger percentage of the axilla in patients whom they knew did not have an ALND. This may be why there were so few regional recurrences despite the knowledge that disease may have been left behind.
If this is the case, we should acknowledge that Z0011 was actually a study of axillary radiation therapy compared with axillary surgery, similar to the AMAROS trial that has now completed accrual.3 As surgeons, we must remember that our surgical decisions have important downstream effects. When we forego ALND in a patient with SLN-positive disease, the radiation oncologist is now put in the awkward position of needing to decide whether to use high tangential fi elds without the guidance of solid prospective trial data.
The more concerning issue is whether we are now applying the results of Z0011 to a group of patients who weren’t well represented in the trial. Looking at the patients in the Z0011 trial, there was clearly selection bias on the part of the participating surgeons. Surgeons readily accrued patients for whom they felt avoidance of ALND would not be clinically significant, while directing patients for whom they had increased concern for regional recurrence toward ALND.
This is reflected in the fact that the majority of women in the trial were older than 50 (64%), had T1 tumors (68%), ER-positive tumors (77%), and only one positive SLN (60%). Another factor that likely biased selection was the tumor burden within the SLN, which is a powerful independent predictor (if not the most signifi cant) of non-SLN involvement.4,5
The exact size of the SLN metastases for the patients in Z0011 was not recorded, but nearly half (40%) of the patients had either micrometastases or isolated tumor cells; it is reasonable to believe that most of the remaining 60% had relatively smaller volumes of disease.
Semantics over Biology
With the results of Z0011, there has been a dramatic shift in our approach to staging the axilla. For example, many surgeons have advocated to no longer obtain axillary ultrasound and fine needle aspiration (FNA) biopsy of suspicious nodes because this practice identifies women with "clinically evident" disease who, in the absence of the ultrasound, would have been "SLN positive" and thus eligible for avoidance of the ALND. Nodal disease identified by ultrasound and FNA biopsy is strongly correlated with tumor burden and with the number of involved nodes.6
The difference between an abnormal node on physical exam and an abnormal node on ultrasound has as much to do with body habitus and physical exam skills as it does with tumor biology. How does one make the argument that a 1.5-cm palpable axillary node in a thin individual has a different biologic implication than a 1.5-cm nonpalpable node in a heavier individual? Yet by not doing ultrasounds, the latter patient would be labeled "SLN positive" and offered no ALND, and the former patient would be "clinically positive" and undergo ALND.
This change in practice takes a population of patients who were not accrued to the Z0011 trial and who were clearly not represented, and now labels them "Z0011-eligible." This decision making seems more semantic than biologic. It is reasonable to believe that tumor burden in the SLN not only predicts non-SLN involvement but also burden of disease in the nonsentinel nodes. It is quite feasible that had these patients been included to any significant degree in Z0011, the results might have been quite different. Thus, we may want to be careful about radically altering our approach. Tumor burden in the SLN should be considered when selecting which patients may safely avoid ALND, and frozen section may still be useful in identifying patients with signifi cant tumor burden for immediate completion dissection.
Preoperative ultrasound of the axilla is still an extremely useful staging test. Although micrometastatic disease in the SLN can be identifi ed by ultrasound and FNA biopsy, this can be reduced by altering the criteria for FNA so as to allow these patients to proceed with SLN and ALND avoidance. Patients with large, abnormal—albeit nonpalpable— nodes should still undergo FNA biopsy and be considered for ALND if positive. The key moving forward will be to better define the clinically relevant thresholds for nodal tumor burden; to do this, more information is needed on the relationship between SLN and non- SLN tumor burden.
About the Author: Dr. Sabel is an associate professor of surgery in the Division of Surgical Oncology at the Michigan Comprehensive Cancer Center. He will be participating in a panel discussion on this topic during today’s General Session III: Controversies in Diagnosis of Early Stage Breast Cancer and Management of Sentinel Nodes.
- Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305(6):569-575.
- Latosinsky S, Berrang TS, Cutter CS, et al. Axillary dissection versus no axillary dissection in women with invasive breast cancer and sentinel node metastasis. Can J Surg. 2012;55(1):66-69.
- Straver ME, Meijnen P, van Tienhoven G, et al. Role of axillary clearance after a tumor-positive sentinel node in the administration of adjuvant therapy in early breast cancer. J Clin Oncol. 2010;28(5):731-737. Epub 2009 Dec 28.
- Hwang RF, Krishnamurthy S, Hunt KK, et al. Clinicopathologic factors predicting involvement of nonsentinel axillary nodes in women with breast cancer. Ann Surg Oncol. 2003;10(3):248-254.
- Mittendorf EA, Hunt KK, Boughey JC, et al. Incorporation of sentinel lymph node metastasis size into a nomogram predicting nonsentinel lymph node involvement in breast cancer patients with a positive sentinel lymph node. Ann Surg. 2012;255(1):109-115.
- Cools-Lartigue J, Meterissian S. Accuracy of axillary ultrasound in the diagnosis of nodal metastasis in invasive breast cancer: A review. World J Surg. 2012;36(1):46-54.
This Expert Editorial was first published in 2012 Breast Cancer Symposium Daily News