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News and Views |
Axillary lymph node dissection (ALND) may be safely omitted in patients with early stage breast cancer and sentinel lymph node (SLN) micrometastases, according to a study published recently by Igor Langer and colleagues (Department of Surgery, University Hospital Lausanne, Lausanne, Switzerland) in Annals of Surgical Oncology (2009 Sep 4. [Epub ahead of print]. PMID: 19760047).
The question of whether to perform ALND has been controversial since the use of SLN mapping and sensitive immunohistochemical tests for identifying micrometastases (and isolated tumor cells) became widespread.
"Seeing metastases larger than 2 mm, now that matters. With micrometastases (clusters of cancer cells larger than 0.2 mm but not larger than 2 mm) or isolated tumor cells (individual cells or cell clusters no larger than 0.2 mm), the prognosis is as if the patient were node-negative. That's a very important message," explains Victor Vogel, MD, MHS. "You don't have to do extensive axillary dissections in those patients. Removing micromets [micrometastases] surgically does not add to the systemic treatment of patients with breast cancer." Dr. Vogel is the American Cancer Society's national vice president for research.
Igor Langer, MD, and colleagues from several Swiss University Hospitals prospectively enrolled 234 women with breast cancers no larger than 3 cm, and no clinically suspicious axillary lymph nodes, between 1998 and 2002.
No SLN was found in 5% of cases. The 224 nodes identified by SLN mapping were serially sectioned and immunohistochemical staining was used when the routine histology was negative.
No malignant cells were found in 123 (55%) of the sentinel lymph nodes, and an additional 3 (1%) had only isolated tumor cells. Both groups were considered negative (N0) according to current AJCC staging rules. Macrometastases were found in 74 (33%) and micrometastases in 27 (12%).
Local therapy for all patients consisted of breast-conserving surgery with adjuvant radiotherapy. None of the patients with negative axillary nodes or with micrometastases received axillary radiotherapy, and none underwent axillary dissection. Decisions on adjuvant systemic therapy in women with micrometastases were based solely on characteristics of the primary tumor.
To date, 26 of 27 patients with micrometastases have received adjuvant therapy. After a median follow-up of 77 months, the patients with SLN micrometastases showed no locoregional metastases and no distant metastases. At 97 months of follow-up, data (unpublished) support the same conclusions that were reached at 77 months, notes Markus Zuber, MD, a coauthor of this article by Langer, et al.
"There were no statistically significant differences for overall survival (P = .656), locoregional disease-free survival (P = .174), or axillary and distant disease-free survival (P = .15) between patients with negative SLN and SLN micrometastases," the authors write. "To our knowledge, this prospective study is the only one in the literature that reports the findings of an unselected group of patients with SLN micrometastases in whom a completion ALND was systematically omitted. This analysis of unselected patients provides evidence that a completion level I and II ALND may be safely omitted in early stage breast cancer patients with SLN micrometastases." However, they acknowledge the relatively small sample size and the limited follow-up time of their study.
Three recent research articles illustrate the complexity of this question. A retrospective analysis of data from the National Cancer Database (Journal of Clinical Oncology 2009;27:2946–2953) found that completion ALND did not influence axillary recurrence or survival for patients with microscopic SLN metastases.
In a prospective study from the John Wayne Cancer Institute (Journal of Clinical Oncology 2009;27:4679–4684), neither micrometastases nor isolated tumor cells seemed to influence 8-year disease-free or overall survival. The vast majority of patients with micrometastases and isolated tumor cells received adjuvant systemic therapy (96.3% and 92.8%, respectively), and the authors expressed concern about overtreatment.
On the other hand, a retrospective study from Maastricht University Medical Center in the Netherlands (New England Journal of Medicine 2009;361:653–663) found that in the absence of adjuvant systemic therapy, isolated tumor cells or micrometastases adversely influenced disease-free survival.
"When I read [the Langer] paper, I get worried about drawing larger conclusions from a small study," says Kimberly Van Zee, MD, MS, an attending surgeon in the breast service at Memorial Sloan-Kettering Cancer Center and professor of surgery at Weill Medical College of Cornell University, both in New York City. "There are other data that very clearly show that micrometastases are associated with a much worse prognosis." This is especially true in patients who do not receive adjuvant systemic therapy, she explains.
Dr. Van Zee expressed concern that the article by Langer and colleagues represented another step in the movement toward the systematic omission of ALND in SLN-positive low-risk patients without adequate evidence that this will not negatively affect long-term outcomes.
"You know that in the absence of axillary dissection, there is a higher chance of residual disease and, therefore, probably a higher local recurrence rate," she explains. "The Langer paper didn't show this, but the groups are small [n=27] and biased toward chemotherapy in the group with micromets. Other groups have shown a higher risk of local recurrence in a selected low-risk group of women with micromets who do not undergo axillary dissection. And we know that local recurrence in the breast does impact on survival, though it takes some time to show it, in a non-one to one ratio. Prevention of 4 local recurrences at 5 years saves 1 life at 15 years. It's not true that every local recurrence leads to death."
"I think it is going to be the case that it's going to have a small, long-term impact on survival. It's going to take us roughly 15 years to figure this out. I don't want people to adopt this now and figure out 15 years later that ALND confers, for example, a 5% survival benefit."
In an editorial referring to the study by Langer and colleagues in the same issue of the Journal of Clinical Oncology, Thomas B. Julian, MD, associate director of the Breast Care Center at Allegheny General Hospital in Pittsburgh, Pennsylvania, and associate professor of human oncology at Drexel University College of Medicine, in Philadelphia, Pennsylvania, suggests that the prognostic significance of isolated tumor cells and micrometastases is influenced by other factors, such as systemic therapy. Dr. Julian notes that 2 randomized trials (the National Surgical Adjuvant Breast and Bowel Project's B-32 trial and the American College of Surgeons Oncology Group's Z0010 study) will provide additional data on the prognostic significance of axillary micrometastases, and that both have completed accrual, and "data are expected to mature in the next 6 to 18 months." 
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