NEW YORK (Reuters Health) – Breast cancer patients whose sentinel nodes show only micrometastases or isolated tumor cells are very unlikely to have other involved nodes, and so they probably don’t need full axillary lymph node dissection (ALND), an Italian research team says.
Doctors at the University of Bologna studied 753 women who had surgery for T2 or smaller breast cancers. All of them had clinically negative axillary nodes. If frozen sections of sentinel nodes showed either macro- or micrometastases, ALND was done immediately. Nodes that were negative on frozen section were carefully searched for evidence of metastatic disease on permanent pathologic sections.
The researchers reported their study online March 19th in Annals of Surgery
Frozen section revealed metastatic disease in 158 women (20.9%). In 135 other cases, the frozen section result was falsely negative. Most of the false negatives (119) were micrometastatic deposits or isolated tumor cells.
Sixty-six of the 135 patients (48.9%) with a false-negative frozen section had ALND done at a second operation. The others did not, either because they were not considered candidates for the second surgery due to age, comorbidities or other factors or because they were entered into a randomized trial specific for this finding. Patients received appropriate hormonal or chemotherapy as indicated by their tumor characteristics.
Altogether, 71 patients with micrometastases or isolated tumor cells on frozen section did not have a complete ALND. After a mean follow-up of 32 months, none of them had axillary recurrences.
Of the 460 patients who had no metastases on final pathologic exam of the sentinel lymph node biopsy (SLNB), just two had axillary recurrences.
Eight of 77 patients with micrometastases or isolated tumor cells who had a complete ALND were found to have more than one node containing metastases.
None of the 753 patients in this series received radiation therapy to the axilla. In email to Reuters Health, Drs. Mario Taffurelli and Isacco Montroni, lead authors of the study, said, “We never perform radiation therapy to the axilla after SLNB in any case so this did not affect our recurrence rate.
Last year, Giuliano et al reported in the Journal of the American Medical Association that axillary node dissection is no longer necessary for T1 and T2 breast cancer patients with clinically negative nodes, even if the SLNB was positive. Commenting on that paper, Dr. Taffurelli and Dr. Montroni told Reuters Health it “is obviously a pivotal work but we still have several concerns.”
“First,” they said, “every patient in that study underwent breast conserving treatment and consecutive radiation therapy, which was performed with tangential breast fields usually involving also the first axillary lymph node level. This could clearly affect the axillary local recurrence rate.”
“Second,” they continued, “about 85% of the patients enrolled underwent adjuvant treatment following surgery. This obviously played a role in disease free and overall survival. Third, the follow up is still immature. Breast cancer needs (a) longer period, 15 to 20 years, to give definitive answers. At this moment, no change in international guidelines has been made and ALND for macrometastases on SLNB remains the standard of practice worldwide.”
The two researchers say that when there are macrometastases in the sentinel node; they still do an ALND. They do not, however, perform ALND if they find isolated tumor cells in the sentinel node, except for patients enrolled in clinical trials – “and we rarely perform completion ALND in cases of micrometastases,” they said. “For those patients, we discuss the scenario at the multidisciplinary meeting, and if the biological and histological characteristics of tumor are clear enough to target the medical treatment, we do not perform completion ALND.”
A surgeon not associated with the study, Dr. Anees Chagpar, Director of the Breast Center at Yale University School of Medicine in New Haven, Connecticut, also compared this paper with the Giuliano study.
“The paper from Bologna really looks at the impact of intraoperative frozen section in the detection of disease in the sentinel lymph nodes and the rate at which isolated tumor cells, micrometastases and macrometastases in sentinel nodes predicted non-sentinel node metastases,” she told Reuters Health. “Giuliano’s paper, which reported findings of the Z-11 trial, asked a different question which was ‘given disease in the sentinel nodes, is axillary node dissection needed?’”
“The Z-11 trial randomized patients with a positive node (including macrometastases) to axillary dissection vs. no axillary dissection in patients who were undergoing partial mastectomy with whole breast radiation therapy, knowing that some of the radiation would cover the lower axilla. In the arm randomized to axillary dissection, 27.3% of patients had further non-sentinel node metastases. The rate of recurrence, however, was low in either arm (0.9% in the SLNB only arm) and so the thought was, ‘Why do the axillary dissection?’”
“The paper from Bologna asks a different question,” Dr. Chagpar said. “They found that frozen section finds most patients who have cancer in their lymph nodes (54% sensitivity and 100% specificity), and is especially good at finding macrometastases. Of the patients with macrometastases in their SLNs, 38.6% had a positive non-SLN, and 10.9% of patients with micrometastases had a positive non-SLN. Overall, they found the rate of non-SLNs was 32.4% (similar to the 27.3% of Z-11). While the two studies ask different questions, and the authors have different interpretations, the data are quite similar.”
Do patients with micrometastases and isolated tumor cells need ALND? “For isolated tumor cells, there is little evidence that there is any benefit to completion axillary dissection,” Dr. Chagpar said. “Not only did this paper demonstrate no non-SLN metastases in this group, but these patients are considered node-negative by AJCC staging. For micrometastases, the jury is still out. This paper truly didn’t ask the question of whether they could avoid ALND, although none of the 24 patients who did not have follow-up axillary dissections after micrometastases had a local recurrence at 32 months.”
In her own practice, Dr. Chagpar said: “For patients meeting the Z-11 criteria, we will discuss avoiding axillary dissections with patients, although many of our patients who have micro- or macrometastases may not meet Z-11 criteria either because they are having a mastectomy, accelerated partial breast irradiation (as we have a number of clinical trials evaluating newer modalities of delivering radiation in this way), neoadjuvant chemotherapy or who have three or more positive nodes.”
“One of the issues we have found was the potential selection bias of patients participating in the Z-11 trial, and we are in the process of opening a protocol in which patients have at least three sentinel nodes evaluated. If they have tumors < 2cm, and have only one of three SLNs positive, we may be able to avoid axillary node dissections, as we know from clinical prediction models that their risk of non-SLN metastases will be low.
Drs. Taffurelli and Montroni agreed. “Patients need to be more involved in the decision-making process, but they also need to be educated that ALND is not free from complications and that they may not have a benefit in terms of disease free and overall survival, especially for patients with isolated tumor cells or micrometastases that are more likely to be overtreated with ALND,” the two authors said.
Problems after ALND may not be as common as once thought, however. “I think the other question is the real morbidity of axillary dissection,” Dr. Chagpar said. “The elephantiasis of lymphedema that had been dreaded in the past seems to be a rarity now. We did a study (not published yet) in which we evaluated subclinical lymphedema by bioimpedence in patients who had either SLNB or ALND. Not one patient had evidence of even subclinical lymphedema at three months, even in patients with 33 nodes removed (25 of which had cancer).”
“We already spare node-negative patients and those with isolated tumor cells an axillary node dissection, and these are the majority of our patients,” she added. ‘I think the next step is to carefully evaluate which node positive patients might be spared ALND, but it behooves us to remember that the benefit of the information and/or tumor debulking in some patients may well be worth the minimal risk of this operation.”
Ann Surg 2012.