A recent prospective trial showed sentinel lymph node surgery has a clinically significant high false negative rate in breast cancer patients with node-positive disease receiving neoadjuvant chemotherapy. In this interview we discuss surgical techniques that detect breast cancer in lymph nodes.
Today we are discussing surgical techniques that detect breast cancer in lymph nodes, with Dr. Kelly K. Hunt, professor in the department of surgical oncology at the University of Texas MD Anderson Cancer Center in Houston. Dr. Hunt was part of a recent prospective trial that showed sentinel lymph node surgery has a clinically significant high false negative rate in breast cancer patients with node-positive disease, who are receiving neoadjuvant chemotherapy.
-Interviewed by Anna Azvolinsky, PhD
Cancer Network: Dr. Hunt, can you first describe the different surgery approaches currently used to detect cancer in lymph nodes for breast cancer patients?
Dr. Hunt: The standard approach for many, many years has been to perform an axillary lymph node dissection, where all of the lymph nodes are removed in the armpit area, and these are level 1 and 2 lymph nodes anatomically. For decades that has been used to, first of all, identify lymph nodes in the area, and second, submit them for pathological processing to determine if there is any metastasis. When sentinel lymph node surgery was developed in the 1990s, it was a method of identifying the lymph nodes that are directly connected to the primary tumor through lymphatic channels, so that those first important lymph nodes, the sentinel lymph nodes, can be removed to assess for any metastasis. This can replace the need to remove all of the lymph nodes in women who actually don’t have any disease in the lymph nodes.
Another tool that we use is ultrasound. This is something that has evolved over the last 10 to 20 years. Breast imaging specialists have been the main individuals using ultrasound to not only look at the tumor in the breast, but also at the lymph nodes, and by looking at anatomical variables, they know the normal architecture of the nodes. If they see changes in the anatomy and architecture of the nodes, that can be a sign that the cancer has spread to the nodes, and they can use fine-needle aspiration biopsy or core needle biopsy to sample that lymph node. So, that is a newer technique, and surgeons have also been gaining experience with that technique in addition to breast imaging specialists.
Cancer Network: What are the strengths and weaknesses of each of these surgical procedures? Do some patients receive one technique over another?
Dr. Hunt: The reason why sentinel lymph node surgery was developed was because we had improvement in screening, and with a lot more public awareness, cancers are detected earlier, when they are developing within the breast, so there is less likelihood that they will have spread to the regional nodes. Doing an axillary lymph node dissection for staging has really fallen out of favor because it is associated particularly with lymphedema. Lymphedema is when there is swelling in the arm that can progress from what looks like just a small amount of increase in the circumference of the arm to a very large, swollen extremity that is more susceptible to infection, and it is very challenging to treat for some women and is not a reversible condition. So, because we know that between 20% to 60% of women will develop lymphedema with axillary lymph node dissection, depending on how measurements are made and how frequently the patients are seen in follow-up, we want to avoid that at all costs. That is a really difficult thing for patients to recover from.
The sentinel lymph node surgery as a replacement for axillary lymph node dissection is associated with a much lower risk of lymphedema. Lymphedema is the one patients worry about the most, but there are other complications that occur, including seroma formation, which is the collection of fluid in the armpit area after axillary lymph node dissection, or infections due to the fluid that has developed there. Or patients develop problems with range of motion when they are trying to move the upper extremity and shoulder, because scar tissue that develops in the armpit area after the axillary nodes are removed can result in a lot of tightening of the tissue and scarring, which can limit the range of motion in the shoulder.
Finally, there are nerves that go through the axillary lymph node area that supply sensation to the upper arm, especially the back of the upper arm area, and so, in doing lymph node dissection those nerves are often disrupted, and women often have numbness or abnormal sensations of pain in the upper arm because of that lymph node surgery. There are a number of reasons why we would not want to do axillary lymph node dissection if we don’t need to because of the potential complications that women have to live with afterwards. But, of course, we want to be certain that we accurately stage the disease, and that we do remove any cancer that may be a source of future problems in terms of metastatic disease in other organs. So, there is definitely a balance between doing the surgery and making sure that we are accurately assessing the stage and disease process, but we do want to limit the amount of side effects for the patients.
Cancer Network: In the study that you and colleagues published recently, you find that the false negative rate of sentinel lymph node surgery is relatively high in patients who have node-positive breast cancer who had neoadjuvant chemotherapy. Can you describe this trial?
Dr. Hunt: The reason we were interested in doing this trial is because, as I said, sometimes we use ultrasound to assess women when they’re first diagnosed with breast cancer, and we identify lymph nodes in the axillary that look abnormal. We do a biopsy to prove that they are abnormal, and that can be an indication to do chemotherapy before any surgical intervention. What we found over the past 10 years of using chemotherapy before surgery is that about 40% of the time, women who had evidence of lymph node involvement based on the biopsy will no longer have any disease in the lymph nodes at surgery, because the chemotherapy can eradicate the disease not only in the breast but also in the lymph nodes and other parts of the body. Now that this neoadjuvant chemotherapy has become more common in women with earlier-stage breast cancer, and we find that we are eradicating the disease more frequently, we wanted to see if we can use a less invasive approach after chemotherapy to see if we had eradicated the disease in the lymph nodes, and therefore, didn’t need to do a full axillary lymph node dissection.
This trial was designed to have women who had evidence of disease in the lymph nodes confirmed by needle biopsy receive chemotherapy. After chemotherapy, they were scheduled to have sentinel lymph node surgery at the same time as the axillary lymph node dissection, and then pathologists would assess how accurate the sentinel lymph node surgery was in determining the status of those lymph nodes. So, what we found was that 91% of the time the sentinel lymph node did reflect the status of the axilla. In women where the sentinel node was negative, the axilla was negative, and when the sentinel node was positive, the axillary lymph nodes were positive; it was accurate. But we know that in some women, the sentinel node was negative for any cancer, but there were axillary lymph nodes that had disease in them, meaning that was a false negative result, and that the sentinel node did not accurately stage the axilla.
The concern there, of course, is that you are leaving disease behind, if you did only the sentinel node surgery and the sentinel node was negative. This has always been a concern since this technique was developed-we knew that there was a chance of a false negative event. Several prospective trials have shown that if you pay attention to how the sentinel lymph node surgery is performed, you can reduce the chance that there will be a false negative result. That is why we had recommended that surgeons use both blue dye and radiolabeled colloid to perform the sentinel lymph node surgery, because we knew that reduces the false negative rate. We also knew that if you remove more than two sentinel nodes, it reduces the false negative rate. The reason for that is that most women do have more than one sentinel node. There are usually two or three, and most studies have shown that there are two or three, because the lymphatic drainage of the breast is quite complex. What we had recommended is that surgeons remove at least two sentinel nodes, not that they should randomly take additional nodes, but that they should really try to be very complete in the sentinel lymph node surgery before they went on to do the axillary lymph node dissection. Previous studies have shown that when surgeons are doing the sentinel node surgery at the same time as the axillary node dissection, oftentimes if they identify one central node, they will stop and then do the axillary node dissection, but we know that that will cause false negative events because the central node they recover may not have been the one that had metastatic disease at presentation, and they still may have disease on axillary lymph node dissection.
So, what we found is that the false negative rate was higher than what we had set as our predefined rate that we would accept, being 10%. We found a rate of 12.6%, but if we look at when the techniques were employed that we had recommended, namely dual agents for the mapping, and more than two sentinel nodes recovered, then the false negative rate falls below that preset endpoint.
Cancer Network: What are the implications of this study?
Dr. Hunt: I think the implications are that if the attention to the surgical procedure is carefully discerned by the surgeon, then we can use this technique for staging the axilla after chemotherapy. But the other thing that we found from this trial is that we need to select the patients very carefully. Just as we would select a patient for using chemotherapy or not, or using hormonal therapy or not, to treat their cancer, we need to select patients very carefully for this type of surgery as well. In other words, we would want to see that the patient had not only had the chemotherapy, but that the lymph nodes that were detected at that initial presentation do show evidence of response based on ultrasound and physical examination, whereas in the trial we are discussing, the patients were just selected based on having a lymph node that was identified at presentation, and then they had chemotherapy and surgery, and we did not exclude them if they still had evidence of disease based on ultrasound or other imaging techniques. The implications are that we can be less invasive with our surgical approaches, but we have to be careful in how we select our patients and how we perform the procedure, and that we are certain that we remove all of the sentinel nodes to be sure we are getting an accurate staging.
Cancer Network: Are there any studies that are following up on these results that you can highlight?
Dr. Hunt: There have been a couple recent studies showing that in women who present initially for breast surgery and have sentinel lymph node surgery and there is a positive sentinel node, if they are randomized to undergo axillary dissection versus axillary radiation, the axillary radiation appears to control any residual disease that might be there just as well as doing an axillary dissection. And it seems to have a lower rate of side effects, mainly lymphedema. One trial that we have that is now open, recently activated through the alliance for clinical trials in oncology, is a study in which we are assessing patients who present with node-positive disease, have chemotherapy, and then if after chemotherapy they had a good response in the lymph nodes, but we do a sentinel node biopsy and it still shows disease in the sentinel node, we are randomizing them to have axillary dissection versus radiation, because we think the radiation may have fewer side effects and will still be a good option for controlling any residual disease that might still be there.
Cancer Network: Thank you so much for joining us today, Dr. Hunt.
Dr. Hunt: Thank you.