Recent Development in Axillary Lymph Node Management in Breast Cancer
By Winkle Kwan
InNorth America, cancer treatment is the most important contributor to the lymphedema problem.
The axillary dissection used for breast cancer therapy has historically been responsible for most of the chronic upper limb lymphedema cases. Fortunately, there have been several key publications from large clinical trials in the last five to six years, resulting in significant decline in the use of full or partial axillary dissection. This article will review these key publications, discuss controversies on the impact of these publications and explore potential development in the axillary nodal management of breast cancer.
Surgeons have been aware of the long-term morbidities of axillary dissection for years. These include lymphedema, nerve injuries (brachial plexopathy and upper arm numbness), upper arm weakness and limited shoulder mobility. While axillary dissection is arguably responsible for most of the long-term physical morbidity of breast cancer surgery, it also plays an important role in breast cancer treatment. It provides prognostic information, guides further management and, until recently, was believed to have therapeutic benefits—after all,
cancer involved lymph nodes should theoretically be surgically removed.
In the last 10 years, however, the importance of axillary dissection has been questioned. Advances in systemic adjuvant treatment with hormones and chemotherapy have cast doubt on whether minimally involved lymph nodes need to be removed. In addition, the use of adjuvant systemic therapy (hormones and chemotherapy) has become wide spread enough that lymph node status may not be crucial in guiding the use of adjuvant therapy. Sentinel node biopsy is a new technique based on the theory that malignant cells from certain cancers first involve one or a few “sentinel nodes” before involving others in the lymph node group.
Sentinel
The late 1990s saw the launch of several large cooperative group randomised trials comparing sentinel node biopsy and axillary nodal dissection. Early results of these trials became available from 2003 onwards and have transformed the strategy of lymph node management in breast cancer.
node biopsy is a new technique based on the theory that malignant cells from certain cancers first involve one or a few “sentinel nodes” before involving others in the lymph node group.
Dr. Winkle Kwan, MBBS FRCPC Dip ABR, is a Radiation Oncologist in Surrey working with the BC Cancer Agency at the Fraser Valley Center. Breast cancer treatment has been his area of exper tise for 15 years. He is an avid suppor ter of the provincial and national efforts in raising the awareness of lymphedema, particularly as a result of cancer treatment.
Key published randomized trials European Institute of Oncology study1 Published in the New England Journal of Medicine in 2003, this single institutional study from the institute of the well known Italian breast oncologist Umberto Veronesi, provided the earliest evidence that sentinel node biopsy results in less arm problems. The study randomized low risk breast cancer patients (≤ 2 cm primary) to Sentinel Node Biopsy (SNB) and Axillary Nodal Dissection (AND) versus SNB followed by AND only if the SNB was positive. As reported in the New England Journal, the follow-up was short, but there was less pain and better arm mobility in patients who underwent SNB only, without AND.
However, morbidity was only reported in 200 patients (out of a total of 516 randomized). The questionnaire for evaluating arm morbidity was not validated.
The ALMANAC trial2
This British trial randomized 1,031 patients with clinically node negative disease to SNB versus AND. Patients with sentinel node metastasis proceeded to delayed axillary clearance or axillary radiotherapy. The primary endpoints were arm morbidity and quality of life, with axillary recurrence rate being the secondary endpoint. Arm morbidity was measured by volume changes as well as the validated FACT-B+4 questionnaire. In the 2006 publication, only results of follow-up within the first 12 months after surgery were presented. The trial reported significant reduction of morbidity when AND was replaced by SNB. The difference is reflected in improvements in multiple domains, including incidence of lymphedema, FACT-B+4 scores and arm functioning subscales scores.
The American College of Surgeons Oncology Group trial Z00113,4
This is a non-inferiority trial which randomized 891 patients with small breast primaries (T1/2) and one or two positive lymph nodes to SNB alone or AND. Overall survival was the primary endpoint with disease free survival as a secondary endpoint. Surgical morbidities were reported first in 2007 followed by survival as data in 2010. In the 2007 publication, subjective lymphedema was 13 percent versus two percent in the SNB and AND groups respectively, at one year. The difference between the two groups in terms of objectively measured lymphedema by arm circumference was not statistically significant, despite a trend towards less lymphedema in the SNB group. The survival data are what convinced a lot of clinicians to not do AND: there was no difference in the overall survival or disease free survival after a median follow up of 6.3 years even in this group of patients with one or two positive nodes.
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Glossary
SNB - Sentinel node biopsy. In this procedure, the surgeon removes a sentinel node(s), which is the first node(s) that lymph fluid from the breast drains into. Removing sentinel nodes and examining them for cancer cells is a very accurate way of finding out whether the breast cancer has started to spread. In this procedure, few lymph nodes are removed for testing. This results in an easier recovery after surgery and less likelihood of complications. If cancer cells are found in the sentinel node(s), an axillary node dissection may also be needed.
AND - Axillary node dissection. This refers to the removal of a number of lymph nodes from the armpit area (also known as the “axillary”). After removal, these nodes are examined under a microscope to see if there are any visible cancer cells.
Source: Canadian Breast Cancer Foundation
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Percentage of breast cancer treated at the BC Cancer Agency with SNB as the sole nodal procedure without an axillary dissection
P.S.: BC Cancer Agency statistics are not truly “provincial” population based statistics but it comprises about 85 percent of all breast cancer cases in the years studied.
fewer axillary dissections done, we will be blessed with much less lymphedema in the next generation of breast cancer patients. The 2009 Cancer Care Ontario guidelines7 state that SNB is recommended as the preferred method of axillary staging for all patients with a clinical presentation of early-stage breast cancer, where there is an absence of clinically or pathologically positive lymph nodes. The National Comprehensive Cancer Network Guidelines8 in 2012 also state that SNB is the “preferred” method of axillary lymph node staging if there is expertise and if the patient’s disease is appropriate for SNB.
The NSABP B-325,6
Patients with clinically negative nodes were randomized to SNB + AND versus SNB with AND only when the SNB was positive. This is the largest randomized trial evaluating the role of SNB without AND in node negative patients (total randomized = 5,611). Both morbidity and early survival results were reported in 2010. At 36 months follow-up, lymphedema by arm circumference measurement developed in eight percent in the SNB group versus 14 percent in the SNB + AND group. Arm symptoms were also significantly more bothersome for the group
with AND. Survival was not different after a follow-up duration of eight years.
Impact of the trial results
As results of SNB became available trial by trial in the last 10 years, confidence in the safety and benefits of the procedure grew. Rates of axillary dissection fell with increasing use of sentinel node biopsy. A 2008 report showed that in Canada that year, 61 percent of surgeons were performing SNB compared to 27 percent in 2001. This rate of increase is slower than the United States, but nevertheless shows the unrelenting trend. With
While SNB is almost firmly established as the standard nodal exploration procedure for small breast cancers with clinically negative nodes, axillary node dissection is not completely abolished yet. AND is still necessary if SNB shows cancer involvement of the nodes. A special category is patients with only one or two nodes involved by disease. While the Z0011 trial showed equivalent disease control of whether an AND is done or not, the follow up (at 6.3 years) is still considered too short to convince all clinicians to abandon AND.
Future developments
Further follow up will clarify whether AND can be omitted in patients with fewer than three lymph nodes involved by cancer. In patients with more advanced disease, trials are ongoing to see whether axillary radiotherapy can safely replace axillary dissection. As SNB becomes the sole nodal assessment for more breast cancer patients, debates are ongoing on how to interpret various types
of findings in the sentinel nodes. For example, isolated tumor cells can be detected in sentinel nodes if highly sensitive methods are used, but whether these have significance in predicting prognosis is unclear.
Summary
Sentinel node biopsy has replaced axillary node dissection as the standard for exploring the axilla in patients with small breast cancers with relatively good prognosis. While axillary dissection is still done for patients with nodal disease, the elimination of the procedure in a large portion of breast cancer cases will result in a significant decline in lymphedema and shoulder stiffness in the next generation of breast cancer survivors. The impact will take years to show, but in time, a lot of women will be happier and more functional after their breast cancer treatment. LP
References:
1. Veronesi U, Paganelli G, Viale G et al.: A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003;349(6):546-53.
2. Mansel RE, Fallowfield L, Kissin M et al.: Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC Trial J Natl Cancer Inst. 2006;98:599-609.
3. Lucci A, McCall LM, Beitsch PD et al.: Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol. 2007;25(24):3657.
4. Giuliano AE, Hunt KK, Ballman KV et al: Axillar y Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis: A Randomized Clinical Trial. JAMA 305(6):569-575, 2011.
5. Ashikaga T, Krag DN, Land SR et al: Morbidity results from the NSABP B-32 trial comparing sentinel lymph node dissection versus axillary dissection. J Surg Oncol 102(2):111, 2010
6. Krag DN, Anderson SJ, Julian TB et al: Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP
B-32 randomised phase 3 trial. The Lancet Oncol 11(10):927-933, 2010.
7. George R, Quan ML, McCready R et al: Cancer Care Ontario Evidence-Based Series 17-5 at Cancer Care Ontario website: http:// www.cancercare.on.ca/toolbox/qualityguidelines/ clin-program/surgery-ebs/
8. NCCN Guidelines version 3.2012 at the NCCN website: www.nccn.org (Accessed on October 18, 2012).
With fewer axillary dissections done, we will be blessed with much less lymphedema in the next generation of breast cancer patients.
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