Should Sentinel Lymph Node Biopsy Be Postponed Until After Neoadjuvant Therapy?

Anees B. Chagpar, MD, MSc, MA, MPH

Arguments Against Delaying Sentinel Lymph Node Biopsy

In the last decade, sentinel lymph node biopsy has become established as an alternative to axillary lymph node dissection for nodal staging in patients with early-stage breast cancer, as a result of several randomized trials showing similar disease-free and overall survival of these two procedures,^1,2 as well as less morbidity (such as reduced arm lymphedema and sensory deficits) and improved quality of life with sentinel lymph node surgery.^3,4 With increasing use of neoadjuvant chemotherapy, however, controversy has erupted regarding the optimal timing of this procedure. Some argue that sentinel node biopsy prior to neoadjuvant chemotherapy provides the most accurate staging, whereas others argue that performing a sentinel node biopsy after neoadjuvant chemotherapy could allow patients with node-positive disease who achieve a pathologic complete response to avoid the morbidity of an axillary node dissection. Anees B. Chagpar, MD, MSc, MA, MPH, associate professor of Surgery at Yale University and director of The Breast Center—Smilow Cancer Hospital at Yale-New Haven, discussed this issue at the 30th Annual Miami Breast Cancer Conference.The primary objection to delaying sentinel node surgery until after neoadjuvant chemotherapy is its false-negative rate. In 2006, a meta-analysis of nearly 1300 patients undergoing sentinel lymph node biopsy after neoadjuvant chemotherapy reported a false-negative rate of 12%,⁵ and a 2012 presentation of the ACOSOG Z1071 trial, which also examined the procedure after neoadjuvant chemotherapy, reported a false-negative rate of 12.6%.⁶ This is in contrast to the 5% to 9.5% false-negative rate reported when the sentinel node procedure is performed prior to any therapy.^2,7,8

It has been hypothesized that the elevated falsenegative rate with delayed sentinel node surgery may be caused by uneven sterilization of the lymph nodes by the chemotherapy; certainly, it raises concern about the impact of this residual disease on the locoregional recurrence rate. When performed after neoadjuvant chemotherapy, sentinel lymph node biopsy also has a poorer identification rate of the sentinel lymph node than when it is performed prior to chemotherapy (87% vs 97%-100%).⁹ This decreased identification rate is postulated to be caused by structural changes in lymphatic drainage, such as fibrosis within the axilla.¹⁰ Finally, pretreatment determination of the pathological status of the lymph nodes can impact decisions regarding postoperative radiation therapy, and this information would be unavailable to patients who delayed sentinel node biopsy until after receiving chemotherapy.

Arguments for Delaying Sentinel Lymph Node Biopsy Proponents of performing sentinel lymph node biopsy after chemotherapy acknowledge both the lower sentinel node identification rate and the higher false-negative rate of this approach, but propose that both are reasonable. “Risk, like beauty,” Chagpar said, “is in the eye of the beholder. For some, the false-negative rate of 12% is too high; for others, it is acceptable.” She argued that there is less worry about residual disease in recent years, with regard to both its impact on locoregional recurrence and survival. For instance, the randomized NSABP B-04 trial, which was designed to determine whether outcomes would be compromised when the extent of surgery was reduced (from radical mastectomy), demonstrated that locoregional recurrences in the arm with the least extensive surgery (having no targeted axillary treatment) produced no worsening of overall survival.¹¹ This suggests that the surgical resection of additional lymph nodes may have little to no impact on survival. It is also true that the timing of axilla staging in patients with locally advanced disease has minimal influence on the type of chemotherapy they will receive, and while upfront sentinel node biopsy may influence the decision to provide post-mastectomy radiation therapy, many of these patients would qualify for radiation therapy on the basis of tumor size alone.

Other Considerations

Those in favor of delaying sentinel node surgery suggest that the benefits of this approach overshadow the modest risks (ie, residual disease in the axilla) associated with it, because it not only provides information regarding patients’ sensitivity to chemotherapy, which may be useful when making future treatment decisions, but it also permits those who achieve a pathologic complete response to chemotherapy to avoid the morbidity and reduced quality of life associated with axillary lymph node dissection.Regardless of when sentinel lymph node biopsy is performed, certain technical considerations are critical to optimal outcomes. For instance, Chagpar said it is now well accepted that nodal status is best determined by evaluating at least two sentinel nodes,¹² and that a dual tracer—both a blue dye and a radioactive isotope—be used, if possible.¹³ A number of studies have tried to identify factors that can predict the status of nonsentinel nodes, but no robust variables have yet been found. However, research continues to search for ways to bolster sentinel lymph node findings. Despite the findings of the ACOSOG Z1071 and SENTINA trials, this remains an area of controversy, and physicians continue to search for the optimal means to stage their patients with locally advanced disease.

References

1. Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes of sentinel-lymph-node resection and conventional axillarylymph- node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol. 2007;8(10):881-888.
2. 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):546-553.
3. 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(9):599-609.
4. Purushotham AD, Upponi S, Klevesath MB, et al. Morbidity after sentinel lymph node biopsy in primary breast cancer: results from a randomized controlled trial. J Clin Oncol. 2005;23(19):4312-4321.
5. Xing Y, Foy M, Cox DD, Kuerer HM, Hunt KK, Cormier JN. Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer. Br J Surg. 2006;93(5):539-546.
6. Boughey JC, Suman VJ, Mittendorf EA, et al. The role of sentinel lymph node surgery in patients presenting with node positive breast cancer (T0-T4, N1-2) who receive neoadjuvant chemotherapy: results from the ACOSOG Z1071 trial. 35th Annual San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract S2-1.
7. Iida S, Haga S, Yamashita K, et al. Evaluation of sentinel lymph node biopsy in clinically node-negative breast cancer. J Nippon Med Sch. 2011;78(2):96-100.
8. Krag DN, Ashikaga T, Harlow SP, et al. Surgeon training, protocol compliance, and technical outcomes from breast cancer sentinel lymph node randomized trial. J Natl Cancer Inst. 2009;101(19):1356-1362.
9. Papa MZ, Zippel D, Kaufman B, et al. Timing of sentinel lymph node biopsy in patients receiving neoadjuvant chemotherapy for breast cancer. J Surg Oncol. 2008;98(6):403-406.
10. Cohen LF, Breslin TM, Kuerer HM, Ross MI, Hunt KK, Sahin AA. Identification and evaluation of axillary sentinel lymph nodes in patients with breast carcinoma treated with neoadjuvant chemotherapy. Am J Surg Pathol. 2000;24(9):1266-1272.
11. Fisher B, Jeong JH, Anderson S, Bryant J, Fisher ER, Wolmark N. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med. 2002;347(8):567-575.
12. Kennedy RJ, Kollias J, Gill PG, Bochner M, Coventry BJ, Farshid G. Removal of two sentinel nodes accurately stages the axilla in breast cancer. Br J Surg. 2003;90(11):1349-1353.
13. Newman LA. Lymphatic mapping and sentinel lymph node biopsy in breast cancer patients: a comprehensive review of variations in performance and technique. J Am Coll Surg. 2004;199(5):804-816.