Correspondence
Sentinel-Node Biopsy in Breast Cancer
N Engl J Med 2003; 349:1968-1971November 13, 2003
- Article
To the Editor:
Veronesi and colleagues (Aug. 7 issue)1 report a sensitivity of 91.2 percent with the use of a meticulous frozen-section method in which at least 60 sections per node are prepared and an immunohistochemical method is used for the detection of metastases in patients with breast cancer. This time-consuming and expensive method is far superior to the conventional method used for the remainder of the axillary nodes for the detection of metastases. Three to six sections were obtained from each of the remaining axillary nodes.
It is a well-known fact that increasing the number of sections improves the rate of detection of metastases.2 Can sensitivity really be calculated when two different methods (6 sections vs. 60 sections) are being used? Would the sensitivity not fall if the same meticulous technique were used for the remaining axillary nodes? What is more important than this sensitivity figure is survival. This study, with such a low event rate, does not have the power to demonstrate that there is no difference in survival between the two groups. We will have to wait for the survival data from other trials before sentinel-node biopsy can be recommended as a standard procedure, irrespective of sensitivity figures, but after a cost–benefit analysis has been performed.
2 ReferencesRajendra A. Badwe, M.D.
Mangesh A. Thorat, M.D., D.N.B.
Vani V. Parmar, M.D., D.N.B.
Tata Memorial Hospital, Parel, Mumbai 400012, India
tmhcrs@vsnl.com 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;349:546-553
Full Text | Web of Science | Medline2
Apostolikas N ,Petraki C ,Agnantis NJ . The reliability of histologically negative axillary lymph nodes in breast cancer: preliminary report. Pathol Res Pract 1988;184:35-38
CrossRef | Web of Science | Medline
To the Editor:
Can we rely on the results presented by Veronesi et al. to establish that sentinel-node biopsy and axillary dissection are equivalent? Figure 2 of the article indicates that survival in the two groups was not significantly different, but this result is probably due to a lack of power to detect a difference, rather than an absence of a difference.1,2 Moreover, the end point of the trial, reported in the Methods section, was the estimated percentage of patients in the sentinel-node group in whom axillary metastases developed; therefore, a randomized comparison was unnecessary and might even have been misleading. We are concerned that the authors' conclusions may lead to the replacement of conventional axillary dissection with sentinel-node biopsy before the results of larger, ongoing, randomized controlled trials are available.
2 ReferencesGian Luca De Salvo, M.D.
Paola Del Bianco, M.Sc.
Cancer Regional Center of Padua, 35128 Padua, Italy
gianluca.desalvo@unipd. it Giorgio Zavagno, M.D.
University Hospital of Padua, 35131 Padua, ItalyTo the Editor:
The surgical oncology community has not “arrived,” as stated by Krag and Ashikaga.1 It will not arrive until quality-of-life indicators generated by patients, not physicians, are included in analyses. In the article by Veronesi et al., which purports to study quality of life and is discussed in Krag and Ashikaga's editorial, the criteria are clearly doctor-set. What other comparisons were made between the groups about factors that affect the quality of life, such as the number of postsurgical visits, the fear of death because of a lesser cancer operation, or the nuisance of intervention (e.g., wound drainage or antibiotic therapy)? Instruments are available to measure these factors, and until we learn to use them beyond mere survival, we will not have “arrived.”
1 ReferencesAndrew M. Munster, M.D.
Johns Hopkins University, Baltimore, MD 212181
Krag D ,Ashikaga T . The design of trials comparing sentinel-node surgery and axillary resection. N Engl J Med 2003;349:603-605
Full Text | Web of Science | Medline
To the Editor:
Krag and Ashikaga recommend that the design of clinical trials start with the selection of a primary end point and sample-size calculations. I propose that it should start with a testable hypothesis and a valid experimental design. They believe that National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 will determine “whether sentinel-node biopsy alone actually reduces the rate of survival when compared with axillary dissection.” The obvious way to test this hypothesis would be to randomly assign patients to standard axillary dissection or sentinel-node biopsy.1 However, in NSABP trial B-32, patients are randomly assigned to sentinel-node biopsy plus axillary dissection or sentinel-node biopsy alone (with axillary dissection for those who have sentinel-node metastases). A survival difference for patients with positive nodes is impossible, since both groups are receiving the same treatment (sentinel-node biopsy and axillary dissection). Therefore, any survival difference must be accounted for by the patients with negative sentinel nodes. Yet axillary dissection cannot possibly benefit patients with normal lymph nodes. Accordingly, a survival difference in NSABP trial B-32 is possible only if sentinel-node biopsy has an unacceptably high false negative rate — a situation that is preventable with adequate surgical training and experience.2,3
The inevitable conclusion of this study will be that sentinel-node biopsy should be performed with a low false negative rate. This we already know from a multitude of nonrandomized validation studies. Overall, NSABP trial B-32 suffers from a convoluted experimental design that seeks to test an implausible hypothesis. It cannot, and will not, prove that sentinel-node biopsy is any more “safe” than we already know it to be.
3 ReferencesKelly M. McMasters, M.D., Ph.D.
University of Louisville, Louisville, KY 40202
kelly.mcmasters@nortonhealthcare. org 1
Clarke D ,Khonji NI ,Mansel RE . Sentinel node biopsy in breast cancer: ALMANAC trial. World J Surg 2001;25:819-822
CrossRef | Web of Science | Medline2
Tafra L ,Lannin DR ,Swanson MS , et al. Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue dye. Ann Surg 2001;233:51-59
CrossRef | Web of Science | Medline3
McMasters KM ,Wong SL ,Chao E , et al. Defining the optimal surgeon experience for breast cancer sentinel lymph node biopsy: a model for implementation of new surgical techniques. Ann Surg 2001;234:292-300
CrossRef | Web of Science | Medline
Author/Editor Response
De Salvo et al. suggest waiting for larger trials before accepting sentinel-node biopsy for routine use. This is in line with the opinion expressed by Krag and Ashikaga, who mention trials that involve the randomization of a large number of patients to identify an “acceptable” reduction in survival of 2 percent to 5 percent. Trials testing a treatment that may lead to reduced survival are difficult to accept on ethical grounds. How can a patient participate in a trial knowing that the new treatment may reduce her chance of survival?
The modern concepts are that metastases in the lymph nodes are “indicators,” not “instigators,” of distant metastases1 and that the extent of treatment of these nodes does not influence survival. We based our study on this principle. In addition, the limited extent of down-staging due to the small percentage of false negative biopsy results (5 percent) is largely compensated for by the up-staging of more than 10 percent as a result of accurate examination of the sentinel node2; moreover, the preservation of normal lymph nodes might be beneficial.
Our statisticians decided on the number of patients needed to evaluate the acceptable number of overt axillary metastases during follow-up — a number that, however, does not influence survival. Randomization was also justified for the evaluation of other end points, including quality of life. Survival was considered because the maintenance of healthy lymphatic tissue in the sentinel-node group might yield a trend toward improvement in survival.
We agree with Krag and Ashikaga that the decision to use sentinel-node biopsy must be based on clinical judgment. In fact, sentinel-node biopsy is a diagnostic procedure. Therefore, the surgeon must decide whether to rely on the sentinel-node biopsy or whether, for clinical reasons, he or she prefers to perform the axillary dissection anyway.
We believe that waiting for the results of larger trials before offering the option of the sentinel-node biopsy will oblige thousands of women to undergo an unpleasant and useless removal of healthy lymph nodes. Sentinel-node biopsy was accepted as a routine procedure for patients with melanoma without any randomized trial and is a clinical practice for tumors of many organs. The 2001 Consensus Conference, in Philadelphia,3 concluded that because sentinel-node biopsy is a diagnostic procedure, randomized trials are not needed and the data available are sufficient to validate it. The results of our trial, conducted four years previously, lend strength to those conclusions.
3 ReferencesUmberto Veronesi, M.D.
Patrick Maisonneuve, Eng.
European Institute of Oncology, 20141 Milan, Italy
umberto.veronesi@ieo. it 1
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;347:567-575
Full Text | Web of Science | Medline2
Giuliano A ,Kirgan D ,Guenther JM ,Morton DL . Lymphatic mapping and sentinel lymphadenopathy for breast cancer. Ann Surg 1994;220:391-401
CrossRef | Web of Science | Medline3
Schwartz GF, Giuliano AE, Veronesi U, Consensus Conference Committee
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Munster points out that the quality-of-life outcomes reported by Veronesi et al. are “doctor-set” and argues for more effective instruments to measure the quality of life. We concur that such instruments are available and should be used. The National Cancer Institute supports this type of research, and cooperative groups in the United States use such instruments. Although not described in the editorial, NSABP trial B-32 does have a thorough quality-of-life component that meets modern standards and is readily available for critique by Dr. Munster.
The rationales for axillary-node resection are to maximize survival, provide long-term regional control, and obtain prognostic information. Collectively, multiple prospective, randomized trials have shown about a 5 percent decrease in survival among patients with breast cancer when axillary-node resection was omitted as the initial therapy.1 Modern reviews of large groups of patients with breast cancer also show that there is a reduction in survival associated with omission of the axillary-node resection.2 This association has been noted even with T1a or T1b early-stage breast cancers.3
Thus far, there are no data that directly compare long-term survival after sentinel-node biopsy alone with that after axillary-node resection alone. Trial B-32 is designed to determine this information in patients with clinically node-negative breast cancer and pathologically negative sentinel nodes. The hypothesis, specific aims, and primary end points of trial B-32 are succinct and clearly stated and have been rigorously peer-reviewed by clinicians, biostatisticians, and the Cancer Therapy Evaluation Program of the National Cancer Institute. Whatever parts of the protocol Dr. McMasters does not seem to understand have been understood by the more than 225 surgeons from 75 institutions that have enrolled more than 5000 patients with breast cancer in trial B-32.
Sentinel-node surgery is a remarkable addition to the surgical toolbox for treating cancers. If this approach were not so promising, there would be little interest in a clinical trial comparing the outcome of sentinel-node surgery with that of conventional regional-node surgery. But is a reduction in survival, even by a small percentage, a reasonable price to pay for the reduction in morbidity offered by sentinel-node surgery? A survey of patients indicates that the answer is no.4 Even though Dr. McMasters states that “we already know it to be,” the data to support that statement do not exist.
4 ReferencesDavid Krag, M.D.
Takamaru Ashikaga, Ph.D.
University of Vermont College of Medicine, Burlington, VT 054051
Orr RK . The impact of prophylactic axillary node dissection on breast cancer survival -- a Bayesian meta-analysis. Ann Surg Oncol 1999;6:109-116
CrossRef | Web of Science | Medline2
Bland KI ,Scott-Conner CE ,Menck H ,Winchester DP . Axillary dissection in breast-conserving surgery for stage I and II breast cancer: a National Cancer Data Base study of patterns of omission and implications for survival. J Am Coll Surg 1999;188:586-596
CrossRef | Web of Science | Medline3
White RE ,Vezeridis MP ,Konstadoulakis M ,Cole BF ,Wanebo HJ ,Bland KI . Therapeutic options and results for the management of minimally invasive carcinoma of the breast: influence of axillary dissection for treatment of T1a and T1b lesions. J Am Coll Surg 1996;183:575-582
Web of Science | Medline4
Gan S ,Magarey C ,Schwartz P ,Papadatos G ,Graham P ,Vallentine J . Women's choice between sentinel lymph node biopsy and axillary clearance. ANZ J Surg 2002;72:110-113
CrossRef | Web of Science | Medline
- Citing Articles (5)
Citing Articles
1
Kim M. van Pul, Ronald J.C.L.M. Vuylsteke, Herman Bril, Hein B.A.C. Stockmann, Tanja D. de Gruijl. (2011) Feasibility of flowcytometric quantitation of immune effector cell subsets in the sentinel lymph node of the breast after cryopreservation. Journal of Immunological Methods
CrossRef2
Rikiya Nakamura, Masahiro Sakakibara, Takeshi Nagashima, Takafumi Sangai, Manabu Arai, Toshihiko Fujimori, Shigetsugu Takano, Takashi Shida, Yukio Nakatani, Masaru Miyazaki. (2009) Accumulation of regulatory T cells in sentinel lymph nodes is a prognostic predictor in patients with node-negative breast cancer. European Journal of Cancer 45:12, 2123-2131
CrossRef3
Holbrook E. Kohrt, Navid Nouri, Kent Nowels, Denise Johnson, Susan Holmes, Peter P. Lee. (2005) Profile of Immune Cells in Axillary Lymph Nodes Predicts Disease-Free Survival in Breast Cancer. PLoS Medicine 2:9, e284
CrossRef4
Anees B Chagpar, Kelly M McMasters. (2004) Sentinel lymph node biopsy for breast cancer: from investigational procedure to standard practice. Expert Review of Anticancer Therapy 4:5, 903-912
CrossRef5
Rakhshanda Layeeque, Julie Kepple, Ronda S. Henry-Tillman, Laura Adkins, Rena Kass, Maureen Colvert, Regina Gibson, Anne Mancino, Soheila Korourian, V Suzanne Klimberg. (2004) Intraoperative Subareolar Radioisotope Injection for Immediate Sentinel Lymph Node Biopsy. Annals of Surgery 239:6, 841-848
CrossRef
