FEATURE

Sentinel Lymph Node Biopsy in Breast Cancer Ten-Year Results of a Randomized Controlled Study Umberto Veronesi, MD,* Giuseppe Viale, MD, FRCPath,†‡ Giovanni Paganelli, MD,§ Stefano Zurrida, MD,*‡¶ Alberto Luini, MD,¶ Viviana Galimberti, MD,¶ Paolo Veronesi, MD,‡¶ Mattia Intra, MD,¶ Patrick Maisonneuve, Eng,储 Francesca Zucca, DSc,¶ Giovanna Gatti, MD,¶ Giovanni Mazzarol, MD,† Concetta De Cicco, MD,§ and Dario Vezzoli, MD**

Objective: Sentinel node biopsy (SNB) is widely used to stage the axilla in breast cancer. We present 10-year follow-up of our single-institute trial designed to compare outcomes in patients who received no axillary dissection if the sentinel node was negative, with patients who received complete axillary dissection. Methods: From March 1998 to December 1999, 516 patients with primary breast cancer up to 2 cm in pathologic diameter were randomized either to SNB plus complete axillary dissection (AD arm) or to SNB with axillary dissection only if the sentinel node contained metastases (SN arm). Results: The 2 arms were well-balanced for number of sentinel nodes found, proportion of positive sentinel nodes, and all other tumor and patient characteristics. About 8 patients in the AD arm had false-negative SNs on histologic analysis: a similar number (8, 95% CI: 3–15) of patients with axillary involvement was expected in SN arm patients who did not receive axillary dissection; but only 2 cases of overt axillary metastasis occurred. There were 23 breast cancer-related events in the SN arm and 26 in the AD arm (log-rank, P ⫽ 0.52), while overall survival was greater in the SN arm (log-rank, P ⫽ 0.15). Conclusions: Preservation of healthy lymph nodes may have beneficial consequences. Axillary dissection should not be performed in breast cancer patients without first examining the sentinel node. (Ann Surg 2010;251: 595– 600)

A

lthough the term “sentinel lymph node” had been coined in the 1970s1 and preliminary studies undertaken in the same decade,2 sentinel lymph node biopsy (SNB) came to fruition in the 1990s. It was first used to detect metastases in the sentinel node (SN) of From the *European Institute of Oncology, Milan, Italy; †Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy; ‡University of Milan School of Medicine, Milan, Italy; §Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy; ¶Division of Senology, European Institute of Oncology, Milan, Italy; 㛳Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy; and **Division of Anaesthesiology, European Institute of Oncology, Milan, Italy. Trial Registration number: NCT00970983. U. Veronesi designed the study and did a large proportion of surgical procedures. G. Paganelli and C. De Cicco did the sentinel node lymphoscintigraphy. G. Viale and G. Mazzarol did pathological assessment of the primary tumors and sentinel nodes. A. Luini, S. Zurrida, V. Galimberti, M. Intra, P. Veronesi, G. Manfredi, and J. Rodriguez Fernandez enrolled, treated, and followed up the patients. G. Gatti supervised data collection. P. Maisonneuve did the statistical analysis. U. Veronesi wrote a draft of the paper which was revised and approved by all authors, who had full access to the data and take full responsibility for the decision to submit for publication. Reprints: Umberto Veronesi, MD, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. E-mail: [email protected]; or [email protected]. Copyright © 2010 by Lippincott Williams & Wilkins ISSN: 0003-4932/10/25104-0595 DOI: 10.1097/SLA.0b013e3181c0e92a

Annals of Surgery • Volume 251, Number 4, April 2010

melanoma patients and identify those most likely to benefit from immediate regional node dissection.3 The procedure was soon extended to breast cancer and today is extensively used to stage the axilla in this disease, allowing axillary lymph node dissection (AD) to be avoided if the SN is metastasis free. Observational studies4,5 had shown that SN status accurately predicts the status of the other axillary lymph nodes. However, objective evidence of the effect of no AD on survival and quality of life in breast cancer patients with a negative SN was not initially available. We therefore conducted a randomized trial6 between 1998 and 1999 to compare SNB followed by routine AD with SNB followed by AD only if the SN was positive. Preliminary results of that trial were published in 20036 and 2006.7 In the present article, we present updated results after 10-years of follow-up.

METHODS Patients and Procedures The single-center randomized trial recruited women with primary breast cancer of 2 cm or less treated with breast-conserving surgery. Eligible patients had no history of other cancer, except nonmelanoma skin cancer, no multicentric breast cancer, and no previous excisional biopsy. Before recruitment, patients were informed of the aims of the study, and the potential side-effects and risks associated with the procedures; all signed a consent form approved by the ethics committee of our Institute. Patients were randomly assigned either to SNB plus complete AD (AD arm) or to SNB followed by AD only if SNs were metastatic (SN arm). Of 516 evaluable patients, 410 (79%) were injected with radioactive tracer the evening before surgery; in the other 106 (21%) patients, scheduled for surgery later in the day, radioactive tracer was injected in the early morning on the day of surgery. In all cases, 5 to 10 MBq of technetium-99m-labeled particles (50 –200 nm) of human colloidal albumin in 0.2 mL saline was injected close to the tumor.8,9 Anterior and anterior-oblique lymphoscintigraphic projections of the breast and axilla were then obtained to precisely locate the SN. SNB was done during breast surgery, 4 to 20 hours after radioactive tracer injection. A gamma ray-detecting probe in a sterile glove was used to identify the “hot” SN and assist its removal during surgery (immediately after wide resection or quadrantectomy of the primary tumor).4,10,11 After the gamma probe had verified the presence of SN, and the macroscopic size of the tumor had been determined, the treatment group to which a patient was randomized was communicated to the surgeon in the operating room by the data manager. Randomization was by computer-generated permutated block allocation and the randomization code was concealed from the surgeons. If the tumor was in the upper-outer breast quadrant, the breast incision was extended to the SN in the axilla using the probe as guide. In the other cases, a separate incision for SNB was necessary. Removed SNs were sent for immediate frozen-section analysis. In www.annalsofsurgery.com | 595

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patients of the SN arm, if the lymph node was negative, the operation was concluded. In patients of the AD arm and in patients of the SN arm with a positive SN, complete AD was done immediately. All lymph nodes at level I (lateral to the lateral margin of the pectoralis minor muscle), level II (behind the pectoralis minor), and level III (medial to the medial margin of the pectoralis minor) were removed.12 Patients who received AD remained in hospital a median of 4 days (range: 2–5); those who had SNB only remained a median of 2 days (range: 0 –3). The SN was bisected along its major axis, embedded (cut surface up) in Optimal Cutting Temperature Compound (OCT) (CellPath, Hemel Hempstead, United Kingdom), and frozen in isopentane cooled with liquid nitrogen. SNs less than 5 mm in diameter were embedded and frozen uncut.13 If more than one SN was obtained from a patient, all SNs were examined. For each SN large enough to be cut, 15 pairs of 4 ␮m-thick frozen sections were cut at 50 ␮m intervals in each half lymph node (60 sections per node). If residual tissue was left, additional pairs of sections were cut at 100 ␮m intervals until the node was sampled completely. One section of each pair was stained with hematoxylin and eosin. If the result was ambiguous, the mirror section was stained for cytokeratins by a rapid method (EPOS cytokeratin reagent with horseradish peroxidase, Dako Glostrup, Denmark) employing the MNF116 monoclonal antibody. The other lymph nodes, removed by conventional AD, were assessed by standard techniques: Nodes ⬎5 mm in diameter were bisected; those of ⱕ5 mm were fixed and embedded uncut. About 3 to 6 sections were obtained from each node at different levels, 100 to 500 ␮m apart, and stained with hematoxylin and eosin. All patients subsequently received radiotherapy to the ipsilateral breast over an 8-week period. The dose was 50 Gy using 2 opposed tangential fields of high-energy photons, and a 10 Gy boost to the skin around the surgical scar. Great care was taken to avoid irradiating the axilla. Systemic adjuvant treatments were given according to protocols in force at our Institute (Table 1).

Statistical Methods The trial was designed as an equivalence trial with sample size originally calculated on patients with negative SNs. On the assumption that axillary metastases would develop in not more than 5% of women with negative SNs in the SN arm5 and not more than 1% of the AD arm, we calculated that 245 patients with negative lymph nodes in each group were required to show equivalence between the groups (difference of not more than 5%) in terms of the proportion of nodal metastases, with a power of 90% and alpha level of 5%. A reassessment of the study power based on the 516 eligible patients (around 30% of whom had positive SNs) randomized up to December 1999, showed that the study had an 84% probability of distinguishing between an acceptable (5%) and an unacceptable (10%) proportion of women with nodal metastases at 5 years using

TABLE 1. Systemic Adjuvant Treatments in the AD and SN Arms

Hormonal therapy Chemotherapy Hormonal therapy plus chemotherapy None

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AD Arm (n ⴝ 257)

SN Arm (n ⴝ 259)

133 (52%) 21 (8%) 99 (39%) 4 (2%)

126 (49%) 16 (6%) 106 (41%) 11 (4%)

a one-sided test. This statistical power was judged sufficient and patient accrual was stopped. The statistical analyses were performed per protocol with patients excluded who were ineligible after surgery due to benign, multicentric, or metastatic disease, and those in whom SN identification was unsuccessful. The main study endpoints were the number of axillary metastases during follow-up in patients in the SN arm with a negative SN, and disease-free and overall survival. Time free of any breast-cancer-related event was calculated from date of surgery to date of event or latest follow-up. Overall survival was defined as time from surgery to death from any cause, or latest follow-up. Disease-free and overall survival curves were calculated according to Kaplan-Meier, and differences assessed by the log-rank test (considered significant for P ⬍ 0.05). Associations between axillary node status and primary tumor characteristics were assessed by Fisher exact test. Logistic regression was used to assess the association between characteristics (age, tumor size, location grade, presence of perivascular invasion,14 estrogen-receptor status, and proliferative rate) and SN metastases. All P values were 2-sided. SAS version 8.02 was used to perform the analyses.

TABLE 2. Characteristics of the 516 Patients in the 2 Study Arms AD Arm (N ⴝ 257) SN Arm (N ⴝ 259) Age, yr Median (range) ⱕ45 yr 46–55 yr 56–65 yr ⬎65 yr Tumor size ⱕ1 cm 1.1–1.5 cm ⬎1.5 cm Tumor location Outer quadrants Inner and central quadrants Histological type Ductal Lobular Other Estrogen receptor status Positive Negative Missing Proliferating fraction (Ki 67)* ⬍20% ⱖ20% Missing Tumor grade I II III Missing Perivascular invasion Present Absent

56 (40–75) 35 (14%) 88 (34%) 92 (36%) 42 (16%)

55 (40–75) 32 (12%) 99 (38%) 92 (36%) 36 (14%)

65 (25%) 123 (48%) 69 (27%)

65 (25%) 120 (46%) 74 (29%)

187 (72%) 70 (27%)

186 (72%) 73 (28%)

212 (83%) 20 (8%) 25 (10%)

209 (81%) 18 (7%) 32 (12%)

236 (92%) 21 (8%) 0

237 (92%) 21 (8%) 1 (⬍1%)

166 (65%) 91 (35%) 0

170 (66%) 88 (34%) 1 (⬍1%)

81 (32%) 119 (46%) 54 (21%) 3 (1%)

82 (32%) 128 (49%) 47 (18%) 2 (1%)

43 (17%) 214 (83%)

44 (17%) 215 (83%)

*Percentage of nuclei expressing the Ki-67 antigen.

© 2010 Lippincott Williams & Wilkins

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RESULTS Between March 1998 and December 1999, 649 consecutively presenting women were candidates for the study: 78 (12%) were ineligible before randomization, 25 (4%) declined to take part, 14 (2%) were not randomized for other reasons, and 532 (82%) were randomized; of the latter 16 (3%) were excluded after pathologic analysis of the resected tumor. Table 2 summarizes the characteristics of the remaining 516 patients included in the present analysis. Table 3 shows primary tumor characteristics predictive of SN status in these 516 patients. By far the most important predictor of SN positivity was presence of perivascular invasion: 61/87 patients (70%) with this condition had a positive SN. Tumor size was also significantly predictive of SN metastasis: 28/130 patients (22%) with tumors ⱕ1.0 cm had SN involvement, rising to 55 of 143 (38%) with tumors ⬎1.5 cm. Age, site of primary carcinoma, estrogen receptor status, grade, and Ki67 index were not significantly related to SN involvement as shown in multivariate analysis. A total of 429 SNs were removed and assessed from the 257 patients in the AD group (mean: 1.66 SNs/patient); 424 SNs were removed from the 259 patients in the SN group (mean: 1.63 TABLE 3. Primary Tumor Characteristics Predictive of SN Status in the Entire Series Odds Radio (95% CI)

Age, yr ⱕ45 46–55 56–65 ⬎65 Tumor size ⱕ1.0 cm 1.1–1.5 cm ⬎1.5 cm Tumor site Outer quadrants Inner and central quadrants Grade I II III Missing Perivascular invasion Absent Present Estrogen receptor status Positive Negative Missing Proliferating fraction (Ki67)* ⬍20% ⱖ20% Missing

N

SN Positive

67 187 184 78

20 (30%) 71 (38%) 62 (34%) 22 (28%)

Univariate

Multivariate

1.00 1.00 1.44 (0.79–2.62) 1.86 (0.94–3.70) 1.19 (0.65–2.19) 1.71 (0.86–3.40) 0.92 (0.45–1.90) 1.35 (0.60–3.03)

SNB in Breast Cancer

SNs/patient). A mean of 24 nonsentinel axillary lymph nodes per patient were removed from the 347 patients who received AD. After a mean follow-up of 95 months (median: 102, range: 1–120), 86 events had occurred (Table 4), 49 of which were associated with the treated breast cancer (local recurrences, regional lymph node metastases, distant metastases): 26 in the AD arm and 23 in the SN log-rank, P ⫽ 0.52 (Fig. 1). A 10-year breast cancer-related event-free survival was 88.8% (95% CI: 84.6%–92.9%) in the AD arm and 89.9% (95% CI: 85.9%–93.9%) in the SN arm. Of the 167 patients, 2 in the SN arm who did not receive AD developed overt axillary metastasis, one patient 6.3 years after surgery and the other 7.2 years after surgery (Table 4). Among the 174 AD arm patients who had a negative SN, 8 (5%) were found to have false-negative SNs on histologic analysis: 3 had micrometastatic disease in 1 axillary lymph node, 3 had 1 or 2 positive axillary nodes, 1 had 4 metastatic axillary nodes, and 1 patient had 17 positive axillary nodes.6 We therefore expected that a similar number of patients in the SN arm would harbor metastases in other axillary nodes even though the SN was negative. In fact, we estimated that 8 (95% CI: 3–15) of the 167 SN arm patients with negative SNs had occult axillary involvement. Figure 2 illustrates this point, showing the cumulative incidence of axillary metastases in the SN arm compared with that expected, assuming that 5% of SNs were false negatives. Two AD arm patients developed metastases in the supraclavicular lymph nodes: in both the SN was positive for micrometastasis (⬍2 mm) but no other axillary nodes were found to be involved. Distant metastases developed in 20 AD arm patients and 17 SN arm patients (log-rank, P ⫽ 0.50) (Fig. 1). Contralateral breast carcinoma developed in 10 AD arm patients, and in 9 SN arm

TABLE 4. Unfavorable Events in the 2 Study Arms 130 243 143

28 (22%) 92 (38%) 55 (38%)

1.00 1.00 2.38 (1.43–3.93) 2.10 (1.23–3.60) 2.47 (1.43–4.27) 2.12 (1.15–3.90)

373 143

134 (36%) 41 (29%)

1.00 1.00 0.72 (0.47–1.09) 0.75 (0.47–1.18)

163 247 101 5

52 (32%) 86 (35%) 36 (36%) 1 (20%)

1.00 1.00 1.14 (0.75–1.74) 0.79 (0.48–1.29) 1.18 (0.70–2.00) 0.58 (0.27–1.28)

429 87

114 (27%) 61 (70%)

1.00 1.00 6.48 (3.91–10.8) 6.37 (3.72–10.9)

473 42 1

159 (34%) 16 (38%) 0

1.00 1.00 1.22 (0.63–2.33) 1.93 (0.89–4.19)

336 179 1

110 (32%) 65 (36%) 0

1.00 1.00 1.17 (0.80–1.71) 1.07 (0.62–1.85)

*Percentage of nuclei expressing the Ki-67 antigen.

© 2010 Lippincott Williams & Wilkins

AD Arm SN Arm P (N ⴝ 257) (N ⴝ 259) (log-rank) First breast cancer-related events Axillary metastasis Supraclavicular metastasis Intra-breast tumor reappearance Distant metastasis Total breast cancer-related events Other primary tumors Contralateral breast cancer Non-breast cancer Melanoma Non-Hodgkin lymphoma Lung cancer Colon cancer Thyroid-parathyroid cancer Pancreatic cancer Ovarian cancer Endometrial cancer Sarcoma Skin cancer Total events Deaths Breast cancer death Death for other cause Death from unknown cause Total deaths

0 2 4 20 26

2 0 4 17 23

0.17 0.15 0.93 0.50 0.52

10 12 1 0 1 2 2 2 1 1 1 1 22

9 6 1 1 2 1 1 0 0 0 0 0 15

0.71 0.13

0.19

14 6 3 23

11 3 1 15

0.15

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FIGURE 1. (A) Overall survival and cumulative incidence of (B) breast cancer-related events, (C) distant metastasis in AD and SN arms, and (D) distant metastasis in women (AD and SN arms combined) with a positive SN according size of SN metastasis (micro ⫽ micrometastatic or ⬍2 mm; macro ⫽ macrometastatic or ⱖ2 mm). patients (log-rank, P ⫽ 0.71). Primary tumors in other organs developed in 12 AD arm patients and in 6 SN arm patients (log-rank, P ⫽ 0.13) (Table 4). Patients with micrometastases in the SN node had lower rates of breast cancer-related events and distant metastasis than those with macrometastases but the differences were not statistically significant (Fig. 1). Of total, 38 patients have died, 23 in the AD arm and 15 in the SN arm (log-rank, P ⫽ 0.15; Table 4). Overall 10-year survival was 89.7% (95% CI: 85.5–93.8) in the AD arm and 93.5% (95% CI: 90.3%–96.8%) in the SN arm (Fig. 1). In the 25 women who died of their treated breast diseases, perivascular invasion was present in 8 cases; Ki67 index was 20% or less in 10 cases, and more than 20% in 15 cases; tumor size was up to 1.0 cm in 5 cases, between 1.1 cm and 1.5 cm in 7 cases, and more than 1.5 cm in the remaining 13 cases.

DISCUSSION FIGURE 2. Observed and expected axillary metastases over time in patients with negative sentinel node in SN arm. 598 | www.annalsofsurgery.com

That radical excision of the primary cancer should be accompanied by regional lymph node removal has been a fundamental precept of cancer surgery since the early 20th century. Regional lymph node removal was considered necessary because the nodes © 2010 Lippincott Williams & Wilkins

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take up malignant cells detaching from the primary, and may be a source of distant metastasis, but when small numbers of malignant cells are present they cannot be detected clinically. This rationale appeared so self-evident that improved cancer survival was in part attributed to wide application of regional node dissection. The regional nodes were preferably removed together with the primary, and whenever possible, the dissection had to be en bloc so that the lymphatic vessels connecting the primary to the nodal station were also removed. However, a randomized trial on melanoma patients published in 1977 indicated that these ideas were not always correct.3 This trial found that therapeutic dissection when nodal metastases became overt was associated with identical disease-free and overall survival to prophylactic dissection of clinically negative lymph nodes. This result was initially greeted with incredulity but nevertheless stimulated efforts to find less aggressive approaches to regional lymph nodes. In the same year (1977), Cabanas1 had published his results on the “sentinel lymph node” as the primary site of metastases from penile carcinoma; he concluded that when the biopsied SN is negative for metastatic disease, further surgical therapy is not indicated. More extensive and convincing studies were conducted in the early 1990s by Morton and his group on melanoma patients.2 They injected blue dye into the skin around the site of the primary and were able to identify and remove the blue regional lymph node (SN) and examine it for metastatic involvement. The technique identified, with a high degree of accuracy, those patients with nodal metastases most likely to benefit from radical lymphadenectomy. Thus, was born SNB—a selective and decidedly more conservative approach to the regional lymph nodes. SNB was soon extended to breast cancer and it was shown, in the early 1990s, that SNB was able to reliably predict axillary status in breast cancer.15,16 Krag et al15 used radiotracer and gamma-detecting probe to identify the SN; Giuliano et al16 used blue dye. In the early 1990s, we in Milan also embarked on a program to identify the SN using radioactive tracer. One problem was find a radionuclide carrier particle whose size was such that it would migrate in the lymphatic ducts after injection close to the tumor, but be held by the first (sentinel) node and not diffuse to other axillary nodes. We found that albumin particles of size 50 to 200 nm were best for this purpose, and they could easily be labeled with 99mTc. We published our first results on 163 cases in 1997, showing that SNB with radiolabeled albumin particles was safe and able to reliably stage the axilla.5 Following this publication, the technique was adopted in many European countries. In the United States, however, SNB procedure was developed that employed radiolabeled colloidal sulfur. These particles are on average considerably smaller than those we use so that an excessive number of “hot” nodes is revealed within the axilla (up to 8 –12). As a result, the biopsy procedure takes longer, while intraoperative pathologic examination of all the “hot” nodes is problematic. Our next step was to formally validate our SNB procedure by means of randomized trial.6,7 The present article presents 10-year follow-up results of that trial. The trial has found that 10-year survival was closely similar in both groups of patients, confirming that the SN policy of foregoing AD when the SN is negative after extensive frozen section examination is as effective as the oncestandard treatment of axillary dissection. Interestingly, overall survival was somewhat better in the SN arm, and new cancers in other organs also occurred less frequently in this arm (15 cases) than the AD arm (22 cases). None of these differences were significant, but they lead us to speculate that not removing healthy axillary lymph nodes may be beneficial to patients. The most important predictors of SN involvement were perivascular invasion and tumor size.17–20 Among patients in the SN arm who did not receive AD, a lower than expected proportion developed overt axillary metastasis © 2010 Lippincott Williams & Wilkins

SNB in Breast Cancer

during the 10-year follow-up. The possibility that occult metastases may never become clinically evident if the axilla has been left intact has been raised many times.21 In a series of 221 patients with small breast cancer (⬍1.2 cm) receiving conservative breast surgery without AD,22 overt axillary metastases developed in only 3 after mean follow-up of 63 months, instead of the 52 cases expected. A similarly low rate of axillary metastases was found in 3548 patients with negative SNs and no AD followed for 10 years.23 It is now known that microscopic cancer foci may be present in various organs (prostate, thyroid, breast, bone marrow) and never develop into overt clinical disease. It is presumed that immunologic surveillance effectively removes these clumps of diseased cells.24 A recent hypothesis is that cancers consist of a large number of non-stem cancer cells and a much smaller number cancer stem cells, and that only the latter can bring about disease progression. According to this hypothesis, some of the 8 patients in our SN group expected harbor axillary disease may have had metastases lacking cancer stem cells, and these metastases may eventually disappear or have a very long dormancy. Another possible reason for the low rate of axillary metastases is that the axillae were incidentally irradiated by the radiotherapy given to the breast. This is unlikely, however, as most patients received conformational radiotherapy to the breast only, including the axillary tail but excluding the first Berg level of the axilla.22 It is noteworthy that in 60 of 175 patients with positive SNs, only micrometastases (foci ⱕ2 mm) were detected in the SNs, and in only 10 (17%) of these cases were other axillary lymph nodes found to be metastatic. It is also noteworthy that patients with micrometastases appeared to have a lower rate of distant metastases than those with macrometastases (Fig. 2). These findings raise the question of the prognostic value of micrometastasis in the SN. To address this question, we are participating in an IBCSG trial to compare complete AD with no AD (follow-up only) in patients with only micrometastasis in the SN. We speculate that patients with micrometastatic SN involvement may not need AD, particularly since follow-up with ultrasonography and PET can detect very small (5 mm) axillary disease,25,26 which may be adequately treated by therapeutic AD. Although our trial is small-only 516 patients recruited—in comparison to ongoing multicentric trials, all patients were treated at a single center by an experienced senology team using a single SN identification technique, a single pathologic assessment technique, and a single radiotherapy protocol. Furthermore, randomization was performed in the operating room during surgery, and follow-up was identical for all patients. Thus, the 2 groups were treated identically except for the variable under assessment (lack of AD when the SN was negative). In medical oncology, study drugs can easily be administered by identical procedures across of numerous centers. This is not the case in surgical oncology since surgical techniques and surgeon experience vary widely10 with the consequent risk of reducing uniformity. To conclude, we have found that the long-term breast cancerrelated event-free survival in the SN arm (89.9%) was similar to that in the AD arm (88.8%) enabling us to affirm not only that SNB is as good as complete axillary dissection at staging the axilla, but that it is as safe as the once standard method of complete axillary dissection. SNB makes it possible avoid AD in the considerable proportion of breast cancer patients with an uninvolved SN, thereby reducing postoperative morbidity and the length of postoperative hospitalization. The lower-than-expected cumulative incidence (0.9%; 95% CI: 0.0%–2.2%) of axillary metastasis in the SN group at 10 years is also noteworthy, and may be due to effective immunologic surveillance by an intact immune system or because only a small fraction cancer foci within the axilla contain cancer stem cells that can www.annalsofsurgery.com | 599

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develop into clinically overt disease. Cancer stem cells may become an important target for future approaches regional lymph node management in cancer. ACKNOWLEDGMENTS The authors thank AIRC (Associazione Italiana per la Ricerca sul Cancro) and the American-Italian Cancer Foundation for support, Maria Grazia Villardita for help in the preparation of the manuscript and Don Ward for help with the English. REFERENCES 1. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456 – 466. 2. Morton D, Wen D, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392–399. 3. Veronesi U, Adamus J, Bandiera DC, et al. Inefficacy of immediate node dissection in stage I melanoma of the limbs. N Engl J Med. 1977;297:627– 630. 4. Giuliano AE, Kirgan DM, Guenther JM, et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994;220:391– 401. 5. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel node biopsy can avoid axillary dissection in breast cancer patients with clinically negative lymphnodes. Lancet. 1997;349:1864 –1867. 6. 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. 7. Veronesi U, Paganelli G, Viale G, et al. Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of randomized controlled study. Lancet Oncol. 2006;7:983–990. 8. De Cicco C, Cremonesi M, Luini A, et al. Lymphoscintigraphy and radioguided biopsy of the sentinel axillary node in breast cancer. J Nucl Med. 1998;39:2080 –2084. 9. Paganelli G, De Cicco C, Cremonesi M, et al. Optimized sentinel node scintigraphy in breast cancer. Q J Nucl Med. 1998;42:49 –53. 10. Krag D, Weaver D, Ashikana T, et al. The sentinel node in breast cancer–a multicenter validation study. N Engl J Med. 1998;339:941–946. 11. Zurrida S, Costa A, Luini A, et al. The Veronesi quadrantectomy: an established procedure for the conservative treatment of early breast cancer. Int J Surg Investig. 2001;2:423– 431.

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