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Jama breast cancer_study
1.
ORIGINAL CONTRIBUTION Axillary Dissection
vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis A Randomized Clinical Trial Armando E. Giuliano, MD Context Sentinel lymph node dissection (SLND) accurately identifies nodal metas- Kelly K. Hunt, MD tasis of early breast cancer, but it is not clear whether further nodal dissection affects Karla V. Ballman, PhD survival. Peter D. Beitsch, MD Objective To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer. Pat W. Whitworth, MD Design, Setting, and Patients The American College of Surgeons Oncology Group Peter W. Blumencranz, MD Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients A. Marilyn Leitch, MD from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases iden- Sukamal Saha, MD tified by frozen section, touch preparation, or hematoxylin-eosin staining on perma- Linda M. McCall, MS nent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, Monica Morrow, MD but the trial closed early because mortality rate was lower than expected. Interventions All patients underwent lumpectomy and tangential whole-breast irra- A XILLARY LYMPH NODE DISSEC- diation. Those with SLN metastases identified by SLND were randomized to undergo ALND tion (ALND) has been part of or no further axillary treatment. Those randomized to ALND underwent dissection of 10 breast cancer surgery since the or more nodes. Systemic therapy was at the discretion of the treating physician. description of the radical mas- Main Outcome Measures Overall survival was the primary end point, with a non- tectomy.1 ALND reliably identifies nodal inferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone metastases and maintains regional con- is noninferior to ALND. Disease-free survival was a secondary end point. trol,2,3 but the contribution of local Results Clinical and tumor characteristics were similar between 445 patients ran- therapy to breast cancer survival is con- domized to ALND and 446 randomized to SLND alone. However, the median num- troversial.4,5 The Early Breast Cancer Tri- ber of nodes removed was 17 with ALND and 2 with SLND alone. At a median fol- alists’ Collaborative Group synthesized low-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% findings from 78 randomized con- (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%- trolled trials, concluding that local con- 95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%- 86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The haz- trol of breast cancer was associated with ard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without improved disease-specific survival.6 adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy. ALND, as a means for achieving lo- Conclusion Among patients with limited SLN metastatic breast cancer treated with cal disease control, carries an indisput- breast conservation and systemic therapy, the use of SLND alone compared with ALND able and often unacceptable risk of com- did not result in inferior survival. plications such as seroma, infection, and Trial Registration clinicaltrials.gov Identifier: NCT00003855 lymphedema.7-9 Sentinel lymph node JAMA. 2011;305(6):569-575 www.jama.com dissection (SLND) was therefore devel- oped to accurately stage tumor- Author Affiliations: John Wayne Cancer Institute at (Dr Leitch); McLaren Regional Medical Center, Michi- draining axillary nodes with less mor- Saint John’s Health Center, Santa Monica, California gan State University, Flint (Dr Saha); American College bidity than ALND.10 SLND alone is the (Dr Giuliano); M. D. Anderson Cancer Center, Hous- of Surgeons Oncology Group, Durham, North Caro- ton, Texas (Dr Hunt); Mayo Clinic Rochester, Roch- lina (Ms McCall); and Memorial Sloan-Kettering accepted management for patients whose ester, Minnesota (Dr Ballman); Dallas Surgical Group, Cancer Center, New York, New York (Dr Morrow). Dallas, Texas (Dr Beitsch); Nashville Breast Center, Corresponding Author: Armando E. Giuliano, MD, John Nashville, Tennessee (Dr Whitworth); Morton Plant Wayne Cancer Institute at Saint John’s Health Cen- For editorial comment see p 606. Hospital, Clearwater, Florida (Dr Blumencranz); Uni- ter, 2200 Santa Monica Blvd, Santa Monica, CA 90404 versity of Texas Southwestern Medical Center, Dallas (giulianoa@jwci.org). ©2011 American Medical Association. All rights reserved. (Reprinted) JAMA, February 9, 2011—Vol 305, No. 6 569 Downloaded from jama.ama-assn.org at Oregon Health & Science University on February 9, 2011
2.
SENTINEL NODE DISSECTION
IN INVASIVE BREAST CANCER they had received neoadjuvant hor- Figure 1. Study Flow monal therapy or chemotherapy. 891 Patients randomized Study Design and Treatment Before randomization, all women un- 445 Randomized to receive ALND 420 Received ALND as 446 Randomized to receive SLND alone 436 Received SLND alone derwent SLND and were stratified ac- randomized as randomized cording to age ( 50 and 50 years), es- 25 Withdrew prior to surgery 10 Withdrew prior to surgery trogen-receptor status, and tumor size ( 1 cm, 1 cm and 2 cm, or 2 cm). 92 Lost to follow-up 74 Lost to follow-up 2 Discontinued intervention 3 Discontinued intervention Eligible women were randomly as- 1 Refused after randomization 2 Refused after randomization but prior to surgery but prior to surgery signed to ALND or no further axillary- 1 Consent obtained after 1 Opted for alternative therapy specific intervention—specifically, no patient registered third-field nodal irradiation. ALND was 420 Included in primary analysis 436 Included in primary analysis defined as an anatomical level I and II dis- 25 Excluded (withdrew prior to surgery) 10 Excluded (withdrew prior to surgery) section including at least 10 nodes. All women were to receive whole-breast ALND indicates axillary lymph node dissection; SLND, sentinel lymph node dissection. opposing tangential-field radiation therapy. The use of adjuvant systemic sentinel lymph nodes (SLNs) are histo- conclusively demonstrated a survival therapy was determined by the treating logically free of tumor, while ALND re- benefit or detriment for omitting ALND physician and was not specified in the mains the standard of care for patients when metastatic breast cancer is identi- protocol. whose SLNs contain metastases.11 fied by SLND. In the late 1990s, the Patients most commonly entered the Cancer biology is much better under- American College of Surgeons Oncol- study post-SLND following identifica- stood now than it was when ALND was ogy Group designed and began the mul- tion of metastases on final pathology re- introduced. Biological factors may affect ticenter Z0011 trial. The primary aim of port. However, of the 891 registered pa- the predilection of some malignant cells this study was to determine the effects tients, 287 were registered pre-SLND to selectively invade lymph nodes rather of ALND on overall survival in patients and assigned to treatment after intraop- than visceral organs, just as certain tu- with SLN metastases treated in the con- erative documentation of SLN metasta- mor types metastasize to certain organs temporary era with lumpectomy, adju- ses. Patients in this group subsequently and not others.12 Recognition of the com- vant systemic therapy, and tangential- found to have 3 or more tumor-involved plexity of tumor biology has changed field radiation therapy. lymph nodes were included in the analy- cancer treatment, with more liberal use sis. Patients were assessed for disease re- of systemic therapy to treat occult can- METHODS currence according to standard clinical cer cells wherever they may be in the Patient Characteristics practice. History and physical examina- body. Consequently, the decision to ad- This multicenter, randomized phase 3 tion were performed every 6 months for minister systemic therapy is influenced trial was registered with the National the first 36 months and yearly thereaf- by a variety of patient- and tumor- Cancer Institute and approved by the in- ter. Annual mammography was re- related factors, with lymph node tumor stitutional review boards of participat- quired; other testing was based on symp- status influencing13,14 but not necessar- ing centers. All patients provided writ- toms and investigator preference. ily dictating the use of chemotherapy.15-18 ten informed consent. Adult women Other factors, such as early cancer de- with histologically confirmed invasive Study End Points tection by screening mammography, breast carcinoma clinically 5 cm or less, The primary end point was overall sur- have led to earlier intervention in breast no palpable adenopathy, and an SLN vival, defined as the time from random- cancer, reducing the incidence of nodal containing metastatic breast cancer ization until death from any cause. A metastases and even the number of tu- documented by frozen section, touch short-term primary end point was oc- mor-involved lymph nodes.19 preparation, or hematoxylin-eosin stain- currence of surgical morbidities. The These evolving concepts have called ing on permanent section were eligible study plan was to report surgical mor- into question the need for ALND.20,21 A for participation. Patients with metas- bidities following the completion of ac- variety of algorithms have been devel- tases identified initially or solely with im- crual and prior to overall survival re- oped to help clinicians decide which pa- munohistochemical staining were ineli- porting after receiving permission from tients would benefit from ALND.22-24 Re- gible. Treatment with lumpectomy to the data and safety monitoring com- view of Surveillance, Epidemiology, and negative margins (no tumor at ink) was mittee. These morbidities have been End Results data has shown that the use required. Women were ineligible if they reported.10 of ALND for SLN metastases has de- had 3 or more positive SLNs, matted A secondary end point was disease- creased in recent years.25 No study has nodes, or gross extranodal disease, or if free survival, defined as the time from 570 JAMA, February 9, 2011—Vol 305, No. 6 (Reprinted) ©2011 American Medical Association. All rights reserved. Downloaded from jama.ama-assn.org at Oregon Health & Science University on February 9, 2011
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IN INVASIVE BREAST CANCER randomization to death or first docu- tained at .05. However, none of the Table 1. Baseline Patient and Tumor mented recurrence of breast cancer. planned interim analyses were per- Characteristics by Study Group Breast cancer recurrence was catego- formed before the study was closed based No. (%) rized as locoregional disease (tumor in on the recommendation of the data and the breast or ipsilateral supraclavicu- safety monitoring committee. Because of ALND SLND Alone Characteristic (n = 420) (n = 436) lar, subclavicular, internal mammary, this, a single terminal hypothesis test with Age, median (range), y 56 (24-92) 54 (25-90) or axillary nodes) or distant metasta- an of .05 is applied to the data, which Missing 7 10 ses. Disease-free survival and its com- makes it consistent with the planned Clinical T stage ponents (locoregional disease and dis- overall significance level of .05 in the T1 284 (67.9) 303 (70.6) tant metastases) are reported instead of original study plan. T2 134 (32.1) 126 (29.4) Missing 2 7 the protocol-specified secondary end Ineligible patients were retained in Tumor size, median 1.7 (0.4-7.0) 1.6 (0.0-5.0) point (eg, distant disease–free sur- all analyses (ie, both the intent-to- (range), cm vival) to facilitate comparison with treat analyses and the treatment- Missing 6 14 other studies. received analyses). Kaplan-Meier sur- Receptor status vival curves for overall survival were ER /PR 256 (66.8) 270 (68.9) Statistical Analysis ER /PR− 61 (15.9) 54 (13.8) compared by log-rank test. The unad- ER−/PR 3 (0.8) 4 (1.0) The primary end point was overall sur- justed HR (and 90% CI) was calcu- ER−/PR− 63 (16.5) 64 (16.3) vival as a measure of noninferiority of lated using a Cox regression analysis, Missing 37 44 no further axillary specified interven- and noninferiority P values are re- LVI tions (SLND-alone group) compared ported. As a secondary analysis, known Yes 129 (40.6) 113 (35.2) with the ALND group. Based on the lit- prognostic factors including adjuvant No 189 (59.4) 208 (64.8) erature at the time of study design, we treatment were included in the Cox re- Missing 102 115 hypothesized that overall survival was gression model to generate an ad- Modified Bloom- Richardson score 80% at 5 years for optimally treated justed HR for overall survival (with a 1 71 (22.0) 81 (25.6) women with positive nodes.26-28 Clini- 90% CI and noninferiority P values). 2 158 (48.9) 148 (46.8) cal noninferiority was defined as the Disease-free survival was analyzed using 3 94 (29.1) 87 (27.5) SLND-alone group having a 5-year sur- Kaplan-Meier curves and univariable Missing 97 120 vival of not less than 75% of that ob- and multivariable Cox regression analy- Tumor type Infiltrating ductal 344 (82.7) 356 (84.0) served in the ALND group. Noninferi- ses with 95% CIs. The fact that there Infiltrating lobular 27 (6.5) 36 (8.5) ority of the SLND-alone treatment was were only 94 deaths limited the num- Other 45 (10.8) 32 (7.5) also considered if the hazard ratio (HR) ber of variables that could be used in a Missing 4 12 for mortality was less than 1.3 when multivariable model without affecting Lymph node compared with ALND. An estimated 500 model stability. We created a base metastases 0 4 (1.2) 29 (7.0) deaths were needed for the study to have model that included the treatment 1 199 (58.0) 295 (71.1) 90% power to confirm noninferiority of group (SLND alone vs ALND), age 2 68 (19.8) 76 (18.3) SLND alone compared with ALND, with ( 50 vs 50 years), and whether the 3 25 (7.3) 11 (2.7) the use of a 2-sided 90% confidence in- patient received adjuvant therapy (yes 4 47 (13.7) 4 (1.0) terval (CI) for the HR from a Cox re- vs no) and added prognostic variables Missing 77 21 gression model.29 Specifically, if the to this model individually. Only vari- Abbreviations: ALND, axillary lymph node dissection; ER, es- trogen receptor; LVI, lymphovascular invasion; PR, proges- 90% CI for the HR was below 1.3, this ables obtained on 90% or more of the terone receptor; SLND, sentinel lymph node dissection. would indicate that patients undergo- patients were included in the multi- ing SLND alone do not have an unac- variable analysis. Locoregional recur- ceptably worse overall survival than pa- rence rates were compared with the 2004 based on a recommendation of the tients undergoing SLND plus ALND. Fisher exact test. Each analysis, other independent data and safety monitor- The use of a 2-sided 90% CI corre- than analysis for the primary end point ing committee because of concerns re- sponds to a 1-sided significance level of of overall survival, was performed with garding the extremely low mortality .05.30 The enrollment of 1900 patients in 2-sided P values, 5% significance, and rate. Even if the trial had accrued the 4 years with a minimum follow-up pe- a 95% CI; all analyses were performed targeted 1900 patients, it would have riod of 5 years was initially planned. Four using SAS release 9.1 (SAS Institute Inc, taken more than 20 years of follow-up formal interim analyses and 1 final analy- Cary, North Carolina). to observe 500 deaths at the realized sis were planned for overall survival, and event rate. At the time of the decision the O’Brien-Flemming -spending strat- RESULTS to terminate the study there had been egy was used to generate stopping Patient Characteristics no formal analysis comparing the sur- boundaries for each planned analysis. The first patient was enrolled in May vival experience between the 2 groups; The overall study significance was main- 1999, and accrual closed in December the decision was based solely on the ob- ©2011 American Medical Association. All rights reserved. (Reprinted) JAMA, February 9, 2011—Vol 305, No. 6 571 Downloaded from jama.ama-assn.org at Oregon Health & Science University on February 9, 2011
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IN INVASIVE BREAST CANCER and 277 of 309 (89.6%) in the SLND- Figure 2. Survival of the ALND Group Compared With SLND-Alone Group alone group. Alive Alive and Disease-Free 100 100 90 90 Overall Survival 80 80 At a median follow-up of 6.3 years (IQR, 70 70 5.2-7.7), there were 94 deaths (SLND- Survival, % 60 60 50 50 alone group, 42; ALND group, 52). The 40 40 30 30 use of SLND alone compared with ALND 20 ALND 20 did not appear to result in statistically 10 SLND alone Log-rank P = .25 10 Log-rank P = .14 inferior survival (FIGURE 2) (P=.008 for 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 noninferiority). The unadjusted HR Years Years No. at risk comparing overall survival between the ALND 420 408 398 391 378 313 223 141 SLND alone 436 421 411 403 387 326 226 142 74 74 420 369 335 310 286 226 152 436 395 363 337 307 231 147 83 81 37 36 SLND-alone group and the ALND group was 0.79 (90% CI, 0.56-1.10), which ALND indicates axillary lymph node dissection; SLND, sentinel lymph node dissection. did not cross the specified boundary of 1.3 (FIGURE 3). The 5-year overall sur- served mortality rate for pooled data number of nodes with histologically vival rates were 92.5% (95% CI, 90.0%- from the 2 groups. The date of last fol- demonstrated tumor involvement (in- 95.1%) in the SLND-alone group and low-up for this analysis was March 4, cluding SLNs) in the ALND group and 91.8% (95% CI, 89.1%-94.5%) in the 2010. SLND-alone group was equal (1 [IQR, ALND group. This was substantially Patients were enrolled from 115 in- 1-2] for both groups). Hematoxylin- greater than the 80% anticipated at pro- stitutions, which included affiliates of the eosin–stained tumor deposits no larger tocol design. The HR for overall sur- Cancer Trials Support Unit and the than 2 mm were defined as microme- vival adjusting for adjuvant therapy North Central Cancer Treatment Group. tastases and were identified in SLNs of (chemotherapy, endocrine therapy, Of 891 patients, 445 were randomly as- 137 of 365 patients (37.5%) in the and/or radiation therapy) and age for signed to the ALND group and 446 to ALND group compared with 164 of 366 the SLND-alone group compared with the SLND-alone group (FIGURE 1). (44.8%) in the SLND-alone group the ALND group was 0.87 (90% CI, Thirty-five patients were excluded af- (P=.05). In the ALND group, 97 of 355 0.62-1.23). The adjusted HRs compar- ter withdrawing consent prior to sur- patients (27.3%) had additional metas- ing the SLND-alone group with the gery. The 103 ineligible patients were tasis in lymph nodes removed by ALND, ALND group in the other multivari- included in the analyses reported here. including 10% of patients with SLN able models ranged from 0.86 to 0.92 Because this was a noninferiority trial, micrometastasis who had macroscopi- (T ABLE 2), all similar to the unad- a more conservative analysis was per- cally involved non-SLNs removed. Total justed rate of 0.79. An exploratory formed on the treatment-received nodal involvement is summarized in analysis revealed that treatment with sample (n=813 patients); 32 patients Table 1; 21.0% of patients undergoing ALND vs SLND alone produced no sta- in the ALND group did not have ALND, ALND had 3 or more involved nodes tistically significant difference in out- and 11 patients in the SLND-alone compared with 3.7% undergoing SLND come among patients grouped by recep- group had ALND. No qualitative alone. Four or more involved nodes tor status of the primary tumor (ER / differences were observed between were seen in 13.7% of patients receiv- PR or ER−/PR−). treatment-received sample and intent- ing ALND and 1.0% of those receiving to-treat sample analyses, so only intent- SLND alone. Disease-Free Survival to-treat results are reported. Disease Adjuvant systemic therapy was de- Disease-free survival (Figure 2) did not characteristics at baseline were well bal- livered to 403 women (96.0%) in the differ significantly between treatment anced between the 2 groups (TABLE 1). ALND group and 423 women (97.0%) groups. The 5-year disease-free survival in the SLND-alone group.31 No differ- was 83.9% (95% CI, 80.2%-87.9%) for Treatment Results ences in the proportion of women re- the SLND-alone group and 82.2% (95% There was an expected difference ceiving endocrine therapy, chemo- CI, 78.3%-86.3%) for the ALND group between ALND and SLND-alone treat- therapy, or both were observed. The (P=.14). The unadjusted HR compar- ment groups in total number of removed type of chemotherapy administered was ing the SLND-alone group with the lymph nodes and total number of similar in the 2 groups; anthracycline- ALND group was 0.82 (95% CI, 0.58- tumor-involved nodes; the median total and taxane-based combination regi- 1.17), and the HR adjusted for adjuvant number of nodes removed was 17 (in- mens were the most common. The ma- treatment and age was 0.88 (95% CI, terquartile range [IQR], 13-22) in the jority of the women (n=605) received 0.62-1.25) (TABLE 3). The adjusted HRs ALND group and 2 (IQR, 1-4) in the whole-breast radiation therapy: 263 comparing the SLND-alone group with SLND-alone group.31 The median total of 296 (88.9%) in the ALND group the ALND group in the other multivari- 572 JAMA, February 9, 2011—Vol 305, No. 6 (Reprinted) ©2011 American Medical Association. All rights reserved. Downloaded from jama.ama-assn.org at Oregon Health & Science University on February 9, 2011
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IN INVASIVE BREAST CANCER able models ranged from 0.84 to 0.89 COMMENT survival. The findings from Z0011 docu- (Table 3), all similar to the unadjusted In the American College of Surgeons ment the high rate of locoregional con- rate of 0.82. Locoregional recurrence and Oncology Group Z0011 randomized trol achieved with modern multimo- its correlates have been previously trial, ALND did not significantly affect dality therapy, even without ALND. reported.31 The 5-year rates of local recur- overall or disease-free survival of In contrast to B04, in which about 40% rence were 1.6% (95% CI, 0.7%-3.3%) patients with clinical T1-T2 breast can- of patients in the radical mastectomy in the SLND-alone group and 3.1% (95% cer and a positive SLN who were treated group were node-positive and the same CI, 1.7%-5.2%) in the ALND group with lumpectomy, adjuvant systemic number in the total mastectomy group (P=.11). Locoregional recurrence–free therapy, and tangential-field whole- were assumed to be node-positive and survival at 5 years was 96.7% (95% CI, breast radiation therapy. These sur- 5-year overall survival was only about 94.7%-98.6%) in the SLND-alone group vival findings are consistent with those 60%, 100% of patients in Z0011 had and 95.7% (95% CI, 93.6%-97.9%) in the of the National Surgical Adjuvant Breast nodal involvement; yet the 5-year over- ALND group (P=.28). and Bowel Project B04 trial, in which women with clinically negative nodes Surgical Morbidities were randomized to treatment by radi- Figure 3. Hazard Ratios Comparing Overall Paresthesias, shoulder pain, weakness, cal mastectomy, total mastectomy plus Survival Between the ALND and SLND-Alone Groups lymphedema, and axillary web syn- nodal irradiation, or total mastectomy drome are recognized morbidities of with delayed ALND if nodal recur- Favors Favors ALND.7-9 As previously reported,10 the rence was observed.4 Initially and at SLND Alone ALND rate of wound infections, axillary sero- each interim analysis for up to 25 years Unadjusted mas, and paresthesias among patients in of follow-up, no statistically signifi- the Z0011 trial was higher for the ALND cant survival differences were observed Adjusted group than for the SLND-alone group between any of the groups. For patients (70% vs 25%, P .001). Lymphedema in treated in the modern era, the rel- 0.5 1.0 1.3 2.0 the ALND group was significantly more evance of the B04 study, which included Hazard Ratio (90% CI) common by subjective report (P .001) patients with larger tumors undergo- for Overall Survival and also tended to be higher by objec- ing mastectomy without adjuvant sys- Blue dashed line at hazard ratio=1.3 indicates non- tive assessment of arm circumference. temic therapy, is uncertain, because an inferiority margin; blue-tinted region to the left of haz- These findings are in accordance with axillary recurrence after SLND in ard ratio=1.3 indicates values for which SLND alone would be considered noninferior to SLND plus ALND. other randomized comparisons of SLND patients with a lower risk of death from ALND indicates axillary lymph node dissection; CI, con- with vs without ALND.32,33 distant disease might negatively affect fidence interval; SLND, sentinel lymph node dissection. Table 2. Adjusted Hazard Ratios for Overall Survival Comparing SLND-Alone vs ALND Groups No. Adjusted HR Noninferiority Model Variables Patients Events (90% CI) P Value Treatment group (SLND alone vs ALND), age ( 50 vs 50 y), 839 92 0.87 (0.62-1.23) .03 adjuvantly treated (yes vs no) Variables in row 1 primary tumor size (per 1 cm, continuous) 818 92 0.89 (0.62-1.25) .03 Variables in row 1 estrogen receptor status (negative vs positive) 778 87 0.92 (0.64-1.30) .05 Variables in row 1 modified Bloom-Richardson score (1 vs 2 vs 3) 839 92 0.86 (0.61-1.21) .02 Variables in row 1 tumor type (ductal vs lobular vs other) 839 92 0.88 (0.63-1.25) .03 Abbreviations: ALND, axillary lymph node dissection; CI, confidence interval; HR, hazard ratio; SLND, sentinel lymph node dissection. Table 3. Adjusted Hazard Ratios for Disease-Free Survival Comparing SLND-Alone vs ALND Groups No. Adjusted HR Model Variables Patients Events (95% CI) P Value Treatment group (SLND alone vs ALND), age ( 50 vs 50 y), 839 127 0.88 (0.62-1.25) .47 adjuvantly treated (yes vs no) Variables in row 1 primary tumor size (per 1 cm, continuous) 818 125 0.86 (0.60-1.22) .40 Variables in row 1 estrogen receptor status (negative vs positive) 778 117 0.84 (0.58-1.20) .33 Variables in row 1 modified Bloom-Richardson score (1 vs 2 vs 3) 839 127 0.87 (0.61-1.23) .43 Variables in row 1 tumor type (ductal vs lobular vs other) 839 127 0.89 (0.62-1.27) .52 Abbreviations: ALND, axillary lymph node dissection; CI, confidence interval; HR, hazard ratio; SLND, sentinel lymph node dissection. ©2011 American Medical Association. All rights reserved. (Reprinted) JAMA, February 9, 2011—Vol 305, No. 6 573 Downloaded from jama.ama-assn.org at Oregon Health & Science University on February 9, 2011
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IN INVASIVE BREAST CANCER all survival was more than 90%. Further- more than 5 years after study entry.4 tastases that would indicate a higher risk more, a 19% rate of axillary first failure Greco et al37 reported that median time for systemic disease and the need for sys- was observed in B04,4 whereas the axil- to axillary recurrence was 30.6 months temic therapy to reduce that risk. Re- lary nodal recurrence rate was only 0.9% for 401 patients who underwent breast- sults from Z0011 indicate that women in the SLND-alone group in Z0011.31 The conserving procedures and radiation with a positive SLN and clinical T1-T2 excellent local and distant outcomes in therapy with no axillary surgery. Re- tumors undergoing lumpectomy with ra- this study highlight the effects of mul- cent reports of long-term follow-up in diation therapy followed by systemic tiple changes in breast cancer manage- randomized trials confirm these find- therapy do not benefit from the addi- ment during the interval between the 2 ings. 38,39 Because the total locore- tion of ALND in terms of local control, studies. These changes, which include gional recurrence rate in the Z0011 disease-free survival, or overall sur- improved imaging, more detailed patho- SLND-alone group at 5 years is only vival. The only additional information logical evaluation, improved planning of 2.5% compared with 3.6% in the ALND gained from ALND is the number of surgical and radiation approaches, and group, it is unlikely that further fol- nodes containing metastases. This prog- more effective systemic therapy, empha- low-up would result in enough addi- nostic information is unlikely to change size the need for ongoing reevaluation tional recurrences to generate a clini- systemic therapy decisions and is ob- of “standard” local therapy. cally meaningful survival difference tained at the cost of a significant in- The well-documented morbidity between groups. The absolute differ- crease in morbidity.10 The only ratio- from ALND has led other investiga- ence in 5-year overall survival be- nale for ALND in these patients would tors to explore alternative methods of tween the treatment groups in Z0011 be if the finding of additional nodal me- axillary treatment in patients with clini- is 0.7%, numerically favoring the SLND- tastases would result in changes in sys- cally negative nodes, including radia- alone group. The HR for overall sur- temic therapy. Because current guide- tion, systemic therapy, and axillary vival comparing the SLND-alone group lines do not support differences in observation. These have consistently with the ALND group was 0.79 (90% adjuvant systemic therapy based on the demonstrated low axillary failure rates, CI, 0.56-1.10). The worst HR (1.10) is number of positive lymph nodes, ex- with no significant differences in sur- less than 1.3, which was hypothesized cept in some uncommon select sub- vival.34,35 The International Breast Can- as the inferiority margin threshold. In groups,40 ALND does not appear to be cer Study Group trial of ALND vs obser- essence, this means that the 5-year over- warranted in this patient population. vation is noteworthy because more than all survival for the SLND-alone group The Z0011 trial did not include pa- half of the patients did not receive breast might be as low as 90.3% if the true tients undergoing mastectomy, those or axillary radiotherapy. In women 60 5-year overall survival for the ALND undergoing lumpectomy without ra- years and older receiving adjuvant group was 91.8% and the HR as high diotherapy, those treated with partial- tamoxifen but no axillary treatment, the as 1.10. Most importantly, there is no breast irradiation, those receiving neo- rate of axillary recurrence was only 3%, suggestion that rates of locoregional re- adjuvant therapy, and those receiving and overall survival was 73% at a median currence, the mechanism by which whole-breast irradiation in the prone follow-up of 6.6 years.36 variations in local therapy result in sur- position, in which the low axilla is not The low rates of locoregional recur- vival differences, differ between groups treated. In those patients, ALND re- rence at 5 years and the nearly identi- to the extent needed to produce sur- mains standard practice when SLND cal overall and disease-free survival be- vival differences or are likely to do so identifies a positive SLN. However, tween treatment groups in Z0011 in the future. Taken together, this sug- ALND may no longer be justified for would suggest that differences in sur- gests that contemporary women may women who have clinical T1-T2 breast vival between study groups are un- sustain the morbidity of ALND with- cancer and hematoxylin-eosin– likely to emerge with longer follow- out any meaningful improvement in detected metastasis in the SLN and who up, because ALND would only affect survival rates. Limitations of the study, are treated with breast-conserving sur- survival by virtue of improved locore- such as failure to achieve target ac- gery, whole-breast irradiation, and ad- gional control. In the Early Breast Can- crual and possible randomization im- juvant systemic therapy. Implementa- cer Trialists’ Collaborative Group over- balance favoring the SLND-alone group, tion of this practice change would view, statistically significant survival must be considered. However, even in improve clinical outcomes in thou- differences between treatments at 15 high-risk women (ER−/PR−) in Z0011, sands of women each year by reduc- years were seen only when differences preliminary analysis suggests no effect ing the complications associated with in locoregional recurrence between of elimination of ALND on survival. ALND and improving quality of life treatments were greater than 10% at 5 Despite limitations of the Z0011 trial, with no diminution in survival. years.6 Axillary recurrence is usually an its findings could have important impli- Author Contributions: Dr Giuliano had full access to early event, occurring at a median of cations for clinical practice. Examina- all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data 14.8 months in B04; in that trial, only tion of the regional nodes with SLND can analysis. 7 of 68 axillary recurrences occurred identify hematoxylin-eosin–detected me- Study concept and design: Giuliano. 574 JAMA, February 9, 2011—Vol 305, No. 6 (Reprinted) ©2011 American Medical Association. All rights reserved. Downloaded from jama.ama-assn.org at Oregon Health & Science University on February 9, 2011
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IN INVASIVE BREAST CANCER Acquisition of data: Giuliano, Beitsch, Whitworth, 9. Ivens D, Hoe AL, Podd TJ, Hamilton CR, Taylor I, illary surgical care for breast cancer in the era of sen- Blumencranz, Leitch, Saha, Morrow. Royle GT. Assessment of morbidity from complete tinel lymph node biopsy. Ann Surg Oncol. 2009; Analysis and interpretation of data: Giuliano, Hunt, axillary dissection. Br J Cancer. 1992;66(1):136- 16(3):687-696. Ballman, Whitworth, Leitch, McCall, Morrow. 138. 26. Fisher B, Redmond C, Poisson R, et al. Eight- Drafting of the manuscript: Giuliano, Ballman, Beitsch, 10. Lucci A, McCall LM, Beitsch PD, et al; American year results of a randomized clinical trial comparing Whitworth, Morrow. College of Surgeons Oncology Group. Surgical com- total mastectomy and lumpectomy with or without Critical revision of the manuscript for important plications associated with sentinel lymph node dissec- irradiation in the treatment of breast cancer. N Engl J intellectual content: Giuliano, Hunt, Ballman, Beitsch, tion (SLND) plus axillary lymph node dissection com- Med. 1989;320(13):822-828. Whitworth, Blumencranz, Leitch, Saha, McCall, pared with SLND alone in the American College of 27. Early Breast Cancer Trialists’ Collaborative Group. Morrow. Surgeons Oncology Group trial Z0011. J Clin Oncol. Systemic treatment of early breast cancer by hor- Statistical analysis: Ballman, McCall. 2007;25(24):3657-3663. monal, cytotoxic, or immune therapy: 133 ran- Administrative, technical, or material support: Giuliano, 11. Lyman GH, Giuliano AE, Somerfield MR, et al; domised trials involving 31,000 recurrences and 24,000 Hunt, Whitworth, Leitch, Saha. American Society of Clinical Oncology. American So- deaths among 75,000 women. Lancet. 1992;339 Study supervision: Giuliano, Whitworth. ciety of Clinical Oncology guideline recommenda- (8785):71-85. Conflict of Interest Disclosures: All authors have com- tions for sentinel lymph node biopsy in early-stage 28. Early Breast Cancer Trialists’ Collaborative Group. pleted and submitted the ICMJE Form for Disclosure breast cancer. J Clin Oncol. 2005;23(30):7703- Systemic treatment of early breast cancer by hor- of Potential Conflicts of Interest and none were re- 7720. monal, cytotoxic, or immune therapy: 133 ran- ported. 12. Fidler IJ. The pathogenesis of cancer metastasis: domised trials involving 31,000 recurrences and 24,000 Funding/Support: This study was supported by Na- the “seed and soil” hypothesis revisited. Nat Rev deaths among 75,000 women. Lancet. 1992;339 tional Cancer Institute grant U10 CA 76001 to the Cancer. 2003;3(6):453-458. (8784):1-15. American College of Surgeons Oncology Group 13. Abrams JS. Adjuvant therapy for breast cancer— 29. Rubinstein LV, Gail MH, Santner TJ. Planning the (ACOSOG). results from the USA consensus conference. Breast duration of a comparative clinical trial with loss to fol- Role of the Sponsor: The National Cancer Institute had Cancer. 2001;8(4):298-304. low-up and a period of continued observation. no role in the design and conduct of the study; the 14. Goldhirsch A, Glick JH, Gelber RD, Senn HJ. Meet- J Chronic Dis. 1981;34(9-10):469-479. collection, analysis, and interpretation of the data; or ing highlights: International Consensus Panel on the 30. Kaji AH, Lewis RJ. Are we looking for superior- the preparation, review, or approval of the manu- Treatment of Primary Breast Cancer. J Natl Cancer Inst. ity, equivalence, or noninferiority? asking the right script. 1998;90(21):1601-1608. question and answering it correctly. Ann Emerg Med. Additional Contributions: We thank the ACOSOG 15. Sørlie T, Perou CM, Tibshirani R, et al. Gene ex- 2010;55(5):408-411. staff, in particular the leadership of Heidi Nelson, MD pression patterns of breast carcinomas distinguish tu- 31. Giuliano AE, McCall L, Beitsch P, et al. Locore- (Mayo Clinic, Rochester, Minnesota), David Ota, MD mor subclasses with clinical implications. Proc Natl Acad gional recurrence after sentinel lymph node dissec- (Duke University, Durham, North Carolina), and Samuel Sci U S A. 2001;98(19):10869-10874. tion with or without axillary dissection in patients with A. Wells Jr, MD (National Cancer Institute, Bethesda, 16. van de Vijver MJ, He YD, van’t Veer LJ, et al. A sentinel lymph node metastases: the American Col- Maryland). All 3 of these individuals contributed to gene-expression signature as a predictor of survival lege of Surgeons Oncology Group Z0011 random- study design, manuscript review, or both; none re- in breast cancer. N Engl J Med. 2002;347(25): ized trial. Ann Surg. 2010;252(3):426-433. ceived compensation for their contributions. We also 1999-2009. 32. Fleissig A, Fallowfield LJ, Langridge CI, et al. Post- thank all of the investigators and their site research 17. 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