Axillary Dissection vs No Axillary Dissection in Women With Invasive ...

ORIGINAL CONTRIBUTIONAxillary Dissection vs No Axillary Dissectionin Women With Invasive Breast Cancerand Sentinel Node MetastasisA Randomized Clinical TrialArmando E. Giuliano, MDKelly K. Hunt, MDKarla V. Ballman, PhDPeter D. Beitsch, MDPat W. Whitworth, MDPeter W. Blumencranz, MDA. Marilyn Leitch, MDSukamal Saha, MDLinda M. McCall, MSMonica Morrow, MDAXILLARY LYMPH NODE DISSECtion(ALND) has been part ofbreast cancer surgery since thedescription of the radical mastectomy.1 ALND reliably identifies nodalmetastases and maintains regional control,2,3 but the contribution of localtherapy to breast cancer survival is controversial.4,5 The Early Breast Cancer Trialists’Collaborative Group synthesizedfindings from 78 randomized controlledtrials, concluding that local controlof breast cancer was associated withimproved disease-specific survival. 6ALND, as a means for achieving localdisease control, carries an indisputableand often unacceptable risk of complicationssuch as seroma, infection, andlymphedema. 7-9 Sentinel lymph nodedissection (SLND) was therefore developedto accurately stage tumordrainingaxillary nodes with less morbiditythan ALND. 10 SLND alone is theaccepted management for patients whoseFor editorial comment see p 606.Context Sentinel lymph node dissection (SLND) accurately identifies nodal metastasisof early breast cancer, but it is not clear whether further nodal dissection affectssurvival.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.Design, Setting, and Patients The American College of Surgeons Oncology GroupZ0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patientsfrom May 1999 to December 2004. Patients were women with clinical T1-T2 invasivebreast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identifiedby frozen section, touch preparation, or hematoxylin-eosin staining on permanentsection. Targeted enrollment was 1900 women with final analysis after 500 deaths,but the trial closed early because mortality rate was lower than expected.Interventions All patients underwent lumpectomy and tangential whole-breast irradiation.Those with SLN metastases identified by SLND were randomized to undergo ALNDor no further axillary treatment. Those randomized to ALND underwent dissection of 10or more nodes. Systemic therapy was at the discretion of the treating physician.Main Outcome Measures Overall survival was the primary end point, with a noninferioritymargin of a 1-sided hazard ratio of less than 1.3 indicating that SLND aloneis noninferior to ALND. Disease-free survival was a secondary end point.Results Clinical and tumor characteristics were similar between 445 patients randomizedto ALND and 446 randomized to SLND alone. However, the median numberof nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-upof 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8%(95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-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 hazardratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) withoutadjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.Conclusion Among patients with limited SLN metastatic breast cancer treated withbreast conservation and systemic therapy, the use of SLND alone compared with ALNDdid not result in inferior survival.Trial Registration clinicaltrials.gov Identifier: NCT00003855JAMA. 2011;305(6):569-575Author Affiliations: John Wayne Cancer Institute atSaint John’s Health Center, Santa Monica, California(Dr Giuliano); M. D. Anderson Cancer Center, Houston,Texas (Dr Hunt); Mayo Clinic Rochester, Rochester,Minnesota (Dr Ballman); Dallas Surgical Group,Dallas, Texas (Dr Beitsch); Nashville Breast Center,Nashville, Tennessee (Dr Whitworth); Morton PlantHospital, Clearwater, Florida (Dr Blumencranz); Universityof Texas Southwestern Medical Center, Dallaswww.jama.com(Dr Leitch); McLaren Regional Medical Center, MichiganState University, Flint (Dr Saha); American Collegeof Surgeons Oncology Group, Durham, North Carolina(Ms McCall); and Memorial Sloan-KetteringCancer Center, New York, New York (Dr Morrow).Corresponding Author: Armando E. Giuliano, MD, JohnWayne Cancer Institute at Saint John’s Health Center,2200 Santa Monica Blvd, Santa Monica, CA 90404(giulianoa@jwci.org).©2011 American Medical Association. All rights reserved. (Reprinted) JAMA, February 9, 2011—Vol 305, No. 6 569Downloaded From: http://jama.jamanetwork.com/ on 05/27/2012

SENTINEL NODE DISSECTION IN INVASIVE BREAST CANCERFigure 1. Study Flow445 Randomized to receive ALND420 Received ALND asrandomized25 Withdrew prior to surgery92 Lost to follow-up2 Discontinued intervention1 Refused after randomizationbut prior to surgery1 Consent obtained afterpatient registered420 Included in primary analysis25 Excluded (withdrew prior to surgery)sentinel lymph nodes (SLNs) are histologicallyfree of tumor, while ALND remainsthe standard of care for patientswhose SLNs contain metastases. 11Cancer biology is much better understoodnow than it was when ALND wasintroduced. Biological factors may affectthe predilection of some malignant cellsto selectively invade lymph nodes ratherthan visceral organs, just as certain tumortypes metastasize to certain organsand not others. 12 Recognition of the complexityof tumor biology has changedcancer treatment, with more liberal useof systemic therapy to treat occult cancercells wherever they may be in thebody. Consequently, the decision to administersystemic therapy is influencedby a variety of patient- and tumorrelatedfactors, with lymph node tumorstatus influencing 13,14 but not necessarilydictating the use of chemotherapy. 15-18Other factors, such as early cancer detectionby screening mammography,have led to earlier intervention in breastcancer, reducing the incidence of nodalmetastases and even the number of tumor-involvedlymph nodes. 19These evolving concepts have calledinto question the need for ALND. 20,21 Avariety of algorithms have been developedto help clinicians decide which patientswould benefit from ALND. 22-24 Reviewof Surveillance, Epidemiology, andEnd Results data has shown that the useof ALND for SLN metastases has decreasedin recent years. 25 No study has891 Patients randomized446 Randomized to receive SLND alone436 Received SLND aloneas randomized10 Withdrew prior to surgery74 Lost to follow-up3 Discontinued intervention2 Refused after randomizationbut prior to surgery1 Opted for alternative therapy436 Included in primary analysis10 Excluded (withdrew prior to surgery)ALND indicates axillary lymph node dissection; SLND, sentinel lymph node dissection.conclusively demonstrated a survivalbenefit or detriment for omitting ALNDwhen metastatic breast cancer is identifiedby SLND. In the late 1990s, theAmerican College of Surgeons OncologyGroup designed and began the multicenterZ0011 trial. The primary aim ofthis study was to determine the effectsof ALND on overall survival in patientswith SLN metastases treated in the contemporaryera with lumpectomy, adjuvantsystemic therapy, and tangentialfieldradiation therapy.METHODSPatient CharacteristicsThis multicenter, randomized phase 3trial was registered with the NationalCancer Institute and approved by the institutionalreview boards of participatingcenters. All patients provided writteninformed consent. Adult womenwith histologically confirmed invasivebreast carcinoma clinically 5 cm or less,no palpable adenopathy, and an SLNcontaining metastatic breast cancerdocumented by frozen section, touchpreparation, or hematoxylin-eosin stainingon permanent section were eligiblefor participation. Patients with metastasesidentified initially or solely with immunohistochemicalstaining were ineligible.Treatment with lumpectomy tonegative margins (no tumor at ink) wasrequired. Women were ineligible if theyhad 3 or more positive SLNs, mattednodes, or gross extranodal disease, or ifthey had received neoadjuvant hormonaltherapy or chemotherapy.Study Design and TreatmentBefore randomization, all women underwentSLND and were stratified accordingto age (50 and 50 years), estrogen-receptorstatus, and tumor size(1cm,1cmand2cm,or2cm).Eligible women were randomly assignedto ALND or no further axillaryspecificintervention—specifically, nothird-field nodal irradiation. ALND wasdefined as an anatomical level I and II dissectionincluding at least 10 nodes. Allwomen were to receive whole-breastopposing tangential-field radiationtherapy. The use of adjuvant systemictherapy was determined by the treatingphysician and was not specified in theprotocol.Patients most commonly entered thestudy post-SLND following identificationof metastases on final pathology report.However, of the 891 registered patients,287 were registered pre-SLNDand assigned to treatment after intraoperativedocumentation of SLN metastases.Patients in this group subsequentlyfound to have 3 or more tumor-involvedlymph nodes were included in the analysis.Patients were assessed for disease recurrenceaccording to standard clinicalpractice. History and physical examinationwere performed every 6 months forthe first 36 months and yearly thereafter.Annual mammography was required;other testing was based on symptomsand investigator preference.Study End PointsThe primary end point was overall survival,defined as the time from randomizationuntil death from any cause. Ashort-term primary end point was occurrenceof surgical morbidities. Thestudy plan was to report surgical morbiditiesfollowing the completion of accrualand prior to overall survival reportingafter receiving permission fromthe data and safety monitoring committee.These morbidities have beenreported. 10A secondary end point was diseasefreesurvival, defined as the time from570 JAMA, February 9, 2011—Vol 305, No. 6 (Reprinted) ©2011 American Medical Association. All rights reserved.Downloaded From: http://jama.jamanetwork.com/ on 05/27/2012

SENTINEL NODE DISSECTION IN INVASIVE BREAST CANCERrandomization to death or first documentedrecurrence of breast cancer.Breast cancer recurrence was categorizedas locoregional disease (tumor inthe breast or ipsilateral supraclavicular,subclavicular, internal mammary,or axillary nodes) or distant metastases.Disease-free survival and its components(locoregional disease and distantmetastases) are reported instead ofthe protocol-specified secondary endpoint (eg, distant disease–free survival)to facilitate comparison withother studies.Statistical AnalysisThe primary end point was overall survivalas a measure of noninferiority ofno further axillary specified interventions(SLND-alone group) comparedwith the ALND group. Based on the literatureat the time of study design, wehypothesized that overall survival was80% at 5 years for optimally treatedwomen with positive nodes. 26-28 Clinicalnoninferiority was defined as theSLND-alone group having a 5-year survivalof not less than 75% of that observedin the ALND group. Noninferiorityof the SLND-alone treatment wasalso considered if the hazard ratio (HR)for mortality was less than 1.3 whencompared with ALND. An estimated 500deaths were needed for the study to have90% power to confirm noninferiority ofSLND alone compared with ALND, withthe use of a 2-sided 90% confidence interval(CI) for the HR from a Cox regressionmodel. 29 Specifically, if the90% CI for the HR was below 1.3, thiswould indicate that patients undergoingSLND alone do not have an unacceptablyworse overall survival than patientsundergoing SLND plus ALND.The use of a 2-sided 90% CI correspondsto a 1-sided significance level of.05. 30 The enrollment of 1900 patients in4yearswithaminimumfollow-upperiodof 5 years was initially planned. Fourformal interim analyses and 1 final analysiswere planned for overall survival, andthe O’Brien-Flemming -spending strategywas used to generate stoppingboundaries for each planned analysis.The overall study significance was maintainedat .05. However, none of theplanned interim analyses were performedbefore the study was closed basedon the recommendation of the data andsafety monitoring committee. Because ofthis, a single terminal hypothesis test withan of .05 is applied to the data, whichmakes it consistent with the plannedoverall significance level of .05 in theoriginal study plan.Ineligible patients were retained inall analyses (ie, both the intent-totreatanalyses and the treatmentreceivedanalyses). Kaplan-Meier survivalcurves for overall survival werecompared by log-rank test. The unadjustedHR (and 90% CI) was calculatedusing a Cox regression analysis,and noninferiority P values are reported.As a secondary analysis, knownprognostic factors including adjuvanttreatment were included in the Cox regressionmodel to generate an adjustedHR for overall survival (with a90% CI and noninferiority P values).Disease-free survival was analyzed usingKaplan-Meier curves and univariableand multivariable Cox regression analyseswith 95% CIs. The fact that therewere only 94 deaths limited the numberof variables that could be used in amultivariable model without affectingmodel stability. We created a basemodel that included the treatmentgroup (SLND alone vs ALND), age(50 vs 50 years), and whether thepatient received adjuvant therapy (yesvs no) and added prognostic variablesto this model individually. Only variablesobtained on 90% or more of thepatients were included in the multivariableanalysis. Locoregional recurrencerates were compared with theFisher exact test. Each analysis, otherthan analysis for the primary end pointof overall survival, was performed with2-sided P values, 5% significance, anda 95% CI; all analyses were performedusing SAS release 9.1 (SAS Institute Inc,Cary, North Carolina).RESULTSPatient CharacteristicsThe first patient was enrolled in May1999, and accrual closed in DecemberTable 1. Baseline Patient and TumorCharacteristics by Study GroupNo. (%)ALND SLND AloneCharacteristic (n = 420) (n = 436)Age, median (range), y 56 (24-92) 54 (25-90)Missing 7 10Clinical T stageT1 284 (67.9) 303 (70.6)T2 134 (32.1) 126 (29.4)Missing 2 7Tumor size, median 1.7 (0.4-7.0) 1.6 (0.0-5.0)(range), cmMissing 6 14Receptor statusER/PR 256 (66.8) 270 (68.9)ER/PR− 61 (15.9) 54 (13.8)ER−/PR 3(0.8) 4(1.0)ER−/PR− 63 (16.5) 64 (16.3)Missing 37 44LVIYes 129 (40.6) 113 (35.2)No 189 (59.4) 208 (64.8)Missing 102 115Modified Bloom-Richardson score1 71(22.0) 81(25.6)2 158(48.9) 148(46.8)3 94(29.1) 87(27.5)Missing 97 120Tumor typeInfiltrating ductal 344 (82.7) 356 (84.0)Infiltrating lobular 27 (6.5) 36 (8.5)Other 45 (10.8) 32 (7.5)Missing 4 12Lymph nodemetastases0 4(1.2) 29(7.0)1 199(58.0) 295(71.1)2 68(19.8) 76(18.3)3 25(7.3) 11(2.7)4 47(13.7) 4(1.0)Missing 77 21Abbreviations: ALND, axillary lymph node dissection; ER, estrogenreceptor; LVI, lymphovascular invasion; PR, progesteronereceptor; SLND, sentinel lymph node dissection.2004 based on a recommendation of theindependent data and safety monitoringcommittee because of concerns regardingthe extremely low mortalityrate. Even if the trial had accrued thetargeted 1900 patients, it would havetaken more than 20 years of follow-upto observe 500 deaths at the realizedevent rate. At the time of the decisionto terminate the study there had beenno formal analysis comparing the survivalexperience between the 2 groups;the decision was based solely on the ob-©2011 American Medical Association. All rights reserved. (Reprinted) JAMA, February 9, 2011—Vol 305, No. 6 571Downloaded From: http://jama.jamanetwork.com/ on 05/27/2012

SENTINEL NODE DISSECTION IN INVASIVE BREAST CANCERFigure 2. Survival of the ALND Group Compared With SLND-Alone GroupSurvival, %1009080706050403020100No. at riskALND 420SLND alone 4361408421ALNDSLND alone23984113 4 5Years391403Alive378387Log-rank P = .25313326served mortality rate for pooled datafrom the 2 groups. The date of last follow-upfor this analysis was March 4,2010.Patients were enrolled from 115 institutions,which included affiliates of theCancer Trials Support Unit and theNorth Central Cancer Treatment Group.Of 891 patients, 445 were randomly assignedto the ALND group and 446 tothe SLND-alone group (FIGURE 1).Thirty-five patients were excluded afterwithdrawing consent prior to surgery.The 103 ineligible patients wereincluded in the analyses reported here.Because this was a noninferiority trial,a more conservative analysis was performedon the treatment-receivedsample (n=813 patients); 32 patientsin the ALND group did not have ALND,and 11 patients in the SLND-alonegroup had ALND. No qualitativedifferences were observed betweentreatment-received sample and intentto-treatsample analyses, so only intentto-treatresults are reported. Diseasecharacteristics at baseline were well balancedbetween the 2 groups (TABLE 1).Treatment ResultsThere was an expected differencebetween ALND and SLND-alone treatmentgroups in total number of removedlymph nodes and total number oftumor-involved nodes; the median totalnumber of nodes removed was 17 (interquartilerange [IQR], 13-22) in theALND group and 2 (IQR, 1-4) in theSLND-alone group. 31 The median total6223226714114287474100908070605040302010042043613693952335363310337ALND indicates axillary lymph node dissection; SLND, sentinel lymph node dissection.Alive and Disease-Free3 4 5Years286307Log-rank P = .14226231number of nodes with histologicallydemonstrated tumor involvement (includingSLNs) in the ALND group andSLND-alone group was equal (1 [IQR,1-2] for both groups). Hematoxylineosin–stainedtumor deposits no largerthan 2 mm were defined as micrometastasesand were identified in SLNs of137 of 365 patients (37.5%) in theALND group compared with 164 of 366(44.8%) in the SLND-alone group(P=.05).IntheALNDgroup,97of355patients (27.3%) had additional metastasisin lymph nodes removed by ALND,including 10% of patients with SLNmicrometastasis who had macroscopicallyinvolved non-SLNs removed. Totalnodal involvement is summarized inTable 1; 21.0% of patients undergoingALND had 3 or more involved nodescompared with 3.7% undergoing SLNDalone. Four or more involved nodeswere seen in 13.7% of patients receivingALND and 1.0% of those receivingSLND alone.Adjuvant systemic therapy was deliveredto 403 women (96.0%) in theALND group and 423 women (97.0%)in the SLND-alone group. 31 No differencesin the proportion of women receivingendocrine therapy, chemotherapy,or both were observed. Thetype of chemotherapy administered wassimilar in the 2 groups; anthracyclineandtaxane-based combination regimenswere the most common. The majorityof the women (n=605) receivedwhole-breast radiation therapy: 263of 296 (88.9%) in the ALND group61521477838183736and 277 of 309 (89.6%) in the SLNDalonegroup.Overall SurvivalAt a median follow-up of 6.3 years (IQR,5.2-7.7), there were 94 deaths (SLNDalonegroup, 42; ALND group, 52). Theuse of SLND alone compared with ALNDdid not appear to result in statisticallyinferior survival (FIGURE 2)(P=.008fornoninferiority). The unadjusted HRcomparing overall survival between theSLND-alone group and the ALND groupwas 0.79 (90% CI, 0.56-1.10), whichdid not cross the specified boundary of1.3 (FIGURE 3). The 5-year overall survivalrates were 92.5% (95% CI, 90.0%-95.1%) in the SLND-alone group and91.8% (95% CI, 89.1%-94.5%) in theALND group. This was substantiallygreater than the 80% anticipated at protocoldesign. The HR for overall survivaladjusting for adjuvant therapy(chemotherapy, endocrine therapy,and/or radiation therapy) and age forthe SLND-alone group compared withthe ALND group was 0.87 (90% CI,0.62-1.23). The adjusted HRs comparingthe SLND-alone group with theALND group in the other multivariablemodels ranged from 0.86 to 0.92(TABLE 2), all similar to the unadjustedrate of 0.79. An exploratoryanalysis revealed that treatment withALND vs SLND alone produced no statisticallysignificant difference in outcomeamong patients grouped by receptorstatus of the primary tumor (ER/PR or ER−/PR−).Disease-Free SurvivalDisease-free survival (Figure 2) did notdiffer significantly between treatmentgroups. The 5-year disease-free survivalwas 83.9% (95% CI, 80.2%-87.9%) forthe SLND-alone group and 82.2% (95%CI, 78.3%-86.3%) for the ALND group(P=.14). The unadjusted HR comparingthe SLND-alone group with theALND group was 0.82 (95% CI, 0.58-1.17), and the HR adjusted for adjuvanttreatment and age was 0.88 (95% CI,0.62-1.25) (TABLE 3). The adjusted HRscomparing the SLND-alone group withthe 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: http://jama.jamanetwork.com/ on 05/27/2012

SENTINEL NODE DISSECTION IN INVASIVE BREAST CANCERable models ranged from 0.84 to 0.89(Table 3), all similar to the unadjustedrate of 0.82. Locoregional recurrence andits correlates have been previouslyreported. 31 The 5-year rates of local recurrencewere 1.6% (95% CI, 0.7%-3.3%)in the SLND-alone group and 3.1% (95%CI, 1.7%-5.2%) in the ALND group(P=.11). Locoregional recurrence–freesurvival at 5 years was 96.7% (95% CI,94.7%-98.6%) in the SLND-alone groupand 95.7% (95% CI, 93.6%-97.9%) in theALND group (P=.28).Surgical MorbiditiesParesthesias, shoulder pain, weakness,lymphedema, and axillary web syndromeare recognized morbidities ofALND. 7-9 As previously reported, 10 therate of wound infections, axillary seromas,and paresthesias among patients inthe Z0011 trial was higher for the ALNDgroup than for the SLND-alone group(70% vs 25%, P.001). Lymphedema inthe ALND group was significantly morecommon by subjective report (P.001)and also tended to be higher by objectiveassessment of arm circumference.These findings are in accordance withother randomized comparisons of SLNDwith vs without ALND. 32,33COMMENTIn the American College of SurgeonsOncology Group Z0011 randomizedtrial, ALND did not significantly affectoverall or disease-free survival ofpatients with clinical T1-T2 breast cancerand a positive SLN who were treatedwith lumpectomy, adjuvant systemictherapy, and tangential-field wholebreastradiation therapy. These survivalfindings are consistent with thoseof the National Surgical Adjuvant Breastand Bowel Project B04 trial, in whichwomen with clinically negative nodeswere randomized to treatment by radicalmastectomy, total mastectomy plusnodal irradiation, or total mastectomywith delayed ALND if nodal recurrencewas observed. 4 Initially and ateach interim analysis for up to 25 yearsof follow-up, no statistically significantsurvival differences were observedbetween any of the groups. For patientstreated in the modern era, the relevanceof the B04 study, which includedpatients with larger tumors undergoingmastectomy without adjuvant systemictherapy, is uncertain, because anaxillary recurrence after SLND inpatients with a lower risk of death fromdistant disease might negatively affectsurvival. The findings from Z0011 documentthe high rate of locoregional controlachieved with modern multimodalitytherapy, even without ALND.In contrast to B04, in which about 40%of patients in the radical mastectomygroup were node-positive and the samenumber in the total mastectomy groupwere assumed to be node-positive and5-year overall survival was only about60%, 100% of patients in Z0011 hadnodal involvement; yet the 5-year over-Figure 3. Hazard Ratios Comparing OverallSurvival Between the ALND and SLND-AloneGroups0.5FavorsSLND AloneUnadjustedAdjustedFavorsALND1.0 1.3Hazard Ratio (90% CI)for Overall Survival2.0Blue dashed line at hazard ratio=1.3 indicates noninferioritymargin; blue-tinted region to the left of hazardratio=1.3 indicates values for which SLND alonewould be considered noninferior to SLND plus ALND.ALND indicates axillary lymph node dissection; CI, confidenceinterval; SLND, sentinel lymph node dissection.Table 2. Adjusted Hazard Ratios for Overall Survival Comparing SLND-Alone vs ALND GroupsModel VariablesTreatment group (SLND alone vs ALND), age (50 vs 50 y),adjuvantly treated (yes vs no)PatientsNo.EventsAdjusted HR(90% CI)NoninferiorityP Value839 92 0.87 (0.62-1.23) .03Variables in row 1 primary tumor size (per 1 cm, continuous) 818 92 0.89 (0.62-1.25) .03Variables in row 1 estrogen receptor status (negative vs positive) 778 87 0.92 (0.64-1.30) .05Variables in row 1 modified Bloom-Richardson score (1 vs 2 vs 3) 839 92 0.86 (0.61-1.21) .02Variables in row 1 tumor type (ductal vs lobular vs other) 839 92 0.88 (0.63-1.25) .03Abbreviations: 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 GroupsModel VariablesTreatment group (SLND alone vs ALND), age (50 vs 50 y),adjuvantly treated (yes vs no)PatientsNo.EventsAdjusted HR(95% CI) P Value839 127 0.88 (0.62-1.25) .47Variables in row 1 primary tumor size (per 1 cm, continuous) 818 125 0.86 (0.60-1.22) .40Variables in row 1 estrogen receptor status (negative vs positive) 778 117 0.84 (0.58-1.20) .33Variables in row 1 modified Bloom-Richardson score (1 vs 2 vs 3) 839 127 0.87 (0.61-1.23) .43Variables in row 1 tumor type (ductal vs lobular vs other) 839 127 0.89 (0.62-1.27) .52Abbreviations: 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 573Downloaded From: http://jama.jamanetwork.com/ on 05/27/2012

SENTINEL NODE DISSECTION IN INVASIVE BREAST CANCERall survival was more than 90%. Furthermore,a 19% rate of axillary first failurewas observed in B04, 4 whereas the axillarynodal recurrence rate was only 0.9%in the SLND-alone group in Z0011. 31 Theexcellent local and distant outcomes inthis study highlight the effects of multiplechanges in breast cancer managementduring the interval between the 2studies. These changes, which includeimproved imaging, more detailed pathologicalevaluation, improved planning ofsurgical and radiation approaches, andmore effective systemic therapy, emphasizethe need for ongoing reevaluationof “standard” local therapy.The well-documented morbidityfrom ALND has led other investigatorsto explore alternative methods ofaxillary treatment in patients with clinicallynegative nodes, including radiation,systemic therapy, and axillaryobservation. These have consistentlydemonstrated low axillary failure rates,with no significant differences in survival.34,35 The International Breast CancerStudy Group trial of ALND vs observationis noteworthy because more thanhalf of the patients did not receive breastor axillary radiotherapy. In women 60years and older receiving adjuvanttamoxifen but no axillary treatment, therate of axillary recurrence was only 3%,and overall survival was 73% at a medianfollow-up of 6.6 years. 36The low rates of locoregional recurrenceat 5 years and the nearly identicaloverall and disease-free survival betweentreatment groups in Z0011would suggest that differences in survivalbetween study groups are unlikelyto emerge with longer followup,because ALND would only affectsurvival by virtue of improved locoregionalcontrol. In the Early Breast CancerTrialists’ Collaborative Group overview,statistically significant survivaldifferences between treatments at 15years were seen only when differencesin locoregional recurrence betweentreatments were greater than 10% at 5years. 6 Axillary recurrence is usually anearly event, occurring at a median of14.8 months in B04; in that trial, only7 of 68 axillary recurrences occurredmore than 5 years after study entry. 4Greco et al 37 reported that median timeto axillary recurrence was 30.6 monthsfor 401 patients who underwent breastconservingprocedures and radiationtherapy with no axillary surgery. Recentreports of long-term follow-up inrandomized trials confirm these findings.38,39 Because the total locoregionalrecurrence rate in the Z0011SLND-alone group at 5 years is only2.5% compared with 3.6% in the ALNDgroup, it is unlikely that further follow-upwould result in enough additionalrecurrences to generate a clinicallymeaningful survival differencebetween groups. The absolute differencein 5-year overall survival betweenthe treatment groups in Z0011is 0.7%, numerically favoring the SLNDalonegroup. The HR for overall survivalcomparing the SLND-alone groupwith the ALND group was 0.79 (90%CI, 0.56-1.10). The worst HR (1.10) isless than 1.3, which was hypothesizedas the inferiority margin threshold. Inessence, this means that the 5-year overallsurvival for the SLND-alone groupmight be as low as 90.3% if the true5-year overall survival for the ALNDgroup was 91.8% and the HR as highas 1.10. Most importantly, there is nosuggestion that rates of locoregional recurrence,the mechanism by whichvariations in local therapy result in survivaldifferences, differ between groupsto the extent needed to produce survivaldifferences or are likely to do soin the future. Taken together, this suggeststhat contemporary women maysustain the morbidity of ALND withoutany meaningful improvement insurvival rates. Limitations of the study,such as failure to achieve target accrualand possible randomization imbalancefavoring the SLND-alone group,must be considered. However, even inhigh-risk women (ER−/PR−) in Z0011,preliminary analysis suggests no effectof elimination of ALND on survival.Despite limitations of the Z0011 trial,its findings could have important implicationsfor clinical practice. Examinationof the regional nodes with SLND canidentify hematoxylin-eosin–detected metastasesthat would indicate a higher riskfor systemic disease and the need for systemictherapy to reduce that risk. Resultsfrom Z0011 indicate that womenwith a positive SLN and clinical T1-T2tumors undergoing lumpectomy with radiationtherapy followed by systemictherapy do not benefit from the additionof ALND in terms of local control,disease-free survival, or overall survival.The only additional informationgained from ALND is the number ofnodes containing metastases. This prognosticinformation is unlikely to changesystemic therapy decisions and is obtainedat the cost of a significant increasein morbidity. 10 The only rationalefor ALND in these patients wouldbe if the finding of additional nodal metastaseswould result in changes in systemictherapy. Because current guidelinesdo not support differences inadjuvant systemic therapy based on thenumber of positive lymph nodes, exceptin some uncommon select subgroups,40 ALND does not appear to bewarranted in this patient population.The Z0011 trial did not include patientsundergoing mastectomy, thoseundergoing lumpectomy without radiotherapy,those treated with partialbreastirradiation, those receiving neoadjuvanttherapy, and those receivingwhole-breast irradiation in the proneposition, in which the low axilla is nottreated. In those patients, ALND remainsstandard practice when SLNDidentifies a positive SLN. However,ALND may no longer be justified forwomen who have clinical T1-T2 breastcancer and hematoxylin-eosin–detected metastasis in the SLN and whoare treated with breast-conserving surgery,whole-breast irradiation, and adjuvantsystemic therapy. Implementationof this practice change wouldimprove clinical outcomes in thousandsof women each year by reducingthe complications associated withALND and improving quality of lifewith no diminution in survival.Author Contributions: Dr Giuliano had full access toall of the data in the study and takes responsibility forthe integrity of the data and the accuracy of the dataanalysis.Study concept and design: Giuliano.574 JAMA, February 9, 2011—Vol 305, No. 6 (Reprinted) ©2011 American Medical Association. All rights reserved.Downloaded From: http://jama.jamanetwork.com/ on 05/27/2012

SENTINEL NODE DISSECTION IN INVASIVE BREAST CANCERAcquisition of data: Giuliano, Beitsch, Whitworth,Blumencranz, Leitch, Saha, Morrow.Analysis and interpretation of data: Giuliano, Hunt,Ballman, Whitworth, Leitch, McCall, Morrow.Drafting of the manuscript: Giuliano, Ballman, Beitsch,Whitworth, Morrow.Critical revision of the manuscript for importantintellectual content: Giuliano, Hunt, Ballman, Beitsch,Whitworth, Blumencranz, Leitch, Saha, McCall,Morrow.Statistical analysis: Ballman, McCall.Administrative, technical, or material support: Giuliano,Hunt, Whitworth, Leitch, Saha.Study supervision: Giuliano, Whitworth.Conflict of Interest Disclosures: All authors have completedand submitted the ICMJE Form for Disclosureof Potential Conflicts of Interest and none were reported.Funding/Support: This study was supported by NationalCancer Institute grant U10 CA 76001 to theAmerican College of Surgeons Oncology Group(ACOSOG).Role of the Sponsor: The National Cancer Institute hadno role in the design and conduct of the study; thecollection, analysis, and interpretation of the data; orthe preparation, review, or approval of the manuscript.Additional Contributions: We thank the ACOSOGstaff, in particular the leadership of Heidi Nelson, MD(Mayo Clinic, Rochester, Minnesota), David Ota, MD(Duke University, Durham, North Carolina), and SamuelA. 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