Axillary management in early breast with onset surgical management and positive sentinel

Lia Pamela Rebaza Vasquez , Jaime Ponce de la Torre, Raul Alarco, Joseana Ayala Moreno and Henry Gomez Moreno

Unit of Basic and Transnational Research, Oncosalud-AUNA Clinic, Lima, Peru ahttps://orcid.org/0000-0002-9620-9460

Abstract

Over the years, the management of early has evolved by leaps and bounds, as has the concept of axillary staging and armpit surgical management. Five randomised studies exist that evaluate the possibility of omitting regional locus surgical axillary treat- ment in patients with early breast cancer and positive sentinel lymph nodes without it having an impact on the prognosis of the disease in selected cases. A review of the litera- ture on the management of the axilla in early breast cancer is presented.

Keywords: breast cancer, positive , radical axillary dissection Review

Introduction

Over the years, has evolved in leaps and bounds. We have moved from radical procedures in the era of Halsted [1] and Urban [2] to the era of con- servation with Veronesi [3] and Fisher [4], followed by the change in the surgical approach of the axilla with sentinel lymph node validation as an axillary staging method Correspondence to: Lia Pamela Rebaza Vasquez and the omission of radical axilla dissection in patients with negative sentinel nodes and Email: [email protected] even in selected patients with positive sentinel lymph nodes as described by Giuliano ecancer 2021, 15:1193 [5] in Z0011. Despite this, there is still a lot of controversy with respect to the surgical https://doi.org/10.3332/ecancer.2021.1193 management of the axilla. There is fear of global de-escalation and ignorance of the real Published: 01/03/2021 impact that locoregional treatment has on breast cancer prognosis. The objective of this Received: 27/08/2020 review is to show evidence to date to establish a clearer concept regarding the manage- Publication costs for this article were supported by ment of the axilla in early breast cancer with positive sentinel lymph nodes. ecancer (UK Charity number 1176307). Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access Sentinel lymph node history article distributed under the terms of the Creative Commons Attribution License (http:// creativecommons.org/licenses/by/3.0), which The concept of the sentinel lymph node was described by Ramón Cabanas and col- permits unrestricted use, distribution, and leagues in 1977, with their proposed idea being to identify by lymphangiography the reproduction in any medium, provided the original first nodes to which the lymphatic flow of the penis is directed, and after removal, carry work is properly cited.

ecancer 2021, 15:1193; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1193 1 considered [15]. sentinelnodes afterlymph neoadjuvanttherapy inbreastcancer patients andcomplete clinicalaxillary response patients iscurrently being Since axillary management haschanged further, theomissionof RADinpositive sentinel lymphnodebreast cancer or even theuseof patients with positive sentinel lymphnodesor clinicalevidence of initialaxillary compromise. consolidated astheelected method for surgical stagingof theaxillainpatients with clinically negative axillary nodes,reserving theRADfor CI: 79.6%–83.4% 95% 81.5%; (HR: CI: 90.4%–93.3%) versus CI:80.5%–84.4%)[12]. 82.4%; 95% HR: Thus, thesentinel lymphnode was patients versus those that had axillary dissection were similar (hazard ratio (HR): 90.3%; 95% CI: 88.8%–91.8% versus 91.8%; HR: 95% ported by multicentreas theNSABP-32,such studies in it which was found that OSanddisease-free survival of sentinel lymphnodebiopsy was oncologically assafe asaxillarybut dissection, same conditionalthe without morbidities.Since then,thesediscoveries have beensup and Veronesi The scientific validationof sentinel the node inbreastlymph cancer was given in2000and2003 studiesbywith Giuliano [9],Giuliano [10] group without significant impactoneither overall survival (OS) nor indisease-free after time(DFT) 20 years of follow-ups. of40% patients the that did not have axillary surgery were left nodaldiseaseinbothwith theradiotherapy groupand thenon-treatment therapy, we see thatwill of40% patients the that underwent radical hadaxillary compromise. This isto say that approximately agementof radicalmastectomy (mastectomy andRAD), totalmastectomy axillarywithout managementand total mastectomy with radio- If we analyse thedata from NSABPin 2002, 04published included 1,079patientswhich with early N0breast cancer andrandomise theman- detect axillary bydescribed Morton for breastcancer, demonstratingthat identificationthe andstudy of thesentinel lymphnode was areliable marker to radical axillary dissection (RAD) for all patients with early breast cancer began to be questioned results study usingsentinelnodes inmelanoma lymph with atechnical modification, by usingpatent blueinstead of lymphangiography, with positive microscopicout study of thesameto determine theneedor not to perform complete nodaldissection[6]. Afterwards, Morton a published ecancer 2021, 15:1193; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1193 axilla versus RAD, andtwo (AMAROS, OTOASOR) compare axillary radiotherapy (AR) versus RAD(Table 1). tive sentinel nodepatients. lymph Of thefivethree studies, (ACOSOG-Z0011, IBCSG23-01, AATRM) compare theobservation (OBS) of the To date, five randomisedexist studies that evaluate thepossibility of omitting locoregional axillary treatment inearly breast cancer andposi- and positive sentinel lymphnode Omission of locoregional axillary treatment in early breast cancer patients, initialsurgical management [6]. At thesametime, data published with from theNational Surgical Adjuvant Breast andBowel Project (NSABP) 04,theneedfor RAD, Radical axillary dissection; AR, Axillary radiotherapy positive sentinel lymphnodes. Table 1.Randomisation of studies that evaluate theomissionof locoregional axillary treatment inpatients with early breast cancer and OTOASOR (474) AMAROS (1,425) AATRM (233) IBCSG 23-01(933) ACOSOG Z0011(856) [11], respectively. They demonstrated thatomission ofthe axillary dissectioninpatients with negative sentinel lymphnodes Tests [16] [17] [14] [8]. [13] [5] Micrometastasis Micrometastasis No extracapsular extension 50% macrometastasis, micrometastasis OBS versus RAD versusOBS Randomisation Macrometastasis, 68%micrometastasis Macrometastasis 60%micrometastasis [7]. In 1994, Giuliano the applied technique RAD versusRAD AR 2 -

Review ecancer 2021, 15:1193; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1193 cancer andtheir acceptance isconditioned by thenumber of patients treated andthenumber of multidisciplinary activities’ [20]. as reported by Morrow et al showstudies best option.be the should Despite resistance this, exists in treating physicians to more precise axillary surgical management of thiscondition inthesuperiorparesthesia, limb(, limitation), functional sode-escalating thetreatment with thesafety that theyimpact will have onthepatients’of qualities life [19].One of themainproblems of axillary treatment inbreast cancer isthe morbidity according to thediseasestage andthetumour biology, always takinginto account theintensity andduration of the secondary effects andthe We are currently in a de-escalation stage in breast cancer treatments, so we should consider making decisions based on the probable benefits for OBSor AR dependingonthetypeof surgery performed breast onthe (Figure). 1 positive sentinelnodes, the indication lymph would beRAD, andifto onehasup two positive sentinel lymph nodes,they could bechosen patients gowho to surgery initially positivewith sentinelnodes lymph will dependontheamount of diseasefound. If onehasthree or more opting foror OBS AR. Therefore, we cannow concludethat thedecisionregarding whether or not to perform RADfor early breast cancer No significantdifference was observed betweenstudies the described within treating or omittingstandard axillary treatment, either by groups, either inOS(77%,84% axillary groupsand thesupraclavicular fossa) (231), a medianfollow-upwith of 8 years. There was nosignificant difference between thetwo The patients were randomisedinto two groups;one underwent (244) andtheotherRAD underwent (50 GyAR in25sessionsthethree The OTOASORstudy recruited 474 T1, T2, T3 andN0breast cancer patients that hadpositive sentinel lymphnodesfor macrometastasis. Despite this,theassessment of non-inferiority hadlittlepower given thefew events recorded [14]. After 10 years of follow-up,no significant difference was found, nor inOS(84.6%, 81.4%p=0.26)nor intheDFT (81.7%,78.2%p=0.19). agement;one underwent other(744) andthe RAD underwent (25 fractionsAR of 2Gy inthethree axillary groups andsupraclavicular nodes). N0 andpositiveT1–T2, sentinelnodes for lymph macrometastasis (Table 2). The patients were randomised into two groups for axillary man- Studiesthat compare AR versus axillary surgery (RAD) highlight the AMAROS study. AMAROS includes4,806breast cancer patients with Studies that compare two types of axillary treatment: surgical axillary management (RAD) versus AR between OBS versus RADintheOS(98.2%,98.4% groups;one was forother(121) andthe RAD was for(no OBS RAD) (112). After 5 years of follow-up,there was nosignificant difference cally negative axillae with positive sentinelnodes for lymph micrometastasis. The patients were randomised for axillary management in two The AATRM048 alsoevaluated topic. thesame It 233 patientsstudied with invasive breast cancer with tumours ofto up 3.5cmandclini- (76.4%, 74.4% follow-up,there was nosignificant difference between thegroup that was under OBS versus thegroupthat underwent RAD, nor intheDFT randomised for axillary management intwo groups;one was for RAD(464)andtheother was for OBS(no RAD) (467). After 10 years of study includes934 patients earlywith breast cancer (T2,N0) atwith leastone sentinel lymph node with micrometastasis. The patients were Another study that considered theomissionof axillary treatment inpositive sentinel lymphnodepatients istheIBCSG23-01. This European axillary recurrence (1.3%,0.6% ence betweengroup theOBS versusgroup, theRAD nor in the OS(83.6%,86.6%p=0.25), nor intheDFT (80.2%,78.2%p=0.31),nor in otherthe was(no OBS RAD) (420). After 10 years of follow-up,in the2016publication, it was reported that there was nosignificant differ underwentconservationinitial surgery (Table 2). These were randomised into two groups for axillary management:one was(436) and RAD totalof 856patients earlywith breastcancer N0) (T1–2, toup twowith positive sentinel lymphnodes(micro and/or macro metastasis) who The ACOSOGstudy initially published in 2011 is perhaps themost important and controversial study that addresses this topic. It included a Studies

that compare axillary surgical management (axillary radical dissection) versus OBS p =0.24),nor intheOS(90.8%,88.2% [20] in2018:‘There isa variationin thesurgeons’ acceptance of more limited surgical management for breast p =0.44)[5]. p =0.06)or DFT (72.1%,77.4% p =0.3)[16]. p =0.2)[13]. p =0.6)[17]. 3 -

Review ecancer 2021, 15:1193; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1193 ). sentinel lymphnodes,they could bechosen for OBSor ARdepending onthetype of surgery performed onthebreast (PN+:positive lymphnodes by Figure 1.If onehasthree or more positive sentinel lymphnodes,theindication wouldbe radicalaxillary dissection,and ifonehas up to twopositive Table 2.Summary tableof randomised studiesonomissionof axillary management andpositive sentinel lymphnodes. Source: A.Re, Axillary recurrence; RAD, Radical axillary dissection;OBS,Observation; DFT, Disease-free time;OS,Overall survival; AR, Axillary radiotherapy OS DFT A.Re. nodes inRAD Positive lymph surgery (%) Conservation Median follow-up No. of patients Table [18] 2translation, Morrow 83.686.6p=0.25 80.278.2p=0.31 1.30.6p=0.44 OBS RAD 27.3% 100% 9.25 years OBS: 420 RAD: 436 Total ACOSOG Z0011[5] 90.8 88.2p=0.2 76.4 74.4p=0.24 2<1(8p) OBS RAD 13% 91% 9.7 years OBS: 467 RAD: 464 Total IBCSG 23-01[13] 98.2 98.4p=0.3 1 0 OBS RAD 13% 84% 5 years OBS: 112 RAD: 121 Total AATRM [16] 84.6 81.4p=0.26 81.7 78.2p=0.19 1.19 0.43 AR RAD 33% 83% 10 years 681 AR: RAD: 744 Total AMAROS [14] 77 84p=0.06 72.1 77.4p=0.6 2 1.7p=1 AR RAD 38.5% 88% 8 years AR: 231 RAD: 244 Total OTOASOR [17] 4

Review ecancer 2021, 15:1193; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1193 predict via anefficient manner the volume of axillary diseaseandthus define theneedfor RAD? If we go further andaskourselves: Can apositive axillarynode lymph inapatient with early breast cancer andclinically negative axilla (Figure 2). mentionedcriteria. This isto say,of 70% patients ultrasonographicallywith abnormalor suspected lymphnodesdidnotrequire RAD axillaryand inpatients dissection, ultrasonographicallywith altered lymphnodes,only 30%required axillary dissectionaccording to the patients that hadaxillary ultrasounds previously, we findthat inpatients with ultrasonographically normallymphnodes,only 12%required 183 patients that didnothave axillary ultrasounds previously, 17%of thecasesrequired axillary dissection.However when we analyse the wherenodes abnormallymph were found in25%of cases. After analysing thoserequiring axillary dissectionusingtheZ0011criteria, of the positive sentinelnode biopsy lymph andalsometZ0011 criteria.the From this,242patients hadaxillary ultrasounds previous to surgery, Melissa Pilewski tions prior to surgery. versussolely observing(ACOSOGstudy),23-01 IBCSG Z0011andthe we will seethat noneof thepatients hadaxillary ultrasound evalua - have a preoperative axillary ultrasound evaluation (Table 3). Further, if we only include the thatstudies compared surgical axillary treatment described above,the studies within which validate theomissionof RADinpositive sentinel lymphnodespatients, more than60%didnot This isa very controversial and many question are probably atodds or indoubt when discussingit.But webegin by should remembering that, Pre-decision axillary ultrasonography: shouldthesonography change our behaviour? would not have animpactontheprognosis of early breast cancer, especially inaselected groupof patients. in OSor DFT after 20 years of follow-up receive axillary surgery were left nodal diseaseinbothwith radiotherapythe groupand thenon-treatment group significantwithout impact the patients that underwent radical mastectomy had axillary compromise. This is to say that approximately 40% of the patients that did not (mastectomy andRAD), totalmastectomy axillarywithout managementand total mastectomy with radiotherapy, we see thatwill 40%of in 2002, 04 published 1,079 patientsincluded which earlywith N0breast cancer andrandomised themanagement of radical mastectomy nosis of our patientsor should we onlyaxillary use surgery asaform of staging? This isnot anew idea.If we analysed thedata from NSABP This questionsthetreatment of theunderarm asseeninbreast cancer. Does thelocoregional axillary treatment actually impacttheprog- axillary treatmentor hadaxillary treatment with thereAR, was anuntreated nodalinvolvementranging from 13%to 38%[5,13,14,16,17]. axillary nodalinvolvement inpatients who didcomplete RAD was between 13%and38.5%. This isto say that inpatients that didnot have treating thediseaseor axillary compromise locoregionally. If we review thestudiescarefully, we will seethat thepercentage of untreated If we analyse why thereresistance issomuch to theomissionof axillary treatment, we will seethat oneof themainfactors isthefear of not treatment inpatients with early breast cancer andpositive sentinel lymphnodes. Table 3.Preoperative axillary ultrasound evaluation instudiesthat evaluate theomissionof locoregional axillary AMAROS ACOSOG-Z0011 [5] OTOASOR ATTM IBCSG 23–01 [22], in a retrospective analysis, evaluated 425 patients with early breast cancer that underwent conservation surgery, [16] [14] Study [17] [13] [7]. With allof thisinformation, we caninfer that theomissionof locoregional axillary treatment Axillary ultrasound Preoperative 1,336 (35%) 474 (100%) 859 (60%) 3 (1.2%) 0 0 No axillary ultrasound Preoperative 230 (98.8%) 2,583 (65%) 856 (100%) 931 (100%) 566 (40%) 0 1,425 (100%) 3,919 (100%) 856 (100%) 931 (100%) 474 (100%) 233 (100%) Total [21] 5

Review and future work will give usmore light. We mustevaluate individually eachcase today. While we could questionaxillary ultrasonography prior to surgery in selected cases, there is still tomuch analyse with respect to this topic example isthestudy publishedby agroup from Memorial Sloan Kettering isthissomething in2017[18],but we shouldgeneralise? Currently, the work that reports theapplicability of Z0011, for the most part, does not axillary utilise ultrasonography prior to surgery. A clear unnecessary radical dissectioninmore than40%of cases(Figure 3)[22]. biopsy the volume of axillary disease in patients with clinically negative axillae with a certain manner. On the contrary, this leads us to perform node inthe lymph vast majority of cases(p thathad more three than positivehad notRAD nodes during lymph only positive needlebiopsy alsomore but thanonesuspected imaging nodes atlymph themoment of RAD. This isto say thatmay theRAD have beenomitted. Furthermore, they observed that 53%of patients that had axillary ultrasounds and positive axillary for metastasis before surgery. Of all of these, 47% had from one to two positive Melissa Pilewskie [21]alsoevaluatedquestion. this They141 studied women with early breast cancer clinicalaxillarywithout compromise ecancer 2021, 15:1193; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1193 Figure 3.Positive axillary biopsy inpatients withclinically negative axillae wouldlead tounnecessary radicaldissectionin morethan40% ofcases. Figure 2.70%of patients withultrasonographically abnormalor suspected lymphnodesdidnot require RAD. No AxillaryDisecco 83% No AxillaryUltrasound 1-2 Abnormalnodes n 183 47% = 0.003). Therefore, theauthors could conclude that we cannot predict with apositive axillary Axillary Disecco 17 % Negave AxillaryNode Posive NodeBiops n Axillary Disecco Breast Cance Disecco Axillary 30% 141 n

Abnormal node r 25% n No Axillary Disecco y Axillary Ultrasound 70%

s 1-3 Abnormalnodes n 242 Diseccon 53% Axillary 88% Normal node 75% No Axillary Diseccon s 12% 6

Review ecancer 2021, 15:1193; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1193 breast surgery are randomised for axillary management, either or OBS axillary treatment via surgery or radiotherapy [24]. patientsincludes with breastand N0 T2 cancer toup twowith sentinel lymphnodes with macrometastases thatregardless of thetypeof absolving many of our doubtsand otheron this scenarios. isapragmatic, POSNOC multicentre, non-inferiority andrandomised trialthat locoregional treatment of theaxillaor if itissimply something we shouldstop doinginthisscenario. The POSNOC Trial promises to finish ‘partially treated’at although suboptimal doses. It remains to bedefined today whether or not there isagroupof patients who benefit from groupof patientsdid not receive axillary andbreastradiotherapy, those who received indirecttangential breast radiotherapy may have been local axillary treatment (surgery or radiotherapy). Nevertheless, there isstillalot of controversy onthisissue,as while itistruethat there is cancer undergoing conservation surgeryto andup two positive sentinel lymphnodes extracapsularwithout extensionnot should receive If we analyse thefindingsto date, weconclude can that resultsthe initially presented by Z0011are valid, sopatients with T2, N0breast received by thepatients [18]. accumulated riskto 5 years of ganglialreoccurrence was 1%,andthere was nosignificant difference dependingonthetypeof radiotherapy of follow-up,there were five node recurrences, of which four were ganglial and at a distance andone was ganglialandto thebreast. The received axillary andbreastradiotherapy. Itbe notedshould thatthe patients who had AR hadincreased riskfactors [18]. After 37months ment).of21% patients the received prone breastradiotherapy, of 58% thepatients received tangential breast supine radiotherapy and21% the information was available, excluding 25that didnot receive standard treatment (partial breast radiotherapy or noradiotherapy treat - the patients who went to sentinelnode biopsy lymph was 93%(IC89%–94%). The irradiation fields were analysed in509patients where cause being the presence of more than three positive sentinel nodes lymph or extracapsular compromise. The overall 5-year survival of had conservation surgery andsentinelnode biopsies.Only lymph 130patients underwent radical axillary surgery, with themostfrequent Morrow locoregionally with either surgery or radiotherapy in100%of cases? [23](Figure 4) receiverRAD radiotherapy treatment at theaxillary groupsI andIIlevel. Thus, we would have to askagain:Is itnecessary to treat theaxilla receive any radiotherapy treatment in the breast nor the axilla and that only 40 cases (6%of the total) of the patients that did not receive a non-treated dose,i.e.at asuboptimaldose. Furthermore, itshouldberemembered that 11%(66patients) of the605 patients didnot Now by cold-analysing theinformation,that itistrue atangential fieldto thebreast will irradiate axillary groups IandIIindirectly, at but and only 40casesreceived breast radiotherapy with hightangential fields,i.e.axillary fieldsIandII were included[23]. Of the124 patients that didnot receive axillary surgical treatment, only 83%received breast radiotherapy with tangential fields(breast only) couldonly obtain detaileddata of radiotherapy treatmentofin 29% cases,i.e.of 228patients (124:sentinel lymphnodebiopsy, 104:RAD). tiveof nodesbeingmost lymph whom received irradiation at thesupraclavicular level. Another point that Jagsi [23]emphasisedisthat they todecision irradiate or notat supraclavicularthe level wasnumber the of positive axillary lymphnodes, with patients with three or more posi- patients that received radiotherapy, 15%received treatment inthesupraclavicular region. However, theonly significant factor related to the of patients received breast radiotherapy, i.e.11%of evaluated patients didnot receive any typeof radiotherapy treatment [23].Of the540 cal treatment. Only 605reportsof radiotherapy treatment were studiedfor allZ0011patients (856).Of these605patients, only 540(89%) Reshma Jagsi the mostcriticisedstudies conservationsurgery andpositive sentinelnodes (macrometastaseslymph 1–2, extracapsularwithout extension). Despite this,itisoneof As we explainedpreviously, Z0011 isoneof the pillars the thatleads to theomissionof axillary treatment inearly breast cancer patients with for thisspecificpoint. treatments isaprocess that hasbeen takingplace andpresents, aseverything changed, someresistance. We will now analyse theevidence management?Could not we say that greater locoregional management would not resolve theproblem of abadbiology? The de-escalation of gery doesnotsolve problem the of abadbiology’. Letanalyseus thisphrase andfocus only onsurgery. Should we not questionlocoregional Before we beginto address thisissue, let usr [18] raisedin 2017,theyquestion; same the a prospective published validation study that included793patients. All of thepatients [23] in2014evaluated radiotherapy asapossiblecauseof theprognosis inZ0011patients in which they omitted axillary surgi- [5]. 7 a -

Review ecancer 2021, 15:1193; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1193 No conflicts of interest exist. Conflict of interest The review hasbeenself-funded. Funding statement team. troversy that stillexists, itisrecommended to consider thepossibility of theomissionof AR inanindividualmanner amultidisciplinarywithin extracapsularwith extension who have initialconservation surgery, axillary surgical treatment canbe omitted. Furthermore, given thecon- Basedcurrent onthe scientific evidence, we consider thatin patients with early breast cancerto andup two positive sentinel lymphnodes Conclusions Figure 4.Review of work by Jagsi [23],Radiation Field Design inthe ACOSOG Z0011(Alliance). Radiotherapy Tangenal Breast radiotherapy (85%) 228 Paents radiotherapy scheme

Only evaluated radiotherapy 540 (11% Supraclavicular region

856 PaentsZ001 ) 605 Paent (15%) s 1 Supraclavicular Area Tangena Evaluated In Did notreceiveanyradiotherapy Tangena detail treatment lA 142 reas la reas 185 s4 65 (11% 3 ) Only SN

High Tangenal Area (40) s7 -A 3 D (33) 8

Review

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Review