Dixon, J Michael

Hunt, Kelly K

Rutgers, Emiel

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     Edinburgh Research Explorer                                      Intraoperative assessment of axillary lymph nodes in patientswith breast cancerCitation for published version:Dixon, JM, Rutgers, E & Hunt, KK 2014, 'Intraoperative assessment of axillary lymph nodes in patients withbreast cancer' BMJ, vol. 349, g6803. DOI: 10.1136/bmj.g6803Digital Object Identifier (DOI):10.1136/bmj.g6803Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:BMJGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 05. Apr. 2019Intraoperative assessment of axillary lymph nodes inpatients with breast cancerTime to abandon?J Michael Dixon professor of surgery 1, Emiel Rutgers clinical director 2, Kelly K Hunt professor ofsurgical oncology 31Edinburgh Breast Unit, Western General Hospital, Edinburgh, UK; 2Netherlands Cancer Institute, Amsterdam, Netherlands; 3University of TexasMD Anderson Cancer Center, Houston, TX 77030, USAThe main advantage of intraoperative assessment of axillarylymph nodes in patients having surgery for breast cancer is thatmetastatic disease can be diagnosed and removed in a singleoperation. However, there are several disadvantages that havecast doubt on its use. These include concerns about its accuracyand the uncertainty that all patients with diseased sentinel nodesneed additional treatment.Accuracy questionedSeveral methods have been used for intraoperative assessmentof axillary nodes, including frozen section analysis, touchpreparation cytology, and one step nucleic acid amplification.The National Institute for Health and Care Excellence (NICE)approved one step nucleic acid amplification in 2011, and it isthe most widely used axillary staging method in the UnitedKingdom.1A recent meta-analysis has raised doubts about the ability ofone step nucleic acid amplification to accurately determine theextent of axillary node involvement.2 The method is based onthe measurement of messenger RNA for cytokeratin 19,expression levels of which vary between and within cancers,with copy numbers ranging from 4700 to 140 000 copies permicrolitre. The meta-analysis concluded that the wide range ofcopy numbers in a fixed tumour volume precluded the accurateidentification of macrometastases (≥2 mm) in lymph nodes.2The positive predictive value of one step nucleic acidamplification compared with histology was only 0.79, and theauthors concluded that up to 21% of patients found to havepositive lymph nodes using this method had micrometastasesand therefore did not require axillary clearance. It is clearly timefor NICE to re-evaluate its guidance on one step nucleic acidamplification.Is treatment necessary?Doubts that patients with positive nodes require additionaltreatment stem from a pivotal US trial with 25 year follow-up.3The National Surgical Adjuvant Breast and Bowel Project(NSABP) B-04 trial found no survival benefit for patients withclinically node negative breast cancer who received axillaryradiotherapy or axillary clearance compared with those whosenodes were treated only when they became palpable. Morerecently, the American College of Surgeons Oncology GroupZ0011 trial evaluated axillary node dissection in clinically nodenegative patients having breast conserving surgery, whole breastradiotherapy, and adjuvant systemic treatment.4 It compared theoutcomes in patients with one or two positive sentinel nodesrandomised to axillary lymph node dissection or sentinel lymphnode biopsy alone. At median follow-up of 6.3 years there wasno difference in the axillary recurrence rates between groups(0.5% versus 0.9%, respectively) and no improvement insurvival with axillary lymph node dissection. Although this trialrecruited fewer patients than originally planned, the findingswere statistically valid.4 5The death rate was low in both armsof the trial, almost certainly because patients received effectivesystemic therapy, thus reducing the chances that axillary surgerycould have influenced survival. Axillary lymph node dissectiondid, however, significantly increase the rate of lymphoedema.5Two trials have since confirmed that patients with small volumeaxillary nodal disease do not require axillary lymph nodedissection. The NSABP B-32 trial randomised 5600 patientswith clinically node negative breast cancer to receive eitheraxillary lymph node dissection or sentinel lymph node biopsyalone.6 Over 4000 of the patients were pathologically nodenegative on haematoxylin and eosin staining, andimmunohistochemistry identified axillary nodal micrometastasesor isolated tumour cells in 616 of these patients. At 10 yearsthere was no significant benefit in local control or overallsurvival in patients with micrometastases who had axillaryclearance compared with those who had sentinel node biopsyalone. Similarly, a large randomised European trial found nobenefits in disease control or survival for axillary node dissectioncompared with sentinel node biopsy alone in patients withmicrometastases (<2 mm).7 These and other studies led theCorrespondence to: K K Hunt khunt@mdanderson.orgFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2014;349:g6803 doi: 10.1136/bmj.g6803 (Published 25 November 2014) Page 1 of 2EditorialsEDITORIALSAmerican Society of Clinical Oncology to advise that patientswith one to two positive nodes on biopsy who have breastconserving surgery, whole breast radiotherapy, and similarclinical and pathological characteristics to those enrolled in theZ0011 trial do not require routine axillary lymph nodeclearance.8Alternative treatmentAxillary radiotherapy is an alternative to complete axillarylymph node dissection for patients with sentinel lymph nodemetastases. Studies performed 30 years ago compared axillaryradiotherapy with axillary lymph node dissection and showedno difference in survival.9 10More recently, a large multicentreEuropean study compared axillary radiotherapy with axillarylymph node dissection in patients with a positive sentinel nodeand showed no significant difference in the rates of axillaryrecurrence and survival.11However, the lymphoedema rate withaxillary radiotherapy was half that seen in patients treated withlymph node dissection. Therefore, for women who are likely tobenefit from axillary treatment, radiotherapy is a viablealternative to axillary dissection, offering similar rates of diseasecontrol but lower rates of morbidity.Many centres in the United States have abandoned intraoperativeassessment of sentinel nodes, but one step nucleic acidamplification continues to be widely used in the UnitedKingdom. Given the results from randomised trials, theguidelines from the American Society of Clinical Oncology,and the alternative options available for patients with diseasednodes, it seems unnecessary for patients to have intraoperativeaxillary lymph node assessment. It is imperative that decisionsabout how to treat axillary nodal disease are made withknowledge of tumour biology, the burden of disease in thesentinel nodes, and any planned radiotherapy and systemictherapy. Most importantly, patients need to participate in thesedecisions. Intraoperative frozen section analysis of breasttumours was abandoned long ago because it denied patients theopportunity to contribute to their treatment planning. It is nowtime to do the same with intraoperative sentinel lymph nodeassessment.Competing interests: We have read and understood BMJ policy ondeclaration of interests and have no relevant interests to declare.Provenance and peer review: Not commissioned; externally peerreviewed.1 National Institute for Health and Care Excellence. Intraoperative tests (RD-100i OSNAsystem and metasin test) for detecting sentinel lymph node metastases in breast cancer.2013. www.nice.org.uk/guidance/dg8.2 Tiernan JP, Verghese ET, Nair A, Pathak S, Kim B, White J, et al. Systematic review andmeta-analysis of cytokeratin 19-based one-step nucleic acid amplification versushistopathology for sentinel lymph node assessment in breast cancer. Br J Surg2014;101:298-306.3 Fisher B, Jeong JH, Anderson S Bryant J, Fisher ER, Wolmark N. Twenty-five-yearfollow-up of a randomized trial comparing radical mastectomy, total mastectomy, andtotal mastectomy followed by irradiation. N Engl J Med 2002;347:567-75.4 Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, et al.Axillary dissection vs no axillary dissection in women with invasive breast cancer andsentinel node metastasis. JAMA 2011;305:569-75.5 Giuliano AE, McCall L, Beitsch P, Whitworth PW, Blumencranz P, Leitch AM, et al.Locoregional recurrence after sentinel lymph node dissection with or without axillarydissection in patients with sentinel lymph node metastases: the American College ofSurgeons Oncology Group Z0011 randomized trial. Ann Surg 2010;252:426-33.6 Julian TB, Anderson SJ, Krag DN, Weaver, DL, Costantino JP, Ashikaga T, et al. 10-yrfollow-up results of occult detected sentinel node disease: NSABP B-32. Abstract S2-05.35th annual San Antonio breast cancer symposium, San Antonio, Texas, 10-14 December2013.7 Galimberti V, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P, et al. Axillary dissectionversus no axillary dissection in patients with sentinel-node micrometastases (IBCSG23-01): a phase 3 randomised controlled trial. Lancet Oncol 2013;14:297-305.8 LymanGH, Temin S, Edge SB, Newman LA, Turner RR,Weaver DL, et al. Sentinel lymphnode biopsy for patients with early-stage breast cancer: American Society of ClinicalOncology clinical practice guideline update. J Clin Oncol 2014;32:1365-83.9 Forrest AP, Everington D, McDonald CC, Steele RJ, Chetty U, Stewart HJ. The Edinburghrandomized trial of axillary sampling or clearance after mastectomy. Br J Surg1995;82:1504-8.10 Chetty U, Jack W, Prescott RJ, Tyler C, Rodger A. Management of the axilla in operablebreast cancer treated by breast conservation: a randomized clinical trial. Edinburgh BreastUnit. Br J Surg 2000;87:163-9.11 Rutgers EJ, Donker M, Straver ME, Meijnen P, Van De Velde CJH, Mansel RE, et al.Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients.Final analysis of the EORTC AMAROS trial (10981/22023) [abstract]. J Clin Oncol2013;31:LBA1001.Cite this as: BMJ 2014;349:g6803© BMJ Publishing Group Ltd 2014For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2014;349:g6803 doi: 10.1136/bmj.g6803 (Published 25 November 2014) Page 2 of 2EDITORIALS

Intraoperative assessment of axillary lymph nodes in patients with breast cancer

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