Sentinel Node Biopsy in Melanoma

8/7/2019 Sentinel Node Biopsy in Melanoma

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Volume 22 Number 1 2008

Sentinel Lymph Node Biopsy inMelanoma in 2008

J. M. Thomas, M.S., F.R.C.P., F.R.C.S., and A. J. Hayes, M.A., F.R.C.S., Ph.D.

Intdctin

Sentinel lymph node biopsy (SLNB) in melanoma has been intensively investigatedand, apart rom the nal results o the Multicenter Selective Lymphadenectomy Trial

(MSLT-1)1 and a ew other renements, sucient inormation is available to cometo an initial consensus about the value o this investigation and its consequences.

Nevertheless, it is dicult to think o a surgical procedure or a therapy that hasgiven rise to such a wide spectrum o opinion despite the act that all parties areinterpreting the same data. The dominant opinion is that SLNB in melanoma shouldbe regarded as standard o care, which implies that patients not oered the pro-cedure are being disadvantaged in some way. It has even been suggested that notoering patients the opportunity or SLNB may have medicolegal consequences.2Although detractors o the procedure are in a minority, some have argued thatSLNB is o no benet and should be abandoned.37

The results o MSLT-1 were rst presented at the meeting in Los Angeles in Decem-ber o 2004 and were ormally announced at the American Society o Clinical On-cology (ASCO) in May o 2005,8 but were not published until September o 2006.1Until these results were known, it was not unreasonable to regard SLNB as the latestand best orm o innovative care, especially in view o the prognostic importance o

sentinel node (SN) status. Furthermore, particularly in the United States and Austra-lia, the SLNB procedure replaced elective lymph node dissection (ELND). Results o

CANCERPrinciples & Practice

of Oncology

Vincent T. DeVita, Jr.

Samuel Hellman

Steven A. Rosenberg

7th Edition

Authors:

J. M. Thomas, M.S., F.R.C.P., F.R.C.S., andA. J. Hayes. M.A., F.R.C.S., Ph.D., Sarcoma and Melanoma Unit,

Department o Academic Surgery, Royal Marsden Hospital, London, England.

The opinions and/or clinical experiences outlined herein are those o the authors and do not necessarily

represent the views o the editors or publisher.


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Sentinel lymph nodeBiopSyin melanoma Volume, numBer 1

our randomized controlled trials o ELND were showing no over-

all survival (OS) advantage,912 but o greater concern was thatno deposits o melanoma were present in approximately 80% othe ELND specimens, meaning that these patients were undergo-ing excessive and unnecessary surgery which was associated withsignicant surgical morbidity, especially chronic lymphedema. Theimmediate attraction o the SLNB procedure was that it selectedpatients or ELND (or completion/early/immediate lymphadenec-tomy as it became known) based on the presence or absence omelanoma deposits in the SN. Subsequently, the identication otiny deposits o melanoma within the SN by immunohistochem-istry (IHC)13 that could not be identied by conventional stainingtechniques ueled urther interest and ascination in the proce-dure. It is or these perectly logical and intuitive reasons that theSLNB procedure became standard o care beore ull evaluationhad been completed.

Over the past decade or so, the SLNB has dominated clinical

practice and research in melanoma. Sucient inormation andoutcome data are now available to allow a more critical analysiso the procedure with a view to renement o clinical practice.

A re-evaluation o the procedure is justied i only because theresults o MSLT-1 do not even show a trend toward an OS advan-tage. Our responsibility as physicians is to provide patients withaccurate inormation on which to base their decisions. We believethat the arguments presented in this review are evidence-basedand deserve careul consideration.

A Fawk f Assssing th us f SlNb inmana

The theoretical basis underpinning the purported value o SLNBand subsequent completion lymphadenectomy in SN-positive cas-es can be summarized by the ollowing three points.

1. Prognostic inormation. Knowing the status o the SN providesprognostic inormation over and above that which is providedby the histologic characteristics o the resected primary tumor.This allows a more accurate stratication o a patients risk orrelapse at distant sites, or the purposes o adjuvant treatment,or or entry into trials o adjuvant therapy. I there is no eec-tive adjuvant treatment, then the only possible benet o theprognostic inormation is in lessening, but not eradicating, pa-tients uncertainty as to whether their disease will recur.

2. Therapeutic benet resulting rom surgical resection. Comple-tion lymphadenectomy in SN-positive patients may have anintrinsic therapeutic benet by removing LNs containing malig-nant cells when they are not apparent clinically or by standard

radiologic techniques. Inevitably this will infuence the patterno disease recurrence, but to achieve a therapeutic advantage,early lymphadenectomy must be shown to reduce the inci-dence o systemic spread.

3. Potential detrimental eects o surgery. The two potential ben-ets o SLNB must be evaluated in the context o morbiditiesassociated with the procedure. There is a small but signicantmorbidity o the procedure itsel. O greater concern (see be-low) is that a proportion o patients will undergo unnecessary

completion lymphadenectomy as a result o prognostic alse-

positivity within the SN. There is also a lingering concern thatcompletion lymphadenectomy in SN-positive patients may in-crease the risk or in-transit recurrence14,1519 despite the actthat, overall, the incidence o in-transit disease is similar in botharms o MSLT-1.1

We would have no objection to the SLNB procedure i it wereknown or were likely that all SN-positive patients would prog-ress to palpable nodal recurrence. The operations o immediateand delayed lymphadenectomy are identical, and we know romthe results o MSLT-1 that the morbidity is similar. Our main con-cern relates to prognostic alse-positivity, meaning that some tinydeposits o melanoma in the SN are destined or destruction ordormancy rather than progression. Furthermore, i the evidencesuggests that SLNB serves only as a prognostic tool or risk strati-cation, then the question must be asked as to how superior thatprognostic inormation is over detailed histologic assessment o

the primary tumor and ultrasound o the SN basins. In the ab-sence o adjuvant treatments, is there any benet to the patientin having imperect prognostic inormation?

Based on these comments, this review is structured as ollows: (a)evidence or therapeutic benet or SLNB and immediate lymph-adenectomy; (b) the role o SLNB as a prognostic tool; (c) theevidence or prognostic alse-positivity within positive SNs, and(d) the importance o ultrasound in screening and surveillance oSN basins.

SlNb as a Thaptic T: mSlT-1

MSLT-1 was designed to compare the survival o SN-positive pa-tients undergoing immediate lymphadenectomy (the biopsy arm)with that o patients treated by delayed lymphadenectomy when

metastatic regional nodes became palpable (the observation arm).

To achieve this primary end point, the trial entered and random-ized 2001 patients,20 but the published results relating to survivaldescribed only a subgroup o 1269 patients with tumors o inter-mediate thickness (1.2 to 3.5 mm).1 No survival inormation or pri-mary tumor-related details have been published about the 732 pa-tients with tumors thinner than 1.2 mm or thicker than 3.5 mm.

Summary of Trial Design and ResultsForty percent o patients were randomized to the observation armand, according to the protocol, were treated by wide local exci-sion (WLE) o the primary tumor and delayed lymphadenectomywhen the regional LNs became palpable. Sixty percent o patientswere randomized to the biopsy arm and ater WLE were investi-gated by SLNB. Immediate lymphadenectomy was perormed i

any SNs contained metastatic melanoma (SN-positive). The resultsshowed no dierence in OS (87.1% biopsy arm vs. 86.6% obser-vation arm) and a 5% dierence at 5 years in disease-ree survival(DFS) in avor o the biopsy arm (78.3% vs.73.1%). The abstractconclusion conrmed the prognostic value o SN status. A post-randomization subgroup analysis claimed a 20% survival advan-tage when the 122 SN-positive patients in the biopsy arm, whounderwent immediate lymphadenectomy, were compared to the78 patients in the observation arm, who were treated by delayedlymphadenectomy1 (Fig. 1).

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Volume, numBer 1 thomaSand hayeS

Is There a Subgroup Survival Advantage?The claim o a 20% survival advantage or immediate lymph-adenectomy in the abstract conclusion1 is based on a subgroupanalysis and is in stark contrast to the absence o any melanoma-specic survival advantage at the point o randomization. Becausethe subgroup analysis result is at such odds with the primary endpoint, this result must be scrutinized to determine i the compari-son is valid.

Subgroup analyses within a randomized trial are valid only i thesubgroup is identied beore randomization such that the char-acteristic that denes the subgroups is randomly allocated.21These two subgroups were not dened beore the randomiza-tion. Rather, they are post-randomization selected subgroups andthe patients in each subgroup were identied by the procedureunder investigation. Within a randomized controlled trial, a de-nitive survival comparison between post-randomization selectedsubgroups is not valid.

The rationale or making the comparison between these twononrandomized subgroups is based entirely on the assumption

that all patients with positive SNs will inevitably progress to pal-pable nodal disease and that these two subgroups are prog-nostically equivalent. As will be shown later, multiple sources

o indirect and direct evidence now indicate that some positiveSNs are not destined to progress to palpable nodal recurrence.Hence the two subgroups are notprognostically equivalent, andthe 20% survival dierence is not the result o any therapeuticadvantage rom immediate lymphadenectomy. The reporting oan invalid subgroup analysis has served only to cloud what is avery clear conclusion o the primary end point o this large trial,i.e., that there is at present no evidence that SLNB oers an OSbenet to patients.

Disease-Free Survival

The 5% advantage in DFS at 5 years means that 100 patientsmust undergo SLNB or ve patients in the biopsy arm to havea DFS advantage. In the absence o any dierence in OS, thiscould simply mean a delay rather than a prevention o recur-rence. In MSLT-1, the site and timing o rst recurrence were

directly infuenced by the SLNB procedure itsel. In patients with

melanoma o intermediate thickness, the most likely site o rst

recurrence is the regional LNs. Patients in the biopsy arm whowere SN-positive underwent a prophylactic lymphadenectomyat the time o diagnosis, and thereore these patients will inevi-tably have ewer regional nodal recurrences. This is conrmedin the results relating to site o rst recurrence, which show athreeold increase in nodal recurrence in the observation armand a small increase in distant recurrence in the biopsy arm(11% vs. 7%). In this cohort o patients, moreover, regionalnodal recurrences invariably appear beore distant recurrences.For these reasons, an apparent advantage in DFS in avor o thebiopsy arm is almost inevitable. To overcome bias caused by trialdesign, regional nodal recurrences should be excluded rom thecalculation o DFS. MSLT-1 was unded by the National CancerInstitute, and an appeal on this matter has now been upheldby its Clinical Investigations Branch (personal communication toJMT). In the uture, DFS in MSLT-1/2 will also be calculated onthe competing incidences o local/in-transit and distant recur-

rences alone.

Differing Practices Among MSLT-1 Centers

Another issue that makes the interpretation o MSLT-1 even moredicult is diering ollow-up practices among participating units.In all publications relating to MSLT-1, as well as in the accom-panying editorial,22 it has been stated or assumed that delayedlymphadenectomy in the observation arm was perormed whenmetastatic nodes became palpable. That is not the case. Almosthal o the patients entered into MSLT-1 (946 o 2001) were romthe Sydney Melanoma Unit. It now transpires that the 378 orso patients entered into the observation arm were investigatedby lymphoscintigraphy at the time o WLE o the primary tumorwhen the site o the SN was marked by a small permanent tat-too to acilitate regular interrogation by ultrasound.23 Delayedlymphadenectomy was perormed not when the regional nodal

metastases became palpable but when nonpalpable metastases

were identied by ultrasound and the diagnosis proven by ul-trasound-guided cytology. In the same publication, the authorsconrmed that ultrasound could identiy metastatic deposits omelanoma in the SN at 4-mm diameter in the groin and neck and4.5-mm diameter in the axilla. It is not known how many monthsit would take or such occult deposits to become palpable, butthis practice directly aected and compromised the primary endpoint o MSLT-1, i.e., OS dierence rom the point o randomiza-tion. This inormation was not mentioned in the New EnglandJournal o Medicine article.1

Unanswered Questions Relating to MSLT-1Several questions relating to MSLT-1 remain unanswered. Whywere 732 patients omitted rom the rst publication o the re-

sults, contrary to CONSORT guidelines?I these 732 patients hadbeen included, how would this have aected the DFS as calcu-lated? I DFS was recalculated, as is now endorsed by NationalCancer Institute, would the small DFS advantage in avor o thebiopsy arm be maintained, lost, or reversed?

Have the results o MSLT-1 been invalidated by the anomalousmanagement at the Sydney Melanoma Unit? The core assump-tion that all positive SNs, i not removed, will eventually progressto palpable nodal recurrence is challenged by the hypothesis oprognostic alse-positivity. Does this prognostic dierence not ex-plain the 20% survival advantage in avor o immediate lymphad-enectomy claimed in the subgroup analysis?

FIG. 1. Trial design and treatment o patients with intermediate-thickness melanoma. Based on data rom Morton et al.1


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Sntin lyph Nd Stats as a Staging andPgnstic T

Sentinel lymph node (LN) status at the time o diagnosis o theprimary tumor is the most important single prognostic actor inmelanoma.2427 It has been shown repeatedly that the disease-specic survival is signicantly better in SN-negative patients com-pared to SN-positive patients (approximately 95% vs. 70% at 3

years) and that SN-positivity predicts or distant spread and death.Unortunately, this prognostic importance does not translate intoa therapeutic benet because no surgical procedure or systemictherapy has been shown to improve OS in melanoma. Algorithmso histologic actors relating to the primary tumor have beenshown to be almost as prognostically accurate as SN status.28

It is noteworthy that prognostic tools are still important in theirown right. There is still no absolute consensus worldwide thatadjuvant therapy should not be used in melanoma despite thelack o an OS benet. The Kirkwood adjuvant intereron regi-men suggests a prolongation o DFS.29 Furthermore, almost allnew adjuvant trials will wish to include SN-positive patients. The

diculty with this is that prognostically alse-positive patients willalso be included, and in the uture there may be a consensus thatonly patients with metastases in the SN greater than a certain size

should be entered into trials o adjuvant therapy.

How eective is SLNB as a prognostic tool compared to inorma-tion available rom the primary tumor and noninvasive imaging othe nodal basins? SLNB was well established beore it was realizedthat high-resolution ultrasound with Doppler was the best meth-od o imaging nonpalpable occult metastatic melanoma in theregional LNs.30 It is known that ultrasound alone can detect occultnodal metastases in up to one-third o SN-positive patients.23,31Experienced radiologists can identiy deposits o melanoma assmall as 3 mm and can conrm the diagnosis by ultrasound-guid-

ed cytology.32

Occult metastases o this diameter are also easilyidentied by SLNB, but it has never been shown that SN statusmaintains its staging and prognostic importance in ultrasound-negative patients. Ultrasound is a simple noninvasive procedureand ultrasound screening o the regional node basin(s) at the

time o diagnosis o the primary tumor may provide the greatestchallenge to SLNB. Those who are skeptical o the importance oultrasound may say that, like SLNB, ultrasound can only antecedethe clinical diagnosis o metastatic melanoma. However, there isone very important dierence. It is likely that all nodal metasta-ses large enough to be visualized by ultrasound are destined toprogress to palpable nodal recurrence. On the other hand, SLNBcan detect most deposits o melanoma likely to progress but alsoreadily identies some tiny deposits likely to be prognostically

alse-positive and destined or dormancy or destruction.

Patterns of Melanoma Recurrence in SN-Negative PatientsUndoubtedly, many patients undergo SLNB hoping or reassur-ance that their SNs are ree o melanoma. However, being SN-negative gives no guarantee o remaining recurrence-ree and, asalways, the incidence o recurrence will increase with prolonged

ollow-up. With reerence to publications providing a median ol-low-up o 2 years or more, the recurrence rate at any site is o theorder o 9.6% to 13.7%.3337 These series agree that the site orst recurrence in SN-negative patients is distant in approximatelyhal the patients, that isolated SN basin recurrence is uncommon,and that the remaining sites o rst recurrence are a combination

o synchronous in-transit and SN basin recurrences. This inor-

mation conrms that, in a small group o patients, melanomadisseminates entirely via the bloodstream rather than via the lym-phatic system.

Pgnstic Fas-Psitivity in th SN in mana

Prognostic (or biological) alse-positivity reers to tiny deposits omelanoma within the SNs that are destined or dormancy or de-struction and not or progression to palpable nodal recurrence. 38This hypothesis undamentally challenges the central tenet o theSLNB procedure, which assumes, without any evidence, that allpositive SNs (i not removed) will inevitably progress to palpablenodal recurrence. Prognostic alse-positivity results in patientsbeing incorrectly up-staged, being given inaccurate prognosticinormation, undergoing unnecessary completion lymphadenec-tomy, and possibly unnecessary adjuvant therapy or entry intosuch trials. A simple mathematical model is presented below to

estimate the incidence o prognostic alse-positivity together withother lines o supporting evidence.

Indirect Evidence for Prognostic False-PositivityIndirect evidence or prognostic alse positivity comes rom oursources. First, many authors have reported that melanoma mi-crometastases below a certain size have no adverse prognosticsignicance.35,3943 For example, Van Akkooi et al.35 state that pa-tients with micrometastases less than 0.1 mm in the SN shouldbe judged to be SN-negative. Spanknebel et al.41 conclude thatpatients whose micrometastases are detectable only by IHC havea prognosis similar to that o patients with negative SNs. Theseobservations, however, depend on the SN being removed or his-tologic examination, which could be construed as contributing tothe therapeutic benet.

Second, there is an unexplained paradox in which younger patients

with melanoma have a signicantly better prognosis than olderpatients despite exhibiting a higher incidence o SN-positivity.44,45As shown in Fig. 2, the mortality rom melanoma rises steeplywith advancing age, whereas the incidence o SN-positivity re-duces with increasing decades o age. In the absence o evidencethat melanoma spreads more commonly by the bloodstream in

FIG. 2. Incidence o SN-positivity with increasing decades o agecompared with melanoma-specic mortality.44,45


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elderly patients, the most likely explanation is that, in younger pa-

tients, a more competent host response can eliminate tiny micro-metastases or induce dormancy. In a study o 3076 patients, Chaoet al.44 showed that the incidence o SN-positivity was 23.1% inpatients less than 30 years o age but that the incidence declinedwith increasing decades o age to 12% in patients between 61and 70 years (P


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The incidence o prognostic alse-positivity will decrease as more

patients in the observation arm develop nodal recurrence. How-ever, because the median time to nodal recurrence in the obser-vation arm o MSLT-1 was 16 months and the median ollow-upwas 60 months,1 it is unlikely that nodal recurrence will increasesuciently to signicantly aect the calculated incidences oprognostic alse-positivity. Nevertheless, i it is assumed that nodalrecurrences in the observation arm and among alse-negative pa-tients in the biopsy arm will increase at the same rate, then a 10%and 20% increase in palpable nodal recurrence among patientswith intermediate-thickness tumors would reduce the incidenceo prognostic alse-positivity to 13% and 8.4%, respectively. Itwould take a 30% increase in nodal recurrence to reduce the inci-dence to less than 1%. For all strata, a 10% and 20% increase innodal recurrence would reduce the incidence o prognostic alse-positivity to 27% and 20%, respectively, and it would take a 50%increase in nodal recurrence to reduce prognostic alse-positivityto less than 1%.

Does RT-PCR Analysis for Tyrosinase Provide AdditionalPrognostic Information in SN-Negative Patients?

Detection o tyrosinase mRNA by reverse transcriptase-poly-merase chain reaction (RT-PCR) in negative SNs was intendedto identiy SN-negative patients who were destined to recurand in the expectation that the incidence o SN alse-negativitycould be reduced. Unlike histology with IHC there was alwaysa risk that molecular staging would introduce an incidence oalse-positivity because o the eect o capsular nevus cells.Review o the literature shows that there is no consensusabout the ability, i any, o RT-PCR to up-stage negative SNs.Several series, including the Sunbelt Melanoma Trial with 1446SN-negative patients, report that RT-PCR in SN-negative pa-tients ailed to detect a subgroup o patients with an increasedprobability o recurrence.51 At the other extreme, many authors

report that RT-PCR can upstage 25% to 65% o histologically

negative SNs.5257

Furthermore, some o these series report aDFS dierence in SN-negative/RT-PCR-negative patients com-pared to SN-negative/RT-PCR positive patients.53,55,56 However,there is agreement that SN-negative/RT-PCR-negative patientshave an extremely low risk or recurrence at any site. Becausepatients entered into MSLT-2 can be deemed to be SN-positiveon RT-PCR criteria alone, it is useul to ocus on the experiencerom the John Wayne Cancer Institute rom which this trial isdirected. Using a multimarker RT-PCR assay55,57 the researchersdemonstrated that histologically negative SNs were RT-PCR-positive in up to 40% o cases. Thereore, using RT-PCR inSN-negative patients in MSLT-2 is likely to increase prognosticalse-positivity even urther.

utasnd in th Assssnt f SN basin(s) inmana

Ultrasound screening o the SN basin(s) in search o occult (non-palpable) metastases in melanoma is a neglected technique and,in general, is poorly understood. Deposits o melanoma as smallas 34 mm can be identied on the basis o morphologic crite-ria, and pathologic neovascularization can be identied on powerDoppler mode. The lesion can then be targeted or cytologicexamination, which is reported to have a specicity o 100%.Ultrasound is operator-dependent and considerable expertise isrequired.30,58,59

High-resolution ultrasound identies a resting inactive LN as being

oval in shape with an echo-poor (black) cortical rim o lymphoidtissue surrounding an echogenic hilus (gray) that demonstrateslittle or no vascularity (Fig. 4A). This appearance has been likenedto the pulp around the stone o a cherry. These appearances maychange in response to inection but are reversible. Progressivelyin melanoma, the ollowing changes occur in a metastatic LN.The earliest sign is irregularity o the lymphoid cortex, which mayprogress to a nodule (Fig. 4B). As the LN becomes increasinglyinvolved with melanoma, it becomes round rather than oval, theechogenic hilus is progressively lost, the neovascularity intensies,and the volume o the LN expands (Fig. 4C).

FIG. 4. High-resolution ultrasound o a normal lymph node (A),o partial replacement o a lymph node by melanoma (B), ando complete replacement by melanoma, with and without powerDoppler, which shows prominent neovascularization (C).

C

B

A


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The American Joint Committee on Cancer (AJCC) staging systemor melanoma60 does not dene the size o a micrometastasis, buta metastatic deposit large enough to be identied by ultrasoundmust be regarded as a macrometastasis or as occult clinical dis-

ease. This entire spectrum o tumor burden is bundled togetherand classied as N1a or N2a. The crucial importance o tumor bur-den to prognosis has been discussed above and, or this reason,the next AJCC classication must dierentiate between micro-metastatic and nonpalpable, occult macrometastatic deposits omelanoma in the SN. Similarly, in the context o prognostic alse-positivity, macrometastases identied by ultrasound will inevitablyprogress to palpable nodal recurrence, which is why SN basinsshould be screened by ultrasound beore patients are reerred orSLNB. Ultrasound can detect occult metastatic melanoma in upto one-third o positive SNs.23,31 In a recent ASCO presentation,Voit et al.32 showed that, when the SN is identied by lymphos-cintigraphy, ultrasound can detect metastatic melanoma in 50%o patients ultimately proven to be SN-positive.32

At our Unit we do not advise SLNB or patients with primary mela-

noma. Relevant regional node basin(s) are screened by ultrasound

at the time o diagnosis. I no suspicious LNs are identied then,ater wide excision o the primary tumor, patients embark onan ultrasound surveillance program o the regional LNs with theintent o perorming delayed lymphadenectomy when nonpal-pable, clinically occult nodal recurrence is detected sonographi-cally and proven by ultrasound-guided cytology. Extrapolatingrom the results o MSLT-1, there is no r isk that patients are beingdisadvantaged by this method o management. On the contrary,patients whose SNs are prognostically alse-positive are protectedrom unnecessary lymphadenectomy because such disease willnot progress to occult or palpable nodal recurrence. Ultrasounddetection o occult clinical disease presents a great challenge toSLNB because SN status has never been shown to have prognosticsignicance in ultrasound-negative patients.

Cncsins: Th Stats f SlNb in 2008

SLNB does not impart a survival benet to patients with mela-noma. It is a prognostically imperect tool because it identies acohort o prognostically alse-positive patients. At present, thesepatients are wrongly up-staged, are given inaccurate prognosticinormation, and undergo unnecessary lymphadenectomy andunnecessary adjuvant therapy or entry into adjuvant trials.

Historically, there has been a trans-Atlantic dierence in percep-tion o the introduction o SLNB. In Europe, ELND was rarely per-ormed and thereore SLNB constitutes an increase in the amounto surgery at the time o diagnosis. However, in the United States

and Australia, because ELND was routinely perormed, the intro-duction o SLNB meant a reduction in the amount o surgery atthe time o diagnosis. This dierence in perception is compound-ed by diering views regarding the ecacy o adjuvant therapy in

melanoma. In some centers in the United States, SN-positive pa-tients are advised to receive intereron, whereas in other centersin the United States and mostly elsewhere in the world, intereronis not advised because any advantage in DFS is not considered asucient benet to outweigh the morbidity o treatment.

Notwithstanding these diering perceptions, we argue that it isnow appropriate or management o the regional LNs in mela-

noma to be rened urther with the replacement o SLNB by ul-trasound screening and surveillance. MSLT-1 has now shown thatSLNB does not give the patient a benet in terms o OS, andthe benet in terms o DFS is unclear. Hence, it is essentially a

prognostic tool. Because, as we have shown, it is an imperecttool with prognostically alse-positive patients being over-treated,we argue that SLNB should not be recommended or routine useoutside o a randomized controlled trial.

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Some compounds discussed in this publication may be in investigative stages and not yet approved by the FDA or uses mentioned. The reader is urgedto check the package insert or each drug or any change in indications and dosage and or added warnings and precautions.

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