Should immediate lymphadenectomy be discontinued in patients with metastasis of a melanoma in the sentinel lymph node? Report of the results of the Multicenter Selective Lymphadenectomy Trial-II

Moreno-Ramírez, David; Vidal-Sicart, Sergi; Puig, Susana; Malvehy, Josep
doi:10.1016/j.medcle.2018.02.006
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">The recently published&#44; long-awaited&#44; Multicenter Selective Lymphadenectomy Trial-II &#40;MSLT-II&#41; results&#44; 10 years after the study started&#44; probably leads us to the biggest change in the surgical treatment of melanoma patients in three decades&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">1&#44;2</span></a> However&#44; transferring the results of a study to clinical practice guidelines requires a detailed analysis not only of the primary results&#44; but especially of the conditions under which the study was conducted&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">During the last 2 decades&#44; the clinical guidelines for melanoma have recommended selective sentinel node biopsy &#40;SNB&#41; in all patients with cutaneous melanoma &#40;CM&#41; with tumour stage T1b and above &#40;Breslow thickness greater than 1<span class="elsevierStyleHsp" style=""></span>mm&#44; or less than 1<span class="elsevierStyleHsp" style=""></span>mm ulcerated or with more than 1<span class="elsevierStyleHsp" style=""></span>mitosis&#47;mm<span class="elsevierStyleSup">2</span>&#41;&#46; Regarding patients with metastasis in the sentinel lymph node &#40;SN&#41;&#44; the recommendation included immediate lymphadenectomy &#40;ILA&#41; of the region in which the SN was located&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">3&#8211;5</span></a> These recommendations have remained in force from the time elective lymphadenectomy was discontinued&#44; following the study of Morton on SNB&#44; a procedure which had been practiced in all patients with CM&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">2&#44;6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">However&#44; different observational studies have repeatedly described the lack of survival benefit of ILA&#44; as well as the low frequency of additional non-sentinel node metastasis observed in these dissections &#40;8&#8211;25&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">7</span></a> These studies were recently completed with the publication of the first clinical trial&#44; the well-known DeCOG-SLT&#44; sponsored by the German Dermatologic Cooperative Oncology Group&#44; in which these results were confirmed&#46; Methodological limitations related to the fact that the number of events necessary to guarantee the expected statistical power were not achieved have prevented a greater transfer of the results of the DeCOG-SLT trial to decisions in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">During these years&#44; any decision regarding the need or not to perform an ILA was postponed until the publication of the results of the MSLT-II&#44; a study whose design &#40;randomized clinical trial&#41;&#44; recruitment &#40;n<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1900 randomized patients&#41; and follow-up &#40;7 years of recruitment and 3 years of additional follow-up&#41; definitively clarifies the need or not of an ILA&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> The final results of the MSLT-II confirm the previous results and lead the authors to conclude that ILA does not improve the overall survival of patients with SN metastasis with respect to ultrasound follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Are the results of the Multicenter Selective Lymphadenectomy Trial II sufficient&#63; To stop offering immediate ganglion dissection&#63; The absence of overall survival benefit observed in the Kaplan-Meier curves of the MSLT-II could be enough to justify the discontinuation of the procedure&#46; However&#44; during the cohort&#39;s follow-up in the MSLT-II trial&#44; 30&#37; of patients in both study groups developed distant metastasis&#44; both individual and associated with lymph node and locoregional metastasis &#40;supplementary data available in NEJM&#46;org&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> This distant progression is responsible for the shortening in these patients&#8217; survival&#44; while the regional disease <span class="elsevierStyleItalic">per se</span> does not cause death&#46; That is why a survival benefit should not be expected from a regional intervention such as ILA&#44; fully oriented to regional control of the patient with microscopic stage III disease&#46; In fact&#44; the MSLT-II does describe the benefit of ILA versus observation in terms of disease-free survival at 3 years &#40;68&#37; versus 63&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; which would be associated with a lower frequency of lymph node recurrence in ILA group and a higher rate of regional control of the disease in ILA group &#40;92&#37; versus 77&#37; at 3 years&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Another question that must be assessed is whether the magnitude of this advantage in terms of regional control justifies the morbidity associated with ILA&#46; The analysis by protocol completed in the MSLT-II provides us with complementary data of interest even when considering the limitations of this type of analysis&#58; 60&#37; of patients with stage IIIA-IIIB disease &#40;micrometastasis in SNB&#41; did not develop locoregional or distant progression at 3 years of follow-up &#40;62&#46;5&#37; in ILA group and 57&#46;6&#37; in the observation group&#41;&#46; Although these were not primary outcome variables&#44; from a strictly descriptive point of view it can be interpreted that in approximately 60&#37; of patients with micrometastasis in the SN&#44; the SNB&#44; with or without ILA&#44; became the final therapeutic intervention &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; With these differences between both study groups and remembering that the starting point for the inclusion of patients in the MSLT-II was the presence of micrometastasis in the SNB&#44; we are not clear if the benefit of the SNB<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ILA with respect to the SNB<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ultrasound follow-up is clinically relevant especially if we incorporate into the debate the frequency of complications of both interventions &#40;24&#37; versus 6&#37; of lymphedema&#41;&#46; On the other hand&#44; the low morbidity observed for SNB and the results in terms of regional disease control observed in the group of SNB without ILA do not seem to pose uncertainty regarding the maintenance of SNB in melanoma protocols as a standard technique for lymph node staging&#44; and in a subset of patients as a treatment for microscopic lymph node disease&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">But beyond the benefits in terms of survival and control of the disease&#44; the greatest concern regarding dissections performed in patients with micrometastasis in SNB was associated with the high frequency of dissections without additional metastasis in non-sentinel lymph nodes&#46; In the Melanoma Unit of the Hospital Cl&#237;nic of Barcelona&#44; during the 2005&#8211;2015 period&#44; a total of 105 ILA were performed in patients with metastasis in the SN&#44; of which 25&#46;7&#37; identified additional metastasis in other nodes &#40;non-sentinel&#41;&#44; while 74&#46;3&#37; did not present additional metastasis &#40;unpublished data&#44; Melanoma Unit&#44; Hospital Cl&#237;nic Barcelona&#41;&#46; In the MSLT-II&#44; 88&#46;5&#37; of the ILA performed did not identify further metastasis and&#44; in addition&#44; the remaining 11&#46;5&#37; of ILA did identify metastasis in non-sentinel lymph nodes&#46; At 5 years&#44; taking into account lymph node recurrences observed in the ILA group&#44; nodal disease after SN micrometastasis increased from 11&#46;5&#37; to 19&#46;9&#37;&#44; a percentage that could be considered &#8220;necessary&#8221; nodal dissections &#40;11&#46;5&#37; of patients with ILA and 8&#46;4&#37; of patients in follow-up who required salvage lymphadenectomy&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#59; and in other words&#44; 80&#37; of patients with positive SNB would not have required a lymphadenectomy&#46; This frequency of events was repeated in the observation group&#44; in which it was necessary to perform dissections due to lymph node recurrence during follow-up in 26&#37; of patients&#46; Therefore&#44; this 75&#8211;80&#37; &#8220;futility&#8221; observed in a quality clinical trial already represents a consistent argument to rethink our clinical practice&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">The debate regarding the need of ILA in the patient with melanoma repeats the recent changes affecting breast cancer treatment protocols&#44; although the differences between both types of cancer in terms of their natural history&#44; aggressiveness and adjuvant protocols cannot be ignored&#46; In breast cancer&#44; none of the retrospective studies conducted showed an overall survival benefit in women with positive SNB who underwent axillary dissection with respect to those who did not undergo dissection&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">9&#44;10</span></a> In addition&#44; none of the subsequent prospective studies &#40;ACOSOG Z0011&#44; IBCSG 23-0&#44; AATRM 048&#47;13&#47;2000&#41; found significant differences in overall survival&#44; disease-free survival or axillary recurrence between the two study groups&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">11&#8211;13</span></a> These results&#44; with their limitations and analysis of risk factors&#44; have ended up being transferred into clinical practice guidelines for the treatment of breast cancer&#46; Thus&#44; the NCCN guidelines does not currently recommend axillary dissection in women with micrometastasis in the SN&#44; nor in those in whom 1 or 2 positive GCs develop T1-T2 tumours or who are going to undergo conservative surgery followed by radiotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Need for lymph node ultrasound implementation during the follow-up of the patient with melanoma</span><p id="par0040" class="elsevierStylePara elsevierViewall">Going back to CM&#44; and beyond the necessary rethinking of therapeutic decisions&#44; the results of the MSLT-II provide information of interest on an aspect of maximum relevance for the care of patients with CM&#58; the role of lymph node ultrasound in the follow-up of patients with melanoma&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Patients randomized to the observation group of the MSLT-II they underwent an ultrasound of the SN region every 4 months during the first 2 years and every 6 months of the 3rd to 5th year of follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> From the perspective of the reproducibility of the MSLT-II results&#44; this aspect is not trivial&#44; since it suggests that the discontinuation of ILA should be accompanied by the full implementation of intensive ultrasound monitoring of the lymph node regions in stage IIIA-IIIB &#40;N1a&#44; N2a&#41; patients&#46; In any case&#44; this recommendation was already being collected in some of the most commonly used melanoma clinical guidelines&#46; The guidelines of the German Society of Dermatology published in 2013 already recommended regional lymph node ultrasound in the follow-up of melanoma patients with stages IB and above&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">3</span></a> Version 1&#46;2017 of the NCCN guidelines on melanoma already states that during the follow-up of the melanoma patient with stage IIB and above&#44; regional ultrasound should be performed in those patients in whom SNB was not performed and in those with SN metastasis who did not undergo ILA&#46; In these patients&#44; the NCCN recommends an ultrasound every 3&#8211;12 months during the first 2&#8211;3 years depending on the risk of lymph node recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">4</span></a> Prospective studies on the role of lymph node ultrasound in patients with melanoma describe a sensitivity and specificity greater than 90&#37;&#44; even with maximum sensitivity in stage III patients &#40;sensitivity<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">14&#8211;17</span></a> In addition&#44; in these same studies&#44; previous regional surgery has not been shown to affect the ability of ultrasound to detect metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">14</span></a> The identification of lymph node metastasis in the MSLT-II has been based on ultrasound criteria widely validated and accepted in previous studies&#58; Solbiati index &#62;2&#44; hypoechoic center&#44; hypoechoic foci and absence of hilar vascularity&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">1&#44;18</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The results of MSLT-II&#44; as well as the already mentioned studies&#44; allow us to conclude that lymph node ultrasound represents a non-invasive procedure that allows identifying low-burden&#44; resectable regional disease with no survival impact with respect to the identification and treatment of microscopic lymph node disease in SN&#46; In addition&#44; in contrast to the high percentage of futility associated with ILA&#44; we think that a pretest probability of 26&#37; &#40;frequency of lymph node disease in the observation group&#41; for a non-invasive diagnostic technique may justify its complete implementation&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Should we discontinue immediate lymphadenectomy in all stage IIIA-IIIB patients with microscopic disease&#63;</span><p id="par0055" class="elsevierStylePara elsevierViewall">While the results of the MSLT-II would prompt us to propose the discontinuation of ILA&#44; is this recommendation applicable to all patients with melanoma metastasis in the SN&#63; Although the multivariate analysis carried out in the MSLT-II did not identify patient or tumour factors that could predict additional metastasis associated with ILA&#44; a detailed analysis of these data recommends the individualization of decisions according to patient subgroups that may have been underrepresented in the MSLT-II&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">With respect to the clinical-pathological characteristics of the primary tumour&#44; the multivariate analysis demonstrated in both study groups an increased risk of mortality from melanoma in patients with Breslow tumours greater than 3&#46;5<span class="elsevierStyleHsp" style=""></span>mm versus patients with Breslow tumours below 1&#46;5<span class="elsevierStyleHsp" style=""></span>mm &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;82&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;32&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 in ILA and observation&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> In addition&#44; a higher mortality risk was observed in the observation group in patients with Breslow tumours 1&#46;5&#8211;3&#46;5<span class="elsevierStyleHsp" style=""></span>mm &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;46&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41;&#46; Approximately 50&#37; of patients randomized in the MSLT-II had tumours with a Breslow thickness 1&#46;5&#8211;3&#46;5<span class="elsevierStyleHsp" style=""></span>mm&#44; 22&#37; Breslow greater than 3&#46;5<span class="elsevierStyleHsp" style=""></span>mm and 28&#37; lower than 1&#46;5<span class="elsevierStyleHsp" style=""></span>mm&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> That is&#44; in the best represented group of patients &#40;Breslow 1&#46;5&#8211;3&#46;5<span class="elsevierStyleHsp" style=""></span>mm&#41; a statistically significant trend towards a higher mortality risk was observed in the observation group compared to the ILA group&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> However&#44; the reference category applied in the analysis was a Breslow thickness lower than 1&#46;5<span class="elsevierStyleHsp" style=""></span>mm in each study group&#44; and there are no univariate or bivariate analyses that allow direct comparisons between both study groups that explain the greater or lesser influence of Breslow thickness on mortality in both study groups&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Another clinical-pathological aspect of interest is the predictive role of the tumour burden of the metastatic SN and&#44; therefore&#44; its influence on the decision not to perform ILA&#46; The MSLT-trial II analyses tumour burden in terms of the number of metastatic GCs and according to Starz&#39;s criteria &#40;diameter of the largest tumour deposit&#41; &#40;MSLT-II protocol&#44; supplementary data available in NEJM&#46;org&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> The multivariate analysis did not demonstrate a predictive mortality role for the number of metastatic SN in any of the study groups&#46; With respect to the tumour diameter in the SN&#44; the univariate analysis showed a greater tendency&#44; without statistical significance&#44; in favour of an increased risk of mortality in patients with tumour deposits greater than 1<span class="elsevierStyleHsp" style=""></span>mm&#46; However&#44; this trend was not statistically significant and was therefore excluded from the multivariate model &#40;supplementary data available in NEJM&#46;org&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> In the MSLT-II cohort&#44; the median diameter of the largest tumour deposit in the SN was 0&#46;61<span class="elsevierStyleHsp" style=""></span>mm and 0&#46;67<span class="elsevierStyleHsp" style=""></span>mm in ILA and observation groups&#44; respectively&#44; with interquartile ranges of 0&#46;27&#8211;1&#46;32 and 0&#46;23&#8211;1&#46;38<span class="elsevierStyleHsp" style=""></span>mm&#44; in each group&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> That is&#44; a large group of patients recruited in the MSLT-II had low tumour burdens as expected by the main inclusion criterion of the study &#8211; SNB positive and therefore without clinically evident regional disease &#8211; with a lower representation of patients with higher tumour burdens&#44; although still subclinical&#46; Therefore&#44; in patients with tumour burdens in the SN higher than those observed in the majority of MSLT-II patients&#44; the decision on ILA must be individualized&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusions</span><p id="par0070" class="elsevierStylePara elsevierViewall">Lymphadenectomy continues to represent a standard practice in the treatment of patients with melanoma lymph node metastasis identified by clinical examination&#44; ultrasound or other imaging studies&#46; This procedure provides an adequate regional control of the disease and it represents a curative treatment for those patients who do not develop distant progression subsequently&#46; Therefore&#44; the debate settled by MSLT-II is not so much the suitability or not of lymphadenectomy&#44; but the time to perform it&#44; which must guarantee an adequate balance between avoidable dissections and morbidity and identification of resectable regional disease and low tumour burden&#46; According to the results of the MSLT-II&#44; the follow-up of patients with stage IIIA-IIIB microscopic disease by means of lymph node ultrasound seems to respond to this need&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Although in certain clinical settings melanoma committees will have to continue individualizing their decisions&#44; from a strictly surgical perspective&#44; the MSLT-II represents an excellent opportunity to justify the substitution of ILA&#44; a surgical intervention regarding which we did not have quality evidence that would allow us to stop offering it&#44; even though we had our reservations&#46; Big clinical questions usually take their time to be answered but&#44; at the end&#44; the answers arrive&#44; even those provided by the MSLT-II results&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conflict of interests</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest in relation to the paper submitted&#46; Dr&#46; Sergi Vidal-Sicart is co-author of the study on which the paper is based&#46;</p></span></span>"
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          "titulo" => "Need for lymph node ultrasound implementation during the follow-up of the patient with melanoma"
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          "titulo" => "Should we discontinue immediate lymphadenectomy in all stage IIIA-IIIB patients with microscopic disease&#63;"
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        3 => array:2 [
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          "titulo" => "Conclusions"
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          "titulo" => "Conflict of interests"
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    "fechaRecibido" => "2017-07-23"
    "fechaAceptado" => "2017-08-30"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Moreno-Ram&#237;rez D&#44; Vidal-Sicart S&#44; Puig S&#44; Malvehy J&#46; &#191;Debe abandonarse la disecci&#243;n ganglionar inmediata en el paciente con met&#225;stasis de melanoma en el ganglio centinela&#63; A prop&#243;sito de los resultados del Multicenter Selective Lymphadenectomy Trial-II&#46; Med Clin &#40;Barc&#41;&#46; 2018&#59;150&#58;323&#8211;326&#46;</p>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The locoregional recurrence includes in-transit and satellite metastasis&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Taken from Faries et al&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Immediate lymphadenectomy group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Observation group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Patients &#40;n&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">744&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">820&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1564&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Without recurrence</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">937&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">With recurrence</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">42&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">627&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Exclusively locoregional&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Exclusively lymph node&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Exclusively distant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">212&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Locorregional and lymph node&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Local and distant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lymph node and distant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">104&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Locoregional&#44; nodal and distant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Patients with locoregional recurrence</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">238&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Patients with lymph node recurrence</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">276&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Patients with distant recurrence</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">467&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Regional control at 3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="middle">Positive sentinel lymph node biopsy n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1939</td><td class="td" title="table-entry  " align="left" valign="top">Observation n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>968&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">77&#46;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="middle">Immediate lymphadenectomy n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>971</td><td class="td" title="table-entry  " align="left" valign="top">Metastasis in ILA 11&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
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        "identificador" => "xack345349"
        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0085" class="elsevierStylePara elsevierViewall">We wish to thank the professionals&#44; members of the Melanoma Committee of the Hospital Cl&#237;nic&#44; who participated in the debate and the analysis from which the current paper was generated&#58; Lara Ferr&#225;ndiz&#44; Cristina Carrera&#44; Marcelo S&#225;nchez&#44; Ana Arance&#44; Ram&#243;n Rull&#44; Alicia Barreiro&#46;</p>"
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