Opinion Article
Models of Melanoma Spread and Final Results of the Multicenter Selective Lymphadenectomy Trial-I
Modelos de diseminación del melanoma y resultado final del multicenter selective lymphadenectomy trial-I
Á. Pizarro
Unidad de Prevención y Diagnóstico Precoz de Melanoma, Clínica Dermatológica Internacional, Clínica Ruber, Madrid, Spain
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Armengot-Carbo, Á. Hernández-Martín, A. Torrelo" "autores" => array:3 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Armengot-Carbo" ] 1 => array:2 [ "nombre" => "Á." "apellidos" => "Hernández-Martín" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Torrelo" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S000173101400043X" "doi" => "10.1016/j.ad.2013.10.019" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S000173101400043X?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014003333?idApp=UINPBA000044" "url" => "/15782190/0000010600000002/v2_201502240233/S1578219014003333/v2_201502240233/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Opinion Article</span>" "titulo" => "Models of Melanoma Spread and Final Results of the Multicenter Selective Lymphadenectomy Trial-I" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "82" "paginaFinal" => "85" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Á. Pizarro" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Á." "apellidos" => "Pizarro" "email" => array:1 [ 0 => "angelpizarro84@gmail.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Prevención y Diagnóstico Precoz de Melanoma, Clínica Dermatológica Internacional, Clínica Ruber, Madrid, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Modelos de diseminación del melanoma y resultado final del <span class="elsevierStyleItalic">multicenter selective lymphadenectomy trial-I</span>" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Although sentinel node biopsy (SNB) is currently offered at most hospitals that treat patients with melanoma, the usefulness of the technique in the management of this disease has been a subject of controversy.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">1–3</span></a> My opinion, which I have held for years, is that the debate about the ability of SNB to increase survival in patients with melanoma is actually a debate about our understanding of how melanoma spreads.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">4,5</span></a> However, I believe that the diagnostic and prognostic value of SNB is beyond question, despite the fact that, as some authors have noted, what patients most want is not an accurate prediction of how likely they are to die from melanoma but rather for their physicians to reduce that likelihood.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Broadly speaking, there are 3 major theoretical models of melanoma spread, which have been defended by, among others, 3 doctors who have made some of the largest contributions to progress in the fight against melanoma and who, unfortunately, are no longer with us. The first is the stepwise progression model defended by Donald L. Morton,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">7</span></a> which holds that melanoma first spreads to the regional lymph nodes before spreading systemically. The second is the simultaneous spread model defended by A. Bernard Ackerman.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">8</span></a> The third is what I call the model of differential spread patterns, which is supported by Wallace H. Clark.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">5,9</span></a> In earlier articles,<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">4,5</span></a> I outlined the basic characteristics of these models and examined the extent to which the initial results of the Multicenter Selective Lymphadenectomy Trial-I (MSLT-I), published in 2006,<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> supported or refuted the validity of each model. My opinion at the time was that Clark's model was correct.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> The final results of the MSLT-I,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a> published in 2014—significantly later than expected<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">12</span></a>—have reaffirmed my opinion. Clark<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> considered that some melanomas do not spread or metastasize (as we all know, a greater Breslow thickness increases the likelihood of metastases but is not a guarantee that they will develop). Of those melanomas that do metastasize, Clark argued, some produce only lymphatic metastases in the regional nodes, others metastasize only through the bloodstream, and still others (the majority) spread by both pathways, ultimately producing both lymphatic and visceral metastases (the fact that macroscopic lymphatic metastases often precede macroscopic visceral metastases does not imply that the former are necessarily the source of the latter).</p><p id="par0015" class="elsevierStylePara elsevierViewall">Clark died in 1997, so he did not participate in the subsequent debate between Morton and Ackerman about their respective models of melanoma spread and the implications of each model for the usefulness of SNB. In this debate, both Morton and Ackerman—like many others who have written on this subject—ignored the model proposed by Clark. In my opinion, the available biological and clinical data favor Clark's hypothesis<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">5,9</span></a> and his model is the one we should consider when designing the basic and clinical studies that are needed in order to speed up progress in the fight against melanoma.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The MSLT-I began in 1994. The theory of stepwise melanoma spread (which Morton called the incubator hypothesis<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">7</span></a>) holds that melanoma first spreads through the lymphatic system to the regional lymph nodes, and that the sentinel node is the first one that the tumor cells can reach. The tumor cells then remain confined in these regional nodes for some time before starting to spread through the bloodstream to visceral sites. The lag time between the 2 types of spread varies among patients. Although the defenders of the stepwise model do not deny that melanoma can spread directly through the bloodstream, they consider this to be the exception rather than the rule.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">13</span></a> According to the stepwise theory, precise detection and early removal of lymph nodes affected by micrometastases should not only reduce the likelihood of subsequent lymphatic recurrence (which it obviously does) but also prevent blood-borne dissemination in many patients, increasing their survival. This was the initial hypothesis that led to the MSLT-I being subdivided into 2 major treatment arms: <span class="elsevierStyleItalic">a</span>) SNB followed by lymphadenectomy if the SNB specimen was positive, and <span class="elsevierStyleItalic">b</span>) observation with therapeutic or delayed lymphadenectomy if regional lymphatic metastases developed during observation.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">7,10,11</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The fundamental finding of the MSLT-I is very clear: survival was similar for patients in both arms of the study (an outcome already evident from the initial findings published in 2006).<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">10,11</span></a> However, the authors—possibly dissatisfied by its implications for their theoretical model of melanoma spread—failed to reflect this finding in their conclusions. Instead, they analyzed the results by subgroups, highlighting a very questionable comparison between patients with a positive SNB result and patients with macroscopic lymphatic metastases—situations that are neither clinically nor biologically comparable—and thereby introducing considerable bias.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">14,15</span></a> Moreover, they submitted the data to a particularly complex statistical analysis for which the study probably was not initially designed (and which may have had something to do with the delay in publication).<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a> Finally, based on the results of this analysis, the authors concluded that SNB may confer an advantage in overall survival.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a> Both the initial MSLT-I results from 2006<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> and the final results from 2014<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a> were published alongside editorials supporting this (probably biased) interpretation. These editorials were authored by individuals who had been closely involved in the introduction and assessment of prophylactic lymphadenectomy and, later, SNB, and who largely shared Morton's view of the stepwise progression of melanoma.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">17,18</span></a> In both cases, the authors’ interpretation of the study's findings was promptly challenged by other melanoma experts, who saw evidence in the MSLT-I results supporting the opposite conclusion. In other words, these experts considered that the MSLT-I results actually supported the conclusion that SNB does not increase overall survival in patients with melanoma.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">14,16,19</span></a> The latter conclusion, which in my opinion is correct, would imply that the hypothesis of stepwise melanoma spread is necessarily incorrect.</p><p id="par0030" class="elsevierStylePara elsevierViewall">One of the greatest opponents of the introduction of SNB in the routine management of melanoma was A. Bernard Ackerman, a brilliant and intelligent dermatopathologist known for his incisive analysis of the issues he studied. Ackerman argued that the presence of tumor cells in the sentinel node was a marker of both lymphatic and systemic spread of melanoma (what Morton called the marker hypothesis).<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">7,8</span></a> This hypothesis holds true for most patients with melanoma who develop lymphatic and visceral metastases during the course of the disease, but not for many patients who develop only lymphatic metastases and who go into long-term complete remission after any type of lymphadenectomy (prophylactic, SNB-guided, or delayed), nor for patients who develop visceral metastases after a negative SNB result.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In a review<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> of the literature on tumor progression published in 1991, Clark clearly outlined his vision of melanoma spread, a model I call the hypothesis of differential spread patterns. This model<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">4,5</span></a> is compatible with the “seed and soil” hypothesis, which was proposed with great foresight by Stephen Paget more than 100 years ago and is based on clinical observation and finely tuned common sense.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</span></a> And it is also compatible with many more recent discoveries that have revealed the enormous complexity of the process leading to metastasis formation.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a> The fact that tumor cells are capable of entering and leaving lymph and blood vessels is important, but there are surely many other factors that help to explain how macroscopic lymphatic and visceral metastases develop. Moreover, the process of metastasis formation generally appears to be very inefficient.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a> Many cells begin the process, but few complete it. In addition, it is clear that many tumor cells, once they reach the target organ, enter a period of dormancy that in some cases can last a very long time.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">22,23</span></a> Some such micrometastases could be detected with highly sensitive techniques such as SNB (especially if immunohistochemical and molecular detection techniques are used), but this would not necessarily mean that these micrometastases are destined to progress to macrometastases.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</span></a> If they do progress to macrometastases, the speed of progression varies widely depending on the genetic and epigenetic characteristics of the primary tumor and probably also certain host-related factors, among which the antitumor immune response would undoubtedly be important. Certain tumor cells develop more quickly in some organs than in others because their interaction with the microenvironment varies between organs. Thus, it is not necessarily the case that the cells reached the organs where the first metastases developed before they reached other organs where metastases may appear later or, in some cases, never.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The results of both earlier trials on the usefulness of prophylactic lymphadenectomy in patients with melanoma and the more recent results relating to SNB from the MSLT-I study show that, while both prophylactic and SNB-guided lymphadenectomy have obvious therapeutic utility, the procedure is only curative in patients with metastases that exclusively affect the regional lymph nodes.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> Therefore, in terms of survival the results obtained following these procedures are similar to those obtained with therapeutic or delayed lymphadenectomy on follow-up. However, given that we do not usually know a priori which patients will have exclusively lymphatic spread and which ones will also have systemic spread, it is reasonable to propose the option of additional adjuvant therapy in all patients (while recognizing that the efficacy of such treatments currently remains very limited). Oncologic surgeons on the other hand recognize that a regional lymphadenectomy guided by a positive SNB result is usually simpler and more likely to be successful than a delayed lymphadenectomy based on the presence of macroscopic lymphatic metastases, which, moreover, carries the risk of extracapsular spread and greater locoregional extent of disease.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> Given the value of the diagnostic and prognostic information that SNB provides, it seems very clear to me that SNB should be offered routinely to patients with melanoma in whom the procedure is indicated. On this point, I agree with Morton and many others who defend the clinical utility of SNB.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> But it is one thing to argue in favor of SNB and another to attribute magical powers to the procedure (although statistical analysis can sometimes yield results that certainly appear magical). Unfortunately, in my opinion some of the conclusions drawn by the authors of the MSLT-I study<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">10,11</span></a> are closer to magic than to the biological and clinical reality of melanoma. As I noted in an earlier paper,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> I am not aware of any biological property of tumor cells that requires them to pass through a lymph node before reaching any other organ. This progression may occur in some cases, but it is not the rule.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The problem with the biased, uncritical interpretation of the MSLT-I results<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">10,11</span></a> is that it prevents us from understanding which model of melanoma spread is likely to be the most accurate—Clark's model, in my opinion<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">5,9</span></a>—and at the same time spurs on those who openly argue against the routine use of SNB. It is easy to criticize the conclusions of the MSLT-I; unfortunately, it is also easy to conflate such criticism with opposition to the routine use of SNB.</p><p id="par0050" class="elsevierStylePara elsevierViewall">If we consider the differential spread model, we can see right away that it is perfectly compatible with the basic results of the MSLT-I, and that it is the only one of the 3 models that predicted the results that were ultimately observed.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> Any type of lymphadenectomy will only cure patients with exclusively lymphatic involvement because lymphatic and systemic metastases are essentially independent events, even though in many patients they may occur consecutively or, in some cases, simultaneously.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">4,5</span></a> The differential spread model also suggests some avenues for research that would certainly help us gain a better understanding of how melanoma progresses and how we can slow its progression. First, we should make an effort to characterize genetic, epigenetic, proteomic, and immunologic signatures, as well as any other kind of signature that would allow us to predict the cases in which melanoma will tend to form exclusively lymphatic metastases, exclusively visceral metastases, or both types. With such a complex problem it is not certain that we will find sufficiently satisfactory answers, but we definitely will not find them if we do not look for them.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Tumor dormancy<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">22,23</span></a> is another very important area for research because it can help us to understand why melanoma progresses more quickly in some patients, and in some organs, than in others. Some researchers believe that, rather than trying to physically eliminate all tumor cells from the body (a formidable goal, considering melanoma's degree of resistance to the available treatments), the most feasible objective in the fight against cancer would be to induce and maintain a very long period of tumor dormancy in the malignant cells. This may be an easier objective to accomplish; in fact, it is one of the goals of adjuvant therapy.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a> But there is a problem. Many adjuvant therapies have been proposed for this purpose because they have been shown to be effective against macroscopic metastases. However, it is becoming increasingly clear that the cells responsible for the growth of macroscopic metastases have very different biological properties from the cells responsible for tumor dormancy and for persistent micrometastases that do not progress for an interval that varies by case.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">23</span></a> SNB provides a valuable means of deepening our understanding of the differential biological properties of melanoma cells in micrometastases and macrometastases as well as the responses of these cells to different treatments.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The MSLT-I was a necessary clinical trial, and Donald L. Morton made an extraordinary personal contribution to progress in the study and treatment of melanoma. Despite the fact that SNB has not met all of Morton's expectations, the procedure remains extremely useful in the diagnostic, prognostic, and therapeutic management of melanoma. In my opinion, when SNB is indicated, all patients should be offered the procedure and given realistic, honest explanations of the expected benefits.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Pizarro Á. Modelos de diseminación del melanoma y resultado final del <span class="elsevierStyleItalic">multicenter selective lymphadenectomy trial-I</span>. Actas Dermosifiliogr. 20145;106:82–85.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib0130" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sentinel lymph node biopsy in melanoma: Facts and controversies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "B.T. Baldwin" 1 => "B.S. Cherpelis" 2 => "V. Sondak" 3 => "N.A. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 14 | 11 | 25 |
| 2024 Octubre | 68 | 41 | 109 |
| 2024 Septiembre | 85 | 24 | 109 |
| 2024 Agosto | 111 | 48 | 159 |
| 2024 Julio | 78 | 29 | 107 |
| 2024 Junio | 82 | 41 | 123 |
| 2024 Mayo | 63 | 26 | 89 |
| 2024 Abril | 55 | 26 | 81 |
| 2024 Marzo | 73 | 26 | 99 |
| 2024 Febrero | 67 | 26 | 93 |
| 2024 Enero | 44 | 30 | 74 |
| 2023 Diciembre | 44 | 16 | 60 |
| 2023 Noviembre | 54 | 23 | 77 |
| 2023 Octubre | 63 | 20 | 83 |
| 2023 Septiembre | 57 | 28 | 85 |
| 2023 Agosto | 39 | 13 | 52 |
| 2023 Julio | 62 | 34 | 96 |
| 2023 Junio | 45 | 21 | 66 |
| 2023 Mayo | 41 | 20 | 61 |
| 2023 Abril | 48 | 20 | 68 |
| 2023 Marzo | 44 | 29 | 73 |
| 2023 Febrero | 50 | 19 | 69 |
| 2023 Enero | 45 | 29 | 74 |
| 2022 Diciembre | 45 | 35 | 80 |
| 2022 Noviembre | 21 | 20 | 41 |
| 2022 Octubre | 20 | 16 | 36 |
| 2022 Septiembre | 25 | 35 | 60 |
| 2022 Agosto | 23 | 24 | 47 |
| 2022 Julio | 25 | 37 | 62 |
| 2022 Junio | 20 | 25 | 45 |
| 2022 Mayo | 32 | 32 | 64 |
| 2022 Abril | 47 | 35 | 82 |
| 2022 Marzo | 44 | 51 | 95 |
| 2022 Febrero | 19 | 25 | 44 |
| 2022 Enero | 32 | 32 | 64 |
| 2021 Diciembre | 26 | 32 | 58 |
| 2021 Noviembre | 36 | 52 | 88 |
| 2021 Octubre | 37 | 38 | 75 |
| 2021 Septiembre | 37 | 33 | 70 |
| 2021 Agosto | 40 | 24 | 64 |
| 2021 Julio | 28 | 26 | 54 |
| 2021 Junio | 27 | 26 | 53 |
| 2021 Mayo | 32 | 44 | 76 |
| 2021 Abril | 57 | 41 | 98 |
| 2021 Marzo | 37 | 23 | 60 |
| 2021 Febrero | 49 | 16 | 65 |
| 2021 Enero | 27 | 25 | 52 |
| 2020 Diciembre | 39 | 18 | 57 |
| 2020 Noviembre | 25 | 17 | 42 |
| 2020 Octubre | 29 | 9 | 38 |
| 2020 Septiembre | 33 | 11 | 44 |
| 2020 Agosto | 31 | 28 | 59 |
| 2020 Julio | 30 | 18 | 48 |
| 2020 Junio | 31 | 18 | 49 |
| 2020 Mayo | 29 | 21 | 50 |
| 2020 Abril | 77 | 16 | 93 |
| 2020 Marzo | 36 | 22 | 58 |
| 2020 Febrero | 5 | 4 | 9 |
| 2020 Enero | 4 | 1 | 5 |
| 2019 Diciembre | 8 | 1 | 9 |
| 2019 Noviembre | 4 | 0 | 4 |
| 2019 Octubre | 0 | 2 | 2 |
| 2019 Septiembre | 0 | 2 | 2 |
| 2019 Agosto | 4 | 0 | 4 |
| 2019 Julio | 8 | 2 | 10 |
| 2019 Junio | 4 | 3 | 7 |
| 2019 Mayo | 7 | 0 | 7 |
| 2019 Abril | 4 | 3 | 7 |
| 2019 Marzo | 2 | 6 | 8 |
| 2019 Febrero | 4 | 1 | 5 |
| 2019 Enero | 2 | 0 | 2 |
| 2018 Diciembre | 1 | 0 | 1 |
| 2018 Noviembre | 1 | 0 | 1 |
| 2018 Octubre | 4 | 1 | 5 |
| 2018 Septiembre | 5 | 0 | 5 |
| 2018 Julio | 1 | 0 | 1 |
| 2018 Abril | 0 | 1 | 1 |
| 2018 Marzo | 1 | 2 | 3 |
| 2018 Febrero | 25 | 7 | 32 |
| 2018 Enero | 22 | 8 | 30 |
| 2017 Diciembre | 27 | 8 | 35 |
| 2017 Noviembre | 22 | 6 | 28 |
| 2017 Octubre | 22 | 5 | 27 |
| 2017 Septiembre | 21 | 9 | 30 |
| 2017 Agosto | 24 | 11 | 35 |
| 2017 Julio | 17 | 7 | 24 |
| 2017 Junio | 23 | 7 | 30 |
| 2017 Mayo | 25 | 6 | 31 |
| 2017 Abril | 16 | 11 | 27 |
| 2017 Marzo | 15 | 23 | 38 |
| 2017 Febrero | 13 | 11 | 24 |
| 2017 Enero | 18 | 5 | 23 |
| 2016 Diciembre | 19 | 15 | 34 |
| 2016 Noviembre | 30 | 9 | 39 |
| 2016 Octubre | 30 | 14 | 44 |
| 2016 Septiembre | 0 | 5 | 5 |
| 2016 Julio | 8 | 1 | 9 |
| 2016 Junio | 14 | 2 | 16 |
| 2016 Mayo | 10 | 9 | 19 |
| 2016 Abril | 10 | 20 | 30 |
| 2016 Marzo | 9 | 10 | 19 |
| 2016 Febrero | 7 | 14 | 21 |
| 2016 Enero | 13 | 3 | 16 |
| 2015 Diciembre | 17 | 1 | 18 |
| 2015 Noviembre | 10 | 1 | 11 |
| 2015 Octubre | 3 | 1 | 4 |
| 2015 Septiembre | 5 | 0 | 5 |
| 2015 Agosto | 0 | 1 | 1 |
| 2015 Julio | 5 | 4 | 9 |
| 2015 Junio | 10 | 5 | 15 |
| 2015 Mayo | 15 | 4 | 19 |
| 2015 Abril | 5 | 4 | 9 |
| 2015 Marzo | 2 | 4 | 6 |
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