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López Montalbán, F. Alarcón Soldevilla, S. Abenza Baeza, M.D. Miranda Rollón, Á. López Ávila, I. Yago Ugarte" "autores" => array:6 [ 0 => array:4 [ "nombre" => "S." "apellidos" => "López Montalbán" "email" => array:1 [ 0 => "silvia.lopezm@um.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "F." "apellidos" => "Alarcón Soldevilla" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "S." "apellidos" => "Abenza Baeza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "M.D." "apellidos" => "Miranda Rollón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Á." "apellidos" => "López Ávila" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 5 => array:3 [ "nombre" => "I." "apellidos" => "Yago Ugarte" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hospital General Universitario Santa Lucía, Cartagena, Murcia, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Metotrexato intralesional y nuevos abordajes para la neoadyuvancia en el carcinoma escamoso cutaneo periocular" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 934 "Ancho" => 1325 "Tamanyo" => 166397 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A) Large-diameter cutaneous squamous cell carcinoma of the right upper eyelid prior to treatment. (B) Decrease in tumor size after two infiltrations of intralesional methotrexate. (C,D) Appearance one week after surgery performing wedge resection with alignment of the palpebral margin and without remains of tumor persistence.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The aim of this study is to review the different types of intralesional and systemic therapy available for neoadjuvant treatment of cutaneous squamous cell carcinoma (CSCC) following a clinical case recently treated in our practice.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Material and methods</span><p id="par0010" class="elsevierStylePara elsevierViewall">We present the evolution of a patient treated with two infiltrations of intralesional methotrexate (MTX) (20 mg/0.8 ml) in neoadjuvant therapy separated by 2 weeks, the reduction of the initial tumor size and its evolution and subsequent surgical outcome (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C and D). <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> shows the therapeutic protocol (figure modified from N. Silvestre Torner et al.).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The dose used in each of the infiltrations was that which achieved bleaching of the lesion. The administration of MTX-il was preceded by a hematological, hepatic and renal function study. Two weeks after the last infiltration, the therapeutic response was reassessed, indicating surgical excision of the residual persistent lesion.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Results</span><p id="par0015" class="elsevierStylePara elsevierViewall">A decrease in initial tumor size of >50% was achieved. Initial tumor measurements were 12 mm in base (lesion width) and 8 mm in height (vertical axis from superior palpebral crease to base of eyelashes) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A) with a reduction in tumor size to only 3 mm in width after the 2 infiltrations (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). The procedure was well tolerated, with a visual analog scale (VAS) of 1/10 pain. After 3 months of follow-up, no adverse effects or signs of local or distant recurrence were reported, and a good functional outcome was achieved (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C and D).</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Discussion</span><p id="par0020" class="elsevierStylePara elsevierViewall">The usual treatment for CSCC is surgery with or without associated radiotherapy, with the latest guidelines of the National Comprehensive Cancer Network (NCCN) establishing surgical excision with safety margins ranging from 4 mm in tumors smaller than or equal to 2 cm to 6 mm in tumors larger than 2 cm as the treatment of choice. However, sometimes in our clinical practice we encounter challenging scenarios: important post-surgical sequelae, poor response to conventional treatment or severe comorbidities of the patient.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Neoadjuvant treatment, whether chemotherapy, radiotherapy or immunotherapy, is the complementary treatment to definitive treatment, which is usually surgical, whose objective is to facilitate reconstruction by reducing the surgical defect and increasing the possibility of cure.</p><p id="par0030" class="elsevierStylePara elsevierViewall">There are very few publications on the use of intralesional therapy in periocular CSCC, and one case of intralesional MTX for palliative use in advanced recurrent periocular CSCC is described.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> There are authors<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> who describe a series of 7 cases of keratoacanthomas with significant tumor size reduction in most patients after MTX injection until tumor bleaching 30 days before surgery, but none of them presented the lesion at the palpebral level. One case of intralesional MTX in palpebral keratoacanthoma resistant to multiple treatments has been reported.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> A clinical trial on neoadjuvant treatment with MTX-il in keratoacanthoma was published in 2011. Two groups were established: 10 cases received MTX infiltration prior to surgery and 15 cases underwent isolated surgery. Of the group of patients treated with neoadjuvant MTX, 2 exhibited the lesion in the periocular area: one of them in the right lower eyelid and the other in the right infraciliary region. A difference in the tumor size of the lesion was found during surgery of 1.3 cm smaller on average in the group treated with MTX-il. Moreover, this size reduction represented a 69% greater decrease in the MTX-il group compared to the group treated with surgery alone (95% CI: 62–77 %), achieving a surgical defect resulting from surgery 1.45 cm smaller on average (95% CI: 1.18–1.72) in the group treated with neoadjuvant therapy.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However, despite the published articles on the use of MTX-il in neoadjuvant CSCC,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> it is difficult to find CSCC with periocular location treated with neoadjuvant. Intralesional MTX is more effective in keratoacanthoma than in CSCC, as are the other drugs available for intralesional therapy<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> that have been used such as 5-fluorouracil, bleomycin or interferon. Although resolution of lesions with 5-fluorouracil appears to be faster, infiltrations of this drug are less well tolerated and there is a higher rate of local complications, including skin necrosis more frequently than with MTX.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The protocol for intralesional MTX in a large series of 157 keratoacanthomas recommends an injection interval ranging from 2 to 4 weeks and greater efficacy in tumors <2 cm<span class="elsevierStyleSup">2</span>.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Regarding systemic treatment, there are data on cetuximab (anti-epidermal growth factor receptor [anti-EGFR]) in neoadjuvant combined or not with platinums, with a dosage of 400 mg/m<span class="elsevierStyleSup">2</span> and then 2 maintenance doses of 200 mg/m<span class="elsevierStyleSup">2</span>, with a total of 3 doses, achieving 92% of unresectable tumors becoming resectable with a pathological complete response (pRC) of 65.3% and good tolerance, the best scenario being locally advanced carcinoma.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> There are also some trials with cemiplimab in neoadjuvant therapy, and the difference between them lies in the number of cycles used and the sample size: in one of them, 2 cycles are prescribed, obtaining a pRC of 70%, considered a good response compared to previous molecules.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> As for the immunomediated adverse effects of cemiplimab, according to the <span class="elsevierStyleItalic">Common Terminology Criteria for Adverse Events</span> (CTCAE) classification, it was of intensity ≥3 in 18%. At present, we cannot affirm that there is sufficient evidence to use this treatment in neoadjuvant therapy because the sample size of the studies is low and they also have a short follow-up time, although the data are promising. Specifically, the NCCN recommends it in the presence of lymph node metastases at the limit of resectability (where we would no longer speak of neoadjuvant treatment, although on many occasions it becomes neoadjuvant), in unresectable tumors or in surgeries with high morbidity and mortality. Despite the greater use of pembrolizumab in clinical practice, cemiplimab is the first and only PD-1 inhibitor (programmed cell death membrane glycoprotein type 1, present in T cells) approved in July 2022 for the treatment of locally advanced or metastatic SCC in those who are not candidates for surgery or radiotherapy.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Although there is currently no therapeutic positioning report in Spain, it can be requested on a compassionate basis in the event that the patient needs anti-PD1 therapy.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusions</span><p id="par0040" class="elsevierStylePara elsevierViewall">The incidence of CSCC is growing exponentially in recent years. We have hardly found any previous articles in the literature describing the use of intralesional MTX in periocular CSCC.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3</span></a> Therefore, our case would be the first periocular SCC treated with intralesional MTX in neoadjuvant therapy. Although there are no protocols for dose and frequency of administration, it is advisable to perform successive infiltrations of MTX, with most studies agreeing on an average of 2 or 3 injections up to a maximum of 3–5 sessions<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> at intervals of 2 weeks between sessions and bearing in mind the option of surgical excision in non-responsive patients.</p><p id="par0045" class="elsevierStylePara elsevierViewall">We can conclude that neoadjuvant treatment raises questions in palpebral tumors at the limit of resectability. What is better: neoadjuvant treatment or attempting complete remission without surgery? Although a good response can be achieved with the systemic or intralesional treatments mentioned above, more scientific evidence is needed.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Immunotherapy represents a paradigm shift in the treatment of CSCC and constitutes a better alternative to the systemic treatment used so far based on conventional chemotherapy (especially platinums) and anti-EGFR, highlighting the need for knowledge and management by oculoplastic ophthalmologists of these drugs and their potential toxicities.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">No conflicts of interest were declared by the authors.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Informed consent</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors have obtained consent for the patient's images.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Funding</span><p id="par0065" class="elsevierStylePara elsevierViewall">This research has not received specific support from public sector agencies, commercial sector or non-profit entities.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres2291533" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1903867" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2291532" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1903866" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Informed consent" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Funding" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2024-02-27" "fechaAceptado" => "2024-05-05" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1903867" "palabras" => array:5 [ 0 => "Cutaneous squamous cell carcinoma" 1 => "Inmunotherapy" 2 => "Intralesional neoadjuvant" 3 => "Skin cancer" 4 => "Eyelids" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1903866" "palabras" => array:5 [ 0 => "Carcinoma escamoso cutáneo" 1 => "Inmunoterapia" 2 => "Neoadyuvancia intralesional" 3 => "Cáncer cutáneo" 4 => "Párpados" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">This study arises from the need to understand the different therapies for cutaneous squamous cell carcinoma (SCC), especially in challenging clinical situations where conventional therapeutic options may not be optimal. The purpose of the study is to assess the efficacy and safety of intralesional methotrexate (MTX) as neoadjuvant therapy in the treatment of periocular SCC.</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The outcome of a patient after two separate intralesional MTX infiltrations 2 weeks apart is described. Therapeutic response was evaluated, achieving a significant reduction in tumor size and subsequently performing surgical excision of the residual lesion. The procedure was well tolerated, with no local or distant recurrences in the follow up.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Intralesional MTX may be an effective and safe option in the neoadjuvant treatment of periocular SCC. Furthermore, we highlight the growing importance of immunotherapy in the approach to SCC and the need to familiarize specialists with these new treatments.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Este estudio surge de la necesidad de conocer las diferentes terapias en el carcinoma escamoso cutáneo (CEC), especialmente en situaciones clínicas desafiantes donde las opciones terapéuticas convencionales pueden no ser óptimas. El propósito del estudio es evaluar la eficacia y seguridad del metotrexato (MTX) intralesional como terapia neoadyuvante en el tratamiento del CEC periocular.</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se describe el resultado obtenido en una paciente tras dos infiltraciones de MTX intralesional separadas 2 semanas. Se evaluó la respuesta terapéutica, logrando una disminución significativa del tamaño tumoral y realizando posteriormente la extirpación quirúrgica de la lesión residual. El procedimiento fue bien tolerado, sin recidivas locales o a distancia en el seguimiento.</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">El uso de MTX intralesional puede ser una opción efectiva y segura en el tratamiento neoadyuvante del CEC periocular. Además, destacamos la importancia creciente de la inmunoterapia en el abordaje del CEC y la necesidad de familiarizar a los especialistas con estos nuevos tratamientos.</p></span>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 934 "Ancho" => 1325 "Tamanyo" => 166397 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A) Large-diameter cutaneous squamous cell carcinoma of the right upper eyelid prior to treatment. (B) Decrease in tumor size after two infiltrations of intralesional methotrexate. (C,D) Appearance one week after surgery performing wedge resection with alignment of the palpebral margin and without remains of tumor persistence.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1151 "Ancho" => 2000 "Tamanyo" => 167001 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Therapeutic protocol for the treatment of cutaneous squamous cell carcinoma (SCC) of periocular location with intralesional methotrexate.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:12 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intralesional methotrexate for keratoacanthomas: a case series" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "N. 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Intralesional methotrexate and new approaches for neoadjuvance treatment in squamous cell periocular carcinoma
Metotrexato intralesional y nuevos abordajes para la neoadyuvancia en el carcinoma escamoso cutaneo periocular