Afectación iatrogénica de la motilidad ocular por fármacos antitumorales inhibidores de los puntos de control / Iatrogenic impairment of ocular motility by immune checkpoint inhibitors

Se encontraron 4 revisiones sistemáticas que incluían este tipo de iatrogenia ocular, así como numerosos reportes de casos aislados. Los efectos adversos reportados comprenden: paresias oculomotoras, neuropatía óptica, atrofia óptica, síndromes miasteniformes, pseudo-orbitopatía tiroidea, síndrome del ápex orbitario e hipofisitis. La mayoría se manejaron sin interrupción o con interrupción parcial del tratamiento oncológico. Se requirieron tratamientos sistémicos agresivos para el manejo adecuado de la iatrogenia ocular.Es imprescindible que el oftalmólogo se familiarice con los nuevos tratamientos oncológicos ICI, capaces de provocar iatrogenia sobre la motilidad ocular grave e incapacitante para el paciente. La comunicación de efectos adversos con los tratamientos empleados puede ayudar al manejo más adecuado de estos pacientes. La investigación debe ir orientada al diagnóstico diferencial complejo y a optimizar las decisiones sobre los tratamientos oncológicos. (AU)

Cancer therapy relies on new antitumoral drugs called immune checkpoint inhibitors (ICI), which produce long-lasting anti-tumor responses and lengthen survival, but cause autoimmune-type toxicity. The clinical characteristics induced by ICI are not well characterized to date and careful collection of clinical data is required to accurately define its safety profile.We conducted a literature search in the main clinical search engines to identify pharmacological ocular iatrogenic events of ICIs related to ocular motility. Four systematic reviews were found that included this type of ocular iatrogenesis as well as numerous isolated case reports. Reported adverse effects include: oculomotor paresis, optic neuropathy, optic atrophy, myastheniform syndromes, thyroid pseudo-orbitopathy, orbital apex syndrome, and hypophysitis. Most were managed without interruption or with partial interruption of cancer treatment. Aggressive systemic treatments were required for adequate management of ocular iatrogenic events.It is essential that the ophthalmologist become familiar with the new ICI oncological treatments, capable of causing severe and disabling motilidad ocular iatrogenesis for the patient. The communication of adverse effects and the report of the treatments used can help the most appropriate management of these patients. Research should be oriented towards complex differential diagnosis and to optimize decisions on cancer treatments. (AU)

Iatrogenic affectation of ocular motility by immune checkpoint inhibitors.

Cancer therapy relies on new antitumoral drugs called immune checkpoint inhibitors (ICI), which produce long-lasting anti-tumor responses and lengthen survival, but cause autoimmune-type toxicity. The clinical characteristics induced by ICI are not well characterized to date and careful collection of clinical data is required to accurately define its safety profile. We conducted a literature search in the main clinical search engines to identify pharmacological ocular iatrogenic events of ICIs related to ocular motility. Four systematic reviews were found that included this type of ocular iatrogenesis as well as numerous isolated case reports. Reported adverse effects include: oculomotor paresis, optic neuropathy, optic atrophy, myastheniform syndromes, thyroid pseudo-orbitopathy, orbital apex syndrome, and hypophysitis. Most were managed without interruption or with partial interruption of cancer treatment. Aggressive systemic treatments were required for adequate management of ocular iatrogenic events. It is essential that the ophthalmologist become familiar with the new ICI oncological treatments, capable of causing severe and disabling motilidad ocular iatrogenesis for the patient. The communication of adverse effects and the report of the treatments used can help the most appropriate management of these patients. Research should be oriented towards complex differential diagnosis and to optimize decisions on cancer treatments.

Diabetes mellitus tipo 1 de presentación súbita inducida por inhibidores del punto de control inmunitario en el tratamiento de cáncer avanzado. Serie de casos / Sudden onset type 1 diabetes mellitus induced by immune checkpoint inhibitors in the treatment of advanced cancer. Cases report

Tres pacientes con cáncer avanzado en tratamiento con inhibidores del punto de control inmunitario (inmune checkpoint inhibitors, ICIs), sin antecedentes de diabetes mellitus (DM), ingresaron al Servicio de Urgencias con poliuria, polidipsia y pérdida de peso, y diagnóstico de cetoacidosis diabética, sin evidencia clínica de infección. Fueron tratados con líquidos e infusión de insulina pasando luego a un régimen de insulina bolo basal que continuó después del alta. Las pruebas de detección de autoanticuerpos para DM resultaron negativas, y se les diagnosticó DM inducida por ICIs, pembrolizumab en dos de ellos y nivolumab en el otro. El propósito de esta serie de casos es demostrar el desarrollo de la DM1 en forma aguda en pacientes tratados con inhibidores de PD-1. Sobre la base de estos casos y la literatura revisada, se buscaron determinar las características clínicas, y sugerir estrategias para la identificación, control, tratamiento precoz y seguimiento de los pacientes tratados con ICIs a fin de minimizar el impacto de la disfunción autoinmune.

Three patients with advanced cancer, treated with inmune checkpoint inhibitors (ICIs), with no history of diabetes mellitus (DM), were admitted to the Emergency Department with polyuria, polydipsia, and weight loss and a diagnosis of diabetic ketoacidosis without clinical evidence of infection. They were treated with fluids and insulin infusion transitioning to a basal-bolus insulin regimen, which continued after discharge. Autoantibody detection tests for DM were negative and they were diagnosed with DM induced by ICIs, pembrolizumab in two of them, and nivolumab in another. The purpose of this case report is to show the development of DM1 in an acute form in patients treated with PD-1 inhibitors. Based on these cases and the reviewed literature, we seek to identify clinical characteristics and suggest strategies for the proper identification, control, treatment, and follow-up of patients treated with ICIs to minimize the impact of autoimmune dysfunction.

Desarrollo e implementación de una unidad de inmunoterapia en un servicio de urología / Development and implementation of an immunotherapy unit in a urology department

Introducción La inmunoterapia está revolucionando el tratamiento del cáncer, siendo los anticuerpos monoclonales dirigidos contra moléculas reguladoras del punto de control la terapia más ampliamente utilizada en la actualidad. Un total de seis fármacos inhibidores del punto de control inmunitario (CPI) han sido aprobados por la U.S. Food and Drug Administration (FDA) y por la European Medicines Agency (EMA) para su uso en diversos tumores sólidos del aparato genitourinario. Material y métodos Se revisó la literatura y se analizó la metodología y experiencia propia adquirida para instaurar el tratamiento con CPI en un servicio de Urología. Resultados Se describen los requisitos recomendables desde el punto de vista formativo, logístico y procedimental para implementar una unidad de inmunoterapia en un servicio de Urología que permita ofrecer con seguridad el tratamiento experto con CPI a los pacientes con tumores genitourinarios. Conclusiones El cumplimiento del programa propuesto garantiza la administración segura de CPI en un entorno hospitalario (AU)

Introduction Immunotherapy is revolutionizing cancer treatment, with monoclonal antibodies directed against checkpoint regulatory molecules currently being the most widely used therapy. A total of six immune checkpoint inhibitor (CPI) drugs have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in various solid tumors of the genitourinary tract. Material and methods the literature is reviewed and the methodology, as well as our own experience, are analyzed to establish treatment with CPI in a urology department. Results The requirements recommended in terms of training, logistics and procedure are described in order to safely offer expert treatment with CPI to patients with genitourinary tumors. Conclusions Compliance with the proposed program ensures safe administration of immune checkpoint inhibitors in a hospital setting (AU)

Development and implementation of an immunotherapy unit in a urology department.

INTRODUCTION: Immunotherapy is revolutionizing cancer treatment, with monoclonal antibodies directed against checkpoint regulatory molecules currently being the most widely used therapy. A total of six immune checkpoint inhibitor (CPI) drugs have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in various solid tumors of the genitourinary tract. MATERIAL AND METHODS: The literature is reviewed and the methodology, as well as our own experience, are analyzed to establish treatment with CPIs in a urology department. RESULTS: The requirements recommended in terms of training, logistics and procedure are described in order to safely offer expert treatment with CPIs to patients with genitourinary tumors. CONCLUSIONS: Compliance with the proposed program ensures safe administration of immune checkpoint inhibitors in a hospital setting.

Incidence and clinical characteristics of thyroid abnormalities in cancer patients treated with immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are a group of drugs that have been used in recent years for the treatment of advanced malignancies such as melanoma, non-small cell lung cancer and other tumors, significantly increasing survival. However, the use of ICI has been associated with an increased risk of autoimmune diseases, with endocrine organs, specifically the thyroid, being highly susceptible to this phenomenon. OBJECTIVE: To describe the incidence and clinical characteristics of patients treated with ICI who develop thyroid disease. METHODS: The medical records of all patients who received ICI treatment within the last three years were retrospectively reviewed, with those who developed thyroid abnormalities being identified. RESULTS: The prevalence of thyroiditis was 7 %, with an incidence of 21.4 % of patients-month. Median time for the development of thyroiditis was 63 days. Most patients had mild or moderate symptoms and did not require hospitalization, although all but one developed permanent hypothyroidism and required hormone replacement therapy with levothyroxine. CONCLUSIONS: Thyroid dysfunction secondary to immunotherapy is a common entity in our population. Clinical presentation is usually mild and does not require treatment discontinuation; however, due to the high incidence of these adverse events, non-oncology specialists must be familiar with the diagnosis and treatment of these alterations in order to provide multidisciplinary management.

INTRODUCCIÓN: Los inhibidores del punto de control inmunológico (IPCi) son utilizados en los últimos años en el tratamiento de neoplasias malignas avanzadas, con ellos se ha logrado un aumento significativo de la supervivencia; sin embargo, su uso se ha asociado a incremento del riesgo de enfermedades autoinmunes. OBJETIVO: Describir la incidencia y las características clínicas de los pacientes tratados con IPCi que desarrollaron tiroidopatía. MÉTODOS: Se revisaron retrospectivamente los expedientes de todos los pacientes que recibieron IPCi en los últimos tres años y se identificaron aquellos que desarrollaron anomalías tiroideas. RESULTADOS: La prevalencia de tiroiditis fue de 7 %, con una incidencia de 21.4 % pacientes/mes. La mediana del tiempo para el desarrollo de tiroiditis fue de 63 días. La mayoría de los pacientes presentó síntomas leves o moderados y no requirió hospitalización, si bien todos menos uno desarrollaron hipotiroidismo permanente y requirieron terapia de reemplazo hormonal con levotiroxina. CONCLUSIONES: La disfunción tiroidea secundaria a inmunoterapia es una entidad común en nuestra población. El cuadro clínico suele ser leve y no requiere suspender el tratamiento; sin embargo, debido a la alta incidencia de este evento adverso, los médicos no oncólogos deben estar familiarizados con su diagnóstico y tratamiento, para brindar un manejo multidisciplinario.

Encefalitis autoinmune por pembrolizumab en anciano con carcinoma no microcítico avanzado de pulmón. Caso clínico / Pembrolizumab-associated autoimmune encephalitis in an elderly patient with advanced non-small cell lung cancer. A clinical case

Los objetivos terapéuticos en el paciente geriátricoson la mejora de su calidad de vida y de su capacidadfuncional frente al mero incremento de su supervivencia. En patología neoplásica, la decisión de iniciar tratamiento curativo, especialmente inmunoterapia, deberealizarse tras una completa valoración de los riesgospotenciales. El paciente geriátrico es más susceptiblea desarrollar reacciones adversas y de mayor gravedadque el paciente más joven.Se presenta el caso de un anciano octogenario concarcinoma no microcítico pulmonar que desarrolló toxicidad neurológica tras tratamiento con pembrolizumab. Se realiza un diagnóstico diferencial de encefalitisy una revisión de los casos de encefalitis autoinmunepor pembrolizumab para mejorar nuestro conocimiento de esta infrecuente toxicidad. El trabajo interdisciplinar y la valoración geriátrica integral son elementosesenciales para prevenir el deterioro funcional del anciano.(AU)

Therapeutic objectives for the geriatric patient areimprovement of quality of life and functional capacityrather than a mere increase in survival. In neoplasticdisease, the decision to initiate administration of curative therapies, especially immunotherapy, shouldbe taken only after any potential risks have been takeninto account. Geriatric patients are more susceptibleto developing more serious adverse reactions than theyounger population.We report the case of an octogenarian patient withnon-small cell lung cancer who developed neurologictoxicity following pembrolizumab therapy. We carryout a differential diagnosis of encephalitis and providea literature review of pembrolizumab-associated au-toimmune encephalitis cases in order to improve ourknowledge of this unusual toxicity. An interdisciplinaryapproach and comprehensive geriatric assessment areessential components to prevent functional decline inthe elderly.(AU)

Incidencia y características clínicas de la enfermedad tiroidea en pacientes con neoplasias malignas tratados con inhibidores de punto de control inmunológico / Incidence and clinical characteristics of thyroid abnormalities in cancer patients treated with immune checkpoint inhibitors

Resumen Introducción: Los inhibidores del punto de control inmunológico (IPCi) son utilizados en los últimos años en el tratamiento de neoplasias malignas avanzadas, con ellos se ha logrado un aumento significativo de la supervivencia; sin embargo, su uso se ha asociado a incremento del riesgo de enfermedades autoinmunes. Objetivo: Describir la incidencia y las características clínicas de los pacientes tratados con IPCi que desarrollaron tiroidopatía. Métodos: Se revisaron retrospectivamente los expedientes de todos los pacientes que recibieron IPCi en los últimos tres años y se identificaron aquellos que desarrollaron anomalías tiroideas. Resultados: La prevalencia de tiroiditis fue de 7 %, con una incidencia de 21.4 % pacientes/mes. La mediana del tiempo para el desarrollo de tiroiditis fue de 63 días. La mayoría de los pacientes presentó síntomas leves o moderados y no requirió hospitalización, si bien todos menos uno desarrollaron hipotiroidismo permanente y requirieron terapia de reemplazo hormonal con levotiroxina. Conclusiones: La disfunción tiroidea secundaria a inmunoterapia es una entidad común en nuestra población. El cuadro clínico suele ser leve y no requiere suspender el tratamiento; sin embargo, debido a la alta incidencia de este evento adverso, los médicos no oncólogos deben estar familiarizados con su diagnóstico y tratamiento, para brindar un manejo multidisciplinario.

Abstract Introduction: Immune checkpoint inhibitors (ICI) are a group of drugs that have been used in recent years for the treatment of advanced malignancies such as melanoma, non-small cell lung cancer and other tumors, significantly increasing survival. However, the use of ICI has been associated with an increased risk of autoimmune diseases, with endocrine organs, specifically the thyroid, being highly susceptible to this phenomenon. Objective: To describe the incidence and clinical characteristics of patients treated with ICI who develop thyroid disease. Methods: The medical records of all patients who received ICI treatment within the last three years were retrospectively reviewed, with those who developed thyroid abnormalities being identified. Results: The prevalence of thyroiditis was 7 %, with an incidence of 21.4 % of patients-month. Median time for the development of thyroiditis was 63 days. Most patients had mild or moderate symptoms and did not require hospitalization, although all but one developed permanent hypothyroidism and required hormone replacement therapy with levothyroxine. Conclusions: Thyroid dysfunction secondary to immunotherapy is a common entity in our population. Clinical presentation is usually mild and does not require treatment discontinuation; however, due to the high incidence of these adverse events, non-oncology specialists must be familiar with the diagnosis and treatment of these alterations in order to provide multidisciplinary management.

Reacciones adversas a medicamentos inhibidores del punto de control inmunitario / Adverse drug reactions associated with immune checkpoint inhibitors

Resumen El manejo de las reacciones adversas inducidas por los inhibidores del punto de control inmunitario (IPCI) en cáncer, demanda un trabajo multidisciplinario. Revisamos las causas y el curso clínico de las consultas e internaciones debidas a reacciones adversas de los IPCI entre septiembre de 2015 y julio de 2019 en el Instituto Alexander Fleming. Se registraron los datos demográficos, diagnóstico oncológico, reacción adversa y su grado, requerimiento de internación, tratamiento, mortalidad y evaluación de la reexposición. Se registraron 124 reacciones adversas por IPCI en 89 pacientes. Sesenta y ocho recibían monoterapia y 21 terapia combinada. Las manifestaciones cutáneas fueron las más frecuentes, seguidas de las generales, endocrinas (con mayor frecuencia hipotiroidismo), colitis, neumonitis, neurológicas y hepatitis. Fueron graves (grado ≥ 3), 26 toxicidades en 25 pacientes. Se internaron 15, y 6 de ellos requirieron terapia intensiva. Un caso fue fatal. Recibieron glucocorticoides 34 (12 de ellos por vía intravenosa). Un paciente recibió micofenolato y uno inmuno globulina endovenosa. En 20 se discontinuó el tratamiento. Ocho se reexpusieron y uno de ellos debió suspender definitivamente. Se presenta en esta serie de casos nuestra experiencia con el diagnóstico y tratamiento de las reacciones adversas de una familia de drogas cuya utilización ha crecido en los últimos años.

Abstract The management of patients with immune-related adverse events (irAEs) frequently demands a multidisciplinary approach. We reviewed the causes and clinical course of medical visits and admissions at the Instituto Alexander Fleming due to irAEs between September 2015 and July 2019. Demographic data, diagnosis, toxicity and its severity, requirement of admission, treatment, mortality, and evaluation of the re-administration of immunotherapy were collected. We found 124 irAEs in 89 patients. Sixty-eight of them received monotherapy (76.4%) and 21 (23.6%) combination of drugs. Cutaneous manifestations were the most frequent cause of irAEs, followed by general manifestations, endocrine dysfunctions (hypothyroidism the most frequent), colitis, pneumonitis, neurologic dis orders, and hepatitis. In 26 adverse events (in 25 patients), severity grade was ≥ 3. Fifteen were admitted and 6 required ICU admission. One patient died. Thirty-four received glucocorticoids, 12 of them by intravenous route. One patient received mycophenolate and one IVIG. In 20, the treatment was discontinued; 8 were re-exposed, with definitive discontinuation in one patient. In this case series we report our experience in the diagnosis and management of adverse reactions related to a family of drugs whose use has grown in recent years.

[Current treatment options and future perspectives on first line metastatic bladder cancer.] / Presente y futuro del tratamiento del carcinoma vesical metastásico en primera línea.

OBJECTIVE: Over the last 30 years researchon metastatic bladder cancer has been slow and limited to chemotherapy. Chemotherapy has provided high initial response rates but very few complete responses that remain overtime. Recently, European medical agency has granted approval to immunotherapy inmetastatic disease. We will review the clinical trials that drove to EMA approval as well as new promising therapies for metastatic bladder cancer. METHODS: A search on PubMed and clinicaltrials.gov through the combination of the following words in English and Spanish was performed: "carcinoma urotelial","cáncer de vejiga", "localmente avanzado","metastásico", "inmunoterapia", "CTLA-4", "PD1","PDL-1", "atezolizumab", "nivolumab", "ipilimubab", "pembrolizumab", "avelumab", "durvalumab", "tremelimumab", "terapia antiangiogénica", "terapia molecular dirigida" e "inhibidores VEGF". RESULTS: Cisplatin chemotherapy-based regimens remain standard treatment for metastatic bladder cancer as per phase III trials. Immunotherapy is available for cisplatin-ineligible patients with high PD-L1 expression,including atezolizumab or pembrolizumab. Trials comparing immunotherapy, chemotherapy or antiangiogenic drugs o targeted drugs are recruiting. CONCLUSIONS: The publication of the comparative studies on chemotherapy and immunotherapy as well as targeted therapy would provide a window of opportunity for an effective personalized treatment. Those treatment would decrease side-effects as well.

OBJETIVO: Durante los últimos 30 años las investigaciones en carcinoma vesical metastásico han estado paralizadas, limitándose el tratamiento de dicha patología al empleo de fármacos quimioterápicos, los cuales, a pesar de presentar una elevada tasa de respuesta inicial, tienen excepcionales respuestas completas y mantenidas en el tiempo. Recientemente, la Agencia Europea del Medicamento ha autorizado el empleo de fármacos inmunoterápicos para el tratamiento de esta patología en estadío metastásico. Este artículo tiene como objeto el análisis de los ensayos clínicos que permitieron dicha autorización, así como la revisión de nuevas terapias para el tratamiento del carcinoma urotelial localmente avanzado o metastásico.MÉTODO: Búsqueda bibliográfica realizada en Pub-Med y ClinicalTrials.gov mediante la combinación de las palabras clave, en español e inglés: "carcinoma urotelial", "cáncer de vejiga", "localmente avanzado","metastásico", "inmunoterapia", "CTLA-4", "PD1", "PDL-1", "atezolizumab", "nivolumab", "ipilimubab", "pembrolizumab","avelumab", "durvalumab", "tremelimumab", "terapia antiangiogénica", "terapia molecular dirigida" e "inhibidores VEGF". RESULTADOS: La poliquimioterapia a base de cisplatino sigue siendo el estándar de tratamiento para el carcinoma vesical metastásico de acuerdo con los resultados de los ensayos clínicos fase III publicados, sólo considerándose la inmunoterapia con atezolizumab o permbrolizumab electiva en aquellos pacientes no aptos para recibir cisplatino con alta expresión PDL1. Actualmente, están en curso estudios comparativos de terapias quimioterápicas frente a inmunoterapia, así como múltiples combinaciones que buscan efecto aditivo con fármacos antiangiogénicos o terapias dirigidas. CONLUSIONES: La publicación de los ensayos comparativos que se encuentran actualmente en curso, junto con los previsibles progresos en terapia dirigida, implicarán la posibilidad de abrir una esperanzadora línea de trabajo dirigida hacia una terapia efectiva y personalizada, que permita reducir los eventos adversos atribuibles al empleo de fármacos quimioterápicos.