Facultad de Ciencias de la Salud

Introduction: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intraindividual variability due to their pharmacokinetic characteristics. Therapeutic drug monitoring (TDM) can be used to optimize the use of several types of medication. Objective: We evaluated the use of TDM of TKIs in routine clinical practice through studying the variability in exposure to erlotinib, imatinib, lapatinib, and sorafenib and dose adjustment. Materials and methods: We conducted a retrospective analytical study involving patients who received treatment with TKIs, guided by TDM and with subsequent recommendation of dose adjustment. The quantification of the plasma levels of the different drugs was performed using high-performance liquid chromatography (HPLC). The Clinical Research Ethics Committee of the Hospital Quirónsalud Torrevieja approved this study. Results: The inter-individual variability in the first cycle and in the last monitored cycle was 46.2% and 44.0% for erlotinib, 48.9 and 50.8% for imatinib, 60.7% and 56.0% for lapatinib and 89.7% and 72.5% for sorafenib. Relationships between exposure and baseline characteristics for erlotinib, imatinib, lapatinib and sorafenib were not statistically significant for any of the variables evaluated (weight, height, body surface area (BSA), age and sex). Relationships between height (p = 0.021) and BSA (p = 0.022) were statistically significant for sorafenib. No significant relationships were observed between Ctrough and progression-free survival (PFS) or overall survival (OS) for any drug, except in the case of sunitinib (correlation between Ctrough and PFS p = 0.023) in the exposure–efficacy analysis. Conclusions: Erlotinib, imatinib, lapatinib and sorafenib show large inter-individual variability in exposure. TDM entails a significant improvement in exposure and enables more effective and safe use of TKIs in routine clinical practice.

Oxidative stress is associated with multiple pathologies such as cancer and can exacerbate the development of them. In this work, we have studied the antioxidant capacity of 5-Fluorouracile (5-FU) which is an antineoplastic drug that is used in the treatment of colorectal cancer. 5-FU is a compound that has a chemical structure similar to uracil and is also fluorinated. New fluorinated derivates previously obtained in our laboratory were tested to study its antioxidant activity. All the compounds analyzed were able to inhibit lipid peroxidation when used in concentrations of 10 μM.

Objective: A review of the literature about the anti-programmed death 1 monoclonal antibody nivolumab permits to verify the existence of several issues still unresolved about their dosing schedule. The aim of the present work was to explore possibilities of nivolumab treatment personalization through therapeutic drug monitoring, in order to improve their effectiveness and efficiency. Method: Observational, prospective study carried out from May 2017 through June 2019 in patients with different tumor diagnoses treated with nivolumab. Blood samples were obtained in the routine clinical practice, once nivolumab steady state was reached. Serum nivolumab levels were determined by means of quantitative ELISA. The standard schedule of 3 mg/kg every two weeks (Q2W) was modified in some patients due to different circumstances, and resulting serum concentrations were compared with those from the non-modified patients and the published data. Results: Blood samples from 19 patients in treatment with nivolumab were analyzed. A total of 39 samples of nivolumab were analyzed between 6th and 27th cycles. The standard schedule of 3 mg/kg every two weeks was modified in 12/19 (60%) patients, with intervals of 3, 4, 5, 6 or 7 weeks, once the steady state was reached. No statistically significant differences were detected when comparing every two weeks and every four week intervals. When the intervals were six or seven weeks, mean plasma concentration showed a statistically significant difference compared with every two weeks. Conclusions: Current data contribute to confirm former suspects about the possibilities of exploring new scenarios to improve and personalize nivolumab dosage. Additional studies to confirm it in bigger series and correlate it with clinical results, and to better define the role of therapeutic drug monitoring in the treatment, are warranted, not only by financial concerns but also for improving quality of life of patients and clinical management aspects. / Objetivo: Una revisión de la literatura sobre nivolumab permite verificar la existencia de diversos aspectos sin resolver sobre su intervalo de dosificación. El objetivo del presente estudio ha sido explorar las posibilidades de personalización del tratamiento con nivolumab mediante la monitorización terapéutica de sus concentraciones séricas para mejorar su efectividad y eficiencia. Método: Estudio observacional, prospectivo, realizado entre mayo de 2017 y junio de 2019 en pacientes tratados con nivolumab que estaban diagnosticados de diferentes tumores. Se obtuvieron muestras de sangre en la práctica clínica habitual, una vez alcanzado el estado de equilibrio de nivolumab. Las concentraciones séricas de nivolumab fueron determinadas mediante ELISA cuantitativo. La pauta posológica habitual de 3 mg/kg cada dos semanas tuvo que ser modificada en algunos pacientes debido a diferentes circunstancias, y las concentraciones séricas resultantes se compararon con las correspondientes a los pacientes en los que no se modificó y con datos publicados. Resultados: Se analizaron muestras de 19 pacientes que recibieron inicialmente 3 mg/kg de nivolumab cada dos semanas. Se analizó un total de 39 muestras, entre los ciclos 6 y 27. La pauta habitual se modificó, una vez alcanzado el estado de equilibrio, en 12/19 (60%) pacientes, en los que se amplió el intervalo a 3, 4, 5, 6 o 7 semanas. No se encontraron diferencias estadísticamente significativas al comparar la maadministración cada dos semanas y cada cuatro semanas. Cuando los intervalos fueron de seis o siete semanas, la concentración sérica media mostró una diferencia estadísticamente significativa en comparación con la administración cada dos semanas. Conclusiones: La información recogida parece confirmar la necesidad de explorar nuevos escenarios para personalizar la dosificación de nivolumab. Se necesitan estudios adicionales en series de mayor tamaño para confirmar esta información, correlacionarla con los resultados clínicos y definir mejor el papel de la monitorización terapéutica, no solo por motivos económicos, sino también para mejorar la calidad de vida de los pacientes y facilitar la administración clínica del tratamiento.

Background: Studies of patients with cancer a ected by coronavirus disease 2019 (COVID-19) are needed to assess the impact of the disease in this sensitive population, and the influence of di erent cancer treatments on the COVID-19 infection and seroconversion. Material and Methods: We performed a retrospective analysis of all patients hospitalized with RT-PCR positive for COVID-19 in our region to assess the prevalence of cancer patients and describe their characteristics and evolution (Cohort 1). Concurrently, a transversal study was carried out in patients on active systemic cancer treatment for symptomatology and seroprevalence (IgG/IgM by ELISA-method) against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (Cohort 2). Results: A total of 215 patients (Cohort 1) were admitted to hospital with a confirmed COVID-19 infection between February 28 and April 30, 2020, and 17 died (7.9%). A medical record of cancer was noted in 43 cases (20%), 6 of them required Intensive care unit ICU attention (14%), and 7 died (16%). There were thirty-six patients (83%) who tested IgG/IgM positive for SARS-CoV-2. Patients on immunosuppressive therapies presented a lower ratio of seroconversion (40% vs. 8%; p = 0.02). In Cohort 2, 166 patients were included in a symptoms-survey and tested for SARS-CoV-2. Any type of potential COVID-19-related symptom was referred up to 67.4% of patients (85.9% vs. 48.2% vs. 73.9%, for patients on chemotherapy, immunotherapy and targeted therapies respectively, p < 0.05). The seroprevalence ratio was 1.8% for the whole cohort with no significant di erences by patient or treatment characteristics. Conclusion: Patients with cancer present higher risks for hospital needs for COVID-19 infection. The lack of SARS-CoV-2 seroconversion may be a concern for patients on immunosuppressive therapies. Patients receiving systematic therapies relayed a high rate of potentially COVID-19-related symptoms, particularly those receiving chemotherapy. However, the seroconversion rate remains low and in the range of general population.

Los tumores de mama representan uno de los tumores más frecuentes en perros y gatos, no existiendo un tratamiento médico de elección en su presentación macroscópica o como terapia adyuvante tras la intervención quirúrgica. Por otro lado, y debido a las similitudes tanto clínicas como genéticas de estos tumores con los tumores mamarios en humanos, los hacen un modelo único de oncología comparada, permitiendo el desarrollo de nuevas estrategias antitumorales que permitan mejorar su tratamiento. En este trabajo se han realizado dos estudios prospectivos con fosfato de toceranib (Palladia®) como monoterapia en gatas con tumores mamarios o en combinación con carprofeno, en perras con carcinoma inflamatorio (CIC). Los objetivos planteados incluyeron evaluar la eficacia antitumoral y tolerabilidad de los tratamientos en ambas especies. En el caso de las perras con CIC, también se incluyó como objetivo la evaluación de la calidad de vida. El protocolo de fosfato de toceranib en gatas o en combinación con carprofeno en perras con carcinoma inflamatorio fue muy bien tolerado y los efectos adversos fueron generalmente leves resolviéndose con tratamiento de soporte. La administración de fosfato de toceranib en tumores mamarios felinos demostró eficacia biológica, con una tasa de respuesta del 35.2% siguiendo criterios RECIST y un beneficio clínico en el 64% de los casos. Los resultados del tratamiento en el caso de los tumores mamarios felinos son comparables con los descritos tras la utilización de quimioterapia tradicional y sugieren que este fármaco podría ser eficaz en enfermedad residual mínima después de un tratamiento quirúrgico, algo que se debería evaluar en estudios prospectivos. El tratamiento con fosfato de toceranib y carprofeno en perras con CIC no mostró eficacia biológica siguiendo criterios RECIST. No obstante, un 64% de los pacientes presentaron beneficio clínico a los dos meses de iniciar el protocolo entendiéndose como una mejoría en la calidad de vida y la no progresión de la enfermedad. La alta tasa de enfermedades estables comparado con otros estudios y la mejoría de la calidad de vida de las perras, convierte esta combinación en otra posibilidad terapéutica a considerar. Finalmente, en este estudio se evaluó de manera subjetiva y a través de un cuestionario dirigido a los propietarios los cambios en la calidad de vida del paciente a lo largo del tratamiento con fosfato de toceranib. Algunas de las categorías del cuestionario de calidad de vida donde los dueños en al menos una de las preguntas percibieron mejoría y que fueron estadísticamente significativas incluyeron: felicidad, estado mental, apetito y movilidad general. Este trabajo en su conjunto describe por primera vez el uso de fosfato de toceranib como nueva estrategia terapéutica para el tratamiento de tumores mamarios felinos y carcinomas inflamatorios caninos. / Mammary tumors represent one of the most frequent tumors in dogs and cats, lacking of a standardized medical treatment in its macroscopic presentation or in the adjuvant setting after surgery. The clinical and genetic similarities of these tumors with breast cancer in women make them a unique model of comparative oncology, allowing the development of new antitumor strategies, which could improve their treatment. This project includes two prospective studies with toceranib phosphate (Palladia®) as monotherapy in cats with mammary tumors, or in combination with carprofen in bitches with inflammatory mammary carcinoma (IMC). The objectives were to evaluate the antitumor efficacy and tolerability of the treatments in both species. In the case of bitches with IMC, quality of life assessment was also included as an objective. The toceranib phosphate protocol in cats or in combination with carprofen in bitches with inflammatory carcinoma was very well tolerated and adverse effects were generally mild and resolved with standard supportive care. The administration of toceranib phosphate in feline mammary tumors demonstrated biological efficacy, with a response rate of 35.2% following RECIST criteria and clinical benefit in 64% of the cases. These results are comparable with traditional chemotherapy response rates and also suggest that this drug may be effective in the microscopic disease setting after surgical treatment, which should be assessed in prospective studies. The combination of toceranib phosphate and carprofen in bitches with IMC did not show biological efficacy following RECIST criteria. However, 64% of the patients presented clinical benefit at two months after initiating the protocol, defined as an improvement in the quality of life and no progression of the disease. The high rate of stable diseases compared to other studies and the improvement of the quality of life of the bitches, makes this combination another option to consider in their treatment. Finally, in this study, subjective changes in quality of life were evaluated through a questionnaire filled by the owners in each visit. Some of the categories of the quality of life questionnaire where the owners perceived statistically significant improvement included: happiness, mental state, appetite and general mobility. This work as a whole describes for the first time the use of toceranib phosphate as a new therapeutic strategy for the treatment of feline mammary tumors and canine inflammatory carcinomas.

La quimioterapia antineoplásica es el tratamiento farmacológico del cáncer, y su objetivo es garantizar la máxima efectividad terapéutica con los mínimos efectos secundarios, de modo que se consiga aumentar la supervivencia del paciente conservando su seguridad y calidad de vida. Los fármacos con el espectro de actividad más amplio son las antraciclinas; hay pocos tipos de cánceres que no responden a dichos fármacos. La doxorubicina (DOX) y la daunorubicina (DAU) fueron las primeras antraciclinas que se desarrollaron en los años 601. Ambos fármacos tienen una estructura muy similar. A pesar de que hoy en día se conocen diferentes análogos de la DOX que poseen menor toxicidad aguda y en consecuencia causan menos cardiopatía a largo plazo, la DOX sigue siendo un pilar fundamental en el tratamiento del cáncer por tener mayor efecto antitumoral2. Por ello se ha desarrollado presentaciones que minimizan su toxicidad como la DOX liposomal (Myocet®) o la DOX liposomal pegilada (Caelyx®).