Medication guide for dose adjustment and management of cardiotoxicity and lipid metabolic adverse events of oral antineoplastic therapy.

Objective: The management of cardiotoxicity concerning the use of oral antineoplastic agents (OAAs) is a challenge for healthcare professionals. Our objective was to create a comprehensive medication management guide with dose adjustment recommendations on OAAs concerning cardiotoxic and lipid metabolic adverse events (AEs) to assist healthcare professionals when prescribing OAAs. Materials and methods: A review of the available information on all dose adjustments necessary to safely prescribe and dispense OAAs concerning cardiotoxicity was conducted. In January 2023, we identified all OAAs authorized by the European Medicines Agency (EMA). For each drug, the latest summary of product characteristics (SPC) approved by the EMA and the tertiary data source Lexicomp® were reviewed. Cardiotoxic AEs were recorded, namely, QT interval prolongation, decrease in left ventricular ejection fraction (LVEF), imbalances in blood pressure (hypertension and hypotension), alterations in heart rate (tachycardia and bradycardia), and thrombosis. Any available dose adjustment recommendations in case of an occurrence of these adverse events were collected. Results: In all, 93 different OAAs had been approved by the EMA and were reviewed. Among them, 51.6% have recognized cardiotoxic AEs and 10.8% can cause alterations in lipid metabolism. A total of 27 (29.0%) OAAs had specific recommendations regarding QT prolongation; 88.9% were listed in the SPC and 59.3% in Lexicomp®. Eight OAAs (9.68%) have reported a decrease in LVEF, and four of these drugs, namely, encorafenib, lorlatinib, ripretinib, and sunitinib, have specific management recommendations. Almost half (49.5%) of currently approved OAAs can potentially alter blood pressure; 34 (36.6%) of them have been reported to cause hypertension and 12 (12.9%) are related to hypotension. Tachycardia and/or bradycardia are associated with 22.6% and 8.6% of the evaluated drugs, respectively. Regarding thrombosis, 30 (32.3%) of the drugs analyzed included the appearance of a thrombus as a possible AE. Conclusions: More than half of the OAAs can produce cardiotoxic effects, with the most frequent being blood pressure alteration and QT interval prolongation with a non-depreciable incidence of LV dysfunction or thrombosis. Before starting the treatment, it is necessary to stratify baseline cardiovascular risk, plan a surveillance schedule, and consider referral to cardio-oncology units.

Complementary and alternative medicine in cancer patients: characteristics of use and interactions with antineoplastic agents.

PURPOSE: Our objectives were to analyze the use of complementary and alternative medicine (CAM) in cancer patients and to describe the incidence and characteristics of interactions between CAM and antineoplastic agents. METHODS: We performed an observational study in cancer outpatients at a university hospital. Variables were collected through a 22-item questionnaire. Potential interactions between CAM and antineoplastic agents were analyzed using the Lexicomp®, the About Herbs®, and the summary of product characteristics. Mechanism of action, reliability, and the potential clinical effect of interactions were analyzed. RESULTS: The study population comprised 937 patients, of whom 65% used CAM (70.6% herbal products, 25.8% dietary supplements, and 3.6% homeopathy). Female sex, younger age, and breast cancer were associated with more frequent use of CAM. The primary source of information about CAM was friends and family (43.5%). A total of 335 (57.1%) patients did not tell their doctor that they took CAM. The five most common CAM were chamomile, green tea, pennyroyal mint, linden, and rooibos. At least one interaction between CAM and antineoplastic agents was reported by 65.0% of CAM users (33.9% of all patients). Depending on the mechanism of action, 80% of CAM diminished the metabolism of the antineoplastic agents. CONCLUSION: Our results reveal a high incidence of interactions between CAM and antineoplastic agents. The most frequent CAM were herbal products. Family and friends were the primary sources of information that led patients to start taking CAM, and more than half of the patients did not tell their doctor that they were taking CAM.

A smartphone app to improve the safety of patients undergoing treatment with oral antineoplastic agents: 4 years of experience in a university hospital.

Objective: This study aims to analyze the impact of the eOncosalud app on the management and follow-up of adverse effects (AE) in patients receiving oral antineoplastic agents. Material and methods: We performed an observational, prospective study of cancer outpatients treated with oral antineoplastic agents (OAA), monitored by the eOncosalud app between August 2017 and October 2021. Safety variables were collected from eOncosalud: the number of AE; severity of the AE according to CTCAE, version 4.03; timelapse from app installation to first recorded AE; automatic recommendations issued; and the patient's acceptance of the recommendations made. To assess the impact of the recommendations generated by the algorithm, we calculated the positive predictive value (PPV) as the number of recommendations accepted out of the total number of recommendations generated. Safety-related patient messages were also analyzed (AE, drug-drug interactions, drug administration). Result: The app was downloaded and used by 186 patients (58.0% women), with a mean age of 59.0 years. A total of 1,368 AE were recorded, the most frequent being fatigue (19.37%), diarrhea (18.20%), and skin changes (9.21%). Regarding the recommendations issued by the app algorithm, 102 patients received 344 information brochures, 39 patients received 51 recommendations for supportive care to control AE, 60 patients received 240 recommendations to visit their primary care doctor, 14 patients received 16 recommendations to contact their specialist pharmacist or oncologist-hematologist, and 34 patients received 73 recommendations to go to the emergency room. The suggestion to go to the emergency room and contact the specialist pharmacist or oncologist-hematologist had a PPV of 0.51 and 0.35, respectively. Half of the patients (50.4%) used the messaging module. A total of 1,668 messages were sent. Of these, 47.8% were related to treatment safety: AE, 22.7%; drug-drug interactions, 20.6%; drug administration, 3.6%; and missing a dose, 1.0%. Conclusions: The eOncosalud app enables close, real-time monitoring of patients treated with OAA. The automatic recommendations through the app's algorithm have optimized available healthcare resources. The app facilitated early detection of AE, thus enabling patients themselves to improve the safety of their treatment.

A New Methodology to Estimate Drug Cost Avoidance in Clinical Trials: Development and Application.

Background: Oncology clinical trials can lead to relevant financial savings in drug acquisition for healthcare providers. Considerable methodological heterogeneity is observed among previous studies estimating these savings. Methods: We developed a methodology to estimate the economic benefit obtained from the enrollment of patients into clinical trials through the analysis of drug cost avoidance. We designed a decision algorithm to determine if a clinical trial is associated with drug cost avoidance. This algorithm is based on five scenarios according to the availability or not of standard treatment, the presence or absence of a control arm (placebo or active treatment), and the provider of the medication. We considered as reference the cost of the standard treatment that the patient would have received in routine clinical practice. We standardized drug doses and treatment durations according to the literature. Costs were considered from a National Health System perspective. We applied this methodology at a single, research-active University Hospital in 2019. A cost avoidance analysis per trial and patient was carried out on cancer patients. Results: We analyzed 140 trials in which 198 patients were recruited. Drug cost avoidance was found in 120 trials (85.7%). The estimated total drug cost avoidance amounted to over €3,200,000. Melanoma and genitourinary tumors were the tumor types associated with the highest cost avoidance. The average drug cost avoidance per patient was €16,245. Conclusion: We describe a standardized method to estimate drug cost avoidance in clinical trials. We have applied it to all ongoing oncology clinical trials in our center. This methodology could be valuable for other centers to analyze the potential saving of clinical trials.

Implementation of a hospital-at-home (HAH) unit for hematological patients during the COVID-19 pandemic: safety and feasibility.

BACKGROUND: "Hospital-at-home" (HAH) programs have been shown to optimize resource utilization, shorten hospitalization and prevent nosocomial infection. METHODS: We retrospectively analysed data regarding implementation of an HAH unit for caring patients with hematological malignancies in our center, during the COVID-19 pandemic. RESULTS: Between January and November 2020, 105 patients were treated in the HAH unit for a total of 204 episodes. Nine patients with multiple myeloma (MM) received autologous HSCT (auto-HSCT). Three patients with acute myeloid leukemia (AML) received consolidation therapy, 32 patients underwent clinical and analytical monitoring, 20 were transplant recipients early discharged (5 auto-HSCT and 15 allo-HSCT) and 2 had received CART cells therapy. Azacitidine, bortezomib and carfilzomib were administered at home to 54 patients with AML, myelodysplastic syndrome (MDS) or MM. A median of 17 (IQR 13-19) days of admission per patient and a total of 239 visits to the Hematology day-care hospital were avoided. Overall, 28 patients (14% of all episodes) needed admission to the hospital, 4 of them due to COVID-19. CONCLUSIONS: Implementation of a Hematology HAH unit was feasible and safe, and provided thorough advanced care to a high-risk population. Advanced care-at-home strategies can be crucial during times of COVID-19 to minimize treatment interruptions and reduce the risk of cross-infections.

Medication guide for the perioperative management of oral antineoplastic agents in cancer patients.

BACKGROUND: Oral antineoplastic agents (OAAs) are high-risk drugs that may increase the risk of bleeding, difficulty in wound healing, or produce alterations in coagulation and/or platelet aggregation. These aspects had to be highly considered throughout the entire perioperative process. Our aim was to create a comprehensive management medication guide based on reconciliation and dose adjustment recommendations for OAAs in patients undergoing a surgical intervention. RESEARCH DESIGN AND METHODS: We analyzed all OAAs approved by the EMA in November 2020. We assessed data related to dose adjustment, drug reconciliation, coagulation disturbances, or anticoagulant interactions from the FDA and EMA summary of product characteristics. RESULTS: We analyzed 67 OAAs. We identified that 51 (76.2%) OAAs can produce alteration in the platelet count, 12 (17.9%) affect the wound healing and recovery process, and 32 (47.8%) require control and monitoring in case of combination with anticoagulants. Only 13 (19.4%) OAAs, most of them antiangiogenics, have specific recommendations for temporary suspension before surgery. CONCLUSIONS: Most OAAs require perioperative monitoring. This review can serve as an easy (simple, effective) tool to help healthcare professionals involved in patient care to manage OAAs during the perioperative process.

Monitorización de las superficies de trabajo de medicamentos peligrosos en los Servicios de Farmacia. Documento de consenso. Guía de práctica farmacéutica de la Sociedad Española de Farmacia Hospitalaria (SEFH) / Monitoring contamination of hazardous drug compounding surfaces at hospital pharmacy departments. A consensus Statement. Practice guidelines of the Spanish Society of Hospital Pharmacists (SEFH)

Objetivo: Establecer unas recomendaciones, en base a la evidencia disponible, para la monitorización de la contaminación de superficies en las áreasde elaboración de medicamentos peligrosos de los Servicios de Farmacia.Método: A partir de una revisión bibliográfica en las bases de datosMedline y Embase desde enero de 2009 a julio de 2019, así como de laconsulta de documentos de estándares y recomendaciones de organizaciones sanitarias, un comité de expertos de la Sociedad Española de FarmaciaHospitalaria ha definido una serie de prácticas seguras sobre manipulaciónde medicamentos peligrosos y monitorización de superficies de trabajo. Lasdecisiones de recomendación se tomaron por consenso entre el grupo deexpertos teniendo en cuenta las recomendaciones encontradas, la situaciónen nuestro entorno y los costes asociados a la monitorización.Resultados: Se han definido 10 recomendaciones estructuradas enocho secciones. Se incluyen aspectos relacionados con los medicamentos a monitorizar; localizaciones a monitorizar; momento de la toma demuestras; determinación del riesgo y plan de muestreo; técnicas analíticas;umbrales de contaminación; plan de acción según los resultados del muestreo y descontaminación. (AU)

Objective: To establish a series of recommendations based on available evidence for monitoring surface contamination in the areas devoted tocompounding hazardous drugs in pharmacy departments.Method: Based on a literature search in the Medline and Embase databases (search period: January 2009 to July 2019), as well as on a reviewof standards and recommendations issued by different healthcare organizations, a committee of experts from the Spanish Society of Hospital Pharmacists defined a series of safe practices for handling hazardous drugsand monitoring compounding work surfaces. Recommendation decisionswere adopted by consensus among the members of the expert group,considering the recommendations reviewed, the monitoring situation inSpanish hospital departments, and the associated costs.Results: Ten recommendations were formulated, structured into eight sections. They include aspects related to the drugs to be monitored; the areasto be monitored; when samples should be taken; risk determination andpreparation of a sampling protocol; analytical techniques; contaminationthresholds; and design of an action plan based on the sampling anddecontamination results obtained. (AU)

Monitoring contamination of hazardous drug compounding surfaces at hospital pharmacy departments. A consensus Statement. Practice guidelines of the Spanish Society of Hospital Pharmacists (SEFH).

OBJECTIVE: To establish a series of recommendations based on available evidence for monitoring surface contamination in the areas devoted to compounding hazardous drugs in pharmacy departments. METHOD: Based on a literature search in the Medline and Embase databases (search period: January 2009 to July 2019), as well as on a review of standards and recommendations issued by different healthcare organizations, a committee of experts from the Spanish Society of Hospital Pharmacists defined a series of safe practices for handling hazardous drugs and monitoring compounding work surfaces. Recommendation decisions were adopted by consensus among the members of the expert group, considering the recommendations reviewed, the monitoring situation in Spanish hospital departments, and the associated costs. RESULTS: Ten recommendations were formulated, structured into eight sections. They include aspects related to the drugs to be monitored; the  areas to be monitored; when samples should be taken; risk determination and preparation of a sampling protocol; analytical techniques; contamination thresholds; and design of an action plan based on the sampling and decontamination results obtained. CONCLUSIONS: Surface monitoring allows hazardous drugs detection and evaluation of the effectiveness of current protocols for the safe handling of such drugs in hospital pharmacy departments. The evaluation should include an analysis of the efficacy of engineering controls, work practices and cleaning and decontamination processes.

Objetivo: Establecer unas recomendaciones, en base a la evidencia disponible, para la monitorización de la contaminación de superficies en las áreas de elaboración de medicamentos peligrosos de los Servicios de Farmacia.Método:A partir de una revisión bibliográfica en las bases de datos Medline y Embase desde enero de 2009 a julio de 2019, así como de la consulta de documentos de estándares y recomendaciones de organizaciones sanitarias, un comité de expertos de la Sociedad Española de Farmacia Hospitalaria ha definido una serie de prácticas seguras sobre manipulación de medicamentos peligrosos y monitorización de superficies de trabajo. Las decisiones de recomendación se tomaron por consenso entre el grupo de expertos teniendo en cuenta las recomendaciones encontradas, la situación en nuestro entorno y los costes asociados a la monitorización.Resultados: Se han definido 10 recomendaciones estructuradas en ocho secciones. Se incluyen aspectos relacionados con los medicamentos a  monitorizar; localizaciones a monitorizar; momento de la toma de muestras; determinación del riesgo y plan de muestreo; técnicas analíticas; umbrales de contaminación; plan de acción según los resultados del muestreo y descontaminación.Conclusiones: La monitorización de superficies permite determinar la presencia de medicamentos peligrosos y evaluar la eficacia del programa de manejo seguro de los mismos en los Servicios de Farmacia. La  evaluación debería incluir un estudio de la eficacia de los controles de  ingeniería, de las prácticas laborales y de los procesos de limpieza y descontaminación.

Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts.

Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.

Assessment of diarrhea as side effect of oral targeted antineoplastic agents in clinical practice.

BACKGROUND: Diarrhea is one of the most frequent class adverse events associated with targeted oral antineoplastic agents (OAAs). Our objective was to analyze the incidence, characteristics, and severity of diarrhea in cancer patients in clinical practice. METHODS: An observational, longitudinal, and prospective study of cancer outpatients treated with targeted OAAs was carried out in a tertiary hospital. Targed OAAs analyzed were anaplastic lymphoma kinase inhibitors, BCR-ABL inhibitors, cyclin-dependent kinase inhibitors, epidermal growth factor receptor inhibitors, mTOR inhibitors, poly (ADP-ribose) polymerase inhibitors, and vascular endothelial growth factor receptor inhibitors. Patients were given a data collection form to record daily the number, severity (CTCAE version 5.0), and characteristics of stools during the first 30 days of treatment with OAAs. Multivariate analysis was performed to identify risk factors associated with the incidence of diarrhea. RESULTS: We analyzed 240 patients, of whom 28.7% experienced diarrhea (25.4% grades 1-2 and 3.3% grades 3-4). Patients treated with EGFR and VEGFR inhibitors had a higher incidence of diarrhea. The multivariate analysis revealed that taking the OAA with food was associated with a lower risk of diarrhea (OR = 0.404 [0.205-0.956], p = 0.038). CONCLUSIONS: More than a third of patients in treatment with OAAs presented diarrhea (any grade), and 22.1% of stools were semi-liquid/liquid. In multivariate analysis, taking the OAA on an empty stomach was associated with a statistically significant increase in the incidence of diarrhea.

Error Detection and Cost Savings With an Image-Based Workflow Management System Connected to a Computerized Prescription Order Entry Program for Antineoplastic Compounding.

OBJECTIVE: The aim of the study was to analyze both the prevalence of errors with the implementation of an image-based workflow management system during the antineoplastic compounding process, and the estimated costs associated with the negative clinical outcome if the errors had not been intercepted. METHODS: Three months after the implementation of Phocus Rx system at a hospital pharmacy department, the identification, classification (type, preparation stage, and cause), and potential severity degree (from negligible to catastrophic) of the errors intercepted were determined. The probability of an error causing an adverse event if it had reached the patient (from nil [0] to high [0.6]) and its consequences was estimated by a team of clinical pharmacists and physicians. Cost-effectiveness analysis from the hospital's perspective was performed. RESULTS: Overall, 9872 antineoplastic medications were prepared using Phocus Rx. The total compounding error rate was 0.8% (n = 78, 56 [69.2%] were related to incorrect dose, 20 [28.2%] to incorrect drug preparation or conditioning technique, and 2 [2.6%] were wrong drugs). Approximately 70% of the detected errors were classified as undetectable via the previous verification practice, with 11.55% judged to be potentially severe (n = 9) and 51.3% moderate (n = 29). Likelihood of occurrence of an adverse event was medium (0.4) to high (0.6) for 37.2% of the errors. Estimated cost ratio and return on investment were €4.21 and 321%, respectively. CONCLUSIONS: The implementation of Phocus Rx prevented antineoplastic preparation errors that would have reached the patient otherwise. In addition, acquisition of this technology was estimated to be cost-effective.

Aggressiveness of end-of-life cancer care: what happens in clinical practice?

PURPOSE: End-of-life cancer care varies widely, and very few centers evaluate it systematically. Our objective was to assess indicators of the aggressiveness of end-of-life cancer care in clinical practice. METHODS: An observational, longitudinal, and retrospective cohort study was conducted at a tertiary hospital. Eligible patients were at least 18 years old, had a solid tumor, were followed up by the Oncology Department, and had died because of cancer or associated complications during 2017. We used the criteria of Earle et al. (J Clin Oncol 21(6):1133-1138, 2003) to assess the aggressiveness of care. Multivariate logistic regression analyses were performed to characterize factors associated with aggressiveness of therapy. RESULTS: The study population comprised 684 patients. Eighty-eight patients (12.9%) received anti-cancer treatment during the last 14 days of their lives, and 62 patients (9.1%) started a new treatment line in the last 30 days. During the last month of life, 102 patients (14.9%) visited the ER, 80 patients (11.7%) were hospitalized more than once, and 26 (3.8%) were admitted to the ICU. A total of 326 patients (47.7%) died in the acute care unit. A total of 417 patients (61.0%) were followed by the Palliative Care Unit, and in 54 cases (13.0%), this care started during the last 3 days of life. CONCLUSIONS: The use of anti-cancer therapies and health care services in our clinical practice, except for the ICU, did not meet the Earle criteria for high-quality care. Concerning hospice care, more than half of the patients received hospice services before death, although in some cases, this care started close to the time of death.

Evaluation of the use, effectiveness and safety of tyrosine kinase inhibitors in chronic myelogenous leukaemia in a general university hospital.

OBJECTIVES: To evaluate the use, effectiveness and safety of tyrosine kinase inhibitors (TKIs) for chronic myelogenous leukaemia (CML) in clinical practice. METHODS: A retrospective longitudinal study of patients with CML who received TKIs for at least 6 months was performed. Endpoints to evaluate effectiveness were haematological, cytogenetic and molecular responses. Safety was assessed according to the occurrence of adverse events. RESULTS: Sixty-two patients were included. All received imatinib as the initial TKI; 8% switched to nilotinib due to lack of major molecular response (MMR) to imatinib and 3% switched to dasatinib because of progression to blast crisis or lack of MMR. At the end of the study all patients had achieved at least a complete cytogenetic response. With regard to safety, in 11 patients the dose of imatinib was decreased and four patients switched to a second-generation TKI due to imatinib toxicity. CONCLUSIONS: Considering the good responses of most patients and its better known safety profile, imatinib should remain a good option for first-line treatment of CML.

Biomarcadores predictivos de respuesta a los inhibidores de los puntos de control inmunitario / Predictive biomarkers of response to immune checkpoint inhibitors

OBJETIVO: El objetivo del presente trabajo es identificar mediante revisión bibliográfica los factores dependientes del tumor que condicionan la respuesta a los inhibidores de los puntos de control inmunitario, incidiendo especialmente en aquellos que se postulan como posibles biomarcadores predictivos. MÉTODO: Búsquedas en Pubmed con los términos biomarkers, PD-1, PD-L1, CTLA-4, checkpoint inhibitors, en el título o el abstract, seleccionando aquellos que incluyeran información relevante sobre factores tumorales que condicionan la respuesta a los inhibidores de los puntos de control inmunitario. Se priorizaron estudios en humanos (ensayos clínicos y revisiones) publica-dos entre enero de 2015 y junio de 2019, en idiomas inglés y español. RESULTADOS: La revisión pone de manifiesto las complejas relaciones entre sistema inmunitario y tumor, con factores que influyen en la respuesta a los inhibidores de los puntos de control inmunitario variados, y aun poco conocidos, lo cual dificulta la obtención de biomarcadores predictivos sencillos y/o universales. CONCLUSIONES: Actualmente los únicos biomarcadores utilizados en práctica clínica, en algunos escenarios, son la expresión del ligando del receptor de muerte celular programada-1 y la inestabilidad de microsatélites/deficiencias en las enzimas de reparación de los apareamientos erróneos durante la replicación del ácido desoxirribonucleico, aunque su utilidad es limitada. La carga mutacional y las firmas génicas asociadas a interferón gamma se postulan como biomarcadores útiles, una vez sistematizadas las técnicas de determinación y los puntos de corte

OBJECTIVE: The present paper provides a literature review aimed at identifying the tumor-dependent factors capable of influencing a subject's response to immune checkpoint inhibitors, with a special emphasis on those that may act as predictive biomarkers. METHOD: A search was performed of the terms biomarkers, PD -1, P D - L1, CTLA-4, and checkpoint inhibitors in the title and the abstract of the re-cords in the PubMed database. Articles including relevant information on the tumor-dependent factors capable of influencing a subject's response of immune checkpoint inhibitors were selected. Priority was given to studies in humans (clinical trials and reviews) published between January 2015 and June 2019, in English and Spanish. RESULTS: The literature review exposed the complex relationship that exists between the immune system and tumors. It also revealed that the factors capable of influencing a subject's response to immune checkpoint inhibitors are multiple, heterogeneous and ill understood, which makes it difficult to obtain simple and/or universal predictive biomarkers. CONCLUSIONS: The only biomarkers currently used in clinical practice include the expression of the programmed cell death ligand-1 and micro-satellite instability/ deficient DNA mismatch repair, but their usefulness is limited. Tumor mutational burden and gene signatures associated to IFN-γ could become useful biomarkers once determination techniques and cutoff points are systematized

Predictive biomarkers of response to immune checkpoint inhibitors.

OBJECTIVE: The present paper provides a literature review aimed at  identifying the tumor-dependent factors capable of influencing a  subject's response to immune checkpoint inhibitors, with a special  emphasis on those that may act as predictive biomarkers. METHOD: A search was performed of the terms biomarkers, PD-1, PD- L1, CTLA-4, and checkpoint inhibitors in the title and the abstract of the  records in the PubMed database. Articles including relevant information  on the tumor-dependent factors capable of influencing a subject's  response of immune checkpoint inhibitors were selected. Priority was  given to studies in humans (clinical trials and reviews) published  between January 2015 and June 2019, in English and Spanish. Results: The literature review exposed the complex relationship that xists between the immune system and tumors. It also revealed that the factors capable of influencing a subject's response to immune  checkpoint inhibitors are multiple, heterogeneous and ill understood,  which makes it difficult to obtain simple and/or universal predictive  biomarkers. CONCLUSIONS: The only biomarkers currently used in clinical practice include the expression of the programmed cell death ligand-1  and microsatellite instability/ deficient DNA mismatch repair, but their  usefulness is limited. Tumor mutational burden and gene signatures  associated to IFN-γ could become useful biomarkers once determination techniques and cutoff points are systematized.

Objetivo: El objetivo del presente trabajo es identificar mediante  revisión bibliográfica los factores dependientes del tumor que  condicionan la respuesta a los inhibidores de los puntos de control  inmunitario, incidiendo especialmente en aquellos que se postulan como posibles biomarcadores predictivos.Método: Búsquedas en Pubmed con los términos biomarkers, PD-1,  PD­L1, CTLA-4, checkpoint inhibitors, en el título o el abstract,  seleccionando aquellos que incluyeran información relevante sobre  factores tumorales que condicionan la respuesta a los inhibidores de los  puntos de control inmunitario. Se priorizaron estudios en humanos  (ensayos clínicos y revisiones) publicados entre enero de 2015 y junio  de 2019, en idiomas inglés y español.Resultados: La revisión pone de manifiesto las complejas relaciones entre sistema inmunitario y tumor, con factores que influyen  en la respuesta a los inhibidores de los puntos de control inmunitario  variados, y aun poco conocidos, lo cual dificulta la obtención de  biomarcadores predictivos sencillos y/o universales.Conclusiones: Actualmente los únicos biomarcadores utilizados en práctica clínica, en algunos escenarios, son la expresión del ligando  del receptor de muerte celular programada-1 y la inestabilidad de  microsatélites/deficiencias en las enzimas de reparación de los  apareamientos erróneos durante la replicación del ácido  desoxirribonucleico, aunque su utilidad es limitada. La carga mutacional  y las firmas génicas asociadas a interferón gamma se postulan como  biomarcadores útiles, una vez sistematizadas las técnicas de  determinación y los puntos de corte.

Risks and medication errors analysis to evaluate the impact of a chemotherapy compounding workflow management system on cancer patients' safety.

A failure modes, effects and criticality analysis was supported by an observational medication error rate study to analyze the impact of Phocus Rx®, a new image-based workflow software system, on chemotherapy compounding error rates. Residual risks that should be a target for additional action were identified and prioritized and pharmacy staff satisfaction with the new system was evaluated. In total, 16 potential failure modes were recognized in the pre-implementation phase and 21 after Phocus Rx® implementation. The total reduction of the criticality index was 67 percent, with a reduction of 46 percent in material preparation, 76 percent in drug production and 48 percent in quality control subprocesses. The relative risk reduction of compounding error rate was 63 percent after the implementation of Phocus Rx®, from 0.045 to 0.017 percent. The high-priority recommendations defined were identification of the product with batch and expiration date from scanned bidimensional barcodes on drug vials and process improvements in image-based quality control. Overall satisfaction index was 8.30 (SD 1.06) for technicians and 8.56 (SD 1.42) for pharmacists (p = 0.655). The introduction of a new workflow management software system was an effective approach to increasing safety in the compounding procedures in the pharmacy department, according to the failure modes, effects and criticality analysis method.

The economic burden of disease of epithelial ovarian cancer in Spain: the OvarCost study.

OBJECTIVE: To assess the economic burden of epithelial ovarian cancer (EOC) in incident patients and the burden by disease stage in Spain. METHODS: We developed a Markov model from a social perspective simulating the natural history of EOC and its four stages, with a 10-year time horizon, 3-week cycles, 3% discount rate, and 2016 euros. Healthcare resource utilization and costs were estimated by disease stage. Direct healthcare costs (DHC) included early screening, genetic counselling, medical visits, diagnostic tests, surgery, chemotherapy, hospitalizations, emergency services, and palliative care. Direct non-healthcare costs (DNHC) included formal and informal care. Indirect costs (IC) included labour productivity losses due to temporary and permanent leaves, and premature death. Epidemiology data and resource use were taken from the literature and validated for Spain by the OvarCost group using a Delphi method. RESULTS: The total burden of EOC over 10 years was 3102 mill euros: 15.1% in stage I, 3.9% in stage II, 41.0% in stage III, and 40.2% in stage IV. Annual average cost/patient was €24,111 and it was €8,641; €14,184; €33,858, and €42,547 in stages I-IV, respectively. Of total costs, 71.2% were due to DHC, 24.7% to DNHC, and 4.1% to IC. CONCLUSIONS: EOC imposes a significant economic burden on the national healthcare system and society in Spain. Investment in better early diagnosis techniques might increase survival and patients' quality of life. This would likely reduce costs derived from late stages, consequently leading to a substantial reduction of the economic burden associated with EOC.

Cost-effectiveness analysis of ribociclib versus palbociclib in the first-line treatment of HR+/HER2- advanced or metastatic breast cancer in Spain.

PURPOSE: The aim of this study was to evaluate the cost-effectiveness of ribociclib compared to palbociclib, both in combination with letrozole, in the first-line treatment of postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC) from the perspective of the Spanish National Health System (NHS). PATIENTS AND METHODS: Disease progression was simulated with a partitioned survival model developed from the parameterization and extrapolation of survival curves of postmenopausal women with HR+/HER2- ABC from clinical trials with ribociclib or palbociclib, both in combination with letrozole. The model was structured on the basis of three health states (progression-free, progressed disease, and death), with a 1-month cycle length and inclusion of subsequent treatments administered for disease progression, over a time horizon of 15 years. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. The use of resources and clinical practice in the Spanish setting was validated by a panel of experts. The Spanish NHS perspective was adopted, taking into account exclusively direct health costs from 2017 expressed in Euros. Drug prices used were the reported ex-factory prices. Uncertainty of the parameters and robustness of the results were evaluated using deterministic and probabilistic sensitivity analyses (2,000 iterations). RESULTS: This cost-effectiveness analysis showed a greater benefit (0.437 and 0.285 life-years gained [LYGs] and quality-adjusted life years [QALYs] gained, respectively) and a slightly higher cost (€439.86) for ribociclib+letrozole compared to palbociclib+letrozole. The resulting incremental cost-effectiveness and cost-utility ratios were €1,007.69 per LYG and €1,543.62 per QALY gained, respectively. The results of the multiple sensitivity analyses showed limited dispersion of the outcomes, thus corroborating their robustness. CONCLUSION: From the NHS perspective, considering the most commonly established willingness-to-pay thresholds in the Spanish setting, ribociclib+letrozole would represent a cost-effective therapeutic option compared to palbociclib+letrozole in the first-line treatment of HR+/HER2- ABC in postmenopausal women.

Oncology Patient Interest in the Use of New Technologies to Manage Their Disease: Cross-Sectional Survey.

BACKGROUND: Information and communication technologies (ICTs) in oncology can revolutionize the medical care of cancer patients. ICTs can promote patients' empowerment and real-time disease monitoring. There is limited information about the impact of ICTs in cancer patients or their level of interest in using these tools for greater management of their condition. OBJECTIVE: This study aimed to understand the ICT usage profile in hematology-oncology patients to identify their needs and determine their level of interest in these technologies as a means of managing their disease. METHODS: A 28-item questionnaire was drawn up by a multidisciplinary team including pharmacists and oncologists. The questions were organized into 3 blocks, which were as follows: block A-sociodemographic characteristics; block B-use of ICTs when searching for health-related information; and block C-usage preferences for health apps. Hematology-oncology patients receiving treatment between May and July 2017 were included. A paper copy of the questionnaire was handed over to patients in either the day hospital or the pharmaceutical care consultancy in pharmacy services. RESULTS: A total of 650 questionnaires were handed out, with a participation of 94.0% (611/650). Patient sociodemographic characteristics were as follows: mean age was 57.8 years (age range: 19-91). Of 611 participants, 40.7% (249/611) had a university education, and 45.1% (276/611) of participants reported their overall state of health to be good. Results from use of ICTs when searching for health-related information were as follows: 87.1% (532/611) of participants were interested in being informed about health-related matters. Of all participants, 75.5% (532/611) sought information from health professionals and 61.3% (375/611) on the internet. Before going to their doctor's appointment, 21.8% (133/611) of patients looked up information about their disease or treatment on the internet. This access to the internet rose to 50.9% (311/611) after their first medical appointment with their oncologist. Usage preferences for health apps were as follows: 82.7% (505/611) had a smartphone, whereas 20.3% (124/611) had a health app installed. Overall, 81.5% (498/611) would use an app if their health professional recommended it to them, but 39.6% (242/611) were not willing to pay for it. CONCLUSIONS: The hematology-oncology patients showed a great deal of interest in searching for health-related information by means of ICTs, especially using smartphones and apps. The issues that drew the most interest in terms of apps were appointment management, advice on disease management, and communication with health professionals. Free access to these features and the recommendation by a health professional are important factors when it comes to their use. Therefore, the health care provider is a key element in the recommendation of ICTs, providing their knowledge and experience concerning their correct usage.

Severe toxicity to capecitabine due to a new variant at a donor splicing site in the dihydropyrimidine dehydrogenase (DPYD) gene.

Severe, life-threatening adverse reactions to capecitabine sometimes occur in the treatment of solid tumors. Screening for dihydropyrimidine dehydrogenase (DPYD) deficiency is encouraged before start of treatment, but the genetic variants that are commonly analyzed often fail to explain toxicities seen in clinical practice. Here we describe the case of a 79-year-old Caucasian female with breast cancer who presented with life-threatening, rapidly increasing toxicity after 1 week of treatment with capecitabine and for whom routine genetic DPYD test resulted negative. DPYD exon sequencing found variant c.2242+1G>T at the donor splicing site of exon 19. This variant is responsible for skipping of exon 19 and subsequent generation of a non-functional DPYD enzyme. This variant has not been described previously but was found in three other members of the patient's family. With this case, we show that exon sequencing of DPYD in patients who experience marked toxicity to fluoropyrimidines and test negative for commonly evaluated variants can prove extremely useful for identifying new genetic variants and better explain adverse reactions causality.