Assessment of hair loss and skin changes during treatment in Asian breast cancer patients: A prospective cohort study.

With the increasing number of young breast cancer (BC) patients worldwide, concerns about hair loss and skin change persist among BC survivors. This study aimed to evaluate the hair loss and skin changes in Asian BC patients and to compare them according to the treatment regimens. This study enrolled 322 patients scheduled to undergo BC surgery. Hair loss and skin changes were assessed at the following two time points: one day before surgery and 6 months after surgery. Patients who had received systemic anticancer treatment before surgery were assigned to the neoadjuvant treatment group, while patients who were scheduled to receive systemic anticancer treatment were assigned to the adjuvant treatment group. In the adjuvant treatment group, patients with taxane-based chemotherapy had significantly higher odds of increased hair loss, a higher melanin index, and an increased volume of wrinkles (p < 0.0001, p = 0.0110, and p = 0.0371, respectively). In the neoadjuvant treatment group, hair loss was reversed in most patients at 6 months after surgery. Clinicians should inform BC patients about the potential for hair loss and skin changes and provide supportive care to mitigate the effects on the patients' quality of life.

Drug-Drug interactions of docetaxel in patients with breast cancer based on insurance claims data.

Despite an increase in the use of targeted anticancer drugs and immunotherapy, cytotoxic anticancer drugs such as docetaxel continue to play a clinically important role. The aim of this study was to evaluate drug-drug interactions between docetaxel and coadministered medicines in patients with breast cancer a claims database. The Health Insurance Review and Assessment Service (HIRA) database (2017 to 2019) was used in this study. We evaluated the risk of neutropenia (defined using receipt of granulocyte colony-stimulating factor (G-CSF) prescriptions) under docetaxel administration or the coadministration of docetaxel and an interacting anticancer drug (predefined based on approval information obtained from the Korean Ministry of Food and Drug Safety and the Lexicomp electronic database). The propensity score matching method was applied to balance covariates in the case (patients with G-CSF prescriptions) and control (patients without G-CSF prescriptions) groups. We identified 947 female patients with breast cancer prescribed with docetaxel and excluded 321 patients based on inclusion criteria. Of the remaining 626 patients, 280 were assigned to the case group and 346 to the control group. Predefined drugs were coadministered to 71 (11.3%) patients during the 7-day period before and after the administration of docetaxel. Adjusted odds ratios (ORs) calculated using the logistic regression model applied to the propensity score matching showed no significant difference between the administration of docetaxel alone and docetaxel coadministration (adjusted OR, 2.010; 95% confidence interval, 0.906, 4.459). In conclusion, we suggest that coadministration of docetaxel and a predefined interacting drug are not associated with G-CSF prescription.

Comparative Assessment of Platinum Salts and Taxane Group Hypersensitivity Reactions, The Role of Skin Tests in Diagnosis?

PURPOSE: We aimed to investigate the role of skin tests (ST) in the diagnosis of hypersensitivity reactions (HSRs) with platinum salts (PS) and taxane (TX) groups drugs and their reliability in patient management. MATERIALS AND METHOD: Patients' data who developed immediate HSR with PS and TX were recorded and ST was performed. The gradual challenge was applied to all patients with ST negative and grade 1-2 with the suspect drug. RESULTS: In total, the data of 104 patients (74 with PS, 30 with TX) who developed HSR against PS and TX were shared. The gradual challenge was applied to 72 ST negative and grade 1-2 patients (46 PS group, 26 TX group). The gradual challenge was negative in 39 patients in the PS group and 23 patients in the Tx group. The negative predictive value (NPV) for PS was 83% and NPV for TX was 88%. We found significantly higher skin test positivity in patients with PS and TX and grade 3 HSR (p = 0.007, p = 0.001). A significant correlation was found between skin test positivity and early onset of symptoms (p = 0.001 for PS, p = 0.015 for TX). In terms of symptoms witnessed in HSR, we observed the itching, urticaria, hypotension, syncope, and abdominal pain symptoms significantly more in the group with a positive skin test (p < 0.024, p < 0.001, p < 0.001, p < 0.002, and p < 0.025, respectively). CONCLUSIONS: We found very high NPV values for PS and TX. We found that the gradual challenge applied to patients with negative skin tests is reliable if Grade 3 HSR is not observed and with this approach, unnecessary desensitization processes and/or drug alterations can be avoided.

Eficacia y seguridad de ixabepilona para el tratamiento de pacientes con cáncer de mama metastásico resistente a antraciclina, taxanos y capecitabina con estado funcional ECOG 0-1 / Efficacy and safety of ixabepilone for the treatment of patients with metastatic breast cancer resistant to anthracyclines, taxanes and capecitabine with ECOG performance status 0-1

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de ixabepilona, comparado con la mejor terapia de soporte, para el tratamiento de pacientes con cáncer de mama metastásico (CMM) resistente a antraciclinas, taxanos y capecitabina con estado funcional ECOG 0-1. El cáncer de mama es la neoplasia más frecuente en mujeres en todo el mundo. En Perú, el cáncer de mama es la tercera causa de muerte por cáncer, con una tasa de mortalidad estandarizada por edad de 9.1 muertes por cada 100,000 habitantes. El cáncer mama metastásico (CMM) es una condición incurable que ocurre cuando la enfermedad se ha diseminado más allá de la mama y los ganglios linfáticos ipsilaterales hacia otros órganos. Se estima que la tasa de sobrevida global (SG) en pacientes con CMM, hasta los 5 años, es de aproximadamente 27 % con una mediana de SG de dos a tres años. Sin embargo, la esperanza de vida es menor a 1 año en pacientes con CMM que ya han recibido tres líneas de quimioterápicos. Asimismo, el 62 % de las pacientes con CMM tienen afectación visceral (hígado, pulmón o pleura), lo que compromete el funcionamiento normal de los órganos y las pacientes pueden presentar crisis visceral. La quimioterapia, dentro de las terapias sistémicas, es la principal opción terapéutica para la mayoría de las pacientes con CMM. No obstante, en casos muy avanzados de la enfermedad (como el CMM) y/o en casos de resistencia a varias líneas de tratamiento, las opciones terapéuticas que se pueden ofrecer a estas pacientes son escasas. Actualmente, EsSalud dispone de agentes quimioterápicos como: antraciclinas (inhibidor de topoisomerasa II), taxanos (agente anti microtúbulo) y capecitabina (inhibidor de nucleósido metabólico) para el tratamiento de pacientes con CMM. No obstante, ciertos pacientes no responden favorablemente a estos tratamientos. Los especialistas sugieren que ixabepilona puede ser una alternativa de tratamiento para los pacientes con CMM resistente a otros agentes como: antraciclinas, taxanos y capecitabina. METODOLOGÍA: Se llevó a cabo una búsqueda de la literatura científica con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de ixabepilona en pacientes con CMM resistente a antraciclinas, taxanos y capecitabina con estado funcional ECOG 0-1. La búsqueda sistemática se realizó en las principales bases de datos PubMed, The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC); incluyendo el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC), la Scottish Intercollegiate Guidelines Network (SIGN), el Institute for Clinical and Economic Review (ICER), el Institut für Qualität und Wirtschaftlichkeit im Gesundheitswese (IQWiG), la Base Regional de Informes de evaluación de tecnologías en Salud de las Américas (BRISA), la Organización Mundial de la Salud (OMS), el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Además, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en oncología como National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) y American Society of Clinical Oncology (ASCO). Finalmente, se realizó una búsqueda manual en la página web de registro de EC de ClinicalTrials.gov del National Institutes of Health (https://clinicaltrials.gov/) para identificar EC en curso o de resultados que no hayan sido publicados aún. RESULTADOS: Se llevó a cabo una búsqueda de evidencia científica con respecto al uso de ixabepilona como tratamiento de pacientes con CMM resistente a antraciclinas, taxanos y capecitabina con estado funcional ECOG 0-1. CONCLUSIONES:  El presente dictamen tuvo como objetivo evaluar la mejor evidencia disponible hasta julio de 2021 sobre la eficacia y seguridad de ixabepilona como terapia para pacientes con CMM resistente a antraciclinas, taxanos y capecitabina con ECOG 0-1.  Luego de la búsqueda sistemática, se identificaron dos GPC elaboradas por la NCCN y por la ESO-ESMO y un ensayo clínico de fase II (NCT00080262). Sobre las GPC, la NCCN señala que la mayoría de pacientes serán candidatos a múltiples líneas de terapia sistémica en función de su estado funcional; sin embargo, no especifica el número de líneas tratamiento a brindar. Dentro estos tratamientos señalan algunos como preferentes (antraciclinas, taxanos, capecitabina, gemcitabina y vinorelbina) y a otros como no preferentes (otros quimioterápicos e ixabepilona). La NCCN y la ESO-ESMO recomiendan la terapia paliativa. La NCCN recomienda que se considere no continuar con la terapia sistémica citotóxica y ofrecer la terapia paliativa en paciente con CMM que ha recibido varias líneas de quimioterápicos. La ESO-ESMO recomienda la terapia paliativa en pacientes con CMM cuyo tratamiento activo (e.g. quimioterapia) ya no sea capaz de controlar la enfermedad metastásica y la toxicidad supere los beneficios. El ensayo clínico de fase II, sin grupo control, evaluó el efecto de ixabepilona en la SG y la seguridad en pacientes con CMM resistente a antraciclina, taxanos y capecitabina. Debido al sesgo de reporte de resultados y, principalmente, la falta de grupo control, no se puede establecer una relación causal entre los resultados observados y el tratamiento con ixabepilona. Por lo tanto, no se puede determinar la eficacia comparativa entre ixabepilona y la mejor terapia de soporte que consiste en continuar con el uso de quimioterápicos y brindar cuidado paliativo. La incidencia de EA de grado 4 (34 %), el 11 % de pacientes que descontinuaron el tratamiento y la una muerte asociada al uso de ixabepilona, reportados en el EC fase II, y que fueron el motivo por que cual la EMA no aprobó su uso, sugieren que el perfil de seguridad de ixabepilona no sería favorable. Las evaluaciones de ixabepilona por parte de la EMA y la DIGEMID, basados en el EC fase II, concluyeron que los riesgos de ixabepilona superan sus potenciales beneficios en el tratamiento de pacientes con CMM. Por lo tanto, para estas instituciones tampoco sería seguro el uso de ixabepilona en el subgrupo de pacientes con CMM resistente a antraciclinas, taxanos y capecitabina.  Por lo expuesto, el IETSI no aprueba el uso de ixabepilona para el tratamiento de paciente con cáncer de mama metastásico resistente a antraciclinas, taxanos y capecitabina con estado funcional ECOG 0-1.

Eficacia y seguridad de ixabepilona en el tratamiento médico oncológico del cáncer de mama triple negativo resistente a antraciclinas y taxanos / Efficacy and safety of ixabepilone in the medical oncological treatment of triple negative breast cancer resistant to anthracyclines and taxanes

INTRODUÇÃO: El cáncer de mama es una enfermedad con una alta incidencia y mortalidad a nivel mundial, latinoamericano y en Perú. Se describen cuatro subtipos de cáncer de mama según la expresión o no de cuatro marcadores (receptor de estrógeno, RE; receptor de progesterona, RP; HER2 y Ki67): Luminal, HER2 y triple negativo; representando este último un 21% de los casos según un estudio llevado a cabo en población institucional. - La ixabepilona es un antineoplásico perteneciente al grupo de las epotilonas que se encargan de estabilizar los microtúbulos causando una muerte celular por apoptosis. Es un medicamento que ha sido evaluado en estudios de fase II obteniendo resultados favorables en pacientes con cáncer de mama avanzando y además se han realizado estudios de fase III que avalan su uso en pacientes con cáncer de mama avanzado que han progresado a terapias con antraciclinas y taxanos. METODOLOGÍA: Se decidió realizar un informe de ETS que permita mostrar la eficacia y seguridad de la ixabepilona con capecitabina comparada con capecitabina sola para el tratamiento oncológico de pacientes con cáncer de mama triple negativo resistentes a antraciclinas y taxanos. Se encontró que una GPC internacional (NCCN) avala el uso de ixabepilona en pacientes con cáncer de mama avanzado y el documento institucional también menciona estudios que avalan su utilidad en estos pacientes; sin embargo, la guía de ESMO no menciona su uso lo cual se debe a que EMA no aprobó su incorporación en Europa y que disponen de otras alternativas como eribulina. Además, se encontraron 04 ETS o informes relacionados en los cuales se ha reportado evidencia sobre el uso de ixabepilona en pacientes con cáncer de mama avanzado. DISCUSIÓN: La discusión con el panel se llevó a cabo durante dos sesiones en las cuales se expuso la PICO, la estrategia de búsqueda, las evidencias con respecto a la guías de práctica clínica, informes de evaluación de tecnologías sanitarias y documentos relacionados. Además, los análisis comparativos de eficacia y seguridad así como los análisis de costos de los diferentes medicamentos disponibles para el tratamiento de cáncer de mama avanzado triple negativo. En la primera sesión se comentó que ixabepilona es un tratamiento que se ha estado usando a nivel institucional en monoterapia para el tratamiento de pacientes con cáncer de mama triple negativo localmente avanzado o metastasico que hayan recibido terapia previa incluyendo una antraciclina, un taxano y/o capecitabina. Los casos se aprueban a través de junta médica y se realiza una vigilancia periódica. A la fecha 18 pacientes han recibido el tratamiento. Además, un integrante del panel manifestó que está de acuerdo con la propuesta brindada por el informe de Instituto de Cáncer de Argentina que especifica "No se sugiere el uso rutinario de Ixabepilona como tratamiento en pacientes con CMM RH positivos HER2 negativos, ECOG 0-1 y enfermedad evaluable salvo en pacientes seleccionadas: resistentes a antraciclinas/taxanos sin neuropatía residual significativa, con enfermedad visceral sintomática. (Condicional, moderada)". Se comentó que se tiene conocimiento de los pacientes que están recibiendo el tratamiento y que es un grupo que presentan bajo riesgo de presentar neutropenia o neuropatía periférica. No ha habido reportes adversos serios hasta el momento a nivel institucional con respecto al uso de este medicamento. Se consultó si es que se disponía de otras terapias que puedan ser comparadas con ixabepilona con respecto a eficacia y seguridad de los pacientes con cáncer de mama triple negativo que progresan a antraciclinas y taxanos. Es necesario conocer que estudios existen y poder concluir si es que ixabepilona sería la mejor intervención farmacológica disponible para estos casos específicos de paciente o existiría alguna otra que esté disponible a nivel nacional y que pueda usarse. Durante segunda reunión se mencionó que a nivel internacional se tiene la disponibilidad del medicamento eribulina que ha reportado mejores resultados con respecto a otros tratamientos en el cáncer de mama avanzado triple negativo a nivel nacional pero no se cuenta con disponibilidad de este medicamento a nivel nacional además que los costos son muy elevados por ello se mencionó que es una necesidad que se continúe con la disponibilidad de este medicamento. Además, en base a lo reportado a nivel institucional se mencionó que es necesario ser más específico en la indicación y los pacientes a los cuales se les va a prescribir el medicamento. Además, ppdría considerarse que Ixabepilona asociado a Capecitabina podría ser utilizado en población mejor seleccionada: ECOG 0 ­ 1, expuestos a antraciclinas y taxanos, que no hayan sido expuesto a capecitabina, donde se haya descartado metástasis cerebral previa al inicio del tratamiento y en pacientes con sospecha de mutación BRCA ofrecerles terapia con sales de platino. Con respecto a la evidencia en supervivencia global, supervivencia libre de progresión, tasa de respuesta objetiva de otras intervenciones farmacológicas se encuentran valores similares a los reportados por ixabepilona. Con respecto al tratamiento brindado a los 11 pacientes a nivel institucional no se ha podido establecer beneficios: tres de 11 pacientes han fallecido, no se ha documentado algún tipo de respuesta parcial. Por otro lado, se mencionó que en base a lo reportado es difícil proponer continuar con la adquisición del medicamento ya que no ha demostrado superioridad en supervivencia global y que no se cuenta con estudios de evaluaciones económicas o análisis de impacto presupuestario que avalen contar con el medicamento además que el costo adicional que implica la prescripción del medicamento es elevado. Se mencionó que al actualmente el SIS no viene cubriendo todos los medicamentos no PNUME, por lo que solicita se considere un tratamiento alterno a Ixabepilona que si se encuentre disponible en la lista PNUME. CONCLUSIONES: En el Instituto Nacional de Enfermedades Neoplásicas (INEN) en base a la información del departamento de oncología médica se han proyectado de maneral anual un promedio de 18 a 35 casos de pacientes con cáncer de mama triple negativo resistentes a antraciclinas y taxanos. Se realizó una búsqueda sistemática y una búsqueda dirigida de la evidencia para evaluar la eficacia y seguridad del uso de ixabepilona con capecitabina comparado con capecitabina sola para el tratamiento médico oncológico de pacientes con cáncer de mama triple negativo resistente a antraciclinas y taxanos. Se incluyó 02 guías de práctica clínica internacionales y un documento técnico institucional, 05 evaluaciones de tecnologías sanitarias o informes relacionados y un estudio de análisis combinado de dos ensayos clínicos que analiza a ixabepilona en monodroga comparado con la combinación de ixabepilona con capecitabina. Adicionalmente, se han incluido 05 estudios de otras opciones terapéuticas disponibles para el tratamiento de cáncer de mama avanzado triple negativo. En las GPC; en una se menciona el uso de ixabepilona en el manejo de cáncer de mama avanzado, en otra GPC no se establece una recomendación pero si colocan otras opciones como capecitabina, gemcitabina, etc; y en el documento institucional se la menciona pero no se especifican recomendaciones dentro del grupo de cáncer de mama triple negativo resistente a antraciclinas y taxanos. n las 04 ETS. Se menciona que en los países donde está permitida su comercialización, su uso se permite para pacientes con características específicas siendo la ETS Argentina la que emite una recomendación débil en contra sobre su uso y reserva el uso de ixabepilona en pacientes con cáncer de mama avanzado con características específicas de manera excepcional. El estudio de Rugo que combina los datos reportados en 02 ensayos clínicos de fase III ha encontrado un aumento en la supervivencia libre de progresión en el grupo de ixabepilona más capecitabina y duplicación en la tasa de respuesta objetivo; sin embargo, no se encontró aumento en el desenlace crítico supervivencia global ni en calidad de vida, encontrándose también un aumento en la frecuencia de eventos adversos relacionados a toxicidad por la terapia combina, neutropenia y neuropatías periféricas. La calidad de evidencia global fue moderada. Con respecto a lo evidenciado por otros medicamentos en pacientes con cáncer de mama avanzado triple negativo resistentes a antraciclinas y/o taxanos no se ha encontrado alguno que logre impactar en supervivencia global, se reportan si otros desenlaces importantes con valores similares a los reportados por el medicamento ixabepilona. El medicamento está disponible a nivel nacional y ha sido aprobado tanto por FDA, y DIGEMID para su uso en pacientes con cáncer de mama metastásico. No está aprobado por EMA. Con respecto al costo, éste podría exceder en 30 mil nuevos soles comparado al resto de alternativas disponibles en la lista PNUME. Se estima que por cada paciente se requiere aproximadamente 8 UIT. Finalmente, el panel multidisciplinario debido a la evidencia mostrada y la experiencia institucional, no tiene como justificar la continuidad de la terapia brindando opinión en contra de la cobertura del medicamento Ixabepilona. Se elevará informe y acta a Comité Farmacoterapéutico sobre los acuerdos de reunión.

Cabazitaxel schedules in metastatic castration-resistant prostate cancer: a review.

Cabazitaxel (25 mg/m2 every 3 weeks) is the standard second-line chemotherapy for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel. It is associated with a risk of neutropenic complications, which may be a barrier to its use in daily clinical practice, particularly in frail elderly patients. Here the authors reviewed key studies conducted with cabazitaxel (TROPIC, PROSELICA, AFFINITY, CARD and the European compassionate use program) and pilot studies with adapted schedules. Based on this review, the use of prophylactic granulocyte colony-stimulating factor from cycle 1 appears crucial to maximize the benefit-risk ratio of cabazitaxel in metastatic castration-resistant prostate cancer. Preliminary data with alternative schedules look promising, especially for frail patients. Results of the ongoing Phase III CABASTY trial (ClinicalTrials.gov: NCT02961257) are awaited.

Incidence and Management of Diarrhea With Adjuvant Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

BACKGROUND: The APHINITY (BIG 4-11) study showed that pertuzumab significantly improved the rates of invasive disease-free survival among patients with human epidermal growth factor receptor 2 (HER2)-positive, operable breast cancer when added to adjuvant trastuzumab and chemotherapy. Because diarrhea was a common adverse event that could compromise treatment administration, we evaluated the incidence and management of diarrhea in the APHINITY study. PATIENTS AND METHODS: The APHINITY trial is a prospective, randomized, multicenter, multinational, double-blind, placebo-controlled trial. The eligible patients were randomly assigned to receive standard adjuvant chemotherapy and 1 year of trastuzumab combined with pertuzumab or placebo. The diarrhea incidence, severity (National Cancer Institute common terminology criteria for adverse events, version 4.0), onset, and management were analyzed. RESULTS: A total of 4805 patients were randomized. Diarrhea of any grade was the most common adverse event and occurred in 71% of patients in the pertuzumab arm versus 45% in the placebo arm. Diarrhea grade 3 to 4 was observed in 10% and 4% in the pertuzumab and placebo arms, respectively. The greatest incidence of diarrhea was reported during the concomitant administration of HER2-targeted therapy and taxane (61% vs. 34% of patients experienced an event with pertuzumab vs. placebo, respectively). A marked decrease was observed on chemotherapy cessation. Antidiarrheal agents were commonly used, and diarrhea rarely caused treatment dose modifications or discontinuation. CONCLUSION: Diarrhea was a common adverse event in the APHINITY study. Most episodes were low grade and were generally manageable with common antidiarrheal agents. The incidence of diarrhea was greater with the combination of a taxane and HER2-targeted treatment and decreased once chemotherapy was stopped.

Taxane-induced peripheral neuropathy: differences in patient report and objective assessment.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side-effect of neurotoxic cancer treatment impacting on long-term quality of life. Symptoms include numbness, tingling, and pain, affecting the distal extremities. However, patients often report symptoms discrepant from the expected symmetrical distribution and the degree of concurrence with objective assessment remains ill-defined. This study aimed to investigate severity and symmetry of neuropathy symptoms to enable comparison of objective measures and patient report. METHODS: Forty-five taxane-treated patients (F = 43, 66 ± 1.5 years, 19 months post-treatment) completed bilateral neuropathy assessments via clinical examination, sensory nerve conduction studies (NCS), and patient questionnaires. The laterality index (LI) was calculated as a ratio of smaller to larger side-to-side differences. RESULTS: Neuropathy was reported by 89% of the cohort. On clinical examination, 83% had ≥ 2 abnormalities, with 38-35% having upper or lower limb sensory amplitudes below normative range. Thirty-five percent indicated side-to-side symptom asymmetry; however, there was no significant asymmetry evident on clinical examination (LI Asym = .60 ± .10, Sym = .76 ± .05, NS) and no difference in side-to-side NCS (median LI:Asym = .69 ± .06, Sym = .81 ± .04, NS; Sural LI:Asym = .80 ± .04, Sym = .81 ± .04, NS). Accordingly, there was no statistical association between patient-reported and objective assessment of side-to-side asymmetry, suggesting discordance between patient experience and objective assessment. Similarly, discrepancies in symptom severity between hands and feet were reported by 32% of the cohort. However, patients reporting differences in symptom severity between the hands and feet were just as likely to present with comparable assessments as to demonstrate objective discrepancies. CONCLUSIONS: Discrepancies may exist between the patient experience of CIPN and objective assessments. Understanding these discrepancies may help to elucidate underlying mechanisms and better inform treatment strategies.

Concept domain validation and item generation for the Treatment-Induced Neuropathy Assessment Scale (TNAS).

PURPOSE: Treatment-induced peripheral neuropathy (TIPN) is a difficult problem experienced by patients with cancer that can interfere with their ability to receive optimal therapy. The Treatment-Induced Peripheral Neuropathy Scale (TNAS) is a patient-reported outcome (PRO) measure developed to assess TIPN symptom burden. However, PRO validation is an ongoing process. The aim of this qualitative study was to define the conceptual model, establish content domain validity, and refine items for the TNAS based on patient input. METHODS: Patients who received bortezomib, oxaliplatin, or platinum-taxane combination therapy reported their experience of TIPN in single qualitative audiotaped interviews. Themes of the TIPN experience were identified by descriptive analysis of the transcribed interviews. RESULTS: Three groups of 10 patients each who had received bortezomib, oxaliplatin, or platinum-taxane combination therapy, for a total of 30 patients, reported their experiences. Two themes reported by patients were TIPN sensations and functional interference. Five sensations (numbness, tingling, pain, heat or burning, and coldness) and five functional impacts (using hands, walking, maintaining balance or falling, wearing shoes, and sleeping) were reported by at least 20% of patients and were selected for inclusion in the TNAS v3.0 for additional psychometric testing. CONCLUSIONS: The assessment of TIPN must be convenient, reliable, and practical for patients, who are the most reliable source of information about symptoms. The TNAS, developed with direct patient input, provides an easily administered and conceptually valid method of patient report of TIPN burden for use in research and practice.

Acute myeloid leukemia and myelodysplastic syndrome after adjuvant chemotherapy: A population-based study among older breast cancer patients.

BACKGROUND: Chemotherapy for early breast cancer is associated with a small risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The aim of this study was to determine the risk of developing AML or MDS after modern adjuvant chemotherapy in older breast cancer patients and to further define the risk of individual chemotherapy regimens. METHODS: Patients diagnosed with stage I to III breast cancer from 2003 to 2009 were identified in the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare linked databases. The development of AML/MDS, chemotherapy use, and comorbidities were identified with International Classification of Diseases, Ninth Revision and Healthcare Common Procedure Coding System codes. Analyses included descriptive statistics, cumulative incidences, and Cox proportional hazards models to estimate the hazard of AML/MDS after adjustments for clinically relevant covariates. RESULTS: In all, 92,110 patients were included; after a median follow-up of 85 months, the overall rates per 1000 person-years were 0.65 for AML and 1.56 for MDS. Patients who received an anthracycline (A) or anthracycline and taxane (A+T) regimen were more likely to develop AML (hazard ratio [HR] for A, 1.70; 95% confidence interval [CI], 1.16-2.50; HR for A+T, 1.68; 95% CI, 1.22-2.30) or MDS (HR for A, 2.18; 95% CI, 1.70-2.80; HR for A+T, 1.62; 95% CI, 1.29-2.03) than patients who did not receive chemotherapy. Patients using docetaxel and cyclophosphamide (TC) were not at increased risk for AML or MDS. CONCLUSIONS: Adjuvant chemotherapy is associated with a small but significant increase in the risk of AML and MDS, especially with regimens that include A. Longer follow-up is needed to confirm that risk is not increased with the recently adopted TC regimen. Cancer 2018;124:899-906. © 2017 American Cancer Society.

Assessment of Antihistamines and Corticosteroids as Premedication in Rapid Drug Desensitization to Paclitaxel: Outcomes in 155 Procedures.

BACKGROUND: In early clinical trials, infusion reactions during the administration of taxanes were managed using systematic premedication with antihistamines and corticosteroids before standard infusions. Consequently, these premedications are also administered before rapid drug desensitization (RDD) with taxanes. However, their role in RDD has not been studied. OBJECTIVE: To assess the need for premedication with antihistamines and corticosteroids to prevent hypersensitivity reactions in RDD to paclitaxel. METHODS: Over a 4-year period, we selected patients with confirmed hypersensitivity to paclitaxel (positive skin testing and/or drug provocation testing results) who had received paclitaxel through RDD. These patients were assigned to 2 prospective noninception cohorts: one cohort premedicated with antihistamine and corticosteroids and another cohort that was not. RESULTS: We assessed 66 paclitaxel-reactive patients, of whom 22 met the inclusion criteria. A total of 155 RDDs to paclitaxel were performed. There were no significant differences in tolerance to RDD between the cohorts. CONCLUSIONS: Administering systematic premedication with corticosteroids and antihistamines had no significant effect on the effectiveness or safety of RDD in patients with confirmed hypersensitivity to paclitaxel in the study population. Moreover, these premedications can mask early signs of hypersensitivity and delay treatment. We believe that systematic premedication with these drugs for patients undergoing RDD should be carefully and individually assessed if their only purpose is to prevent breakthrough reactions during RDD.

Docetaxel in hormone-sensitive advanced prostate cancer; GENESIS-SEFH evaluation reporta.

Prostate cancer (PC) is the most common urogenital malignancy in older men and the second leading cause of death by cancer in men in Europe. Current therapeutic practice considers Androgen Deprivation Therapy (ADT) as first line treatment for clinically localized prostate cancer at high-risk, either locally advanced or metastatic. ADT can be achieved through orchiectomy (surgical castration), luteinizing hormone-releasing hormone (LHRH) agonists, or through complete androgen blockade (LHRH agonist combined with an anti-androgen). Docetaxel in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone-refractory metastatic prostate cancer. The CHAARTED and STAMPEDE clinical trials studied the effect of bringing forward the use of docetaxel added on to ADT in the context of hormone-sensitive patients. The CHAARTED clinical trial showed a significant increase in a variable with maximum relevance such as Overall Survival (OS), with a difference of 13.6 months between medians. There was also clinical benefit in the secondary variables: median time until castration-resistant disease or until clinical progression. In the STAMPEDE clinical trial, which included 39% of non-metastatic patients, a 10-month difference between medians was demonstrated in OS, and 17 months in the primary co-variable of Progression Free Survival. The most frequent adverse events were: neutropenia, febrile neutropenia, leucopenia, and general disorders such as asthenia, lethargy or fever. According to data from the CHAARTED and STAMPEDE studies, and the incremental cost of € 3 196.98 for adding on docetaxel to standard treatment, the estimated additional cost for each year of life gained is compatible with an incremental cost-effectiveness ratio between € 2 267.36 and € 3 851.78. In view of the efficacy and safety results, the proposed positioning is: to advance the use of docetaxel added to androgen deprivation therapy to first-line metastatic hormone-sensitive prostate cancer, regardless of metastatic volume, in those patients who meet the CHAARTED study criteria.

El cáncer de próstata (CP) es el tumor maligno urogenital más frecuente en hombres de edad avanzada y la segunda causa de muerte por cáncer en hombres en Europa. La práctica terapéutica actual considera como primera línea la terapia de privación de andrógenos (ADT; androgen deprivation therapy) en el cáncer de próstata clínicamente localizado de alto riesgo, localmente avanzado o metástasico. La ADT se realiza mediante orquiectomía (castración quirúrgica), agonistas de la hormona liberadora de hormona luteinizante (LHRH), o bien mediante el bloqueo androgénico completo (agonista LHRH más antiandrógeno). El docetaxel en combinación con prednisona o prednisolona está indicado para el tratamiento de pacientes con cáncer de próstata hormono-refractariometastásico. Los ensayos clínicos CHAARTED y STAMPEDE analizaron el efecto de adelantar el uso de docetaxel añadido a la ADT en el contexto del paciente hormonosensible. En el ensayo CHAARTED se demostró un aumento significativo en la variable de máxima relevancia como es la supervivencia global (SG), con una diferencia de medianas de 13,6 meses. También se obtuvo beneficio clínico en las variables secundarias mediana de tiempo hasta enfermedad resistente a la castración o hasta progresión clínica. En el ensayo STAMPEDE, en el que se incluyeron un 39% de pacientes no metastásicos, se demostró una diferencia de medianas de 10 meses en la SG y de 17 meses en la covariable principal de supervivencia libre de progresión. Los eventos adversos más frecuentes fueron: neutropenia, neutropenia febril, leucopenia y alteraciones generales tales como astenia, letargia o fiebre. Según los datos del estudio CHAARTED y STAMPEDE y el coste incremental de 3.196,98 € de añadir docetaxel a la terapia de referencia, por cada año de vida ganado el coste adicional estimado es compatible con un coste/eficacia incremental (CEI) entre 2.267,36 € y 3.851,78 €. A la vista de los importantes resultados de eficacia y el perfil manejable de seguridad, el posicionamiento propuesto es adelantar el uso de docetaxel añadido a la ADT a la primera línea del cáncer de próstata metastásico hormonosensible, en aquellos pacientes que cumplan los criterios básicos del estudio CHAARTED.

Clinical Assessment of Sarcopenia and Changes in Body Composition During Neoadjuvant Chemotherapy for Esophageal Cancer.

AIM: The aim of this study was to assess changes in body composition during neoadjuvant chemotherapy (NAC) and investigate whether chemotherapy-related toxicities affect body composition in patients with esophageal cancer. PATIENTS AND METHODS: In ninety-four patients who underwent NAC for esophageal cancer, body composition was assessed before and after NAC. Associations between the incidence of toxicities and change in body composition during NAC were investigated. RESULTS: Forty-four (46.8%) and 50 (53.2%) out of 94 patients were defined as having sarcopenia before and after NAC, respectively. There was no significant difference in the incidence of any toxicity pre-treatment between patients with sarcopenia and those without sarcopenia. No significant reduction in skeletal muscle mass or fat mass was observed in the patients during NAC (p=0.501 and p=0.072). However, patients who experienced grade 4 neutropenia or febrile neutropenia during NAC showed a significantly larger decrease in change of skeletal muscle mass compared to patients who did not experience those toxicities (p=0.013 and 0.036, respectively). CONCLUSION: The incidence of serious adverse events such as febrile neutropenia and grade 4 neutropenia is associated with a significant reduction of skeletal muscle mass during NAC. We should make an effort to reduce the incidence of adverse events in order to maintain an appropriate body composition during NAC.

Budgetary Impact of Cabazitaxel Use After Docetaxel Treatment for Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: With the approval of several new treatments for metastatic castration-resistant prostate cancer (mCRPC), budgetary impact is a concern for health plan decision makers. Budget impact models (BIMs) are becoming a requirement in many countries as part of formulary approval or reimbursement decisions. Cabazitaxel is a second-generation taxane developed to overcome resistance to docetaxel and is approved for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen. OBJECTIVE: To estimate a 1-year projected budget impact of varying utilization rates of cabazitaxel as a second-line treatment for mCRPC following docetaxel, using a hypothetical U.S. private managed care plan with 1 million members. METHODS: A BIM was developed to evaluate costs for currently available treatment options for patients with mCRPC previously treated with docetaxel. Treatments included in the model were cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, with utilization rates derived from market research data. Medication costs were calculated according to published pricing benchmarks factored by dosing and duration of therapy as stated in the prescribing information for each agent. Published rates and costs of grade 3-4 adverse events were also factored into the model. In addition, the model reports budget impact under 2 scenarios. In the first base-case scenario, patient out-of-pocket costs were subtracted from the total cost of treatment. In the second scenario, all treatment costs were assumed to be paid by the plan. RESULTS: In a hypothetical 1 million-member health plan population, 100 patients were estimated to receive second-line treatment for mCRPC after treatment with docetaxel. Using current utilization rates for the 4 agents of interest, the base-case scenario estimated the cost of second-line treatment after docetaxel to be $6,331,704, or $0.528 per member per month (PMPM). In a scenario where cabazitaxel use increases from the base-rate case of 24% to a hypothetical rate of 33%, the PMPM cost would decrease to $0.524, reflecting a cost saving of $0.004 PMPM and equating to incremental savings of $49,546, or $497 per patient per year (PPPY). In the second scenario, when out-of-pocket costs were not considered, the cost of second-line treatment after docetaxel was estimated as $6,733,594, or $0.561 PMPM. With a hypothetical increase in cabazitaxel use (24%-33%), the PMPM cost would decrease to $0.554, reflecting savings of $0.007 PMPM and equating to incremental savings of $86,136, or $864 PPPY. The primary driver of cost savings with increased cabazitaxel use was lower acquisition cost. One-way sensitivity analyses revealed that the model results were robust over a wide range of input values (utilization, prevalence, and population parameters). CONCLUSIONS: In the presented BIM, an increase in cabazitaxel use is expected to result in modest cost savings to the health plan. Patient coinsurance savings may also be realized based on applicable Medicare Part B and Part D calculations. This BIM presents an objective, comprehensive, robust, and user-adaptable tool that health plans and medical decision makers may use to evaluate potential economic impact of formulary and reimbursement decisions. DISCLOSURES: Research and analysis were funded by Sanofi US. The sponsor had the opportunity to review the final draft; however, the authors were responsible for all content and editorial decisions. Flannery, Drea, Hudspeth, and Miao are employees of Sanofi. Miao is an owner of stock in Sanofi. Corman, Gao, and Xue are employees of Pharmerit International and served as consultants to Sanofi during this study. All authors contributed to study design and data collection and analysis. The manuscript was written by Flannery, along with the other authors, and revised by all the authors.

Assessment of a prognostic model, PSA metrics and toxicities in metastatic castrate resistant prostate cancer using data from Project Data Sphere (PDS).

BACKGROUND: Prognostic models in metastatic castrate resistant prostate cancer (mCRPC) may have clinical utility. Using data from PDS, we aimed to 1) validate a contemporary prognostic model (Templeton et al., 2014) 2) evaluate prognostic impact of concomitant medications and PSA decrease 3) evaluate factors associated with docetaxel toxicity. METHODS: We accessed data on 2,449 mCRPC patients in PDS. The existing model was validated with a continuous risk score, time-dependent receiver operating characteristic (ROC) curves, and corresponding time-dependent Area under the Curve (tAUC). The prognostic effects of concomitant medications and PSA response were assessed by Cox proportional hazards models. One year tAUC was calculated for multivariable prognostic model optimized to our data. Conditional logistic regression models were used to assess associations with grade 3/4 adverse events (G3/4 AE) at baseline and after cycle 1 of treatment. RESULTS: Despite limitations of the PDS data set, the existing model was validated; one year AUC, was 0.68 (95% CI 95% CI, .66 to .71) to 0.78 (95%CI, .74 to .81) depending on the subset of datasets used. A new model was constructed with an AUC of .74 (.72 to .77). Concomitant medications low molecular weight heparin and warfarin were associated with poorer survival, Metformin and Cox2 inhibitors were associated with better outcome. PSA response was associated with survival, the effect of which was greatest early in follow-up. Age was associated with baseline risk of G3/4 AE. The odds of experiencing G3/4 AE later on in treatment were significantly greater for subjects who experienced a G3/4 AE in their first cycle (OR 3.53, 95% CI 2.53-4.91, p < .0001). CONCLUSION: Despite heterogeneous data collection protocols, PDS provides access to large datasets for novel outcomes analysis. In this paper, we demonstrate its utility for validating existing models and novel model generation including the utility of concomitant medications in outcome analyses, as well as the effect of PSA response on survival and toxicity prediction.

Population pharmacokinetic-pharmacodynamic modeling and model-based prediction of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer.

PURPOSE: Docetaxel is used to treat many cancers, and neutropenia is the dose-limiting factor for its clinical use. A population pharmacokinetic-pharmacodynamic (PK-PD) model was introduced to predict the development of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer (NSCLC). METHODS: Forty-seven advanced or recurrent Japanese patients with NSCLC were enrolled. Patients received 50 or 60 mg/m2 docetaxel as monotherapy, and blood samples for a PK analysis were collected up to 24 h after its infusion. Laboratory tests including absolute neutrophil count data and demographic information were used in population PK-PD modeling. The model was built by NONMEM 7.2 with a first-order conditional estimation using an interaction method. Based on the final model, a Monte Carlo simulation was performed to assess the impact of covariates on and the predictability of neutropenia. RESULTS: A three-compartment model was employed to describe PK data, and the PK model adequately described the docetaxel concentrations observed. Serum albumin (ALB) was detected as a covariate of clearance (CL): CL (L/h) = 32.5 × (ALB/3.6)0.965 × (WGHT/70)3/4. In population PK-PD modeling, a modified semi-mechanistic myelosuppression model was applied, and characterization of the time course of neutrophil counts was adequate. The covariate selection indicated that α1-acid glycoprotein (AAG) was a predictor of neutropenia. The model-based simulation also showed that ALB and AAG negatively correlated with the development of neutropenia and that the time course of neutrophil counts was predictable. CONCLUSION: The developed model may facilitate the prediction and care of docetaxel-induced neutropenia.

Risk of Neutropenia-Related Hospitalization in Patients Who Received Colony-Stimulating Factors With Chemotherapy for Breast Cancer.

Purpose To describe outcomes after granulocyte colony-stimulating factor (G-CSF) prophylaxis in patients with breast cancer who received chemotherapy regimens with low-to-intermediate risk of induction of neutropenia-related hospitalization. Patients and Methods We identified 8,745 patients age ≥ 18 years from a medical and pharmacy claims database for 14 commercial US health plans. This retrospective analysis included patients with breast cancer who began first-cycle chemotherapy from 2008 to 2013 using docetaxel and cyclophosphamide (TC); docetaxel, carboplatin, and trastuzumab (TCH); or doxorubicin and cyclophosphamide (conventional-dose AC) regimens. Primary prophylaxis (PP) was defined as G-CSF administration within 5 days of beginning chemotherapy. Outcome was neutropenia, fever, or infection-related hospitalization within 21 days of initiating chemotherapy. Multivariable regressions and number-needed-to-treat analyses were used. Results A total of 4,815 patients received TC (2,849 PP; 1,966 no PP); 2,292 patients received TCH (1,444 PP; 848 no PP); and 1,638 patients received AC (857 PP; 781 no PP) regimen. PP was associated with reduced risk of neutropenia-related hospitalization for TC (2.0% PP; 7.1% no PP; adjusted odds ratio [AOR], 0.29; 95% CI, 0.22 to 0.39) and TCH (1.3% PP; 7.1% no PP; AOR, 0.19; 95% CI, 0.12 to 0.30), but not AC (4.7% PP; 3.8% no PP; AOR, 1.21; 95% CI, 0.75 to 1.93) regimens. For the TC regimen, 20 patients (95% CI, 16 to 26) would have to be treated for 21 days to avoid one neutropenia-related hospitalization; with the TCH regimen, 18 patients (95% CI, 13 to 25) would have to be treated. Conclusion Primary G-CSF prophylaxis was associated with low-to-modest benefit in lowering neutropenia-related hospitalization in patients with breast cancer who received TC and TCH regimens. Further evaluation is needed to better understand which patients benefit most from G-CSF prophylaxis in this setting.

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials.

BACKGROUND: Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. METHODS: We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. RESULTS: A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. CONCLUSION: We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist.

Taxanes in the treatment of breast cancer: Have we better defined their role in older patients? A position paper from a SIOG Task Force.

Along with anthracyclines, taxanes are the most active cytotoxics in breast cancer (BC). Balancing efficacy against toxicity in older patients with reduced physiological reserves and significant comorbidities is both important and difficult. This is especially so given the under-representation of elderly patients in major trials and a consequent lack of evidence for drug, dose and schedule. However, BC is frequent in elderly women, who are a growing proportion of the population. Careful consideration of their care is therefore imperative. Treatment that can cure or extend the duration and quality of life should not be restricted by age, but needs to be tailored to the circumstances of elderly patients. In adjuvant use, taxane toxicity in older women is greater than in their younger counterparts, limiting its sequential combination with anthracyclines for high-risk disease unless patients are in very good health. More frequently taxanes are used alone (weekly paclitaxel, three-weekly docetaxel) or combined with cytotoxics other than anthracyclines (e.g. docetaxel plus cyclophosphamide) to reduce cardiac risk, especially in HER-2-positive patients who may develop additional trastuzumab-related cardiac events. In elderly patients with metastases, weekly paclitaxel and three-weekly docetaxel are among the cornerstones of treatment, with generally acceptable toxicity. Three-weekly docetaxel at the approved dose of 100mg/m(2) is not appropriate for the elderly. Nab-paclitaxel has efficacy comparable with solvent-based taxanes without need for steroid premedication but has been little studied in older BC patients. A head-to-head comparison with weekly paclitaxel favoured the solvent-free formulation for pathologic response, but those studied were a general adult population. Compared with early stage disease, choice of taxane and regimen in the metastatic setting relies even more on availability and preferences with regard to schedule, toxicity profile and cost, especially for recently developed formulations.