RESUMEN
BACKGROUND: Trabectedin has shown efficacy against soft tissue sarcomas (STS) and has manageable toxicity. Trabectedin is administered through central venous access devices (VAD), such as subcutaneous ports with tunneled catheters, Hickman catheters and PICC lines. Venous access related adverse events are common, but have not yet been reported in detail. METHODS: A retrospective analysis of patient files of STS patients receiving trabectedin monotherapy between 1999 and 2014 was performed in all five STS referral centers in the Netherlands. This survey focused on adverse events related to the VAD and the actions taken in response to these events. RESULTS: In the 127 patients included in this analysis, 102 venous access ports (VAP), 15 Hickman catheters and 10 PICC lines were used as primary means of central venous access. The most frequently reported adverse events at the VAD site were erythema (30.7%), pain (28.3%), inflammation (11.8%) and thrombosis (11.0%). Actions taken towards these adverse events include oral antibiotics (17.3%), VAD replacement (15.0%) or a wait-and-see policy (13.4%). In total, 45 patients (35.4%) with a subcutaneous port developed a varying degree of inflammation along the trajectory of the tunneled catheter. In all but three patients, this was a sterile inflammation, which was considered a unique phenomenon for trabectedin. Microscopic leakage of trabectedin along the venous access device and catheter was considered the most plausible cause for this adverse event. Placing the catheter deeper under the skin resolved the issue almost completely. CONCLUSION: Trabectedin infusion commonly leads to central venous access related adverse events. Sterile inflammation along the catheter trajectory is one of the most common adverse events and can be prevented by placing the catheter deeper under the skin.
RESUMEN
Regorafenib is an oral multikinase inhibitor that has shown antitumor activity in a range of solid tumors. Based on data from phase III clinical trials, regorafenib is indicated for the treatment of adult patients with metastatic colorectal cancer who have previously been treated with, or are not considered candidates for, other available therapies, and in patients with advanced gastrointestinal stromal tumors that cannot be surgically removed and no longer respond to other appropriate treatments. A panel of oncology nurses, research coordinators, and other medical oncology experts, experienced in the care of patients treated with regorafenib, met to discuss the best practice for the management of regorafenib-associated adverse events (AEs). The panel agreed that, in clinical trials and daily practice with regorafenib, AEs are common but mostly manageable. The most common and/or important AEs associated with regorafenib were considered to be hand-foot skin reaction, rash or desquamation, stomatitis, diarrhea, hypertension, liver abnormalities, and fatigue. This manuscript describes the experience and recommendations of the panel for managing these AEs in everyday clinical practice. Appropriate education, monitoring, and management are considered essential for reducing the incidence, duration, and severity of regorafenib-associated AEs.
Asunto(s)
Antineoplásicos/efectos adversos , Compuestos de Fenilurea/efectos adversos , Piridinas/efectos adversos , Adulto , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Exantema/inducido químicamente , Exantema/prevención & control , Fatiga/inducido químicamente , Fatiga/prevención & control , Pie/patología , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mano/patología , Humanos , Hipertensión/inducido químicamente , Hipertensión/prevención & control , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéuticoRESUMEN
PURPOSE: The Functional Assessment of Cancer Therapy-Epidermal Growth Factor Receptor Inhibitor 18 (FACT-EGFRI-18) is a patient-reported outcomes questionnaire developed to assess the effect of EGFRI on patients. The FACT-EGFR-18 was translated into Dutch and evaluated in order to document that the translation adequately captures the concepts of the original English-language version of the questionnaire and is readily understood by subjects in the target population. METHOD: Translation of the FACT-EGFRI-18 from English to Dutch was accomplished by employing the Functional Assessment of Chronic Illness Therapy (FACIT) multilingual translation methodology. Ten native-speaking residents of the target country who reported EGFRI associated dermatological adverse events (dAEs) were asked to review the translation of the harmonized FACT-EGFRI-18. RESULTS: Participants generally found the Dutch FACT-EGFRI-18 easy to understand and complete. In addition, the translation retained the original meaning of the FACT-EGFRI-18 items and instructions. Based on the results of the cognitive debriefing interviews, no changes to improve clarity and comprehension of translations were identified. CONCLUSIONS: The Dutch FACT-EGFRI-18 demonstrates content validity and linguistic validity, and was found conceptually equivalent to its English source, thus confirming linguistic validation. The results suggest that the Dutch FACT-EGFRI-18 can be applied to measure dAE related health related quality of life in Dutch-speaking patients undergoing EGFRI therapy. Formal validation of the Dutch FACT-EGFRI-18 is ongoing.
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Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/psicología , Calidad de Vida , Encuestas y Cuestionarios , Traducción , Anciano , Comprensión , Erupciones por Medicamentos/diagnóstico , Erupciones por Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Inglaterra , Factor de Crecimiento Epidérmico/efectos adversos , Factor de Crecimiento Epidérmico/uso terapéutico , Femenino , Humanos , Lingüística/métodos , Masculino , Persona de Mediana Edad , Países Bajos , Medición de Riesgo , Autoinforme , Resultado del TratamientoRESUMEN
BACKGROUND: Oral adverse events (OAEs) associated with multitargeted tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORIs) are underestimated but frequent and novel presentations of mucosal manifestations. Because optimal antitumor activity requires maintaining the optimal dose, it is essential to avoid unintended treatment delays or interruptions. METHODS: We review the reported prevalence and appearance of OAEs with TKIs and mTORIs and the current oral assessment tools commonly used in clinical trials. We discuss the correlations between OAEs and hand-foot skin reaction (HFSR) and rash. RESULTS: The reported prevalence of oral mucositis/stomatitis of any grade is 4% for pazopanib, 28% for sorafenib, 38% for sunitinib, 41% for temsirolimus, and 44% for everolimus. Oral lesions associated with these agents have been reported to more closely resemble aphthous stomatitis than OM caused by conventional agents. In addition, these agents may result in symptoms such as oral mucosal pain, dysgeusia, and dysphagia, in the absence of clinical lesions. Because of these factors, OAEs secondary to targeted agents may be underreported. In addition, a correlation between OAEs and HFSR was identified. CONCLUSIONS: OAEs caused by TKIs and mTORIs may represent dose-limiting toxicities, especially considering the fact that even low grades of OAEs may be troubling to the patient. We discuss how these novel AEs can be assessed because current mucositis assessment tools have limitations. Prospective studies investigating the pathogenesis, risk factors, and management of OAEs are needed in order to minimize the impact on patient's health-related quality of life.
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Antineoplásicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Mucositis/inducido químicamente , Inhibidores de Proteínas Quinasas/uso terapéutico , Estomatitis/inducido químicamenteRESUMEN
A 41-year-old man with metastases of a gastrointestinal stroma tumour was treated with an angiogenesis inhibitor. He presented with a distinct painful erythematous hyperkeratotic bullous hand-foot skin reaction. This was thought to be caused by the oral angiogenesis inhibitor and resolved after discontinuation of the therapy. This is a known adverse effect of angiogenesis inhibitors and is dose dependent.
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Inhibidores de la Angiogénesis/efectos adversos , Erupciones por Medicamentos/etiología , Dermatosis del Pie/inducido químicamente , Dermatosis de la Mano/inducido químicamente , Enfermedades Cutáneas Vesiculoampollosas/inducido químicamente , Adulto , Relación Dosis-Respuesta a Droga , Erupciones por Medicamentos/patología , Dermatosis del Pie/patología , Dermatosis de la Mano/patología , Humanos , Masculino , Enfermedades Cutáneas Vesiculoampollosas/patologíaRESUMEN
PURPOSE: To provide oncology nurses with an overview of the toxicity management associated with the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer. METHODS: Monoclonal antibodies such as cetuximab and panitumumab that target EGFR have provided patients with metastatic colorectal cancer with effective treatment options. Both antibodies can be used as monotherapy; cetuximab is also approved for use in combination with chemotherapy. We reviewed the literature regarding the signs and symptoms, assessment of severity, and strategies available to prevent and manage adverse events associated with these agents. KEY RESULTS: This class of therapeutics is associated with an overall acceptable adverse event profile that is distinctly different from conventional chemotherapeutics. In contrast to cytotoxic chemotherapy, which causes myelosuppression, mucositis, and nausea and vomiting, common toxicities reported for anti-EGFR therapy include the more frequent cutaneous toxicities, electrolyte imbalances, and diarrhoea, as well as the less frequent ocular toxicities. Infusion reactions are also observed with the chimerical monoclonal antibody cetuximab. CONCLUSIONS: Oncology nurses play a key role in the administration of multi-agent treatment regimens, especially with respect to the identification and management of toxicities, patient education, and patient support. By reducing the incidence and severity of the adverse events associated with anti-EGFR therapy, oncology nurses have the potential to sustain patient adherence to completion of treatment, identify signs and symptoms early, proactively manage adverse events, and provide appropriate treatment interventions, thereby improving patient quality of life.
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Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Enfermería Oncológica/métodos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Benchmarking , Cetuximab , Neoplasias Colorrectales/enfermería , Diarrea/inducido químicamente , Erupciones por Medicamentos/etiología , Monitoreo de Drogas/métodos , Monitoreo de Drogas/enfermería , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/efectos de los fármacos , Receptores ErbB/fisiología , Oftalmopatías/inducido químicamente , Humanos , Hipercalciuria/inducido químicamente , Nefrocalcinosis/inducido químicamente , Rol de la Enfermera , Evaluación en Enfermería/métodos , Panitumumab , Guías de Práctica Clínica como Asunto , Defectos Congénitos del Transporte Tubular Renal/inducido químicamenteRESUMEN
PURPOSE: Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m(2) in the 6-hour IVS, and from 250 mg/m(2) in the 3-hour IVS, were studied. RESULTS: Fifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m(2) for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m(2) or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients. CONCLUSION: Dose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m(2) infused over 6 hours on days 1, 8, and 15 every 28 days.
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Benzamidas/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Adulto , Anciano , Aurora Quinasa B , Aurora Quinasas , Benzamidas/farmacocinética , Benzamidas/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Adulto JovenRESUMEN
PURPOSE: Telatinib (BAY 57-9352) is an orally available tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor-beta, and c-Kit. This phase I dose escalation study was conducted to evaluate the safety and tolerability of telatinib, with additional pharmacokinetic, pharmacodynamic, and efficacy assessments. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Doses of continuously administered telatinib were escalated from 20 mg once daily to 1,500 mg twice daily. RESULTS: Fifty-three patients were enrolled. Most frequently observed drug-related adverse events were nausea (26.4%; grade >or= 3, 0%) and hypertension (20.8%; grade 3, 11.3%; grade 4, 0%). Two dose-limiting toxicities were observed: one poorly controlled hypertension (600 mg twice daily), and one grade 2 weight loss, anorexia, and fatigue (1,500 mg twice daily). A formal maximum-tolerated dose was not reached. Telatinib was rapidly absorbed, with median time to peak concentration (t(max)) lower than 3 hours after dose. A nearly dose-proportional increase in exposure was observed with substantial variability. Telatinib half-life averaged 5.5 hours. Biomarker analyses showed dose-dependent increase in VEGF levels and decrease in plasma soluble VEGFR-2 levels, with a plateau at 900 mg twice daily. A decrease in tumor blood flow (K(trans) and IAUC(60)) was observed with dynamic contrast-enhanced magnetic resonance imaging. Best tumor response was stable disease, observed in 50.9% of patients. CONCLUSION: Telatinib was safe and well tolerated up to 1,500 mg twice daily. Based on pharmacodynamic and pharmacokinetic end points, telatinib 900 mg twice daily is the recommended dose for subsequent phase II studies.
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Inhibidores de la Angiogénesis/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Piridazinas/administración & dosificación , Piridinas/administración & dosificación , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 3 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Adolescente , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Biomarcadores de Tumor/sangre , Medios de Contraste , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/irrigación sanguínea , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Piridazinas/efectos adversos , Piridazinas/farmacocinética , Piridinas/efectos adversos , Piridinas/farmacocinética , Factores de Tiempo , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adulto JovenRESUMEN
A rapid, sensitive and specific method was developed and validated using LC/MS/MS for determination of sunitinib in human plasma. Sample preparation involved a liquid-liquid extraction by the addition of 0.2mL of plasma with 4.0mL tert-butyl-methyl-ether extraction solution containing 25ng/mL of the internal standard clozapine. Separation of compounds was achieved on a C18 (50mmx2.1mm i.d., 3.5microm) analytical column using a mobile phase consisting of acetonitrile/H20 (65:35, v/v) containing 0.1% formic acid and isocratic flow at 0.150mL/min for 3min. The analytes were monitored by tandem-mass spectrometry with electrospray positive ionization. Linear calibration curves in human plasma were generated over the range of 0.2-500ng/mL with values for the coefficient of determination of >0.9950. Within- and between day precision and accuracy were < or =10%. The method was applied to the quantitation of sunitinib in plasma samples from a patient receiving daily oral therapy with sunitinib.
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Cromatografía Líquida de Alta Presión/métodos , Indoles/sangre , Pirroles/sangre , Espectrometría de Masas en Tándem/métodos , Humanos , Indoles/química , Estructura Molecular , Pirroles/química , Reproducibilidad de los Resultados , SunitinibRESUMEN
PURPOSE: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. EXPERIMENTAL DESIGN: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day 1) and on the third day (day 4). The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes. RESULTS: In 11 evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days 1 and 4 were 42.6 (33.0-54.9) microg.h/mL and 41.2 (32.1-53.1) microg.h/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 micromol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro. CONCLUSION: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically.
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Antineoplásicos/farmacocinética , Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/farmacocinética , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Ritonavir/farmacocinética , Anciano , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Benzamidas , Disponibilidad Biológica , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Interacciones Farmacológicas , Inhibidores Enzimáticos/uso terapéutico , Femenino , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Humanos , Mesilato de Imatinib , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Ritonavir/uso terapéuticoAsunto(s)
Anemia/enfermería , Educación en Enfermería , Educación en Salud , Neoplasias/tratamiento farmacológico , Neutropenia/enfermería , Trombocitopenia/enfermería , Anemia/inducido químicamente , Anemia/prevención & control , Antineoplásicos/efectos adversos , Europa (Continente) , Humanos , Neoplasias/complicaciones , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Trombocitopenia/inducido químicamente , Trombocitopenia/prevención & control , Apoyo a la Formación Profesional , Estados UnidosRESUMEN
Haematological toxicities such as neutropenia, anaemia and thrombocytopenia have a significant impact on patients with cancer. They can have a life-threatening effect on the health of the patient and, importantly, may lead to the interruption and/or dose reduction of ongoing cancer therapies, such as chemotherapy. Nurses play a pivotal role in haematological toxicity prevention, detection and management, however, the current level of involvement and understanding varies widely across Europe. Continuing Professional Education (CPE) is an important tool in maximising nurses' contributions to such healthcare issues, enabling them to maintain awareness of recent research, refreshing their knowledge, and facilitating consistency of best practice. As such, the European Oncology Nursing Society (EONS) is developing a Europe-wide training programme in haematological toxicities. This is based on the unmet CPE needs identified through a Learning Needs Assessment (LNA) carried out amongst European cancer nurses in 2003. This article discusses the results of the LNA and how the key issues that it has revealed are being addressed in EONS' nurse education programme, 'Training Initiative in Thrombocytopenia, Anaemia and Neutropenia (TITAN)'.