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1.
Int J Radiat Oncol Biol Phys ; 106(1): 124-133, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494181

RESUMO

PURPOSE: Preoperative therapy in borderline resectable pancreatic cancer (BRPC) is intended to increase R0 resection rates. An optimal approach in BRPC is yet to be defined. METHODS AND MATERIALS: Patients with BRPC, confirmed adenocarcinoma, performance status ≤1, and adequate organ function enrolled in a single-institution, phase 2 trial. Patients received FOLFIRINOX × 6 cycles, then radiation therapy (50 Gy in 25 fractions) concurrent with fixed-dose rate gemcitabine (1 g/m2 over 100 minutes) followed by 2 additional gemcitabine infusions. Computed tomography scans were performed at 2-month intervals during treatment. Patients without distant disease were offered surgical exploration. The primary objective was R0 resection rate with an alternate hypothesis of 55%. Secondary objectives included median progression-free survival (PFS), median overall survival (OS), response rate, and safety. The trial registration number is NCT01661088. RESULTS: Twenty-five patients with median age of 60 years (range, 47-77 years) enrolled from November 2011 through January 2017. Twenty-one (84%) completed FOLFIRINOX and 19 (76%) completed all protocol therapy. Treatment-related grade 3 to 4 toxicities included neutropenia (40%), nausea and vomiting (28%), diarrhea (16%), and fatigue (12%). Eighteen patients (72%) underwent laparotomy, 13 (52%) were resected (all R0). The median PFS and OS in 25 patients were 13.1 months (95% confidence interval [CI], 7.3-24.7) and 24.4 months (95% CI, 12.6-40.0), respectively. For resected patients, median PFS was 21.6 months (95% CI, 8.2-37.1) and OS was 37.1 months (95% CI, 15.4-not reached). CONCLUSIONS: Neoadjuvant therapy with FOLFIRINOX, followed by intensity modulated radiation therapy concurrent with fixed-dose-rate gemcitabine in BRPC is feasible and tolerated. Although the alternate hypothesis was not met, the OS of the resected cohort was favorable.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Terapia Neoadjuvante/métodos , Neoplasias Pancreáticas/terapia , Radioterapia de Intensidade Modulada/métodos , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno CA-19-9/metabolismo , Quimiorradioterapia/métodos , Desoxicitidina/administração & dosagem , Fracionamento da Dose de Radiação , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Neutropenia/induzido quimicamente , Oxaliplatina/administração & dosagem , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Radioterapia de Intensidade Modulada/efeitos adversos
2.
Lancet Haematol ; 7(2): e112-e121, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31866281

RESUMO

BACKGROUND: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING: Acerta Pharma.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Neoplasias/antagonistas & inibidores , Neutropenia/induzido quimicamente , Dor/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Qualidade de Vida , Recidiva , Infecções Respiratórias/etiologia , Terapia de Salvação , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/enzimologia , Macroglobulinemia de Waldenstrom/genética
3.
Medicine (Baltimore) ; 98(45): e17777, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702630

RESUMO

RATIONALE: Phlegmonous gastritis is a rare bacterial infection of the gastric wall with high mortality. However, diagnosis of phlegmonous gastritis is difficult and standard treatment remains unestablished. PATIENT CONCERNS: We report a 33-year-old male patient with mixed-phenotype acute leukemia who developed acute phlegmonous gastritis during the neutropenia phase on induction chemotherapy and was successfully treated. DIAGNOSES: The patient was diagnosed with phlegmonous gastritis, which might be caused by Stenotrophomonas maltophilia on the basis of clinical manifestation, physical examination, enhanced computed tomography scan, histological finding, and microorganism culture of biopsied specimen in endoscopy. INTERVENTIONS: The patient was treated with gastrointestinal decompression and broad-spectrum antibiotics. OUTCOMES: He recovered from phlegmonous gastritis and received the 2nd cycle of chemotherapy with no complaint of abdominal discomfort. LESSONS: Early recognition and proper management including broad-spectrum antibiotics are key approaches to phlegmonous gastritis.


Assuntos
Antibacterianos/uso terapêutico , Gastrite/tratamento farmacológico , Gastrite/microbiologia , Leucemia Aguda Bifenotípica/tratamento farmacológico , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Gastrite/diagnóstico por imagem , Humanos , Masculino , Neutropenia/induzido quimicamente , Stenotrophomonas maltophilia/isolamento & purificação , Resultado do Tratamento
4.
Medicine (Baltimore) ; 98(45): e17852, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702645

RESUMO

RATIONALE: Fusidic acid (FA) is an active agent against gram-positive bacteria such as Staphylococcus, it is generally well tolerated and the major adverse effects are mild gastrointestinal discomfort, diarrhea, and headache. However, some rare side effects such as granulocytopenia and thrombocytopenia have also been reported. Here we report a case of FA-induced hepatotoxicity and hematologic toxicity. PATIENT CONCERNS: A 54-year-old woman with hepatitis B cirrhosis was referred to us because of fever, Staphylococcus aureus was identified in the twice blood culture, and intravenous FA was given (0.5 g, q8 hours). Twelve days after FA therapy, she developed nausea and jaundice. Meanwhile, complete blood cell count showed neutropenia (white blood cell count of 1360/µL, neutrophil of 619/µL) and aggravated thrombocytopenia (platelet count of 18,000/µL). Adverse drug reaction was suspected, and FA was stopped immediately, after 1 day of discontinuation of FA, nose bleeding occurred and the platelet count declined further and reached the lowest value of 4000/µL. DIAGNOSES: Hepatotoxicity and hematologic complications induced by FA were diagnosed. INTERVENTIONS AND OUTCOMES: The FA was stopped immediately, and concentrated platelet transfusion was used. Five days after withdrawal of FA, jaundice resolved and the hematologic index returned to the level before the medication. LESSONS: Hematologic adverse effect accompanying with hepatotoxicity may be induced by FA. Though the risk is rather low, it should not be overlooked.


Assuntos
Ácido Fusídico/administração & dosagem , Icterícia/induzido quimicamente , Neutropenia/induzido quimicamente , Infecções Estafilocócicas/tratamento farmacológico , Administração Intravenosa , Feminino , Ácido Fusídico/efeitos adversos , Hepatite B/complicações , Humanos , Cirrose Hepática/virologia , Pessoa de Meia-Idade , Neutropenia/terapia , Transfusão de Plaquetas , Infecções Estafilocócicas/diagnóstico , Staphylococcus aureus/isolamento & purificação , Resultado do Tratamento
5.
BMJ Case Rep ; 12(9)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570359

RESUMO

A 20-year-old college student presented with high grade, intermittent fever for 10 days associated with blood stained loose stools after taking tablet levamisole for 17 days for vitiligo vulgaris. He was febrile, had a toxic appearance and appeared pale. Investigations showed neutropaenia with thrombocytopaenia. Blood cultures were sterile and stool cultures did not grow any enteric pathogens. His bone marrow examination was suggestive of an aplastic anaemia. He was administered empirical antibiotics, granulocyte colony stimulating factor and platelet transfusions. However, his fever and blood stained stools persisted. A repeat bone marrow examination after 2 weeks still revealed a hypoplastic marrow. Hence, a diagnosis of a levamisole induced bone marrow failure was made. While being worked up for an allogeneic stem cell transplantation, he developed neutropaenic enterocolitis and refractory septic shock with carbapenem resistant Klebsiella pneumoniae and succumbed to his illness.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Levamisol/efeitos adversos , Choque Séptico/induzido quimicamente , Vitiligo/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Diarreia/induzido quimicamente , Evolução Fatal , Febre/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos , Humanos , Levamisol/administração & dosagem , Masculino , Neutropenia/induzido quimicamente , Transfusão de Plaquetas , Choque Séptico/fisiopatologia , Adulto Jovem
6.
J Med Eng Technol ; 43(5): 323-333, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31578101

RESUMO

Between-individual variability of body temperature has been little investigated, but is of clinical importance: for example, in detection of neutropenic sepsis during chemotherapy. We studied within-person and between-person variability in temperature in healthy adults and those receiving chemotherapy using a prospective observational design involving 29 healthy participants and 23 patients undergoing chemotherapy. Primary outcome was oral temperature. We calculated each patient's mean temperature, standard deviation within each patient (within-person variability), and between patients (between-person variability). Secondary analysis explored temperature changes in the three days before admission for neutropenic sepsis. 1,755 temperature readings were returned by healthy participants and 1,765 by chemotherapy patients. Mean participant temperature was 36.16 C (95% CI 36.07-36.26) in healthy participants and 36.32 C (95% CI 36.18-36.46) in chemotherapy patients. Healthy participant within-person variability was 0.40 C (95% CI 0.36-0.44) and between-person variability was 0.26 C (95% CI 0.16-0.35). Chemotherapy patient within-person variability was 0.39 C (95% CI 0.34-0.44) and between-person variability was 0.34 C (95% CI 0.26-0.48). Thus, use of a population mean rather than personalised baselines is probably sufficient for most clinical purposes as between-person variability is not large compared to within-person variability. Standardised guidance and provision of thermometers to patients might help to improve recording and guide management.


Assuntos
Antineoplásicos/uso terapêutico , Temperatura Corporal , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Idoso , Variação Biológica Individual , Variação Biológica da População , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/fisiopatologia , Neutropenia/induzido quimicamente , Neutropenia/fisiopatologia , Adulto Jovem
7.
Pharm Res ; 36(12): 163, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31617004

RESUMO

PURPOSE: There is ongoing concern regarding increased toxicity from paclitaxel in elderly patients, particularly of severe neutropenia. Yet, data so far is controversial and this concern is not supported by a clinically relevant age-dependent difference in pharmacokinetics (PK) of paclitaxel. This study assessed whether age is associated with increased risk for paclitaxel-induced neutropenia. METHODS: Paclitaxel plasma concentration-time data, pooled from multiple different studies, was combined with available respective neutrophil count data during the first treatment cycle. Paclitaxel pharmacokinetic-pharmacodynamic (PK-PD) data was modeled using a non-linear mixed effects approach and a semiphysiological neutropenia model, where systemic paclitaxel exposure was linked to reduced proliferation of neutrophils. The impact of age was evaluated on relevant variables in the model, using a significance threshold of p < 0.005. RESULTS: Paclitaxel PK-PD data was evaluated from 300 patients, with a median age of 65 years (range 23-84 years), containing 116 patients ≥70 years (39%). First cycle neutrophil counts were adequately described by a threshold effect model of paclitaxel on the proliferation rate of neutrophils. Age as a continuous or dichotomous variable (≥70 versus <70 years) did not significantly impact sensitivity of the bone marrow to paclitaxel nor the average maturation time of neutrophils (both p > 0.005), causing a decline in the respective interindividual variability of <1%. CONCLUSION: Results from this large retrospective patient cohort do not suggest elderly patients to be at an increased risk of developing paclitaxel-associated neutropenia during the first treatment cycle. Reflexive dose reductions of paclitaxel in elderly patients are unlikely to improve the risk of severe neutropenia and may be deleterious.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Neutropenia/induzido quimicamente , Paclitaxel/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Estudos Retrospectivos
8.
Farm. hosp ; 43(5): 158-162, sept.-oct. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-183928

RESUMO

Objetivo: Analizar las reacciones adversas en pacientes con cáncer colorrectal no metastásico debidas al tratamiento con capecitabina innovadora o genérica, y/o al régimen quimioterápico empleado, capecitabina en monoterapia o en combinación con oxaliplatino (XELOX). Método: Estudio descriptivo retrospectivo llevado a cabo en un hospital de segundo nivel en dos periodos de estudio (noviembre de 2013-abril de 2014 y agosto de 2016-mayo de 2017). Las variables recogidas fueron variables de exposición (esquema quimioterápico y/o medicamento recibido), variables de control (datos demográficos, de enfermedad y de tratamiento) y variables de respuesta (reacciones adversas). El análisis estadístico de los datos se efectuó con el programa SPSS(R) 15.0. Resultados: Se incluyeron 50 pacientes. Según el esquema quimioterápico administrado, se encontraron diferencias estadísticamente significativas en la aparición de eritrodisestesia palmo-plantar, más frecuente con monoterapia (p < 0,05), y neurotoxicidad, trombopenia y neutropenia, más frecuentes con XELOX (p < 0,05). Según el medicamento de capecitabina administrado, no se observaron diferencias estadísticamente significativas en las reacciones adversas estudiadas. Conclusiones: El perfil de seguridad de dos formulaciones de capecitabina, innovadora y genérica, parece estar asociado al esquema quimioterápico empleado, y no al medicamento en cuestión. La mayor eritrodisestesia palmo-plantar para monoterapia se debe probablemente a la mayor dosis de capecitabina empleada en dicho esquema, y la mayor neurotoxicidad, trombopenia y neutropenia para XELOX se debe probablemente a la toxicidad acumulada de dos fármacos antineoplásicos


Objective: To analyze adverse reactions in patients with nonmetastatic colorectal cancer due to treatment with either innovative or generic capecitabine and/or to the chemotherapeutic regimen employed, to the capecitabine alone, or in combination with oxaliplatin (XELOX). Method: Descriptive retrospective study carried out in a secondary level hospital in two study periods (November 2013-April 2014 and August 2016-May 2017). The collected variables were: exposure (chemotherapy scheme and/or received medication), control (demographics, disease and treatment data), and response (adverse reactions). The statistical analysis of data was performed with the SPSS(R) 15.0 program. Results: Fifty patients were included. According to the administered chemotherapeutic scheme, statistically significant differences were found in the appearance of palmar-plantar erythrodysesthesia, which is more frequent with monotherapy (p < 0.05), and neurotoxicity, thrombocytopenia and neutropenia, which is more frequent with XELOX (p < 0.05). Concerning the capecitabine drug administered, no statistically significant differences were found in the studied adverse reactions. Conclusions: The safety profile of two capecitabine formulations -innovative and generic- appears to be associated with the chemotherapy scheme employed, and not the drug itself. Most palmar-plantar erythrodysesthesia for monotherapy is likely due to the higher dose of capecitabine used in said scheme. The increase in neurotoxicity, thrombocytopenia and neutropenia for XELOX is probably due to cumulative toxicity of two antineoplastic drugs


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Capecitabina/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Oxaliplatina/administração & dosagem , Estudos Retrospectivos , Análise Estatística , Síndromes Neurotóxicas/complicações , Trombocitopenia/complicações , Neutropenia/induzido quimicamente
9.
Am J Case Rep ; 20: 1407-1410, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31548541

RESUMO

BACKGROUND Renal Transplant recipients are at risk for developing neutropenia from a multitude of causes. The cause is often multifactorial, and reversal of the most common causes/insults is sometimes insufficient. CASE REPORT We present the case of a renal transplant recipient who developed a prolonged course of post-transplant (PTx) neutropenia that resolved after switching from tacrolimus (tac) to cyclosporine (CsA). CONCLUSIONS Transplant recipients with persistent neutropenia, sometimes despite discontinuation of potential myelosuppressive agents like mycophenolic acid (MPA), valganciclovir, and sulfamethoxazole-trimethoprim (SMZ-TMP), and with introduction of granulocyte colony-stimulating factor (G-SF), and ruling out alternative diagnoses, may benefit from changing from tac to CsA.


Assuntos
Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/uso terapêutico , Ciclosporina/uso terapêutico , Neutropenia/induzido quimicamente , Tacrolimo/efeitos adversos , Transplantados , Feminino , Humanos , Transplante de Rim , Pessoa de Meia-Idade
10.
N Engl J Med ; 381(12): 1136-1147, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31532960

RESUMO

BACKGROUND: Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known. METHODS: In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment. RESULTS: Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir. CONCLUSIONS: Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/fisiologia , Ribonucleosídeos/uso terapêutico , Valganciclovir/uso terapêutico , Viremia/tratamento farmacológico , Adulto , Idoso , Aloenxertos , Antivirais/efeitos adversos , Antivirais/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/virologia , Disgeusia/induzido quimicamente , Feminino , Gastroenteropatias/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Transplante de Órgãos/efeitos adversos , Ribonucleosídeos/efeitos adversos , Ribonucleosídeos/farmacologia , Valganciclovir/efeitos adversos , Valganciclovir/farmacologia , Ativação Viral/efeitos dos fármacos
11.
Cancer Sci ; 110(11): 3573-3583, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31505087

RESUMO

This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m2 amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72 , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m2 for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor.


Assuntos
Antraciclinas/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neutropenia/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/farmacocinética , Antineoplásicos/farmacocinética , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Superfície Corporal , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Esquema de Medicação , Feminino , Humanos , Japão , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Índice de Gravidade de Doença
12.
Clin Drug Investig ; 39(10): 1009-1018, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31489570

RESUMO

Mecapegfilgrastim (HHPG-19K) is a long-acting pegylated recombinant human granulocyte-colony stimulating factor (rhG-CSF) that is administered subcutaneously as prophylaxis once per chemotherapy cycle as a weight-adjusted dose of 100 µg/kg or as a 6 mg fixed dose. It is approved in China to reduce the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer therapy associated with a clinically significant incidence of febrile neutropenia. In phase III trials, once per cycle prophylaxis with mecapegfilgrastim was more effective than placebo in reducing the incidence of grade ≥ 3 neutropenia in cycle 1 in patients with advanced non-small cell lung cancer and was more effective than filgrastim at reducing the mean duration of grade ≥ 3 neutropenia in cycle 1 in patients with breast cancer. The tolerability and safety profiles of mecapegfilgrastim were similar to those of filgrastim, with no unexpected adverse events (AEs); most adverse reactions in cycle 1 were mild or moderate in severity. Thus, mecapegfilgrastim is an effective and generally well tolerated treatment option for patients with non-myeloid malignancies receiving myelosuppressive chemotherapy, and extends the options available for managing chemotherapy-induced neutropenia in China.


Assuntos
Antineoplásicos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Polietilenoglicóis/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , China/epidemiologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/epidemiologia , Masculino , Neutropenia/epidemiologia , Proteínas Recombinantes/uso terapêutico
13.
Recenti Prog Med ; 110(7): 325-329, 2019.
Artigo em Italiano | MEDLINE | ID: mdl-31379366

RESUMO

TAS-102 represents an important therapeutic resource for patients with metastatic refractory colorectal cancer. Albeit generally well tolerated, clinically relevant neutropenia may interfere with the regular delivery of full-dose cycles with a possible detrimental effect on the dose-intensity. Judicious and personalized use of colony-stimulating growth factors as well as alterative schedules of drug delivery could mitigate neutropenia, so contributing to an even better therapeutic index of the drug.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neutropenia/induzido quimicamente , Pirrolidinas/efeitos adversos , Trifluridina/efeitos adversos , Uracila/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Humanos , Neutropenia/prevenção & controle , Pirrolidinas/administração & dosagem , Trifluridina/administração & dosagem , Uracila/administração & dosagem , Uracila/efeitos adversos
14.
Rev Esp Quimioter ; 32 Suppl 3: 34-36, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31364340

RESUMO

Ceftobiprole is a fifth generation cephalosporin with a series of characteristics differentiating it from other beta-lactams, including its antibacterial activity, mainly against methicillin-resistant Staphylococcus aureus, resistant Streptococcus pneumoniae and also Gram-negative microorganisms such as Pseudomonas aeruginosa. This antibiotic has been subjected to various clinical trials and the results of these have led to its approval in Spain for the treatment of nosocomial pneumonia, excluding that associated with mechanical ventilation, and community-acquired pneumonia. The results of various ceftobiprole clinical studies provide consistent information on efficacy and tolerability. Ceftobiprole as monotherapy has been shown to be non-inferior to comparator antibiotics in different settings. Information is available on its compatibility with other drugs in Y-site administration, important from the point of view of the intravenous treatment of patients who present venous access limitation. On the other hand, and in contrast to other cephalosporins, ceftobiprole presents a low risk of infection due to Clostridium difficile and, in comparison with ceftaroline, neutropenia has not been reported to present any significant issues.


Assuntos
Antibacterianos/efeitos adversos , Cefalosporinas/efeitos adversos , Administração Intravenosa , Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase III como Assunto , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Neutropenia/induzido quimicamente , Pneumonia Bacteriana/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos
15.
Farm Hosp ; 43(5): 158-162, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31469628

RESUMO

OBJECTIVE: To analyze adverse reactions in patients with nonmetastatic colorectal cancer due to treatment with either innovative  or generic capecitabine and/or to the chemotherapeutic regimen  employed, to the capecitabine alone, or in combination with oxaliplatin  (XELOX). METHOD: Descriptive retrospective study carried out in a secondary level hospital in two study periods (November 2013-April 2014 and  August 2016-May 2017). The collected variables were: exposure  (chemotherapy scheme and/or received medication), control  (demographics, disease and treatment data), and response (adverse  reactions). The statistical analysis of data was performed with the  SPSS® 15.0 program. Results: Fifty patients were included. According to the administered chemotherapeutic scheme, statistically significant  differences were found in the appearance of palmar-plantar  erythrodysesthesia, which is more frequent with monotherapy (p <  0.05), and neurotoxicity, thrombocytopenia and neutropenia, which is  more frequent with XELOX (p < 0.05). Concerning the capecitabine drug  administered, no statistically significant differences were found in  the studied adverse reactions. CONCLUSIONS: The safety profile of two capecitabine formulations - innovative and generic- appears to be associated with the  chemotherapy scheme employed, and not the drug itself. Most palmar- plantar erythrodysesthesia for monotherapy is likely due to the higher  dose of capecitabine used in said scheme. The increase in neurotoxicity,  thrombocytopenia and neutropenia for XELOX is probably due to  cumulative toxicity of two antineoplastic drugs.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Relação Dose-Resposta a Droga , Composição de Medicamentos , Medicamentos Genéricos , Feminino , Gastroenteropatias/induzido quimicamente , Síndrome Mão-Pé/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Neutropenia/induzido quimicamente , Oxaliplatina/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos Retrospectivos , Trombocitopenia/induzido quimicamente
16.
Am J Health Syst Pharm ; 76(16): 1183-1202, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369120

RESUMO

PURPOSE: The pharmacology, clinical activity, safety, and place in therapy of the cyclin-dependent kinase (CDK) inhibitors palbociclib, ribociclib, and abemaciclib are reviewed. SUMMARY: CDK 4 and CDK 6 are downstream agents in the estrogen signaling pathway that control entry into the cell cycle. CDK4/6 inhibition may prevent tumor cell progression in the cell cycle. Three CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are available for women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. These medications' indications in the treatment of HR+/HER2- advanced breast cancer include use with an aromatase inhibitor (AI) as initial therapy in postmenopausal women and with fulvestrant in women whose disease progressed during endocrine therapy. Ribociclib is also indicated as initial therapy with an AI in premenopausal or perimenopausal women and as initial therapy with fulvestrant in postmenopausal women. Abemaciclib is also indicated as monotherapy in women with disease progression after endocrine therapy and prior chemotherapy. A significant increase in progression-free survival (PFS) was seen with use of all 3 agents as initial therapy with an AI in controlled trials. Each agent also was demonstrated to produce a significant increase in PFS when used with fulvestrant in women whose disease progressed with prior endocrine therapy. Neutropenia is a dose-limiting adverse effect of palbociclib and ribociclib. Fatigue is more common with use of palbociclib and abemaciclib, and gastrointestinal effects are more common with abemaciclib use. CONCLUSION: CDK4/6 inhibitors have significant demonstrated clinical activity in combination with AIs or fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer and are becoming a standard of care in these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/epidemiologia , Humanos , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Purinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Ann Hematol ; 98(9): 2131-2138, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31286196

RESUMO

The optimal dose, schedule, and other aspects of bendamustine plus rituximab treatment remain unclear for patients with relapsed or refractory follicular lymphoma (FL). Herein, we analyzed the efficacy of bendamustine combined with rituximab (RB-120) treatment for Japanese patients with relapsed or refractory FL. This phase II clinical trial included patients with relapsed or refractory FL who received 375 mg/m2 rituximab on day 1 and 120 mg/m2 bendamustine on days 2 and 3 every 28 days for up to 6 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included the complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Thirty-seven patients were enrolled in the trial (median age 62 years, range 42-75 years). All patients were previously treated with rituximab-containing chemotherapy, and 83.8% were previously treated with the R-CHOP regimen. A median of 5 cycles (range 1-6) and 48.6% of patients completed 6 cycles. The ORR was 91.9% (95% confidence interval [CI] 78.1-98.3%), with a CR rate of 86.5% (95% CI 71.2-95.5%). The 3-year PFS and OS were 70.9% (95% CI 52.3-83.3%) and 88.9% (95% CI 73.1-95.7%), respectively, with the median 39.5 months follow-up duration. The most-frequently observed grade 3/4 adverse events were hematologic: lymphopenia (95%) and neutropenia (70%). No treatment-related deaths were observed. RB-120 showed a good efficacy with equivalent toxicities, compared with the bendamustine 120 mg/m2 monotherapy. However, the problem of high drop-out incidences cannot be ignored.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Folicular , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/mortalidade , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Taxa de Sobrevida
18.
Jpn J Clin Oncol ; 49(11): 1004-1008, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31287877

RESUMO

BACKGROUND: Malignant peritoneal mesothelioma (MPeM) is a rare cancer for which no standard systemic chemotherapy has been established. While cisplatin plus pemetrexed, the standard treatment for malignant pleural mesothelioma (MPlM), is usually used for MPeM, its efficacy remains unclear. METHODS: We retrospectively reviewed the medical charts of MPeM patients who had received cisplatin plus pemetrexed as first-line chemotherapy between January 2001 and July 2016 at the National Cancer Center Hospital. Patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day1, repeated every 3 weeks until progressive disease, unacceptable toxicities or patient's refusal to continue. RESULTS: A total of 29 MPeM patients received cisplatin plus pemetrexed. Median progression-free survival and overall survival were 7.1 months (95% CI: 4.8-9.3) and 15.4 months (95% CI: 9.5-21.2), respectively. Among 16 patients with measurable lesions, the response rate was 38%. Incidences of grade 3/4 leukopenia, neutropenia, anemia and thrombocytopenia were 21%, 17%, 14% and 3%, respectively. Non-hematological toxicities were mild, and there were no treatment-related deaths. CONCLUSIONS: Cisplatin plus pemetrexed, showing consistent efficacy with MPlM, can be recommended as first-line treatment for unresectable MPeM patients.


Assuntos
Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Pemetrexede/efeitos adversos , Pemetrexede/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Estudos Retrospectivos , Trombocitopenia/induzido quimicamente
19.
Anticancer Res ; 39(7): 3967-3969, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262929

RESUMO

BACKGROUND/AIM: The aim of this report was to evaluate the onset of grade≥3 neutropenia during the first-cycle in patients with metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil and its relationship with clinical parameters of interest, such as overall survival (OS). PATIENTS AND METHODS: We performed a retrospective analysis of all consecutive patients with mCRC, treated with trifluridine/tipiracil in third or later treatment lines in mCRC, at our Medical Oncology Unit between July 2017 and December 2018. We evaluated 15 patients. RESULTS: Median age was 63 years (range: 46-80 years). Trifluridine/tipiracil was used in third-line treatment in 10 patients (66.7%). The only serious adverse events were grade 3 (26.7%) and grade 4 (13.3%) neutropenia. Median follow-up time (FUT) was 53 months (range=17-91 months). At the last FUT, 5 patients (33.3%) were deceased. Median OS was 5 months (range=1-15 months). At the univariate analysis, the onset of grade ≥3 neutropenia at the first cycle showed a statistically positive impact on OS (p=0.046). CONCLUSION: The onset of grade ≥3 neutropenia at the first-cycle is associated with longer median OS compared to no onset of neutropenia also in real-life.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neutropenia/induzido quimicamente , Trifluridina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Análise de Sobrevida , Uracila/análogos & derivados
20.
BMC Cancer ; 19(1): 652, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269916

RESUMO

BACKGROUND: There is no standard first-line chemotherapy for advanced gastric cancer with severe peritoneal metastasis. Although fluoropyrimidine is often used, its efficacy is limited, and it remains unclear whether combination therapy with platinum improves clinical outcomes. METHODS: This retrospective study involved patients at six Japanese academic hospitals between 2010 and 2016. Patients with advanced gastric cancer and severe peritoneal metastasis were included if they had massive ascites and/or inadequate oral intake requiring intravenous nutritional support. We then compared the efficacy and safety of fluoropyrimidine monotherapy with those of fluoropyrimidine/platinum combination therapy. RESULTS: Compared with the combination therapy group (n = 64), the monotherapy group (n = 65) had worse general health (more patients with elderly age, performance status > 2, and having both massive ascites and inadequate oral intake). Both overall survival (9.0 vs 5.0 months, p < 0.01) and progression-free survival (4.3 vs 2.3 months, p < 0.01) were significantly longer in the combination group, and the significance remained after adjusting for prognostic variables (hazard ratios of 0.47 and 0.41, respectively; p < 0.01). Improvements in ascites and oral intake were also greater in the combination group. Although neutropenia (grade ≥ 3) occurred more frequently with combination therapy, both treatments in this study were tolerable. CONCLUSIONS: Combination therapy with fluoropyrimidine and platinum might be more effective than monotherapy with fluoropyrimidine and was tolerable for patients with advanced gastric cancer and severe peritoneal metastasis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ascite/tratamento farmacológico , Cisplatino/administração & dosagem , Combinação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Masculino , Desnutrição/tratamento farmacológico , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Compostos Organoplatínicos/administração & dosagem , Ácido Oxônico/administração & dosagem , Neoplasias Peritoneais/secundário , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem , Resultado do Tratamento , Suspensão de Tratamento , Adulto Jovem
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