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1.
World J Surg Oncol ; 19(1): 124, 2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33865416

RESUMO

BACKGROUND: Adjuvant tegafur-gimeracil-oteracil (S-1) is commonly used for gastric cancer in Asia, and tegafur-uracil (UFT) is another oral fluoropyrimidine when S-1 is unavailable. The real-world data of adjuvant UFT has less been investigated. METHODS: Patients with pathological stage II-IIIB (except T1) gastric cancer receiving adjuvant UFT or S-1 monotherapy after D2 gastrectomy were included. Usage of UFT or S-1 was based on reimbursement policy of the Taiwanese healthcare system. The characteristics, chemotherapy completion rates, and 5-year recurrence-free survival (RFS) and overall survival (OS), were compared between these two groups. RESULTS: From 2005 to 2016, 86 eligible patients were included. Most tumor characteristics were similar between the UFT group (n = 37; age 59.1 ± 13.9 years) and S-1 group (n = 49; age 56.3 ± 10.7 years), except there were significantly more Borrmann type III/IV (86.5% versus 67.3%; p = 0.047) and T4 (56.8% versus 10.2%; p < 0.001) lesions in the UFT group than in the S-1 group. The chemotherapy complete rates were similar in the two groups. The 5-year RFS was 56.1% in the UFT group and 59.6% in the S-1 group (p = 0.71), and the 5-year OS was 78.3% in the UFT group and 73.1% in the S-1 group (p = 0.48). The hazard ratio of adjuvant chemotherapy (S-1 versus UFT) on RFS was 1.25 (95% confidence interval = 0.53-2.94) when Borrmann type and T and N stages were adjusted. CONCLUSIONS: This small cohort study showed adjuvant UFT, and S-1 monotherapy had a comparable long-term outcome for pathological stage II-IIIB gastric cancer following D2 gastrectomy.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Ácido Oxônico/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Tegafur/uso terapêutico , Uracila/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Estudos de Coortes , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias Gástricas/patologia , Resultado do Tratamento
2.
Gan To Kagaku Ryoho ; 48(3): 419-421, 2021 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-33790174

RESUMO

Trifluridine/tipiracil (TAS-102) is an important chemotherapeutic agent recommended by the Japanese guidelines as third- or fourth-line treatment for colorectal cancer. Some studies have reported that administration of TAS-102 concomitant with bevacizumab prolongs progression-free and overall survival in colorectal cancer. We describe 2 patients treated with a chemotherapeutic regimen comprising TAS-102 concomitant with bevacizumab for recurrent colorectal cancer. No adverse events ≥Grade 3(except for hematotoxicity)were observed in these patients. The patient received several courses of chemotherapy with adjustments of the dose and dosing intervals to prevent neutropenia. Combination therapy using TAS-102 and bevacizumab is a feasible Late-line chemotherapeutic regimen for colorectal cancer.


Assuntos
Neoplasias Colorretais , Trifluridina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Combinação de Medicamentos , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Pirrolidinas , Timina , Trifluridina/uso terapêutico , Uracila/uso terapêutico
3.
Lancet ; 396(10253): 759-769, 2020 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-32871100

RESUMO

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.


Assuntos
Benzilaminas/uso terapêutico , Miosinas Cardíacas/antagonistas & inibidores , Cardiomiopatia Hipertrófica/tratamento farmacológico , Uracila/análogos & derivados , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Benzilaminas/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cardiomiopatia Hipertrófica/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Método Duplo-Cego , Tolerância ao Exercício/fisiologia , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Avaliação de Resultados da Assistência ao Paciente , Uracila/efeitos adversos , Uracila/uso terapêutico
4.
PLoS One ; 15(8): e0237162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750098

RESUMO

Viral diversity is an important feature of hepatitis C virus (HCV) infection and an important predictor of disease progression and treatment response. HIV/HCV co-infection is associated with enhanced HCV replication, increased fibrosis, and the development of liver disease. HIV also increases quasispecies diversity of HCV structural genes, although limited data are available regarding the impact of HIV on non-structural genes of HCV, particularly in the absence of direct-acting therapies. The genetic diversity and presence of drug resistance mutations within the RNA-dependent RNA polymerase (NS5B) gene were examined in 3 groups of women with HCV genotype 1a infection, including those with HCV mono-infection, antiretroviral (ART)-naïve women with HIV/HCV co-infection and CD4 cell count <350 cells/mm3, and ART-naïve women with HIV/HCV co-infection and CD4 cell count ≥350 cells/mm3. None had ever been treated for HCV infection. There was evidence of significant diversity across the entire NS5B gene in all women. There were several nucleotides and amino acids with distinct distributions across the three study groups, although no obvious clustering of NS5B sequences was observed based on HIV co-infection or CD4 cell count. Polymorphisms at amino acid positions associated with resistance to dasabuvir and sofosbuvir were limited, although the Q309R variant associated with ribavirin resistance was present in 12 individuals with HCV mono-infection, 8 HIV/HCV co-infected individuals with CD4 <350 cells/mm3, and 12 HIV/HCV co-infected individuals with CD4 ≥350 cells/mm3. Previously reported fitness altering mutations were rare. CD8+ T cell responses against the human leukocyte antigen (HLA) B57-restricted epitopes NS5B2629-2637 and NS5B2936-2944 are critical for HCV control and were completely conserved in 44 (51.8%) and 70 (82.4%) study participants. These data demonstrate extensive variation across the NS5B gene. Genotypic variation may have a profound impact on HCV replication and pathogenesis and deserves careful evaluation.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/genética , Coinfecção/genética , Variação Genética , HIV , Hepacivirus/genética , Hepatite C/genética , Proteínas não Estruturais Virais/genética , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adulto , Sequência de Aminoácidos , Antivirais/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Coinfecção/tratamento farmacológico , Coinfecção/virologia , Farmacorresistência Viral/genética , Feminino , Genótipo , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Filogenia , RNA Viral/genética , RNA Viral/isolamento & purificação , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/análogos & derivados , Uracila/uso terapêutico
5.
J Cancer Res Clin Oncol ; 146(10): 2575-2587, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32715436

RESUMO

BACKGROUND: Limited treatment options are available in chemotherapy-refractory metastatic colorectal cancer (mCRC). The objective was to conduct a systematic literature review (SLR) and exploratory network meta-analysis (NMA) to compare the tolerability and effectiveness of SIRT with Y-90 resin microspheres, regorafenib, TAS-102 (trifluridine/tipiracil), and best supportive care (BSC) as third-line treatment in patients with mCRC. METHODS: An SLR was conducted to identify studies comparing two or more of the treatments and reporting overall survival (OS), progression-free survival, tumor response, or adverse event (AE) incidence. An exploratory NMA was conducted to compare hazard ratios (HRs) for OS using Markov chain Monte Carlo (MCMC) techniques. RESULTS: Seven studies were identified in the SLR: two double-blind randomized-controlled trials (RCT) for each drug, one open-label RCT, and two non-randomized comparative studies for SIRT. Patient selection criteria differed between studies, with SIRT studies including patients with liver-dominant colorectal metastases. Nausea and vomiting were more frequent with TAS-102 than regorafenib or SIRT; diarrhea was more common with TAS-102 and regorafenib than SIRT. The exploratory NMA suggested that all active treatments improved OS, with HRs of 0.48 (95% CrI 0.30-0.78) for SIRT with Y-90 resin microspheres, 0.63 (0.38-1.03) for TAS-102, and 0.67 (0.40-1.08) for regorafenib each compared to BSC. CONCLUSIONS: Regorafenib, TAS-102 and SIRT using Y-90 resin microspheres are more effective than BSC in third-line treatment of mCRC; however, study heterogeneity made comparisons between active treatments challenging. SIRT is a viable treatment for third-line mCRC and its favorable AE profile should be considered in the therapeutic decision-making process.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia/métodos , Neoplasias Colorretais/dietoterapia , Neoplasias Colorretais/radioterapia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Radioisótopos de Ítrio/administração & dosagem , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Microesferas , Metástase Neoplásica , Metanálise em Rede , Cuidados Paliativos/métodos , Compostos de Fenilureia/administração & dosagem , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Timina , Trifluridina/administração & dosagem , Uracila/administração & dosagem , Uracila/uso terapêutico
6.
Anticancer Res ; 40(7): 4157-4163, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620665

RESUMO

BACKGROUND/AIM: The efficacy of trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) plus bevacizumab as later-line treatment for metastatic colorectal cancer (mCRC) has been demonstrated. However, little is known about the impact of a usage history of bevacizumab in front-line treatment on the clinical benefit of combining bevacizumab with FTD/TPI. PATIENTS AND METHODS: A total of 62 patients with mCRC treated with FTD/TPI±bevacizumab was enrolled and assessed for chemotherapeutic efficacy and adverse events. RESULTS: Regardless of the usage history of bevacizumab in front-line treatment, the FTD/TPI plus bevacizumab group had a significantly better progression-free survival rate than the FTD/TPI monotherapy group, and no significant differences in the safety profile were observed between the two groups. CONCLUSION: Combining bevacizumab with FTD/TPI improves the survival outcomes with manageable toxicity, regardless of the usage history of bevacizumab in front-line treatment, in patients with mCRC.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/uso terapêutico , Timidina Fosforilase/antagonistas & inibidores , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Timina , Uracila/uso terapêutico , Adulto Jovem
7.
PLoS One ; 15(6): e0234314, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530932

RESUMO

Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) showed survival benefits in metastatic colorectal cancer patients previously treated with standard chemotherapies; therefore, we compared the efficacy and safety of these two treatments. Patients with metastatic colorectal cancer treated with REG or FTD/TPI as a salvage-line therapy from May 2014 to December 2017 were included. We retrospectively analyzed long-term survival, safety, and clinical outcomes. Among 134 patients, 57 and 77 received REG and FTD/TPI, respectively. The REG group received more prior systemic chemotherapies and significantly more frequent additional chemotherapies than the FTD/TPI group did. The median follow-up was 6.2 months, whereas the median overall survival was 9.9 and 11.4 months in the REG and FTD/TPI groups, respectively (hazard ratio = 0.954, p = 0.837). The median progression-free survival was 2.0 and 3.3 months in the REG and FTD/TPI groups, respectively (hazard ratio = 0.52, p = 0.00047), indicating significant differences, whereas the objective response and disease control rates did not differ. The median overall survival of patients with additional subsequent chemotherapies after disease progression was longer than that of patients without additional chemotherapy. The most frequent grade ≥3 adverse events were hypertension and neutropenia in the REG and FTD/TPI groups, respectively. Our study suggested that sequential use of both drugs may prolong survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Terapia de Salvação , Timina , Resultado do Tratamento , Uracila/uso terapêutico
8.
Circ Heart Fail ; 13(6): e006853, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32498620

RESUMO

BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study. METHODS: EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. CONCLUSIONS: EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03470545.


Assuntos
Benzilaminas/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Uracila/análogos & derivados , Benzilaminas/efeitos adversos , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/fisiopatologia , Fármacos Cardiovasculares/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Resultado do Tratamento , Uracila/efeitos adversos , Uracila/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos
9.
Crit Rev Oncol Hematol ; 152: 102987, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32485527

RESUMO

TAS-102 is a preconstituted drug combination comprising an oral fluoropyrimidine (trifluridine, TFT) and a potent inhibitor of thymidine phosphorylase (tipiracil hydrochloride, TPI). TFT/TPI has recently received Food and Drug Administration (FDA) approval also for the treatment of gastric cancer after at least two lines of chemotherapy. The approval was based on a large phase 3 trial (TAGS), in which TAS-102 showed a 31 % decrease in the risk of death compared with placebo. Here, we review the pharmacological properties, clinical development and potential future directions of TAS-102 in gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pirrolidinas/uso terapêutico , Neoplasias Gástricas , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Fenômenos Bioquímicos , Combinação de Medicamentos , Humanos , Neoplasias Gástricas/tratamento farmacológico , Timina , Uracila/uso terapêutico
10.
Asia Pac J Clin Oncol ; 16 Suppl 1: 3-12, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32348018

RESUMO

Trifluridine/tipiracil is available on the Australian Pharmaceutical Benefits Scheme for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-vascular endothelial growth factor agents and anti-epidermal growth factor receptor agents. This article reviews trifluridine/tipiracil clinical data and presents practical information on its use in the management of refractory mCRC in Australia. Whereas the primary mechanism of action of fluoropyrimidines such as fluorouracil (5-FU) and capecitabine is enzyme inhibition of nucleotide synthesis, trifluridine/tipiracil primarily acts by incorporation into DNA, resulting in DNA dysfunction. Trifluridine/tipiracil has activity in patients with 5-FU-resistant tumors and can be considered in patients with prior intolerance or toxicity to 5-FU. In the pivotal phase III RECOURSE trial evaluating trifluridine/tipiracil in chemotherapy-refractory mCRC, efficacy benefits were observed across all a priori prognostic subgroups including those defined by age (≥65 and ≥75 years), geographical origin, primary tumor site or KRAS status. Trifluridine/tipiracil therapy benefits appropriately selected patients who have an ECOG performance status of 0 or 1, with no more than mild hepatic impairment or mild-to-moderate renal impairment, and who are capable of adhering to oral therapy safely. Appropriate dosing, monitoring for adverse events and effective management of side effects are essential.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/uso terapêutico , Qualidade de Vida/psicologia , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Austrália , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pirrolidinas/farmacologia , Timina , Trifluridina/farmacologia , Uracila/farmacologia , Uracila/uso terapêutico
11.
BMC Infect Dis ; 20(1): 264, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245397

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. METHODS: An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants. RESULTS: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness. CONCLUSION: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. TRIAL REGISTRATION: NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).


Assuntos
Anilidas/uso terapêutico , Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C/tratamento farmacológico , Compostos Macrocíclicos/uso terapêutico , Inibidores de Proteases/uso terapêutico , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/análogos & derivados , Anilidas/efeitos adversos , Antivirais/efeitos adversos , Carbamatos/efeitos adversos , Quimioterapia Combinada , Feminino , Genótipo , Hepatite C/virologia , Humanos , Compostos Macrocíclicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores de Proteases/efeitos adversos , Ribavirina/efeitos adversos , Ritonavir/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Uracila/efeitos adversos , Uracila/uso terapêutico
12.
Oncol Res Treat ; 43(5): 237-244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32146471

RESUMO

BACKGROUND: Metastatic colorectal carcinoma (mCRC) is one of the most prevalent types of cancer worldwide. After tumor progression with first- and second-line treatment, trifluridine (FTD) and tipiracil (TPI) has been shown to be a treatment option. SUMMARY: Data from a pivotal phase 3 trial (RECOURSE) and an ongoing phase 3b trial (PRECONNECT) have shown that, in mCRC patients who experienced disease progression after 2 lines of standard therapy, treatment with FTD/TPI is safe and efficacious. Other third-line options include regorafenib, rechallenge with previous treatment lines or personalized approaches based on comprehensive molecular profiling. Randomized trials or sequential studies aiming for the right treatment sequence or predefined subtypes for FTD/TPI or regorafenib as well for rechallenge are missing. However, FTD/TPI as well as regorafenib are recommended by the current ESMO, German S3, and National Comprehensive Cancer Network (NCCN) guidelines in the same situation, thus offering physicians a number of alternatives for the treatment of mCRC patients after the second progression. Key Message: This narrative review summarizes published data and their impact for FTD/TPI as well for regorafenib and rechallenge chemotherapy in clinical practice settings of refractory situations of colorectal cancer.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Combinação de Medicamentos , Humanos , Metástase Neoplásica , Taxa de Sobrevida , Suíça , Timina , Resultado do Tratamento , Uracila/uso terapêutico
13.
BMC Cancer ; 20(1): 91, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013902

RESUMO

BACKGROUND: The standard first- and second- line chemotherapy backbone regimens for metastatic colorectal cancer (mCRC) are 5-fluorouracil (5-FU)/capecitabine-based with addition of irinotecan or oxaliplatin. Until recently, evidence for optimal sequencing post second-line was sparse. Trifluridine/tipiracil (indicated for mCRC and gastric cancer after standard chemotherapies) was made available to UK patients via a named patient programme (NPP) before receiving marketing authorisation in Europe in 2016, allowing characterisation of UK treatment pathways, and evaluation of trifluridine/tipiracil in a UK non-trial population. METHODS: Data collected routinely for the NPP were analysed to describe the patient demographics, clinical characteristics and treatment pathways. Patients eligible for the programme were adults (≥18 years) with histologically or cytologically confirmed mCRC who had previously received chemotherapy treatment(s). RESULTS: Of the 250 eligible patients enrolled in the NPP, 194 patients received ≥1 dose of trifluridine/tipiracil and 56 patients did not receive trifluridine/tipiracil. The following results are reported first for patients who received trifluridine/tipiracil and second for those who did not receive trifluridine/tipiracil: median (IQR) age was 63.0 (54.0-69.0) and 62.0 (54.8-69.0) years; Eastern Cooperative Oncology Group performance status score was 0 for 28 and 14%, 1 for 65 and 70%, 2 for 7 and 16%. In terms of previous systemic treatments 47 and 43% had 2 prior lines of therapy. FOLFOX-, FOLFIRI- and CAPOX-based therapies were the most common first-line regimens in patients receiving trifluridine/tipiracil (37, 35 and 21%, respectively), and in patients not receiving trifluridine/tipiracil (41, 30 and 20%, respectively). Second-line treatment regimens in patients receiving and not receiving trifluridine/tipiracil were most commonly FOLFIRI-based (48 and 41%, respectively) and FOLFOX-based (19 and 21%, respectively). Patients received a median of 2 cycles of trifluridine/tipiracil with a median treatment duration of 1.8 (95% CI: 1.8-2.4) months. In patients who discontinued treatment due to disease progression, the median progression-free duration was 2.8 (95% CI: 2.4-2.9) months. CONCLUSIONS: The results highlight the number of treatment pathways used to treat mCRC in routine UK clinical practice prior to the marketing authorisation and National Institute for Health and Care Excellence approval of trifluridine/tipiracil and highlight the lack of clinical guidelines for mCRC.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/administração & dosagem , Trifluridina/administração & dosagem , Uracila/análogos & derivados , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Progressão da Doença , Combinação de Medicamentos , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/uso terapêutico , Pirrolidinas/uso terapêutico , Timina , Resultado do Tratamento , Trifluridina/uso terapêutico , Reino Unido , Uracila/administração & dosagem , Uracila/uso terapêutico
14.
Nefrología (Madrid) ; 40(1): 46-52, ene.-feb. 2020. tab
Artigo em Inglês | IBECS | ID: ibc-198954

RESUMO

BACKGROUND AND AIMS: The advent of direct-acting antiviral agents promises to change the management of hepatitis C virus infection (HCV) in patients with chronic kidney disease (CKD), a patient group in which the treatment of hepatitis C was historically challenging. We investigated the safety and efficacy of all-oral, interferon-free direct-acting antiviral agents for the treatment of hepatitis C in a 'real-world' cohort of patients with CKD. METHODS: We performed an observational single-arm multi-centre study in a large (n = 198) cohort of patients with stage 1-3 CKD who underwent antiviral therapy with DAAs for the treatment of HCV. The primary end-point was sustained virologic response (serum HCV RNA < 15 IU/mL, 12 weeks after treatment ended) (SVR12). We collected data on on-treatment adverse events (AEs), severe AEs, and laboratory abnormalities. RESULTS: The average baseline eGFR (CKD-EPI equation) was 70.06 ± 20.1 mL/min/1.72 m2; the most common genotype was HCV 1b (n = 93, 51%). Advanced liver scarring was found in 58 (46%) patients by transient elastography. Five regimens were adopted: elbasvir/grazoprevir (n = 5), glecaprevir/pibrentasvir (n = 4), ritonavir-boosted paritaprevir/ombitasvir/dasabuvir (PrOD) regimen (n = 40), simeprevir ± daclatasvir (n = 2), and sofosbuvir-based combinations (n = 147). The SVR12 rate was 95.4% (95% CI, 93.8%; 96.8%). There were nine virological failures - eight being relapsers. Adverse events occurred in 30% (51/168) of patients, and were managed clinically without discontinuation of therapy or hospitalization. One of the most common AEs was anaemia (n = 12), which required discontinuation or dose reduction of ribavirin in some cases (n = 6); deterioration of kidney function occurred in three (1.7%). CONCLUSIONS: All-oral, interferon-free therapy with DAAs for chronic HCV in mild-to-moderate CKD was effective and well-tolerated in a 'real-world' clinical setting. Studies are in progress to address whether sustained viral response translates into better survival in this population


ANTECEDENTES Y OBJETIVOS: La aparición de los antivíricos de acción directa (AAD) promete cambiar el tratamiento de la infección por el virus de la hepatitis C (VHC) en los pacientes con nefropatía crónica (NC), un grupo de pacientes en el que el tratamiento de la hepatitis C siempre supuso una dificultad. Se investiga la seguridad y la eficacia de los antivíricos de acción directa, sin interferones orales, en todos los casos para el tratamiento de la hepatitis C en una cohorte en condiciones reales de pacientes con NC. MÉTODOS: Se llevó a cabo un estudio multicéntrico, de un solo grupo y observacional en una cohorte amplia (n = 198) de pacientes con NC en estadio 1-3 a los que se administró tratamiento antivírico con AAD para el VHC. El criterio principal de valoración fue la respuesta virológica sostenida (ARN sérico del VHC < 15 UI/ml, 12 semanas después de la finalización del tratamiento) (RVS12). Se recogieron los datos sobre acontecimientos adversos (AA) surgidos durante el tratamiento, AA graves y anomalías analíticas. RESULTADOS: La FGe inicial media (ecuación de CKD-EPI) fue de 70,06 ± 20,1 ml/min/1,72 m2; el genotipo más frecuente fue VHC 1b (n = 93; 51%). Se observó cicatrización hepática avanzada en 58 (46%) pacientes mediante elastografía transitoria. Se adoptaron 5 pautas: elbasvir/grazoprevir (n = 5), glecaprevir/pibrentasvir (n = 4), pauta de paritaprevir/ombitasvir/dasabuvir (PrOD) potenciada con ritonavir (n = 40), simeprevir ± daclatasvir (n = 2) y combinaciones basadas en sofosbuvir (n = 147). La tasa de RVS12 fue del 95,4% (IC del 95%: 93,8; 96,8%). Hubo 9 fracasos virológicos, 8 de ellos recidivantes. Se produjeron acontecimientos adversos en el 30% (51/168) de los pacientes, que se trataron clínicamente sin suspensión del tratamiento ni hospitalización. Uno de los AA más frecuentes fue la anemia (n = 12), que precisó la suspensión o la reducción de la dosis de ribavirina en algunos casos (n = 6); se produjo deterioro de la función renal en 3 casos (1,7%). CONCLUSIONES: El tratamiento sin interferón oral en todos los casos con AAD para el VHC crónico en la NC de leve a moderada fue eficaz y bien tolerado en un contexto de la práctica clínica real. Hay estudios en curso para abordar si la respuesta viral sostenida se traduce en una mejor supervivencia en esta población


Assuntos
Humanos , Masculino , Feminino , Idoso , Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Ritonavir/uso terapêutico , Simeprevir/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Uracila/análogos & derivados , Amidas/uso terapêutico , Antivirais/efeitos adversos , Benzimidazóis/uso terapêutico , Benzofuranos/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Genótipo , Hepacivirus/genética , Hepatite C/complicações , Imidazóis/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Uracila/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico
15.
Acta Diabetol ; 57(6): 689-696, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31955260

RESUMO

AIMS: Observational studies and meta-analyses of randomized trials on dipeptidyl peptidase-4 inhibitors (DPP4i) reported discordant results on the risk of malignancies with this class of drugs. Aim of the present meta-analysis is the assessment of the effect of DPP4i treatment on the incidence of different types of cancer, collecting all available evidence from randomized controlled trials. METHODS: An extensive MEDLINE, EMBASE, and Cochrane database search for sitagliptin or vildagliptin or omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥ 24 weeks, and comparing of DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel-Haenszel odds ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes. RESULTS: A total of 157 eligible trials were identified. DPP-4i were not associated with an increased risk of overall cancer (MH-OR 0.93 [0.86, 1.00]; p = 0.07), with no significant differences across individual molecules of the class. When compared with placebo/none, a lower risk of cancer with DPP-4i was observed in placebo-controlled trials (MH-OR 0.90 [0.82, 0.99], p = 0.030), whereas no significant differences have been detected with any other comparators. DPP-4i was associated with a significant reduction in colorectal cancer (MH-OR 0.70 [0.53, 0.94], p = 0.020). CONCLUSIONS: Available data do not support the hypothesis of an association of DPP4i treatment with malignancies, with a possible beneficial effect for colon-rectal cancer.


Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Dipeptídeos/uso terapêutico , Humanos , Incidência , Piperidinas/uso terapêutico , Fatores de Risco , Fosfato de Sitagliptina/uso terapêutico , Uracila/análogos & derivados , Uracila/uso terapêutico , Vildagliptina/uso terapêutico
16.
Int J Clin Oncol ; 25(4): 614-621, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31838590

RESUMO

BACKGROUND: Although regorafenib or trifluridine/tipiracil (FTD/TPI) has been recognized as a later-line standard treatment in patients with metastatic colorectal cancer (mCRC), not all patients have beneficial outcomes. This study aimed to develop a prognostic scoring system for evaluating the overall survival (OS) benefit. METHODS: Patients included in the REGOTAS study, which comprised 489 patients (regorafenib group: 199; FTD/TPI group: 290 patients), were evaluated. OS was analyzed using multivariate Cox proportional model. The prognostic score was calculated using the worst four individual factors weighted by hazard ratio, and the total scores were categorized as low-, moderate-, and high-OS benefit. RESULTS: The worst four factors in the regorafenib group were AST > 40 IU/dL (point, + 3), CRP ≥ 1.0 mg/dL (+ 2), number of metastatic organ site ≥ 3 (+ 2), and duration from initiation of 1st-line chemotherapy < 18 months (+ 2), while they were AST (+ 2), CRP (+ 2), CA19-9 > 37.0 U/mL (+ 2), and ECOG PS ≥ 1 (+ 2) in the FTD/TPI group. These corresponded to a total prognostic score of > 5, 2-4, and 0 points in the regorafenib group and 8, 2-6, and 0 points in the FTD/TPI group. The median OS in the low, moderate, and high OS benefit group was 3.3 (95% CI 3.0-3.7), 8.1 (95% CI 6.4-9.7), and 12.6 months (95% CI 10.6-14.6) in the regorafenib group and 2.8 (95% CI 2.0-3.5), 7.5 (95% CI 6.6-8.3), and 15.4 months (95% CI 9.7-21.2) in the FTD/TPI group. CONCLUSION: These prognostic scores are useful for identifying patients with mCRC who will obtain survival benefits from these drugs.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Idoso , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Timina , Resultado do Tratamento , Uracila/uso terapêutico
17.
Clin Transl Oncol ; 22(3): 351-359, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31073972

RESUMO

INTRODUCTION: Trifluridine/tipiracil combination has shown a benefit over placebo in the treatment of patients with chemorefractory metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of this combination in the real-life setting at eight Galician centers in Spain. PATIENTS AND METHODS: This is a retrospective study of a cohort of patients with mCRC in treatment with trifluridine/tipiracil within usual clinical practice who have been previously treated or are not considered candidates for treatment with available therapies. RESULTS: A total of 160 mCRC patients were included. Our data showed that 11.9% of patients achieved disease control. Median progression-free survival was 2.75 months; at 5.66 months follow-up, median overall survival was 7.94 months. Asthenia and neutropenia (48.1% both) were the most frequent adverse events. Overall survival was lower in patients with ECOG 2, multiple metastatic sites, platelets count 350,000/µl, alkaline phosphatase > 500 IU/l, and carcinoembryonic antigen > 10 ng/ml. CONCLUSION: The results of this study confirm the efficacy and safety of trifluridine/tipiracil in chemorefractory mCRC patients. However, patients in clinical practice differ from patients in clinical trials. Due to this, prognostic factors have special importance to offer the best therapeutic approach.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Nomogramas , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Intervalo Livre de Progressão , Pirrolidinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Espanha , Taxa de Sobrevida , Timina , Trifluridina/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêutico
18.
Int J Colorectal Dis ; 35(2): 295-306, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31848739

RESUMO

PURPOSE: Direct randomized comparisons of regorafenib, TAS-102, and fruquintinib for treating metastatic colorectal cancer (mCRC) are lacking. Here, we evaluated the efficacy and safety of three agents by a systematic review and a network meta-analysis. METHODS: We included phase III randomized controlled trials in the PubMed, Embase, and Scopus Cochrane databases and ClinicalTrials.gov registry from initiation until January 2019. Data from randomized controlled trials including overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were extracted. Direct meta-analysis and indirect meta-analysis using network meta-analysis were assessed. RESULTS: Five trials comprising a total of 2586 patients were included. For efficacy analysis of OS, no statistically significant differences were observed between regorafenib and TAS-102 (HR 0.945, 95% CI [0.677, 1.320], P = 0.753), regorafenib and fruquintinib (HR 1.056, 95% CI [0.690, 1.621], P = 0.814), or TAS-102 and fruquintinib (HR 1.117, 95% CI [0.740, 1.685], P = 0.610). However, fruquintinib was superior in PFS compared with TAS-102 (HR 1.756, 95% CI [1.079, 2.857], P = 0.023). Regorafenib and TAS-102 appeared to have a similar effect on PFS (HR 0.907, 95% CI [0.611, 1.346], P = 0.641), as did regorafenib and fruquintinib (HR 1.592, 95% CI [0.968, 2.618], P = 0.067). None of the three agents were better in terms of all grade AEs or any grade of 3-5 AEs. However, subgroup analysis of AEs exhibited different toxicity profiles between the three drugs. CONCLUSIONS: Indirect comparison suggested that the three agents had similar OS but that fruquintinib was superior in terms of PFS compared with that of TAS-102. These three agents had different toxicity profiles.


Assuntos
Antineoplásicos/uso terapêutico , Benzofuranos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Quinazolinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Antineoplásicos/efeitos adversos , Benzofuranos/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Metanálise em Rede , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Quinazolinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Timina , Fatores de Tempo , Trifluridina/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêutico
19.
Clin Transl Oncol ; 22(3): 337-343, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31041716

RESUMO

BACKGROUND AND AIM: Trifluridine/tipiracil (TAS102), a novel oral cytotoxic chemotherapy, significantly improved overall survival compared with placebo in heavily pretreated advanced gastric cancer. This study aimed to evaluate the cost-effectiveness of TAS102 in the third-line or later treatment for this population from the US payer perspective. METHODS: A Markov model was developed to simulate advanced gastric cancer, including three health states: progression-free survival (PFS), progressive disease (PD) and death. Model inputs were derived from a randomised, double-blind, placebo-controlled, phase 3 trial (TAGS trial, NCT02500043). Utilities were extracted from public resources. Costs were calculated from an American payer perspective. Sensitivity analyses were conducted to explore the impact of uncertainty. RESULTS: From the US payer perspective, treatment with TAS102 for patients with heavily pretreated advanced gastric cancer was estimated to increase costs by $59,180 compared with the placebo, with a gain of 0.06 quality-adjusted life years (QALYs) for an incremental cost-effectiveness ratio (ICER) of $986,333 per QALY. The costs for progression-free survival of TAS102 group had the greatest impact on the ICERs, as well as the cost of TAS102. CONCLUSION: Trifluridine/tipiracil (TAS102) is not a cost-effective choice for patients with heavily pretreated metastatic gastric cancer from an American payer perspective.


Assuntos
Pirrolidinas/economia , Neoplasias Gástricas/tratamento farmacológico , Trifluridina/economia , Uracila/análogos & derivados , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Combinação de Medicamentos , Custos de Medicamentos , Humanos , Cadeias de Markov , Intervalo Livre de Progressão , Pirrolidinas/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Neoplasias Gástricas/secundário , Timina , Trifluridina/uso terapêutico , Uracila/economia , Uracila/uso terapêutico
20.
J Diabetes Investig ; 11(2): 373-381, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31389201

RESUMO

INTRODUCTION: To investigate the efficacy and safety of trelagliptin 25 mg in patients with type 2 diabetes mellitus with severe renal impairment or end-stage renal disease. MATERIALS AND METHODS: This multicenter, randomized, phase 3 study comprised a 12-week double-blind phase followed by a 40-week open-label phase. Patients had type 2 diabetes mellitus with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease (undergoing hemodialysis), and were receiving diet and/or exercise therapy with/without one antidiabetic drug. RESULTS: Patients were randomized to trelagliptin (A/A, n = 55) or placebo (P/A, n = 52; double-blind phase). Both groups received trelagliptin in the open-label phase. The least square mean change (95% confidence interval [CI]) from baseline in hemoglobin A1c at the end of the double-blind phase was -0.71% (95% CI -0.885, -0.542) and 0.01% (95% CI -0.170, 0.183) in the A/A and P/A groups, respectively (intergroup least square means difference -0.72%, 95% CI -0.966, -0.473; P < 0.0001). Mean hemoglobin A1c decreased after trelagliptin treatment in the P/A group to similar levels observed in the A/A group and remained comparable in both groups versus baseline up to week 52. In the double-blind phase, the incidence of treatment-emergent adverse events (TEAEs) was 72.7% and 61.5% in the A/A and P/A group, respectively; most TEAEs were mild-to-moderate, except in one patient (P/A group), who experienced two severe TEAEs. The incidence of serious TEAEs was 7.3% and 3.8% in the A/A and P/A group, respectively. CONCLUSIONS: Once-weekly trelagliptin 25 mg was efficacious, with no major safety concerns, and represents a meaningful treatment option in this patient population.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Falência Renal Crônica/complicações , Insuficiência Renal/complicações , Uracila/análogos & derivados , Idoso , Grupo com Ancestrais do Continente Asiático , Diabetes Mellitus Tipo 2/complicações , Dietoterapia , Método Duplo-Cego , Terapia por Exercício , Feminino , Hemoglobina A Glicada/análise , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Uracila/uso terapêutico
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