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1.
Cochrane Database Syst Rev ; 10: CD012796, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33058158

RESUMO

BACKGROUND: Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review. OBJECTIVES: To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy. SEARCH METHODS: We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020. SELECTION CRITERIA: We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach. MAIN RESULTS: We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants.  4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants. AUTHORS' CONCLUSIONS: Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/uso terapêutico , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Viés , Carcinoma de Células Renais/mortalidade , Everolimo/efeitos adversos , Everolimo/uso terapêutico , Humanos , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Qualidade de Vida , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sirolimo/efeitos adversos , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Sorafenibe/efeitos adversos , Sorafenibe/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Sunitinibe/efeitos adversos , Sunitinibe/uso terapêutico
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(10): 1488-1492, 2020 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-33118519

RESUMO

OBJECTIVE: To compare the effects of medical ozone oil and urea ointment for prevention and treatment of hand-foot skin reaction (HFSR) caused by sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: A total of 99 patients diagnosed with advanced HCC according to National Comprehensive Cancer Network (NCCN) who were scheduled to receive sorafenib treatment for the first time were enrolled in this study between April, 2018 and January, 2020. The patients were randomized into medical ozone oil group (n=49) and urea ointment group (control group, n=49) for treatment with local application of 1 mL medical ozone oil (experimental group) and 10% urea ointment (2 g) on the palm and plantar skin (including the fingers and joints) for 12 weeks (3 times per day) starting at the beginning of sorafenib treatment, respectively. The patients were observed for occurrence of HFSR every 2 weeks for 14 weeks. RESULTS: Eight patients were excluded for poor compliance or protocol violations, leaving a total of 91 patients for analysis, including 44 in medical ozone oil group and 47 in urea ointment group. Sixteen (36.4%) of patients in ozone oil group developed HFSR, a rate significantly lower than that in urea ointment group (57.4%; P < 0.05). The incidence of grade 2/3 HFSR was also lower in ozone oil group than in urea ointment group (15.9% [7/44] vs 27.7 [13/47]). CONCLUSIONS: Medical ozone oil can significantly reduce the incidence and severity of HFSR to improve the quality of life of HCC patients receiving sorafenib treatment.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular , Síndrome Mão-Pé , Neoplasias Hepáticas , Ozônio , Sorafenibe/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Síndrome Mão-Pé/tratamento farmacológico , Síndrome Mão-Pé/etiologia , Síndrome Mão-Pé/prevenção & controle , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/uso terapêutico , Ozônio/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Qualidade de Vida , Sorafenibe/uso terapêutico
4.
Anticancer Res ; 40(9): 5271-5276, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878816

RESUMO

BACKGROUND/AIM: Hepatic encephalopathy is an adverse event resulting from lenvatinib use in patients with hepatocellular carcinoma (HCC). We analyzed the influence of lenvatinib on portal venous flow velocity (PVV) and serum ammonia concentration. PATIENTS AND METHODS: Eleven patients with unresectable HCC were enrolled, including three with modified albumin-bilirubin (mALBI) grade 1, three with grade 2a, and five with grade 2b. PVV was measured by Doppler ultrasound sonography before and on day 2 of administration. RESULTS: Out of 11 patients, one developed hepatic encephalopathy. PVV was reduced in 10 patients, and the change from baseline was significantly correlated with lenvatinib dosage. The increase in serum ammonia concentration was affected by lenvatinib dose and baseline hepatic function as a threshold between mALBI grade 2a and 2b statistically. There was no correlation between changes in PVV and serum ammonia concentration. CONCLUSION: Lenvatinib might directly disturb hepatocyte metabolism to result in increased serum ammonia concentration.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/tratamento farmacológico , Hiperamonemia/etiologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Bilirrubina/sangue , Carcinoma Hepatocelular/diagnóstico , Suscetibilidade a Doenças , Feminino , Encefalopatia Hepática/diagnóstico , Encefalopatia Hepática/etiologia , Humanos , Hiperamonemia/diagnóstico , Testes de Função Hepática , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Veia Porta/fisiopatologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Fatores de Risco
5.
Ann Hematol ; 99(9): 1989-2007, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32683457

RESUMO

Several small molecule inhibitors (SMIs) have been recently approved for AML patients. These targeted therapies could be more tolerable than classical antineoplastics, but potential drug-drug interactions (DDI) are relatively frequent. Underestimation or lack of appropriate awareness and management of DDIs with SMIs can jeopardize therapeutic success in AML patients, which often require multiple concomitant medications in the context of prior comorbidities or for the prevention and treatment of infectious and other complications. In this systematic review, we analyze DDIs of glasdegib, venetoclax, midostaurin, quizartinib, gilteritinib, enasidenib, and ivosidenib. CYP3A4 is the main enzyme responsible for SMIs metabolism, and strong CYP3A4 inhibitors, such azoles, could increase drug exposure and toxicity; therefore dose adjustments (venetoclax, quizartinib, and ivosidenib) or alternative therapies or close monitoring (glasdegib, midostaurin, and gilteritinib) are recommended. Besides, coadministration of strong CYP3A4 inducers with SMIs should be avoided due to potential decrease of efficacy. Regarding tolerability, QTc prolongation is frequently observed for most of approved SMIs, and drugs with a potential to prolong the QTc interval and CYP3A4 inhibitors should be avoided and replaced by alternative treatments. In this study, we critically assess the DDIs of SMIs, and we summarize best management options for these new drugs and concomitant medications.


Assuntos
Antineoplásicos/sangue , Inibidores do Citocromo P-450 CYP3A/sangue , Aprovação de Drogas , Interações Medicamentosas/fisiologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/metabolismo , Humanos , Síndrome do QT Longo/sangue , Síndrome do QT Longo/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Estaurosporina/efeitos adversos , Estaurosporina/análogos & derivados , Estaurosporina/sangue , Sulfonamidas/efeitos adversos , Sulfonamidas/sangue
6.
Expert Opin Pharmacother ; 21(14): 1667-1674, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32674616

RESUMO

INTRODUCTION: Uterine fibroids (UF) are benign tumors common in premenopausal women, with strong impact on the health-care systems. For many years, surgery represented the only therapy for symptomatic fibroids. However, clinicians are observing a switch from surgery to noninvasive methods; in particular, medical treatment has been shown to be efficacious in obtaining a bleeding reduction and in ameliorating patient conditions. AREAS COVERED: The authors review the current options available for the treatment of women with UF, with a special focus on the newest one, relugolix. It is an orally active non-peptide Gonadotropin-releasing hormone (GnRH)-receptor antagonist recently licensed for women with symptomatic fibroids. Relugolix is a well-tolerated safe drug; it is effective in inducing a dose-dependent decrease in menstrual blood loss, with faster reduction of heavy menstrual bleeding (HMB) and a greater shrinkage in fibroid volume compared to the current standard of GnRH agonist treatment. EXPERT OPINION: Relugolix is a promising drug for the non-surgical treatment of women with UF. To date, the only published data come from a well-selected Japanese female population study while results from worldwide ongoing studies are ongoing in order to confirm the efficacy of this GnRH agonist receptor.


Assuntos
Leiomioma/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinonas/uso terapêutico , Receptores LHRH/antagonistas & inibidores , Neoplasias Uterinas/tratamento farmacológico , Feminino , Humanos , Histerectomia , Leiomioma/metabolismo , Leiomioma/cirurgia , Menstruação/efeitos dos fármacos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Pré-Menopausa/efeitos dos fármacos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/cirurgia
7.
Medicine (Baltimore) ; 99(26): e20719, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590747

RESUMO

BACKGROUND: Regorafenib, a multitargeted tyrosine kinase inhibitor, proved to be active in patients with soft tissue sarcomas (STS). METHODS: We conducted an open-label, non-randomized, single-center phase II study in advanced pretreated STS patients. Patients received regorafenib 160 mg daily on days 1 enrule 21 of a 28-day cycle. The primary endpoint was the progression-free survival (PFS) at 8 weeks. Toxicity was registered. RESULTS: Between April 2015 and November 2016, 21 patients were enrolled in the trial. A total of 13 out of 21 evaluable patients (61.9%) were progression-free at 8 weeks. Median PFS was 3.8 months (95% CI: 2.1-9.4). Median overall survival was 14.8 months (95% CI: 7.7-27.8). In the intention-to-treat population, we reported a PFS of 66.7% at 3 months (95% CI: 40.4-83.4) and 16.7% at 12 months (95% CI: 4.1-36.5). As per the RECIST criteria, the response rate was 4.7% (1 partial response out of 21 evaluable patients) with a clinical benefit rate of 61.9%; no complete response was observed. Treatment was well tolerated. CONCLUSION: Regorafenib shows signs of clinical activity in patients with advanced STS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02307500.


Assuntos
Neoplasias Ovarianas , Neoplasias Pancreáticas , Compostos de Fenilureia , Piridinas , Sarcoma , Timoma , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Monitoramento de Medicamentos/métodos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Timoma/tratamento farmacológico , Timoma/patologia , Resultado do Tratamento
8.
Lancet Oncol ; 21(6): 843-850, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502444

RESUMO

BACKGROUND: Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma. METHODS: This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777. FINDINGS: Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p<0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events. INTERPRETATION: The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma. FUNDING: Center for Clinical Trials, Japan Medical Association.


Assuntos
Antineoplásicos/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Progressão da Doença , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Timoma/enzimologia , Timoma/mortalidade , Timoma/secundário , Neoplasias do Timo/enzimologia , Neoplasias do Timo/mortalidade , Neoplasias do Timo/patologia , Fatores de Tempo
9.
Lancet Oncol ; 21(8): 1057-1065, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32589866

RESUMO

BACKGROUND: Pembrolizumab, an anti-PD-1 antibody, results in tumour response in around 15% of patients with advanced gastric cancer who have a PD-L1 combined positive score of at least 1. Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased tumour-associated macrophages and increased infiltration of CD8 T cells, resulting in enhanced anti-tumour activity of PD-1 inhibitors in an in-vivo model. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced gastric cancer in a phase 2 study. METHODS: This study was an open-label, single-arm, phase 2 trial undertaken at the National Cancer Center Hospital East (Chiba, Japan). Eligible patients were aged 20 years or older and had metastatic or recurrent adenocarcinoma of the stomach or gastro-oesophageal junction, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), irrespective of the number of previous lines of treatment. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks until disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate according to RECIST, analysed in all patients who were eligible and received protocol treatment at least once. The safety analysis included all those who received protocol treatment at least once, regardless of eligibility. This study is registered at ClinicalTrials.gov, NCT03609359, and enrolment is complete. FINDINGS: Between Oct 15, 2018, and March 25, 2019, 29 patients were enrolled in the first-line or second-line settings. At data cutoff (March 20, 2020), the median follow-up was 12·6 months (IQR 10·5-14·3). 20 (69%, 95% CI 49-85) of 29 patients had an objective response. The most common grade 3 treatment-related adverse events were hypertension (in 11 [38%] patients), proteinuria (five [17%]), and platelet count decrease (two [7%]). No grade 4 treatment-related adverse events, serious treatment-related adverse events, or treatment-related deaths occurred. INTERPRETATION: Lenvatinib plus pembrolizumab showed promising anti-tumour activity with an acceptable safety profile in patients with advanced gastric cancer. On the basis of these results, a confirmatory trial will be planned in the future. FUNDING: Merck Sharp & Dohme.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos
11.
N Engl J Med ; 382(23): 2187-2196, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32469183

RESUMO

BACKGROUND: Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known. METHODS: In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients. RESULTS: A total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88). CONCLUSIONS: In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.).


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Leuprolida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Pirimidinonas/uso terapêutico , Testosterona/sangue , Adenocarcinoma/sangue , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Injeções Subcutâneas , Leuprolida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Neoplasias da Próstata/sangue , Pirimidinonas/efeitos adversos
12.
Anticancer Res ; 40(4): 2089-2093, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234901

RESUMO

BACKGROUND/AIM: The outcomes of ramucirumab after lenvatinib failure for hepatocellular carcinoma (HCC) patients with alpha fetoprotein (AFP) levels of ≥400 ng/ml are unknown. PATIENTS AND METHODS: Of 12 patients treated with ramucirumab after lenvatinib failure, 10 patients were enrolled in this retrospective study. RESULTS: The disease control rate of 80% at 6 weeks and the median time to progression of 3.1 months were the same by both the Response Evaluation Criteria in Solid Tumors (RECIST) and the modified RECIST. AFP reduction was seen in 5 patients at 2 weeks and in 3 patients at 6 weeks. The incidence of grade 3 adverse events was low at 10%. The albumin-bilirubin scores within 6 weeks did not worsen. CONCLUSION: Ramucirumab might have potential therapeutic efficacy and safety in advanced HCC patients after lenvatinib failure. Further studies are needed to confirm the outcomes of ramucirumab after lenvatinib failure.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/genética , Bilirrubina/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos de Fenilureia/efeitos adversos , Quinolinas/efeitos adversos , Estudos Retrospectivos , alfa-Fetoproteínas/genética
13.
Int J Clin Oncol ; 25(7): 1278-1284, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32347432

RESUMO

BACKGROUND: Proteinuria induced by lenvatinib is a class effect that occurs secondary to VEGFR suppression. Withholding of lenvatinib is required in cases with severe proteinuria. Urine protein-creatinine ratio (UPCR, g/gCre) has recently attracted attention as an alternative to 24-h urine collection for assessing proteinuria. The aim of this study was to examine the correlation between the results of proteinuria assessed by the dipstick test and UPCR, and to investigate the influence of proteinuria grading with UPCR on lenvatinib dose adjustment compared to that with only the dipstick test. METHOD: Three hundred and ten urine samples from 63 patients with advanced thyroid cancer under treatment with lenvatinib, which were tested by both the dipstick test and UPCR were analyzed. Lenvatinib was withheld when there was evidence of CTCAE grade 3 proteinuria, and restarted when it resolved. The frequency of proteinuria, correlation between the results of the dipstick test and UPCR test, and the effect of dose withholding in cases with results of 3 + in the dipstick test were calculated. RESULTS: Proteinuria was seen in 56 (88.9%) patients. Of the 154 dipstick 3 + samples, only 56 (36.4%) were judged as more than 3.5 g/gCre by UPCR (grade 3 proteinuria), although none of the 1 + and only 3.7% of 2 + samples were judged as grade 3 proteinuria. We were able to prevent unnecessary lenvatinib interruption due to proteinuria in 63.6% of dipstick 3 + samples by assessment of UPCR. CONCLUSIONS: Urinalysis by combination of the dipstick test and UPCR assessment might be a better strategy for preventing unnecessary interruption of lenvatinib.


Assuntos
Antineoplásicos/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Proteinúria/induzido quimicamente , Quinolinas/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Urinálise/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Creatinina/urina , Feminino , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Proteinúria/diagnóstico , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/urina
14.
PLoS One ; 15(4): e0231828, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32310967

RESUMO

Lenvatinib is an approved first-line therapy for unresectable hepatocellular carcinoma (HCC), but the effect of dose modification on its efficacy is unclear. We analyzed the relationship between the relative dose intensity during the initial 4 weeks of therapy [4W-relative dose intensity (RDI)] and the efficacy of lenvatinib therapy in the real-world setting. A total of 48 consecutive patients with unresectable HCC who received lenvatinib therapy for more than 4 weeks were included. The 4W-RDI was calculated as the cumulative dose in the initial 4 weeks divided by the weight-based standard dose, and we evaluated its association with overall survival (OS) and best response by modified Response Evaluation Criteria in Solid Tumor (mRECIST). The baseline factors predicting high 4W-RDI were analyzed further. The median durations of follow-up and of therapy among the 48 participants were 7.6 and 6.6 months, respectively. The median OS was not reached. Drug interruption and/or dose reduction were necessary in 30 patients (62.5%) and the median 4W-RDI was 70% (range 22%-100%). Patients with 4W-RDI ≥70% had longer OS [hazard ratio (HR) 0.28, 95% confidential interval (CI):0.09-0.90, p = 0.03], and longer duration of lenvatinib therapy (HR 0.39, 95%CI:0.16-0.92, p = 0.03). Patients with 4W-RDI ≥70% showed higher disease control rate compared to those with 4W-RDI <70% (91.7% vs. 54.2%, p = 0.008). A baseline albumin level >3.4g/dL or ALBI score less than -2.171 were significantly associated with achieving 4W-RDI ≥70%. In conclusion, 4W-RDI of lenvatinib therapy is associated with favorable radiological response and longer OS.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Análise de Sobrevida
15.
PLoS One ; 15(3): e0229772, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126131

RESUMO

BACKGROUND: Fatigue is a common adverse event during lenvatinib treatment in patients with hepatocellular carcinoma. One mechanism contributing to development of fatigue might involve abnormal adenosine triphosphate synthesis that is caused by carnitine deficiency. To address this possibility, we examined the relationship between carnitine levels and fatigue during lenvatinib treatment. METHODS: This prospective study evaluated 20 patients with hepatocellular carcinoma who underwent lenvatinib treatment. Both blood and urine samples were collected from the patients before starting lenvatinib therapy (day 0), and on days 3, 7, 14, and 28 thereafter. Plasma and urine concentrations of free and acyl carnitine (AC) were assessed at each time point. The changes in daily fatigue were evaluated using the Brief Fatigue Inventory (BFI). RESULTS: Plasma levels of free carnitine (FC) at days 3 and 7 were significantly higher compared with baseline (p = 0.005, p = 0.005, respectively). The urine FC level at day 3 was significantly higher compared with baseline (p = 0.030) and that of day 7 tended to be higher compared with baseline (p = 0.057). The plasma AC concentration at days 14 and 28 was significantly higher compared with that of baseline (p = 0.002, p = 0.005, respectively). The plasma AC-to-FC (AC/FC) ratio on days 14 and 28 was significantly higher compared with baseline (p = 0.001, p = 0.003, respectively). There were significant correlations between the plasma AC/FC ratio and the change in the BFI score at days 14 and 28 (r = 0.461, p = 0.041; r = 0.770, p = 0.002, respectively). CONCLUSIONS: Longitudinal assessments of carnitine and fatigue in patients with hepatocellular carcinoma suggest that lenvatinib affects the carnitine system in patients undergoing lenvatinib therapy and that carnitine insufficiency increases fatigue. The occurrence of carnitine insufficiency may be a common cause of fatigue during the treatment.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Cardiomiopatias/induzido quimicamente , Carnitina/deficiência , Fadiga/etiologia , Hiperamonemia/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Quinolinas/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/urina , Cardiomiopatias/sangue , Cardiomiopatias/complicações , Cardiomiopatias/dietoterapia , Carnitina/administração & dosagem , Carnitina/sangue , Carnitina/urina , Suplementos Nutricionais , Fadiga/sangue , Fadiga/diagnóstico , Fadiga/prevenção & controle , Feminino , Humanos , Hiperamonemia/sangue , Hiperamonemia/complicações , Hiperamonemia/dietoterapia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/urina , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doenças Musculares/sangue , Doenças Musculares/complicações , Doenças Musculares/dietoterapia , Estudos Prospectivos , Resultado do Tratamento
16.
Tokai J Exp Clin Med ; 45(1): 18-23, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32219805

RESUMO

A 61-year-old female was diagnosed with multiple endocrine neoplasia type 2A (MEN2A), caused by a heterozygous point mutation in the RET gene (TGC to TAC at codon 634) resulting in the substitution of cytosine with leucine (C634Y). The patient had pheochromocytoma (PCC) in the left adrenal gland and medullary thyroid carcinoma (MTC) with liver metastasis. Primary hyperparathyroidism (PHP) was not evident. Family history data suggested that the RET gene mutation was inherited from the father. The PCC was removed laparoscopically, but the MTC was observed conservatively for 7 years because the status of the MTC was compatible with T1N1M1 and stage IVC; therefore, it was not curable with surgery. The MTC liver metastasis increased in size. Lenvatinib, an oral multi-tyrosine kinase inhibitor, was administered until the patient had received a total dose of 1336mg, and then administration was stopped because of nausea. The reduction rate of the MTC liver metastasis was 31%, which was considered partial response. At this point, the patient was doing well, suggesting that lenvatinib was effective in treating the MTC liver metastasis and may be one of the treatment for advanced MTC caused by C634Y mutation in the RET gene.


Assuntos
Carcinoma/etiologia , Carcinoma/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasia Endócrina Múltipla Tipo 2a/complicações , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/etiologia , Carcinoma/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/genética , Compostos de Fenilureia/efeitos adversos , Mutação Puntual , Proteínas Proto-Oncogênicas c-ret/genética , Quinolinas/efeitos adversos , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia
18.
Expert Opin Pharmacother ; 21(5): 523-530, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32027196

RESUMO

Introduction: Despite recent advances in the treatment of adult acute myelogenous leukemia (AML), the overall outcome remains dismal especially in high-risk AML patients, including the elderly and the relapsed/refractory populations. In this setting, various clinical trials have recently explored novel therapeutic agents either used alone or in combination with intensive chemotherapy or low-intensity treatments.Areas covered: The current paper reviews the clinical development of glasdegib, a selective inhibitor of the Hedgehog signaling pathway through binding to its target SMO, for the treatment of AML.Expert opinion: Glasdegib confirmed its efficacy and showed an acceptable tolerability, especially when used in combination either with '3 + 7' chemotherapy or with low-intensity therapies. In 2018, glasdegib was approved by the Food and Drug Administration (FDA) in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients older than 75 years or presenting with severe comorbidities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Citarabina/uso terapêutico , Proteínas Hedgehog/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Humanos , Leucemia Mieloide Aguda/metabolismo , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Transdução de Sinais , Estados Unidos , United States Food and Drug Administration
19.
Cancer Treat Rev ; 84: 101966, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32044644

RESUMO

Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.


Assuntos
Inibidores da Angiogênese/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Anilidas/efeitos adversos , Anilidas/farmacologia , Anilidas/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/farmacologia , Axitinibe/uso terapêutico , Interações Medicamentosas , Humanos , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Sorafenibe/efeitos adversos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Sunitinibe/efeitos adversos , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico
20.
Eur J Cancer ; 126: 45-55, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31918233

RESUMO

BACKGROUND: Metastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib. PATIENTS AND METHODS: This double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours-based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743). RESULTS: From December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4-not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15-0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23-1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0). CONCLUSION: The present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dor no Peito/induzido quimicamente , Estudos Cross-Over , Diarreia/induzido quimicamente , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento
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