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1.
Anticancer Res ; 39(9): 5149-5156, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519627

RESUMO

BACKGROUND: Factors associated with response to lenvatinib have not been clarified in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This study retrospectively analyzed 50 patients treated with lenvatinib as first-line therapy between March 2018 and March 2019. Patients were divided into two groups by the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) (responders and non-responders, whose best overall responses were complete (CR)/partial response (PR) and stable (SD)/progressive disease (PD), respectively). Factors associated with response were assessed, including the relative dose intensity 8 weeks after lenvatinib induction (8W-RDI). RESULTS: The best overall responses were 0/22/14/14 of CR/PR/SD/PD. Multivariate analysis revealed that only 8W-RDI was significantly associated with response. The receiver operating characteristic curve for 8W-RDI in differentiating responders from non-responders revealed a cut-off value of 75%. Patients with 8W-RDI ≥75% experienced a higher response rate and longer progression-free survival than patients with 8W-RDI <75%. CONCLUSION: Our results suggest that maintaining an RDI ≥75% during the initial 8 weeks of lenvatinib treatment has a favorable impact on response.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento
2.
Anticancer Res ; 39(7): 3871-3878, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262915

RESUMO

BACKGROUND: Lenvatinib has become an important treatment option for advanced thyroid cancer. Fistula and tumor-related bleeding are life-threatening adverse effects that are triggered by tumor shrinkage. The aim of this study was to evaluate basic parameters, such as time and tumor shrinkage level, and analyze patient characteristics that might be related to onset of complications. PATIENTS AND METHODS: A retrospective study of 16 patients who received lenvatinib for thyroid cancer treatment was performed. RESULTS: Fistula was observed in two patients (12.5%), while tumor-related bleeding was observed in one (6.3%). Complications were found to appear at 10.4 weeks from initiation and with tumor decrease of 19.2%. Risk factors for complications were identified as anaplastic histological type, tumor invasion, and leukocytopenia induced by lenvatinib. CONCLUSION: Individual dose adjustment is needed with respect to these features in order to manage severe adverse effects induced by lenvatinib.


Assuntos
Antineoplásicos/efeitos adversos , Fístula/induzido quimicamente , Hemorragia/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/patologia
3.
BMC Cancer ; 19(1): 582, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200667

RESUMO

BACKGROUND: Thyroid cancer is the most common endocrine malignancy. Some advanced disease is, or becomes, resistant to radioactive iodine therapy (refractory disease); this holds poor prognosis of 10% 10-year overall survival. Whilst Sorafenib and Lenvatinib are now licenced for the treatment of progressive iodine refractory thyroid cancer, these treatments require continuing treatment and can be associated with significant toxicity. Evidence from a pilot study has demonstrated feasibility of Selumetinib to allow the reintroduction of I-131 therapy; this larger, multicentre study is required to demonstrate the broader clinical impact of this approach before progression to a confirmatory trial. METHODS: SEL-I-METRY is a UK, single-arm, multi-centre, two-stage phase II trial. Participants with locally advanced or metastatic differentiated thyroid cancer with at least one measureable lesion and iodine refractory disease will be recruited from eight NHS Hospitals and treated with four-weeks of oral Selumetinib and assessed for sufficient I-123 uptake (defined as any uptake in a lesion with no previous uptake or 30% or greater increase in uptake). Those with sufficient uptake will be treated with I-131 and followed for clinical outcomes. Radiation absorbed doses will be predicted from I-123 SPECT/CT and verified from scans following the therapy. Sixty patients will be recruited to assess the primary objective of whether the treatment schedule leads to increased progression-free survival compared to historical control data. DISCUSSION: The SEL-I-METRY trial will investigate the effect of Selumetinib followed by I-131 therapy on progression-free survival in radioiodine refractory patients with differentiated thyroid cancer showing increased radioiodine uptake following initial treatment with Selumetinib. In addition, information on toxicity and dosimetry will be collected. This study presents an unprecedented opportunity to investigate the role of lesional dosimetry in molecular radiotherapy, leading to greater personalisation of therapy. To date this has been a neglected area of research. The findings of this trial will be useful to healthcare professionals and patients alike to determine whether further study of this agent is warranted. It is hoped that the development of the infrastructure to deliver a multicentre trial involving molecular radiotherapy dosimetry will lead to further trials in this field. TRIAL REGISTRATION: SEL-I-METRY is registered under ISRCTN17468602 , 02/12/2015.


Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Radioisótopos do Iodo/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Humanos , Terapia de Alvo Molecular , Estudos Multicêntricos como Assunto , Metástase Neoplásica , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Sorafenibe/efeitos adversos , Sorafenibe/uso terapêutico , Neoplasias da Glândula Tireoide/patologia , Reino Unido
4.
Drugs ; 79(6): 665-674, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30993651

RESUMO

Lenvatinib (Lenvima®) is an oral small molecule inhibitor of multiple receptor tyrosine kinases, and is approved for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) in the USA, EU, Japan and China. The approval of lenvatinib was based on results of the randomized, open-label, multinational, non-inferiority phase III REFLECT trial in patients with unresectable HCC, who had not received treatment for advanced disease. In REFLECT, lenvatinib was non-inferior, but not superior, to sorafenib (current standard of care) for overall survival (OS). However, lenvatinib was associated with significant improvements compared with sorafenib in terms of all secondary endpoints [higher objective response rate (ORR), and longer progression-free survival (PFS) and time to progression (TTP)]. Lenvatinib had a generally manageable tolerability profile in REFLECT, with the most common treatment-emergent adverse events being hypertension, diarrhoea, decreased appetite and decreased weight. Given its non-inferior efficacy to sorafenib and manageable tolerability profile, lenvatinib represents a long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC. Further clinical experience may be required to fully define the position of lenvatinib in this setting.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Resultado do Tratamento , Tirosina/antagonistas & inibidores
5.
Drugs ; 79(6): 675-679, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30937733

RESUMO

The orally active nonpeptide gonadotropin-releasing hormone (GnRH)-receptor antagonist relugolix (Relumina) is being developed by Takeda and ASKA Pharmaceutical as a treatment for various sex hormone related disorders. Relugolix was recently approved for marketing in Japan as a treatment for symptoms associated with uterine fibroids, and studies evaluating the efficacy of the drug as treatment for endometriosis-associated pain and prostate cancer are currently underway. This article summarizes the milestones in the development of relugolix leading to this first approval for the treatment of symptoms associated with uterine fibroids.


Assuntos
Antagonistas de Hormônios/uso terapêutico , Leiomioma/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinonas/uso terapêutico , Receptores LHRH/antagonistas & inibidores , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Aprovação de Drogas , Endometriose/tratamento farmacológico , Feminino , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/efeitos adversos , Antagonistas de Hormônios/farmacocinética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Neoplasias da Próstata/tratamento farmacológico , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Resultado do Tratamento
6.
J Cancer Res Clin Oncol ; 145(4): 1037-1042, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820715

RESUMO

PURPOSE: Antiangiogenic treatment approaches have failed to improve outcome in randomized trials of high-grade astrocytoma. One key mechanism of resistance to antiangiogenic treatment may concern the upregulation of alternative pro-angiogenic pathways. Regorafenib is a potent multikinase inhibitor that may alter some of those pathways. In this retrospective study, we investigated efficacy and radiographic tumor growth patterns of regorafenib in recurrent high-grade astrocytoma. METHODS: We screened for patients with high-grade astrocytoma in whom regorafenib was administered for at least 4 weeks. We assessed treatment efficacy in terms of progression-free survival (PFS), overall survival, and adverse events defined by Common Toxicity Criteria (CTC). In addition, radiographic tumor growth patterns were determined at baseline and recurrence. RESULTS: A total of 6 patients met eligibility criteria. The number of recurrences prior to regorafenib varied between 2 and 6. Patients were on regorafenib treatment for at least 4 weeks and maximally 14 weeks. Median PFS was 3.5 months and ranged from 2.0 to 4.0 months. Radiographic response was progressive disease in all patients with an objective response rate of 0%. CTC°3 adverse events were observed in all but one patient. The most common radiographic growth pattern was local with no change in growth pattern at recurrence. An infiltrative tumor growth was not induced in any patient. CONCLUSIONS: This retrospective study indicates a very poor performance of regorafenib in recurrent high-grade astrocytoma with a fairly high number of CTC°3 adverse events. In addition, regorafenib does not seem to bear a potential for infiltrative tumor growth promotion.


Assuntos
Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Adolescente , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Astrocitoma/irrigação sanguínea , Astrocitoma/diagnóstico por imagem , Astrocitoma/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Estudos Retrospectivos
7.
Medicine (Baltimore) ; 98(10): e14774, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30855484

RESUMO

Some patients with differentiated thyroid cancer (DTC) may require an initial low dose (LD) of lenvatinib. However, few studies have investigated the efficacy of LD lenvatinib. We compared the efficacy and tolerability of lenvatinib at an initial LD to those of the standard initial dose of 24 mg in patients with DTC.In this cross-sectional study, records of patients with DTC treated with lenvatinib were retrospectively reviewed. Patients were divided into 2 groups based on the initial dose of lenvatinib: a full-dose (FD) group that received an initial dose of 24 mg/d and a LD group that received an initial dose of less than 24 mg/d. Categorical variables were compared with the Fisher exact test and continuous variables with Student t test. A progression-free survival (PFS) curve was constructed with the Kaplan-Meier method. A probability (P) value of < .05 was considered statistically significant.Thirty-six patients with DTC were treated with lenvatinib (30 in the FD group and 6 in the LD group). The response rates were 43% and 33% in the FD and LD groups, respectively. The median PFS duration was 696 [95% confidence interval (CI): 318-not available (NA)] days in the FD group. The median PFS of the LD group was not reached (95% CI: 124-NA) (P = .293). Treatment interruptions were required in 25 (83%) patients in the FD group and 4 (67%) in the LD group (P = .573). Dose reductions were required in 28 (93%) patients in the FD group and 4 (67%) in the LD group (P = .121). There were no significant differences in the incidences of common adverse events between the 2 groups.The LD group also required dose reduction and interruption frequently. Since these findings are only the short-term results of a limited number of cases, a large number of cases and long-term observations are needed to determine whether an initial LD is effective for patients with DTC in poor general condition.


Assuntos
Antineoplásicos/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Quinolinas/efeitos adversos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
8.
Med Oncol ; 36(5): 39, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30919115

RESUMO

The aim of this study was to examine the association of lenvatinib-induced adverse events with the trough plasma concentration (C0) in Japanese patients with thyroid cancer. Patients received lenvatinib 24 mg as an initial dose, and sequential dose reductions were conducted based on the grade of each side effect. Assessment of adverse events, assay of lenvatinib C0, and analysis of clinical laboratory tests were performed at the same time of day and were retrospectively analyzed. There were no significant differences in lenvatinib C0 among grades of hypertension, proteinuria, hand-foot syndrome, and diarrhea. However, levels of aspartate transaminase, alanine transaminase, and total bilirubin were significantly higher in lenvatinib C0 quartile (Q) 4 (≥ 88 ng/mL) than in Q1 (< 42 ng/mL) and Q2-3 (42-88 ng/mL). Additionally, platelet counts were highest in the lowest Q1 group. The median dose of lenvatinib in patients with UGT1A1*6/*6 or *6/*28 (poor metabolizers [PMs]) was significantly lower than that in patients with UGT1A1*1/*1 (10 and 14 mg, respectively), whereas the median bilirubin levels were significant higher in UGT1A1 PMs (0.9 and 0.5 mg/dL, respectively). There were no significant differences in median lenvatinib C0 values between patients with UGT1A1*1/*1 and PMs (58.0 and 50.0 ng/mL, respectively). The threshold between the C0 and toxicity of lenvatinib may be more than 88 ng/mL. Therefore, the dose of lenvatinib could be controlled to maintain a lower C0 of less than 88 ng/mL. The target C0 for lenvatinib as the threshold between the C0 and optimal response may be in the range from 42 to 88 ng/mL; however, further studies are necessary.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Feminino , Genótipo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/sangue , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/sangue , Quinolinas/farmacocinética , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/genética
9.
Oncology ; 96(4): 200-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30763946

RESUMO

PURPOSE: Hand-foot skin reaction (HFSR) can deteriorate quality of life in patients receiving regorafenib. Cutaneous toxicity is a main adverse effect of multikinase inhibitors and has also been associated with clinical outcome. This study assessed the association between the antitumor efficacy of regorafenib and HFSR in patients with metastatic colorectal cancer (mCRC). METHODS: Patients who received regorafenib at 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they developed HFSR between May 2013 and October 2015. Estimates of overall survival and progression-free survival were calculated using the Kaplan-Meier method. RESULTS: Ninety-seven patients received at least one dose of regorafenib in this retrospective study. Of these patients, 81.4% (n = 79) experienced HFSR of any grade, and 34.0% (n = 33) had grade 3 HFSR. Among those patients with HFSR at any time during the study, 68.0% (n = 66) underwent the first HFSR event (any grade) during cycle 1. Both overall survival and progression-free survival were improved in patients who had HFSR grade ≥2 at any time compared with those who had HFSR grade ≤1. Multivariate logistic regression analysis revealed a history of HFSR grade ≥2 induced by capecitabine as a significant risk factor for severe HFSR (grade ≥2). CONCLUSIONS: Patients with mCRC treated using regorafenib who experienced severe HFSR showed better overall survival than patients without severe HFSR. Severe HFSR may offer an early surrogate marker for the efficacy of regorafenib in patients with mCRC.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Síndrome Mão-Pé/etiologia , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Síndrome Mão-Pé/diagnóstico , Síndrome Mão-Pé/mortalidade , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo
10.
Drugs ; 79(2): 207-213, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30666593

RESUMO

Glasdegib (DAURISMO™) is an oral inhibitor of the Hedgehog signalling pathway, the activation of which is associated with a number of malignancies. It has been developed by Pfizer and was approved in November 2018 in the USA for use in combination with low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukaemia (AML) in patients aged ≥ 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy. Glasdegib is the first Hedgehog pathway inhibitor to be approved for AML in the USA. It received orphan designation for the treatment of AML in the USA in June 2017 and in the EU in October 2017, and for the treatment of myelodysplastic syndrome (MDS) in the USA in October 2017. It is also undergoing clinical development for use in select haematological and other malignancies, including MDS, in various countries worldwide. This article summarizes the milestones in the development of glasdegib leading to its use in combination with low-dose cytarabine for the treatment of newly-diagnosed AML in patients aged ≥ 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Citarabina/uso terapêutico , Aprovação de Drogas , Europa (Continente) , Proteínas Hedgehog/metabolismo , Humanos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Transdução de Sinais , Estados Unidos
11.
Hepatol Int ; 13(2): 199-204, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30671808

RESUMO

BACKGROUND/PURPOSE: Lenvatinib (an inhibitor of vascular endothelial growth factor (GF) receptors 1-3, fibroblast GF receptors 1-4, platelet-derived GF receptor α, rearranged during transfection, and stem cell factor receptor) was non-inferior to sorafenib in a phase 3 (REFLECT) trial of advanced hepatocellular carcinoma. This study examined the efficacy and safety of lenvatinib in a real-world setting. METHODS: This was a retrospective, multicenter, observational study. Inclusion and exclusion criteria were based on the phase 3 trial, and participants were observed for at least 12 weeks. Therapeutic effect was determined using the modified Response Evaluation Criteria In Solid Tumors (m-RECIST) at the 8th week. Patients received oral lenvatinib 12 mg/day (body weight > 60 kg) or 8 mg/day (body weight < 60 kg). Dose interruptions followed by reductions for lenvatinib-related toxicities were permitted. Grades of adverse events (AEs) complied with the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: All 16 patients included in this study had prior treatment history, and a median 3.9 years had passed since the first treatment. Fatigue, hypertension, and proteinuria were the most frequent AEs, and were higher than Grade 2. AEs could be controlled by appropriate dose reduction, interruption, and symptomatic treatment according to the protocol. In the m-RECIST evaluation at the 8th week, 0, 6, 8, and 1 patients had achieved complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 40%. CONCLUSION: Lenvatinib treatment could be accomplished with safety and good response in a real-world setting.


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/efeitos adversos , Fadiga/induzido quimicamente , Feminino , Humanos , Hipertensão/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Proteinúria/induzido quimicamente , Quinolinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Resultado do Tratamento
12.
Semin Oncol ; 46(1): 57-64, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30685073

RESUMO

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, RET, KIT, and platelet-derived growth factor receptor-α. Lenvatinib is approved as a monotherapy for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the second-line treatment of advanced renal cell carcinoma. Lenvatinib is also under investigation for the treatment of several malignancies including unresectable hepatocellular carcinoma. Although lenvatinib is associated with favorable efficacy, it is associated with adverse events (AEs) that the clinician will have to closely monitor for and proactively manage. Most of these AEs are known class effects of VEGF-targeted therapies, including hypertension, diarrhea, fatigue or asthenia, decreased appetite, and weight loss. This review summarizes the safety profile of lenvatinib and offers guidance for the management of both frequent and rare AEs. We discuss the potential mechanisms underlying these AEs and present practical recommendations for managing toxicities. The development of treatment plans that include prophylactic and therapeutic strategies for the management of lenvatinib-associated AEs has the potential to improve patient quality of life, optimize adherence, minimize the need for dose reductions, treatment interruptions, or discontinuations, and maximize patient outcomes.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Radioisótopos do Iodo/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Quinolinas/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Everolimo/efeitos adversos , Everolimo/uso terapêutico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/epidemiologia
13.
Future Oncol ; 15(7): 717-726, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30638399

RESUMO

AIM: To investigate the safety and efficacy of lenvatinib in advanced thyroid cancer. PATIENTS/METHODS: In this Phase II study, 51 Japanese patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC), medullary thyroid cancer (MTC) or anaplastic thyroid cancer (ATC) received once-daily lenvatinib 24 mg. The primary end point was safety. RESULTS: All patients experienced ≥1 adverse event (AE); only one patient experienced an AE leading to discontinuation. The most common any-grade AEs were hypertension, decreased appetite, palmar-plantar erythrodysesthesia, fatigue and proteinuria. Response rates for RR-DTC: 68%; MTC: 22%; ATC: 24%. Median progression-free survival for RR-DTC: 25.8 months; MTC: 9.2 months; ATC: 7.4 months. CONCLUSION: Lenvatinib demonstrated a manageable safety profile, proven antitumor activity in RR-DTC and promising efficacy in MTC and ATC. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01728623.


Assuntos
Antineoplásicos/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Resistencia a Medicamentos Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Radioisótopos do Iodo/farmacologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento , Adulto Jovem
15.
Medicine (Baltimore) ; 97(41): e12705, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30313066

RESUMO

BACKGROUND: The present comparative meta-analysis was conducted to evaluate the cardiovascular events of regorafenib in patients with solid tumors. METHODS: Eligible studies from MEDLINE, Google Scholar, Cochrane Library, Clinical key, EBSCO publishing and Ovid, which had reported cardiovascular adverse events potentially caused by regorafenib were absorbed. Data of clinical characteristics and cardiovascular events including hypertension, hemorrhage, thrombosis, and heart failure were extracted from selected literatures for the final analysis. Pooled analysis of cardiovascular adverse events was developed by relative risks (RRs) and corresponding 95% confidence intervals (CIs) with software STATA 13.0 and RevMan 5.3. RESULTS: Thirty studies including 3813 patients were fit into analysis. The incidences of cardiovascular events of all-grade were: hypertension, 36.8% (95% CI, 29.8%-43.8%), hemorrhage, 8.6% (95% CI, 3.2%-14%), thrombosis, 1.4% (95% CI, 0.1%-2.8%), and heart failure, 2.9% (95% CI, 0.3%-5.6%). The incidences of cardiovascular events of high-grade were: hypertension, 9.9% (95% CI, 7.4%-12.4%), hemorrhage, 1.2% (95% CI, 0.3%-2.2%), thrombosis, 1.6% (95% CI, 0.2%-3.4%), and heart failure, 2.9% (95% CI, 0.3%-5.6%). The RRs and their 95% CIs of all-grade cardiovascular events among patients treated with regorafenib were: hypertension, 4.10 (95% CI, 3.07-5.46; P < .00001), hemorrhage, 2.71 (95% CI, 1.45-5.08; P = .002), thrombosis, 1.27 (95% CI, 0.49-3.27; P = .62), and heart failure, 0.79 (95% CI, 0.16-3.94; P = .77). The RRs and their 95% CIs of high-grade cardiovascular events among patients treated with regorafenib were: hypertension, 5.82 (95% CI, 3.46-9.78; P < .00001), hemorrhage, 0.90 (95% CI, 0.50-1.61; P = .72), thrombosis, 1.28 (95% CI, 0.48-3.41; P = .62), and heart failure, 1.15 (95% CI, 0.23-5.69; P = .86), respectively. CONCLUSION: The present meta-analysis has demonstrated that regorafenib is associated with an increasing risk of hypertension at all-grade and high-grade, as well as hemorrhage at all-grade. Adequate awareness of cardiovascular adverse events of regorafenib should be established for clinicians.


Assuntos
Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/efeitos adversos , Piridinas/efeitos adversos , Antineoplásicos/uso terapêutico , Humanos , Incidência , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Medição de Risco , Fatores de Risco
16.
Medicine (Baltimore) ; 97(40): e12635, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30290640

RESUMO

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) often suffer from progressive disease despite previous therapy. It has been a great challenge for those patients. In 2012, regorafenib was approved for mCRC. In this meta-analysis, we aimed to collect and present existing data to explorethe clinical use of regorafenib. METHODS: The online electronic databases, such as PubMed, Embase, and the Cochrane library, updated to November 2017 were systematically searched. Trials on the effectiveness of regorafenib in patients who suffer from treatment-refractory metastatic colorectal cancer were included, of which the main outcomes included 3 parameters: overall survival (OS), progression-free survival (PFS), and grade 3/4 AE. RESULTS: Totally, 4 trials were included in this meta-analysis. The OD was significantly better with the use of regorafenib (OR = 0.78, 95%CI = 0.65-0.94, I = 69%, P = .008), and PFS (OR = 0.52, 95%CI = 0.34-0.79, I = 97%, P = .002). However, the most common toxicities occurred more frequently in the regorafenib group than the control group (OR = 3.73, 95%CI = 1.68-8.28, I = 79%, P = .001). CONCLUSION: Regorafenib demonstrates better efficacy and has manageable adverse-event profile for treatment-refractory mCRC. Considering the safety feature of regorafenib, further studies and clinical trials are warranted to investigate the dosing of regorafenib and alternative approaches are needed to explore predictive biomarker fortherapy selection.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Humanos , Metástase Neoplásica , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Análise de Sobrevida
17.
Anticancer Res ; 38(9): 5283-5288, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30194179

RESUMO

BACKGROUND/AIM: The aim of the present study was to examine the effect of orally administered sorafenib (Nexavar®), sunitinib (Sutent®) and capecitabine (Xeloda®), which cause palmoplantar erythrodysesthesia (PPE), on the antioxidant status of the skin and the formation of free radicals. PATIENTS AND METHODS: A total of 42 patients were enrolled, of which 36 (85%) completed the study. Overall, 19 received capecitabine (2,000-4,000 mg per day), 10 sunitinib (25-50 mg per day) and 7 sorafenib (400-800 mg per day). Cutaneous carotenoids as markers of the antioxidant status of the skin were measured 1 day before the first oral administration (Tbase) and at day 18 of treatment (T1). RESULTS: The mean antioxidant concentrations increased significantly in patients treated with sunitinib from 3.99±1.01 to 4.68±1.32, p=0.047 and sorafenib from 4.83±0.74 to 5.3±0.78, p=0.007. Treatment with capecitabine did not significantly increase the mean antioxidant concentration. CONCLUSION: Formation of free radicals may not be the underlying patho-mechanism of tyrosine kinase inhibitors (TKI)- and capecitabine-associated PPE.


Assuntos
Antioxidantes/metabolismo , Capecitabina/efeitos adversos , Carotenoides/metabolismo , Síndrome Mão-Pé/metabolismo , Indóis/efeitos adversos , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Pirróis/efeitos adversos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Capecitabina/administração & dosagem , Feminino , Humanos , Indóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Pirróis/administração & dosagem , Pele/efeitos dos fármacos , Pele/metabolismo , Sorafenibe , Sunitinibe
18.
Expert Opin Drug Saf ; 17(11): 1095-1105, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30264594

RESUMO

INTRODUCTION: Lenvatinib, a multi-kinase inhibitor, has demonstrated improved outcomes for patients with hepatocellular carcinoma (HCC) in clinical trials. The phase 3 REFLECT trial confirmed the noninferiority of lenvatinib to sorafenib for overall survival of HCC patients and indicated clinical benefits in efficacy over sorafenib. Adverse events (AEs) included hypertension, diarrhea, decreased appetite, decreased weight, fatigue, palmar-plantar erythrodysesthesia, and proteinuria. Areas covered: AEs arising in HCC patients during lenvatinib treatment often lead to treatment interruption, dose reduction, or treatment discontinuation. However, reduced lenvatinib exposure may prevent patients from getting the full potential benefit of lenvatinib therapy. We first review the clinical data on lenvatinib, including efficacy and safety. Next, we review the common AEs associated with lenvatinib therapy and provide guidance on how to optimally prevent, detect, and manage these events while minimizing interruptions in lenvatinib treatment. Expert opinion: By fully understanding the common AEs associated with lenvatinib therapy and the proper management of emerging AEs, clinicians may ensure that HCC patients can fully benefit from the potential clinical efficacy of lenvatinib, with fewer unnecessary safety risks.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/efeitos adversos , Sorafenibe , Taxa de Sobrevida
19.
BMC Gastroenterol ; 18(1): 138, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30180810

RESUMO

BACKGROUND: Transarterial chemoembolization (TACE) is the recommended treatment for hepatocellular carcinoma (HCC) patients at Barcelona Clinic Liver Cancer (BCLC) B-stage, whereas sorafenib is an orally administered small molecule target drug for BCLC C-stage. This updated systemic review and meta-analysis focuses on identifying the efficacy of the combination of TACE with sorafenib, which remains controversial despite years of exploration. METHODS: PubMed, EMBASE, Scopus and the Cochrane Library were systematically reviewed to search for studies published from January 1990 to May 2017. Studies focusing on the efficacy of combination therapy for unresectable HCC were eligible. The hazard ratio (HR) with 95% confidence intervals (95% CIs) for time to progression (TTP), overall survival (OS), disease control rate (DCR) and aetiology were collected. The data were then analysed through fixed/random effects meta-analysis models with STATA 13.0. The incidence and severity of treatment-related adverse events (AEs) were also evaluated. RESULTS: Twenty-seven studies were included. Thirteen non-comparative studies reported median OS (ranging from 18.5 to 20.4 months), median TTP (ranging from 7 to 13.9 months) and DCR (ranging from 18.4 to 95%). Fourteen comparative studies provided median OS (ranging from 7.0 to 29.7 months) and median TTP (ranging from 2.6 to 10.2 months). Five comparative studies provided DCR (ranging from 32 to 97.2%). Forest plots showed that combination therapy significantly improved TTP (HR = 0.66, 95% CI 0.50-0.81, P = 0.002) rather than OS (HR = 0.63, 95% CI 0.55-0.71, P = 0.058), compared to TACE alone. DCR increased significantly in the combination therapy group (OR = 2.93, 95% CI 1.59-5.41, P = 0.005). Additional forest plots were drawn and no significant differences were observed with regard to survival outcome among various aetiologies. Forest plots for separate analysis of regions showed the HR for TTP was 0.62 (95% CI 0.45-0.79, P = 0.002) in the Asian countries group, and 0.82 (95% CI 0.59-1.05, P = 0.504)) in western countries. The HR for OS was 0.61 (95% CI 0.48-0.75, P = 0.050) in the Asian countries group and was 0.88 (95% CI 0.56-1.20, P = 0.845) in western countries. These data may indicate positive TTP outcome in Asian patients but not in European patients while no positive findings regarding OS were observed in either region. The most common AEs included fatigue, hand-foot skin reaction, diarrhoea and hypertension. CONCLUSIONS: Combination therapy may benefit unresectable HCC patients in terms of prolonged TTP and DCR. More well-designed studies are needed to investigate its superiority for OS.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Neoplasias Hepáticas/terapia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Terapia Combinada , Progressão da Doença , Humanos , Estadiamento de Neoplasias , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Sorafenibe , Análise de Sobrevida , Fatores de Tempo
20.
Int Heart J ; 59(5): 1174-1179, 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30158382

RESUMO

Angiogenesis inhibitors, such as sorafenib and axitinib, which target vascular endothelial growth factor (VEGF) signaling, are widely used for renal cell carcinoma, including metastasis. In this study, we report a case of cardiovascular adverse events of aortic dissection and cardiac dysfunction during treatment with sorafenib and axitinib for metastatic renal cell carcinoma. A 66-year-old man had been administered sorafenib for 2 years after nephrectomy due to renal cell carcinoma. To control the progression of metastatic lung tumor, axitinib was started after sorafenib for four years. During the treatment, angiotensin II type 1 receptor blockers and Ca antagonists were used to strictly control the axitinib-induced hypertension and proteinuria. Aortic dissection and cardiac dysfunction occurred coincidentally. Considering the critical role of VEGF signaling in the homeostasis of the cardiovascular system, we speculated that the long-term use of axitinib and sorafenib directly influenced the initiation of aortic dissection and cardiac dysfunction. Although the precise mechanisms underlying the aortic dissection and cardiac dysfunction induced by angiogenesis inhibition are still elusive, onco-cardiologists and oncologists should pay careful attention to cardiovascular toxicity and complications in patients with cancer, particularly patients undergoing long-term cancer treatment.


Assuntos
Aneurisma Dissecante/induzido quimicamente , Inibidores da Angiogênese/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Cardiopatias/induzido quimicamente , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/secundário , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Idoso , Aneurisma Dissecante/complicações , Axitinibe , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Cardiopatias/complicações , Cardiopatias/fisiopatologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Indazóis/administração & dosagem , Indazóis/uso terapêutico , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Metástase Neoplásica , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
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