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2.
Medicine (Baltimore) ; 100(35): e27182, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477177

RESUMO

ABSTRACT: In this single-center retrospective study, we intended to evaluate the frequencies and characteristics of computed tomography findings of pancreatobiliary inflammation (PBI) in patients treated with lenvatinib and the relationship of these findings with treatment-planning changes.We included 78 patients (mean ±â€Šstandard deviation, 69.8 ±â€Š9.4 years, range: 39-84 years, 62 men) with hepatocellular carcinoma (n = 62) or thyroid carcinoma (n = 16) who received lenvatinib (June 2016-September 2020). Two radiologists interpreted the posttreatment computed tomography images and assessed the radiological findings of PBI (symptomatic pancreatitis, cholecystitis, or cholangitis). The PBI effect on treatment was statistically evaluated.PBI (pancreatitis, n = 1; cholecystitis, n = 7; and cholangitis, n = 2) was diagnosed in 11.5% (9/78) of the patients at a median of 35 days after treatment initiation; 6 of 9 patients discontinued treatment because of PBI. Three cases of cholecystitis and 1 of cholangitis were accompanied by gallstones, while the other 5 were acalculous. The treatment duration was significantly shorter in patients with PBI than in those without (median: 44 days vs. 201 days, P = .02). Overall, 9 of 69 patients without PBI showed asymptomatic gallbladder subserosal edema.Lenvatinib-induced PBI developed in 11.5% of patients, leading to a significantly shorter treatment duration. Approximately 55.6% of the PBI cases were acalculous. The recognition of this phenomenon would aid physicians during treatment planning in the future.


Assuntos
Antineoplásicos/efeitos adversos , Doenças Biliares/induzido quimicamente , Pancreatite/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Quinolinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Biliares/diagnóstico por imagem , Doenças Biliares/epidemiologia , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Pancreatite/diagnóstico por imagem , Pancreatite/epidemiologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
3.
World J Gastroenterol ; 27(32): 5424-5437, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34539142

RESUMO

BACKGROUND: Sorafenib is an oral drug that prolongs overall survival (OS) in patients with hepatocellular carcinoma. Adverse events, including hand-foot skin reaction (HFSR), lead to permanent sorafenib discontinuation. AIM: To clarify the association between interventions for adverse events and patient prognosis. METHODS: We performed a retrospective, multicenter study of patients treated with sorafenib monotherapy between May 2009 and March 2018. We developed a mutual cooperation system that was initiated at the start of sorafenib treatment to effectively manage adverse events. The mutual cooperation system entailed patients receiving consultations during which pharmacists provided accurate information about sorafenib to alleviate the fear and anxiety related to adverse events. We stratified the patients into three groups: Group A, patients without HFSR but with pharmacist intervention; Group B, patients with HFSR and pharmacist interventions unreported to oncologists (nonmutual cooperation system); and Group C, patients with HFSR and pharmacist interventions known to oncologists (mutual cooperation system). OS and time to treatment failure (TTF) were evaluated using the Kaplan-Meier method. RESULTS: We enrolled 134 patients (Group A, n = 41; Group B, n = 30; Group C, n = 63). The median OS was significantly different between Groups A and C (6.2 vs 13.9 mo, p < 0.01) but not between Groups A and B (6.2 vs 7.7 mo, P = 0.62). Group A vs Group C was an independent OS predictor (HR, 0.41; 95%CI: 0.25-0.66; P < 0.01). In Group B alone, TTF was significantly lower and the nonadherence rate was higher (P < 0.01). In addition, the Spearman's rank correlation coefficients between OS and TTF in each group were 0.41 (Group A; P < 0.01), 0.13 (Group B; P = 0.51), and 0.58 (Group C; P < 0.01). There was a highly significant correlation between OS and TTF in Group C. However, there was no correlation between OS and TTF in Group B. CONCLUSION: The mutual cooperation system increased treatment duration and improved prognosis in patients with HFSR. Future prospective studies (e.g., randomized controlled trials) and improved adherence could help prevent OS underestimation.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Estudos Prospectivos , Estudos Retrospectivos , Sorafenibe/uso terapêutico , Resultado do Tratamento
4.
J Med Case Rep ; 15(1): 481, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34544494

RESUMO

BACKGROUND: Sorafenib is an oral multikinase inhibitor that targets Raf serine/threonine receptor tyrosine kinases and inhibits tumor cell growth and angiogenesis. Cutaneous toxicities of sorafenib are common, including cutaneous eruptions (such as truncal erythema and seborrheic-dermatitis-like changes) and hand-foot syndrome. Keratoacanthomas and squamous cell carcinomas have been reported previously; however, we report a case of multiple eruptive keratoacanthomas in the form of Grzybowski syndrome after initiation of sorafenib. CASE PRESENTATION: We report a 63-year-old Caucasian male who developed multiple cutaneous eruptive keratoacanthomas after starting sorafenib 400 mg twice daily. He had a known history of hepatitis-C-related cirrhosis and hepatocellular carcinoma, and previously had actinic keratosis and skin squamous cell carcinoma excision. Approximately two and a half months after starting sorafenib, the patient initially developed two lesions, one on each forearm, and after excision, these lesions demonstrated histological features of squamous cell carcinoma. One month later, the patient presented with approximately 48 new skin lesions of varying size on the back, bilateral upper limbs, and face requiring excisional biopsy of a large number of these lesions. Histopathology showed eruptive invasive keratoacanthomas (Grzybowski syndrome). Sorafenib was temporarily stopped and subsequently restarted at a lower dose. Acitretin 25 mg daily was commenced after few weeks, and no further keratoacanthomas developed during his treatment. CONCLUSIONS: We report a unique case of sorafenib-associated Grzybowski syndrome. Temporary interruption and dose reduction of sorafenib and use of acitretin appeared to prevent further development of keratoacanthomas.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Exantema , Ceratoacantoma , Dermatopatias , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Ceratoacantoma/induzido quimicamente , Ceratoacantoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Sorafenibe/efeitos adversos
5.
Oncology ; 99(10): 641-651, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34515171

RESUMO

AIM: Atezolizumab plus bevacizumab (atezo + bev) shows a good overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients. However, the OS of patients with nonviral infection is quite worse than that in those with viral infection. The present study investigated the efficacy and safety of lenvatinib in patients with nonviral infection, who were unlikely to obtain benefit from atezo + bev. METHODS: We conducted a multicenter retrospective study that included 139 advanced HCC patients treated with lenvatinib between March 2018 and September 2020. RESULTS: The median age was 72 years, and 116 patients (83.5%) were male. Based on the etiology of liver disease, 84 (60.4%) and 55 patients (39.6%) were assigned to the viral infection and nonviral infection groups, respectively. The significant extents in patient characteristics were not observed in both groups. The objective response rate per mRECIST and progression-free survival (PFS) did not differ significantly between the viral infection and nonviral infection groups (36.0 vs. 33.0%, p = 0.85; and 7.6 vs. 7.5 months, p = 0.94, respectively). The 1-year survival rates were 68.7% (95% confidence interval [CI] 57.7-79.7%) in the viral infection group and 59.5% (95% CI 45.2-73.8%) in the nonviral infection group. The viral infection group was not a significant factor associated with the PFS or OS in a multivariate analysis. CONCLUSIONS: Lenvatinib shows no significant difference in response between patients with and without viral infection. Treatment strategies based on the etiology of liver disease may lead to good clinical outcome.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/microbiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/microbiologia , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/virologia , Feminino , Humanos , Imunoterapia , Infecções/diagnóstico , Neoplasias Hepáticas/virologia , Masculino , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Quinolinas/efeitos adversos , Estudos Retrospectivos , Viroses/diagnóstico
6.
Front Immunol ; 12: 653437, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349755

RESUMO

Programmed cell death 1 (PD-1) blockade is considered contraindicated in liver transplant (LT) recipients due to potentially lethal consequences of graft rejection and loss. Though post-transplant PD-1 blockade had already been reported, pre-transplant use of PD-1 blockade has not been thoroughly investigated. This study explores the safety and efficacy of neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC) after registration on the waiting list. Seven transplant recipients who underwent neoadjuvant PD-1 blockade combined with lenvatinib and subsequent LT were evaluated. The objective response rate (ORR) and disease control rate (DCR) was 71% and 85% according to the mRECIST criteria. Additionally, a literature review contained 29 patients were conducted to summarize the PD-1 blockade in LT for HCC. Twenty-two LT recipients used PD-1 inhibitors for recurrent HCC. 9.1% (2/22) and 4.5% (1/22) recipients achieved complete remission (CR) and partial remission (PR), respectively; 40.9% (9/22) recipients had progressive disease (PD). Allograft rejection occurred in 45% of patients. In total, seven patients from our center and three from the literature used pretransplant anti-PD-1 antibodies, eight patients (80%) had a PR, and the disease control rate was 100%. Biopsy-proven acute rejection (BPAR) incidence was 30% (3 in 10 patients), two patients died because of BPAR. This indicated that neoadjuvant PD-1-targeted immunotherapy plus tyrosine kinase inhibitors (TKI) exhibited promising efficacy with tolerable mortality in transplant recipients under close clinical monitoring.


Assuntos
Carcinoma Hepatocelular/terapia , Rejeição de Enxerto/epidemiologia , Neoplasias Hepáticas/terapia , Transplante de Fígado/efeitos adversos , Terapia Neoadjuvante/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Incidência , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Receptor de Morte Celular Programada 1/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Taxa de Sobrevida
7.
Lancet Gastroenterol Hepatol ; 6(10): 803-815, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34358484

RESUMO

BACKGROUND: Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10-16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment. METHODS: This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing. FINDINGS: Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2-15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6-32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths. INTERPRETATION: Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting. FUNDING: QED Therapeutics and Novartis.


Assuntos
Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Metástase Neoplásica/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopecia/induzido quimicamente , Alopecia/epidemiologia , Coriorretinopatia Serosa Central/induzido quimicamente , Coriorretinopatia Serosa Central/epidemiologia , Colangiocarcinoma/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Progressão da Doença , Síndromes do Olho Seco/induzido quimicamente , Síndromes do Olho Seco/epidemiologia , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Humanos , Hiperfosfatemia/induzido quimicamente , Hiperfosfatemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Descolamento Retiniano/induzido quimicamente , Descolamento Retiniano/epidemiologia , Segurança , Estomatite/induzido quimicamente , Estomatite/epidemiologia , Resultado do Tratamento
8.
BMC Cancer ; 21(1): 894, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34353305

RESUMO

BACKGROUND: Because lenvatinib is well known to induce proteinuria by blocking the vascular endothelial growth factor (VEGF) pathway, renal function is a concern with long-term administration of lenvatinib. The long-term effects of lenvatinib on renal function in patients with advanced differentiated thyroid carcinoma (DTC) were analyzed. METHOD: This study involved 40 DTC patients who continued lenvatinib therapy for ≥6 months. Estimated glomerular filtration rate (eGFR) was calculated as an indicator of renal function. The temporal course of eGFR, effects of baseline eGFR on eGFR changes, and factors affecting renal impairment were investigated. RESULTS: The overall cohort showed sustainable decreases in eGFR, with decreased values of 11.4, 18.3, and 21.0 mL/min/1.73 m2 at 24, 36, and 48 months after starting treatment, respectively. No differences in eGFR decrease every 6 months were seen for three groups classified by baseline eGFR ≥90 mL/min/1.73 m2 (n = 6), < 90 but ≥60 mL/min/1.73 m2 (n = 26), or < 60 but ≥45 mL/min/1.73 m2 (n = 8). Grade 3 proteinuria was associated with declines in eGFR (p = 0.0283). Long observation period was also associated with decreases in eGFR (p = 0.0115), indicating that eGFR may decrease in a time-dependent manner. CONCLUSION: Lenvatinib can induce declines in eGFR, particularly with treatment duration > 2 years, regardless of baseline eGFR. Proteinuria is a risk factor for declines in eGFR. Patients who start lenvatinib with better renal function show a renal reserve capacity, prolonging clinical outcomes. Decision-making protocols must balance the benefits of lenvatinib continuation with acceptable risks of harm.


Assuntos
Antineoplásicos/efeitos adversos , Rim/efeitos dos fármacos , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/etiologia , Nefropatias/fisiopatologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/epidemiologia , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
9.
Medicine (Baltimore) ; 100(31): e26820, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397843

RESUMO

ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.


Assuntos
Bilirrubina/análise , Carcinoma Hepatocelular , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Albumina Sérica/análise , Sorafenibe , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores Farmacológicos/análise , Proteína C-Reativa/análise , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Correlação de Dados , Monitoramento de Medicamentos/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Japão/epidemiologia , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos
11.
World J Surg Oncol ; 19(1): 168, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112190

RESUMO

BACKGROUND: Sorafenib was reported as a useful adjuvant treatment in patients with hepatocellular carcinoma who underwent surgical resection. However, its therapeutic value remains controversial. This meta-analysis examined the available data regarding the efficacy and safety of sorafenib in patients with hepatocellular carcinoma after radical surgery. METHODS: The meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered in advance with PROSPERO (CRD42021233868). We searched PubMed, Embase, Cochrane Library, and Web of Science to identify eligible studies. Overall survival, recurrence-free survival, and recurrence rates were analyzed, and adverse events were reviewed. Hazard ratios or pooled risk ratios with 95% CIs were collected and analyzed using STATA version 12.0 in a fixed-effects or random-effects meta-analysis model. RESULTS: In total, 2655 patients from 13 studies were ultimately included in this meta-analysis. The combined results illustrated that sorafenib was associated with better overall survival than the control (hazard ratio = 0.71, 95% CI = 0.59-0.86; P < 0.001). Similarly, the drug also improved recurrence-free survival (hazard ratio = 0.68, 95% CI = 0.54-0.86, P = 0.001). Combined data revealed that patients treated with sorafenib after resection had a lower recurrence rate (pooled risk ratio = 0.78, 95% CI = 0.68-0.90, P < 0.001). The primary adverse events were hand-foot skin reaction, fatigue, and diarrhea of mild-to-moderate severity, whereas grade 4 adverse events were rare (< 1%). CONCLUSIONS: This meta-analysis demonstrated that adjuvant sorafenib therapy after resection in patients with hepatocellular carcinoma could prolong overall survival and recurrence-free survival and reduce recurrence rates without intolerable side effects. However, more evidence is needed before reaching a definitive conclusion.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Prognóstico , Sorafenibe/uso terapêutico , Resultado do Tratamento
12.
Lancet Oncol ; 22(7): 946-958, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143969

RESUMO

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/secundário , Europa (Continente) , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
13.
BMC Cancer ; 21(1): 564, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001059

RESUMO

BACKGROUND: The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer. METHODS: FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, ß = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150-180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle. DISCUSSION: FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer. TRIAL REGISTRATION: EudraCT: 2018-003541-42 ; ClinicalTrials.gov: NCT03828799 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Estudos Multicêntricos como Assunto , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Piridinas/efeitos adversos , Adulto Jovem , Proteínas ras/genética
14.
Anticancer Res ; 41(5): 2553-2561, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952483

RESUMO

BACKGROUND/AIM: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice. PATIENTS AND METHODS: Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region. RESULTS: We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18). CONCLUSION: The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Timina/efeitos adversos , Trifluridina/efeitos adversos
16.
Crit Rev Oncol Hematol ; 163: 103366, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34051303

RESUMO

Lenvatinib is a non-selective tyrosine kinase inhibitor (TKI) with high in vitro potency against vascular endothelial growth factor receptors. Although this drug is used to treat several cancer types, it is the most effective TKI used in patients with thyroid cancer. Lenvatinib is well tolerated and the most common adverse drug reactions can be adequately managed by dose adjustment. Particularly, blood pressure and cardiac function monitoring, as well as antihypertensive treatment optimization, may be required in patients treated with lenvatinib. Dose reduction should be taken into account in patients with body weight <60 kg or severe hepatic failure. No significant change in lenvatinib pharmacokinetics has been observed with other patient-related factors and very few data are available on lenvatinib pharmacogenetics. Lenvatinib can be administered orally regardless of food and no clinically relevant drug-drug interactions have been reported.


Assuntos
Preparações Farmacêuticas , Farmacologia Clínica , Quinolinas , Neoplasias da Glândula Tireoide , Interações Medicamentosas , Humanos , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular
17.
Liver Int ; 41(9): 2200-2211, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33966333

RESUMO

BACKGROUND AND AIMS: The effectiveness of systemic treatment in advanced hepatocellular carcinoma (HCC) depends on the selection of patients, management of cirrhosis complications and expertise to treat adverse events. The aims of the study are to assess the frequency and management of cardiovascular events in HCC patients treated with sorafenib (SOR) and to create a scale to predict the onset of major adverse cardiovascular events (MACE). METHOD: Observational retrospective study with consecutive HCC patients treated with SOR between 2007 and 2019 in a western centre. In order to classify cardiovascular risk pre-SOR, we designed the CARDIOSOR scale with age, hypertension, diabetes, dyslipidaemia and peripheral vascular disease. Other adverse events, dosing and outcome data were collected during a homogeneous protocolled follow-up. RESULTS: Two hundred ninety-nine patients were included (219 BCLC-C). The median overall survival was 11.1 months (IQR 5.6-20.5), and duration of treatment was 7.4 months (IQR 3.3-14.7). Seventeen patients (6%) stopped SOR due to cardiovascular event. Thirty-three patients suffered MACE (7 heart failure, 11 acute coronary syndrome, 12 cerebrovascular accident and 8 peripheral vascular ischemia); 99 had a minor cardiovascular event, mainly hypertension (n = 81). Age was the only independent factor associated to MACE (HR 1.07; 95% CI 1.03-1.12; P = .002). The CARDIOSOR scale allows to identify the group of patients with higher risk of MACE (sHR 3.4; 95% CI 1.4-6.7; P = .04). CONCLUSION: The incidence of cardiovascular events in HCC patients treated with SOR is higher than expected. Multidisciplinary approach and clinical tools like CARDIOSOR scale could be helpful to manage these patients.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Doenças Cardiovasculares , Neoplasias Hepáticas , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Estudos Retrospectivos , Sorafenibe/uso terapêutico , Resultado do Tratamento
18.
Expert Rev Clin Pharmacol ; 14(7): 927-935, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33993815

RESUMO

PURPOSE: To characterize the effect of glasdegib on cardiac repolarization (QTc) in patients with advanced cancer. METHODS: A concentration-QTc model was developed using data from two glasdegib single-agent, dose-escalation trials. Triplicate electrocardiogram was performed at pre-specified timepoints paired with pharmacokinetic blood collections after a single dose and at steady-state. Changes in QTc from baseline were predicted by model-based simulations at the clinical dose (100 mg QD) and in a supratherapeutic setting. RESULTS: Glasdegib did not affect the heart rate, but had a positive effect on the corrected QT interval, described by a linear mixed-effects model with ΔQTcF (QTc using Fridericia's formula) as the dependent variable with glasdegib plasma concentrations from doses of 5-640 mg QD. The predicted mean QTcF change (upper bound of the 95% CI) was 5.30 (6.24) msec for the therapeutic 100-mg QD dose; at supratherapeutic concentrations (40% and 100% increase over the therapeutic Cmax), it was 7.42 (8.74) and 12.09 (14.25) msec, respectively. CONCLUSIONS: The relationship of glasdegib exposure and QTc was well characterized by the model. The effect of glasdegib on the QTc interval did not cross the threshold of clinical concern for an oncology drug. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01286467 and NCT00953758.


Assuntos
Antineoplásicos/administração & dosagem , Benzimidazóis/administração & dosagem , Eletrocardiografia , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Simulação por Computador , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Humanos , Compostos de Fenilureia/efeitos adversos
19.
Oncology ; 99(8): 507-517, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33946070

RESUMO

INTRODUCTION: We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (n = 88) with intermediate-stage hepatocellular carcinoma (HCC). METHODS: Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated. RESULTS: After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087-0.802, p = 0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070-0.704, p = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, p = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable. CONCLUSION: For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Pontuação de Propensão , Quinolinas/efeitos adversos , Estudos Retrospectivos , Taxa de Sobrevida
20.
Oncology ; 99(8): 491-498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34000725

RESUMO

INTRODUCTION: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma. METHODS: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy. RESULTS: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients. CONCLUSION: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Estudos Retrospectivos , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Taxa de Sobrevida , Resultado do Tratamento
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