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1.
J Clin Oncol ; 38(34): 4064-4075, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33052759

RESUMO

PURPOSE: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sorafenibe/uso terapêutico , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Placebos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Risco , Sorafenibe/efeitos adversos , Taxa de Sobrevida
2.
Eur Urol ; 78(6): 783-785, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32938569

RESUMO

Tivozanib is a potent and selective inhibitor of the VEGF receptor. In an open-label, randomized phase 3 trial, we compared tivozanib to sorafenib in patients with metastatic renal cell carcinoma (mRCC) who had received two or three prior therapies. We have previously reported that the study met its primary endpoint, demonstrating an improvement in progression-free survival with tivozanib versus sorafenib (5.6 mo vs 3.9 mo; hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.56-0.94; p=0.016). The current report reflects the final assessment of overall survival, showing no difference between treatment with tivozanib and sorafenib (HR 0.97, 95% CI 0.75-1.24). Given its activity and distinct tolerability profile, tivozanib represents a treatment option for patients with previously treated mRCC. PATIENT SUMMARY: We show that tivozanib, a targeted therapy, can delay tumor growth relative to an already approved targeted therapy (sorafenib) in patients with kidney cancer who have received two or three prior treatments. No difference in survival was observed.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Sorafenibe/uso terapêutico , Carcinoma de Células Renais/secundário , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Retratamento , Taxa de Sobrevida
3.
Clin Cancer Res ; 26(11): 2506-2514, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32127394

RESUMO

PURPOSE: Patient-reported outcomes (PRO) were evaluated in the phase III IMmotion151 trial (NCT02420821) to inform overall treatment/disease burden of atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Patients were randomized 1:1 to receive atezolizumab 1,200 mg intravenous (i.v.) infusions every 3 weeks (q3w) plus bevacizumab 15 mg/kg i.v. q3w or sunitinib 50 mg per day orally 4 weeks on/2 weeks off. Patients completed the MD Anderson Symptom Inventory (MDASI), National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and Brief Fatigue Inventory (BFI) at baseline, q3w during treatment, at end of treatment, and during survival follow-up. Longitudinal and time to deterioration (TTD) analyses for core and RCC symptoms and their interference with daily life, treatment side-effect bother, and health-related quality of life (HRQOL) were evaluated. RESULTS: The intent-to-treat population included 454 and 461 patients in the atezolizumab plus bevacizumab and sunitinib arms, respectively. Completion rates for each instrument were 83% to 86% at baseline and ≥ 70% through week 54. Milder symptoms, less symptom interference and treatment side-effect bother, and better HRQOL at most visits were reported with atezolizumab plus bevacizumab versus sunitinib. The TTD HR (95% CI) favored atezolizumab plus bevacizumab for core (HR, 0.50; 0.40-0.62) and RCC symptoms (HR, 0.45; 0.37-0.55), symptom interference (HR, 0.56; 0.46-0.68), and HRQOL (HR, 0.68; 0.58-0.81). CONCLUSIONS: PROs in IMmotion151 suggest lower overall treatment burden with atezolizumab plus bevacizumab compared with sunitinib in patients with treatment-naïve mRCC and provide further evidence for clinical benefit of this regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma de Células Renais/patologia , Feminino , Seguimentos , Humanos , Neoplasias Renais/patologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Sunitinibe/administração & dosagem , Taxa de Sobrevida
4.
Lancet Oncol ; 21(1): 95-104, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31810797

RESUMO

BACKGROUND: Treatment for renal cell carcinoma has been revolutionised by inhibitors of VEGF receptor. Previous studies have suggested that treatment with a VEGF receptor (VEGFR) tyrosine kinase inhibitor might be effective in patients who had previous checkpoint inhibitor therapy. Therefore, TIVO-3 was designed to compare the efficacy and safety of tivozanib (a potent and selective VEGFR inhibitor) with those of sorafenib as third-line or fourth-line therapy in patients with metastatic renal cell carcinoma. METHODS: In this open-label, randomised, controlled trial done at 120 academic hospitals in 12 countries, we enrolled eligible patients older than 18 years with histologically or cytologically confirmed metastatic renal cell carcinoma and at least two previous systemic treatments (including at least one previous treatment with a VEGFR inhibitor), measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received previous treatment with tivozanib or sorafenib. Patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category and type of previous therapy and randomised (1:1) with a complete permuted block design (block size of four) to either tivozanib 1·5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily continuously. Investigators and patients were not masked to treatment. The primary endpoint was progression-free survival by independent review in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02627963. FINDINGS: Between May 24, 2016, and Aug 14, 2017, 350 patients were randomly assigned to receive tivozanib (175 patients) or sorafenib (175 patients). Median follow-up was 19·0 months (IQR 15·0-23·4). Median progression-free survival was significantly longer with tivozanib (5·6 months, 95% CI 5·29-7·33) than with sorafenib (3·9 months, 3·71-5·55; hazard ratio 0·73, 95% CI 0·56-0·94; p=0·016). The most common grade 3 or 4 treatment-related adverse event was hypertension (35 [20%] of 173 patients treated with tivozanib and 23 [14%] of 170 patients treated with sorafenib). Serious treatment-related adverse events occurred in 19 (11%) patients with tivozanib and in 17 (10%) patients with sorafenib. No treatment-related deaths were reported. INTERPRETATION: Our study showed that tivozanib as third-line or fourth-line therapy improved progression-free survival and was better tolerated compared with sorafenib in patients with metastatic renal cell carcinoma. FUNDING: AVEO Oncology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Feminino , Seguimentos , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Prognóstico , Quinolinas/administração & dosagem , Projetos de Pesquisa , Sorafenibe/administração & dosagem , Taxa de Sobrevida
5.
Expert Rev Anticancer Ther ; 18(11): 1113-1124, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30084668

RESUMO

INTRODUCTION: The efficacy of VEGF-targeting therapies in clinical trials led to their recommendation in clinical guidelines for use across the advanced or metastatic renal cell carcinoma (RCC) treatment landscape, however, tolerability (including off-target effects) has remained a challenge. Tivozanib is a selective inhibitor of all three VEGFRs, with limited off-target interaction, which demonstrates efficacy with improved tolerability relative to multikinase VEGFR-TKIs. Areas covered: Covered here is the clinical development of tivozanib in advanced RCC, including the pivotal Phase III, multicenter, open-label, randomized clinical study comparing tivozanib with sorafenib for the treatment of VEGF- and mTOR therapy-naïve advanced RCC patients. Also covered are ongoing trials, exploring the efficacy and safety of tivozanib in the setting of refractory disease and the utility of tivozanib in combination with checkpoint inhibitors for advanced RCC. Combination of a VEGFR-TKI and immunotherapy is promising in advanced RCC, if the treatment regimens have acceptable tolerability. Here the selectivity of tivozanib may contribute to an acceptable tolerability profile when used in combination therapy. Expert commentary: The approval of tivozanib provides an additional option for the first-line treatment of advanced or metastatic RCC patients in Europe and allows use of a VEGFR-TKI with selectivity for VEGFRs in this setting.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Metástase Neoplásica , 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/efeitos adversos , Quinolinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sorafenibe/administração & dosagem
6.
Clin Genitourin Cancer ; 15(6): e1081-e1088, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28888866

RESUMO

BACKGROUND: Everolimus (E) and axitinib (A) have been standard treatments for patients with metastatic renal cell carcinoma after failure of first-line therapy (1L) with vascular endothelial growth factor-targeted therapy. This study aims to compare both drugs in a large comprehensive cancer center. METHODS: Patient characteristics and outcome data from all patients with metastatic renal cell carcinoma who received E or A as second-line therapy at Gustave Roussy from April 2007 to May 2015 have been recorded. RESULTS: A total of 81 patients were treated with E and 45 patients with A. There were no major differences between the 2 groups. The most common 1L was sunitinib (79% in the E group and 82.2% in the A group). The median follow-up was 29 months; 26 months for A and 33 months for E (P = .046). The median overall survival (OS) was 21.5 months for E and 14.9 months for A (P = .23). The median progression-free survival (PFS) was 5.3 and 7.7 months for E and A, respectively (P = .39). Partial response was achieved in 4% and in 24% of patients (P = .002) in the E and A cohort, respectively. In the A group, the median PFS and OS were statistically different according to response, tumor burden, and 1L duration. No differences were found in the E arm. CONCLUSION: In this series, there are no significant differences for PFS and OS with E and A. A appears to provide more objective response. A appears to be more effective in patients with small tumor burden, responders to 1L, and 1L therapy > 12 months.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Everolimo/administração & dosagem , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Axitinibe , Everolimo/uso terapêutico , Feminino , Humanos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
7.
Eur J Cancer ; 79: 185-192, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28511146

RESUMO

BACKGROUND: Axitinib has shown activity in metastatic renal cell carcinoma (mRCC) in a large phase III clinical trial and was approved in patients who failed first-line therapy. This drug has been available in France since November 2012. The objective is to report efficacy and safety of axitinib in mRCC outside of clinical trials. METHODS: A prospective evaluation of mRCC patients treated by axitinib in second or further next-line therapy at Gustave Roussy was conducted from 2012 to 2015. Objective response rate (ORR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and toxicities were analysed. The correlation between clinical markers and ORR, PFS, TTF and OS were explored. RESULTS: One-hundred and sixty patients with mRCC, received axitinib in second (40%) or further next-line therapy (60%). International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification was good, intermediate and poor in 13%, 54% and 32%, respectively. Dose titration (DT) to 7 mg twice a day (bid) was performed in 38% and to 10 mg bid in 19% of the patients. Hypertension was the most common adverse event, (grade (G)3: 39%; G4: 2%). ORR occurred in 32% (n = 33, only partial response). Median PFS, TTF and OS were 8.3, 5.8 and 16.4 months, respectively. IMDC risk group and DT at 2 weeks are associated to ORR while grade 3 hypertension is marginally associated. IMDC risk group and grade 3 hypertension are significantly associated with better PFS, TTF and OS while DT at 2 weeks is associated to PFS and TTF. CONCLUSION: Efficacy of axitinib in routine practice is similar to that previously reported, not only in second- but also in further next-lines of therapy.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Fatores Etários , Idade de Início , Antineoplásicos/efeitos adversos , Axitinibe , Institutos de Câncer , Relação Dose-Resposta a Droga , Feminino , Humanos , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento
8.
Eur Urol ; 71(6): 845-847, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27815086

RESUMO

Despite great interest, two randomised controlled trials (RCTs) of cytoreductive nephrectomy in the tyrosine kinase inhibitor setting in metastatic renal cell carcinoma have either closed early (SURTIME) or are recruiting very slowly (CARMENA) after 7 yr. Challenges in RCT delivery in uro-oncologic surgery are many. Multiple steps are needed to ensure strong recruitment to trials addressing important urologic cancer questions. Feasibility/pilot studies are key stepping stones towards successful delivery of surgical RCTs.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/terapia , Procedimentos Cirúrgicos de Citorredução/métodos , Neoplasias Renais/terapia , Nefrectomia , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/patologia , Quimioterapia Adjuvante , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Medicina Baseada em Evidências , Humanos , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Nefrectomia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
9.
Cancer Treat Rev ; 50: 109-117, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27664394

RESUMO

Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab. The identification of predictive and prognostic factors of survival is increasing, and both clinical predictive factors and pathology-related prognostic factors are being evaluated. Serum-based biomarkers and certain histologic subtypes of RCC, as well as clinical factors such as dose intensity and the development of some class effect adverse events, have been identified as predictors of survival. Expression levels of microRNAs, expression of chemokine receptor 4, hypermethylation of certain genes, VEGF polymorphisms, and elevation of plasma fibrinogen or d-dimer have been shown to be prognostic indicators of survival. In the future, prognosis and treatment of patients with mRCC might be based on genomic classification, especially of the 4 most commonly mutated genes in RCC (VHL, PBRM1, BAP1, and SETD2). Median overall survival has improved for patients treated with a first-line targeted agent compared with survival of patients treated with first-line interferon-α, and results of clinical trials have shown a survival benefit of sequential treatment with targeted agents. Prognosis of patients with mRCC will likely improve with optimization and individualization of current sequential treatment with targeted agents.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Fatores Imunológicos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Anilidas/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Axitinibe , Bevacizumab/uso terapêutico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/secundário , Proteínas de Ligação a DNA , Everolimo/uso terapêutico , Histona-Lisina N-Metiltransferase/genética , Humanos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Indóis/uso terapêutico , Interferon-alfa/uso terapêutico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , MicroRNAs/genética , Terapia de Alvo Molecular/métodos , Mutação , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Nivolumabe , Proteínas Nucleares/genética , Compostos de Fenilureia/uso terapêutico , Medicina de Precisão/métodos , Prognóstico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Quinolinas/uso terapêutico , Receptores CCR4/genética , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Sorafenibe , Sulfonamidas/uso terapêutico , Sunitinibe , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Fator A de Crescimento do Endotélio Vascular/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
11.
Clin Genitourin Cancer ; 13(4): 328-337.e3, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25816720

RESUMO

BACKGROUND: In the phase III axitinib second-line (AXIS) trial, axitinib significantly prolonged progression-free survival (PFS) versus sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC). Analyses of associations between germline single-nucleotide polymorphisms (SNPs) and outcomes are reported. PATIENTS AND METHODS: DNA samples from blood were genotyped using TaqMan allelic discrimination. Logistic/Cox regression analyses were used to evaluate association of 15 SNPs in vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)1, VEGFR2, or hypoxia-inducible factor (HIF)-1α with outcomes for blood pressure (BP; Grade ≥ 3 hypertension, diastolic BP > 90 mm Hg, and increase ≥ 15 mm Hg from baseline) and efficacy (independent review committee-assessed objective response rate and PFS, and overall survival [OS]). Multivariate analyses assessed SNPs and baseline characteristics as potential predictors of PFS and OS. RESULTS: Genotype data were available for 305 (42.7%) of 714 patients; 159 received axitinib and 146 sorafenib. After Bonferroni adjustment, no SNP was associated with BP outcomes. In axitinib-treated patients, VEGF-A rs699947 (A/A vs. C/C) and rs833061 (C/C vs. T/T) were associated with longer OS (27.0 vs. 13.4 months; hazard ratio [HR], 0.39; Padjusted = .015). In sorafenib-treated patients, VEGFR2 rs2071559 (G/G vs. A/A) was associated with longer OS (26.8 vs. 13.8 months; HR, 0.41; Padjusted = .030). In multivariate analyses, no SNP predicted axitinib efficacy; VEGFR2 rs2071559 predicted PFS (P = .0053) and OS (P = .0027) for sorafenib. Sensitivity/specificity of VEGFR2 rs2071559 for OS was < 80%. CONCLUSION: No SNP predicted axitinib outcomes. Although VEGFR2 rs2071559 predicted sorafenib efficacy in patients with mRCC, sensitivity/specificity limitations preclude its use for selecting individual patients for sorafenib treatment.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Idoso , Inibidores da Angiogênese/farmacologia , Axitinibe , Pressão Sanguínea/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/fisiopatologia , Intervalo Livre de Doença , Feminino , Estudos de Associação Genética , Humanos , Imidazóis/farmacologia , Indazóis/farmacologia , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/fisiopatologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Fenilureia/farmacologia , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Sorafenibe , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
12.
Eur Urol ; 67(1): 100-110, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24841777

RESUMO

CONTEXT: The introduction of novel molecular-targeted agents has revolutionised the management of patients with metastatic renal cell carcinoma (mRCC). However, uncertainties remain over sequential or simultaneous combination therapies. OBJECTIVE: To systematically review relevant literature comparing the clinical effectiveness and harms of different sequencing and combinations of systemic targeted therapies for mRCC. EVIDENCE ACQUISITION: Relevant databases (including Medline, Cochrane Library, trial registries, and conference proceedings) were searched (January 2000 to September 2013) including only randomised controlled trials (RCTs). Risk of bias assessment was performed. A qualitative and quantitative synthesis of the evidence was presented. EVIDENCE SYNTHESIS: The literature search identified 5149 articles. A total of 24 studies reporting on 9589 patients were eligible for inclusion; data from four studies were included for meta-analysis. There were generally low risks of bias across studies; however, clinical and methodological heterogeneity prevented pooling of data for most studies. Overall, the data showed several targeted therapies were associated with an improvement in progression-free survival in patients with mRCC. There were limited data from RCTs regarding the issue of sequencing; studies on combination therapies have been hampered by difficulties with tolerability and safety. CONCLUSIONS: Although the role of vascular endothelial growth factor/vascular endothelial growth factor receptor targeting therapies and mammalian target of rapamycin inhibition in the management of mRCC is now established, limited reliable data are available regarding sequencing and combination therapies. Although data from retrospective cohort studies suggest a potential benefit for sequencing systemic therapies, significant uncertainties remain. Presently, mRCC systemic treatment should follow international guidelines (such as the European Society for Medical Oncology, National Comprehensive Cancer Network, and European Association of Urology) for patients fit to receive several lines of systemic therapies. PATIENT SUMMARY: We thoroughly examined the literature on the benefits and harms of combining drugs for the treatment of kidney cancer that has spread and on the sequence in which the drugs should be given.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células Renais/secundário , Intervalo Livre de Doença , Esquema de Medicação , Humanos , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem
13.
Lancet Oncol ; 15(3): 286-96, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24556040

RESUMO

BACKGROUND: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. METHODS: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. FINDINGS: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). INTERPRETATION: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. FUNDING: Novartis Pharmaceuticals Corporation.


Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolonas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Quinolonas/efeitos adversos , Sorafenibe , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
14.
World J Urol ; 32(1): 109-14, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23624719

RESUMO

OBJECTIVE: To assess the effect of neoadjuvant targeted molecular therapies (TMTs) on size and level of inferior vena cava tumor thrombi and to evaluate their impact on surgical management. METHODS: We retrospectively analyzed the data of 14 patients treated for a clear cell renal cell carcinoma with inferior vena cava thrombi by neoadjuvant TMT before nephrectomy. Clinical, pathological and perioperative data were gathered retrospectively at each institution. The primitive tumor size and the thrombus size were defined by computed tomography before TMT. The tumor thrombus level was defined according to the Novick's classification. RESULTS: Before TMT, thrombus level was staged I for 1 (7%), II for 10 (72%) and III (21%) for 3 patients. First-line therapy was sunitinib in 11 cases and sorafenib in 3 cases. Median therapy duration was two cycles (1-5). Three patients experienced major adverse effects (grade III) during TMT. Following TMT, 6 (43%) patients had a measurable decrease, 6 (43%) had no change, and 2 (14%) had an increase in the thrombus. One patient (7%) had a downstage of thrombus level, 12 (85%) had stable thrombi, and 1 (7%) had an upstage. Regarding primary tumor, 7 (50%), 5 (36%) and 2 (14%) patients had a decrease, stabilization and an increase in tumor size, respectively. CONCLUSION: Neoadjuvant TMT appears to have limited effects on renal tumor thrombi. This retrospective study failed to demonstrate a significant impact of neoadjuvant TMT on surgical management of clear cell renal cell carcinoma with inferior vena cava tumor thrombi.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Terapia de Alvo Molecular , Terapia Neoadjuvante , Nefrectomia , Trombectomia , Trombose/cirurgia , Veia Cava Inferior/cirurgia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/epidemiologia , Terapia Combinada , Comorbidade , Relação Dose-Resposta a Droga , Feminino , França , Humanos , Indóis/uso terapêutico , Neoplasias Renais/epidemiologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Pirróis/uso terapêutico , Estudos Retrospectivos , Sorafenibe , Sunitinibe , Trombose/epidemiologia , Resultado do Tratamento
15.
Eur Urol ; 65(4): 713-20, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23993162

RESUMO

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST) criteria may not be sufficient to evaluate the response of targeted therapies in metastatic renal cell carcinoma (mRCC). The tumor growth rate (TGR) incorporates the time between evaluations and may be adequate. OBJECTIVE: To determine how TGR is modified along the treatment sequence and is associated with outcome in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: Medical records from all patients prospectively treated at Gustave Roussy (IGR) in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) (sorafenib vs placebo, n=84) and the RECORD (everolimus vs placebo, n=43) phase 3 trials were analyzed. TGR was computed across clinically relevant periods: BEFORE treatment introduction (wash-out), UNDER (first cycle), at PROGRESSION (last cycle) and AFTER treatment discontinuation (washout). The association between TGR and outcome (overall survival [OS] and progression-free survival [PFS]) was computed in the entire TARGET cohort (n=903). INTERVENTION: Sorafenib, everolimus, or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: TGR, RECIST, OS, and PFS rates. RESULTS AND LIMITATIONS: Although nearly all the patients (IGR) were classified as stable disease (RECIST) after the first cycle, the great majority of the patients exhibited a decrease in TGR UNDER compared with BEFORE (sorafenib: p<0.00001; everolimus: p<0.00001). In sorafenib-treated but not in everolimus-treated patients (IGR), TGR at PROGRESSION (last cycle) was still lower than TGR BEFORE (washout) (p=0.012), while TGR AFTER progression (washout) was higher than TGR at PROGRESSION (last cycle) (p=0.0012). Higher TGR (first cycle) was associated with worse PFS (hazard ratio [HR]: 3.61; 95% confidence interval [CI], 2.45-5.34) and worse OS (HR: 4.69; 95% CI, 1.54-14.39), independently from the Motzer score and from the treatment arm in the entire TARGET cohort. CONCLUSIONS: Computing TGR in mRCC patients is simple and provides clinically useful information for mRCC patients: (1) TGR is independently associated with prognosis (PFS, OS), (2) TGR allows for a subtle and quantitative characterization of drug activity at the first evaluation, and (3) TGR reveals clear drug-specific profiles at progression.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Sirolimo/análogos & derivados , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Everolimo , Humanos , Niacinamida/uso terapêutico , Estudos Prospectivos , Sirolimo/uso terapêutico , Sorafenibe , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
16.
J Clin Oncol ; 32(8): 760-7, 2014 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-24297950

RESUMO

PURPOSE: This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib. PATIENTS AND METHODS: In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non-clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points. RESULTS: Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies. CONCLUSION: In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/uso terapêutico , Sirolimo/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/enzimologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Sorafenibe , Sunitinibe , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Falha de Tratamento , Adulto Jovem
17.
Cancer ; 119(18): 3377-84, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23801109

RESUMO

BACKGROUND: Studies have shown that skeletal muscle and adipose tissue are linked to overall survival (OS) and progression-free survival (PFS). Because targeted therapies have improved the outcome in patients with metastatic renal cell carcinoma (mRCC), new prognostic parameters are required. The objective of the current study was to analyze whether body composition parameters play a prognostic role in patients with mRCC. METHODS: Adipose tissue, skeletal muscle, and skeletal muscle density (SMD) were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues and mean muscle Hounsfield units (HU). A high level of mean HU indicates a high SMD and high quality of muscle. OS and PFS were estimated using the Kaplan-Meier method and compared with the log-rank test. The multivariable Cox proportional hazards model was adjusted for Heng risk score and treatment. RESULTS: In the 149 patients studied, the median OS was 21.4 months and was strongly associated with SMD; the median OS in patients with low SMD was approximately one-half that of patients with high SMD (14 months vs 29 months; P = .001). After adjustment for Heng risk score and treatment, high SMD was associated with longer OS (hazards ratio, 1.85; P = .004) and longer PFS (hazards ratio, 1.81; P = .002). Adding SMD will separate the intermediate-risk and favorable-risk groups into 3 groups, with different median OS periods ranging from 8 months (95% confidence interval [95% CI], 6 months-12 months) for an intermediate-risk Heng score/low SMD to 22 months (95% CI, 14 months-27 months) for an intermediate-risk Heng score/high SMD and a favorable-risk Heng score/low SMD to 35 months (95% CI, 24 months-43 months) for a favorable-risk Heng score/high SMD. CONCLUSIONS: High muscle density appears to be independently associated with improved outcome and could be integrated into the prognostic scores thereby enhancing the management of patients with mRCC.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Músculo Esquelético/patologia , Idoso , Antineoplásicos/uso terapêutico , Composição Corporal , Carcinoma de Células Renais/tratamento farmacológico , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Prognóstico , Sorafenibe , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento
18.
Lancet Oncol ; 14(6): 552-62, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23598172

RESUMO

BACKGROUND: In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. METHODS: Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392. FINDINGS: Median overall survival was 20.1 months (95% CI 16.7-23.4) with axitinib and 19.2 months (17.5-22.3) with sorafenib (hazard ratio [HR] 0.969, 95% CI 0.800-1.174; one-sided p=0.3744). Median investigator-assessed PFS was 8.3 months (95% CI 6.7-9.2) with axitinib and 5·7 months (4.7-6.5) with sorafenib (HR 0.656, 95% CI 0.552-0.779; one-sided p<0.0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand-foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20.7 months (95% CI 18.4-24.6) versus 12.9 months (10.1-20.4) in the axitinib group (p=0.0116), and 20.2 months (17.1-32.0) versus 14.8 months (12.0-17.7) in the sorafenib group (one-sided p=0.0020). INTERPRETATION: Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. FUNDING: Pfizer Inc.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Axitinibe , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Intervalo Livre de Doença , Feminino , Humanos , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Neoplasias Renais/enzimologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/efeitos adversos , Qualidade de Vida , Sorafenibe , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento
19.
Eur J Cancer ; 49(8): 1898-904, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23490648

RESUMO

BACKGROUND: Sequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. The goal of this study was to evaluate these questions in a large series of pts treated in our institution. PATIENTS AND METHODS: Data from all mRCC patients treated at the IGR from 2005 to 2009 with first line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mammalian target of rapamycin - mTOR)) were analysed. Only patients with subsequent follow-up have been included in this analysis. Patients were defined as 'non-eligible' for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response) or (iii) if they refused a second line treatment. RESULTS: 251 patients, median age 60 years, median follow-up 20.2 months were treated with targeted therapy with a median overall survival (OS) of 25.8 months. Median OS with SU (127), SO (60) or B (61) were 26.3, 16.4 and 32.5 months respectively. Only three patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n=61/103), 52% (n=30/58) and 79% (n=38/48) for Su, So and B, respectively. Memorial Sloan-Kettering Cancer Centre (MSKCC) classification (P=0.02) and first line agent (P=0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of performance status score (PS)=0 compared to SO (53%) and SU (48%) (P=0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8 months for a tyrosine kinase inhibitor (TKI) (n=98; 75%) and 16.6 months for an mTOR (n=32; 42%) (P=0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively. CONCLUSION: The median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2 years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for second line treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carcinoma de Células Renais/patologia , Doenças Cardiovasculares/induzido quimicamente , Progressão da Doença , Esquema de Medicação , Everolimo , Feminino , Seguimentos , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/análogos & derivados , Sorafenibe , Sunitinibe , Resultado do Tratamento , Adulto Jovem
20.
Clin Genitourin Cancer ; 11(2): 128-33, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23332872

RESUMO

BACKGROUND: Because the response to treatment is limited, patients with metastatic renal cell carcinoma (mRCC) typically receive multiple treatments. Guidelines recommend everolimus for patients previously treated with tyrosine kinase inhibitors (TKI) sunitinib or sorafenib. This study evaluated the efficacy of TKI re-treatment in patients with disease progression after a TKI-everolimus sequence. PATIENTS AND METHODS: Data were reviewed for patients enrolled in RECORD-1 (Renal Cell Cancer Treatment With Oral RAD001 Given Daily) at French sites. Response, progression-free survival (PFS), and overall survival were evaluated in patients treated with a TKI-everolimus-TKI sequence. RESULTS: Thirty-six patients received a TKI after everolimus: sunitinib in 17 patients, sorafenib in 15, and dovitinib (TKI258) in 4. The response rate with TKI re-treatment was 8%, and the disease-control rate (response plus stable disease) was 75%. The median PFS with each component of the TKI-everolimus-TKI sequence was 10.7 months (95% CI, 1.8-28.5 months), 8.9 months (95% CI, 1.7-34.6 months), and 8.2 months (95% CI, 5.2-11.9 months), respectively. The median overall survival from the start of everolimus was 29.1 months (95% CI 21.1 to not reached months), which suggests a benefit in using TKI in this setting. CONCLUSIONS: Administration of a TKI-everolimus-TKI sequence may be associated with clinical benefit and should be prospectively investigated.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Pirróis/uso terapêutico , Sirolimo/análogos & derivados , Adulto , Idoso , Benzimidazóis/uso terapêutico , Carcinoma de Células Renais/secundário , Intervalo Livre de Doença , Everolimo , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolonas/uso terapêutico , Terapia de Salvação , Sirolimo/uso terapêutico , Sorafenibe , Sunitinibe , Serina-Treonina Quinases TOR/antagonistas & inibidores , Falha de Tratamento , Resultado do Tratamento
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