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1.
Ann Oncol ; 34(11): 1047-1054, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37678672

RESUMO

INTRODUCTION: This exploratory analysis evaluated efficacy and safety data for enfortumab vedotin versus chemotherapy over a median follow-up of ∼2 years from EV-301. MATERIALS AND METHODS: Patients with locally advanced/metastatic urothelial carcinoma with prior platinum-containing chemotherapy and disease progression during/after programmed cell death protein 1/ligand 1 inhibitor treatment were randomized to enfortumab vedotin or chemotherapy (docetaxel, paclitaxel, vinflunine). Endpoints were overall survival (primary), progression-free survival (PFS), objective response, and safety. RESULTS: In total, 608 patients were included (enfortumab vedotin, n = 301; chemotherapy, n = 307). With a median follow-up of 23.75 months, 444 deaths had occurred (enfortumab vedotin, n = 207; chemotherapy, n = 237). Risk of death was reduced by 30% with enfortumab vedotin versus chemotherapy [hazard ratio (HR) 0.70 (95% confidence interval [CI] 0.58-0.85); one-sided, log-rank P = 0.00015]; PFS improved with enfortumab vedotin [HR 0.63 (95% CI 0.53-0.76); one-sided, log-rank P < 0.00001]. Treatment-related adverse event rates were 93.9% for enfortumab vedotin and 91.8% for chemotherapy; grade ≥ 3 event rates were 52.4% and 50.5%, respectively. Grade ≥ 3 treatment-related decreased neutrophil count (14.1% versus 6.1%), decreased white blood cell count (7.2% versus 1.4%), and anemia (7.9% versus 2.7%) were more common with chemotherapy versus enfortumab vedotin; maculopapular rash (7.4% versus 0%), fatigue (6.8% versus 4.5%), and peripheral sensory neuropathy (5.1% versus 2.1%) were more common with enfortumab vedotin. Of special interest adverse events, treatment-related skin reactions occurred in 47.3% of patients receiving enfortumab vedotin and 15.8% of patients receiving chemotherapy; peripheral neuropathy occurred in 48.0% versus 31.6%, respectively, and hyperglycemia in 6.8% versus 0.3%. CONCLUSIONS: After a median follow-up of ∼2 years, enfortumab vedotin maintained clinically meaningful overall survival benefit versus chemotherapy, consistent with findings from the EV-301 primary analysis; PFS and overall response benefit remained consistent. Adverse events were manageable; no new safety signals were observed.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Docetaxel
3.
Ann Oncol ; 29(12): 2302-2312, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30016395

RESUMO

Urothelial malignancies, including carcinomas of the bladder, ureters, and renal pelvis comprised ∼8% of new cancer cases in the USA in 2016. In the metastatic setting, 15% of patients exhibit long-term survival following cisplatin-based chemotherapy and in patients with recurrent disease, response rates to second-line chemotherapy are generally 15%-20% with a 3-month progression-free survival. However, recent advances in immunotherapy represent an opportunity to significantly improve patient outcomes. Moreover, the advent of next-generation sequencing has resulted in both an improved understanding of the fundamental genetic changes that characterize urothelial carcinoma (UC) and identification of several candidate biomarkers of response to various therapies. Incorporation of prospective genotyping into clinical trials will allow for the identification and enrichment of patients most likely to respond to specific targeted therapies and chemotherapy. Combining different therapeutic classes to enhance outcomes is also an area of active research in UC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Genotipagem , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Terapia de Alvo Molecular/métodos , Taxa de Mutação , Intervalo Livre de Progressão , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Urotélio/patologia
4.
Urol Oncol ; 36(7): 345-346, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29859727

RESUMO

PURPOSE: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. EXPERIMENTAL DESIGN: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. RESULTS: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable effect on clinical outcomes. CONCLUSIONS: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment.


Assuntos
Carcinoma de Células de Transição , Platina , Dano ao DNA , Humanos , Mutação , Neoplasias Urológicas
5.
Ann Oncol ; 28(12): 3044-3050, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28950298

RESUMO

BACKGROUND: Conventional criteria for tumor progression may not fully reflect the clinical benefit of immunotherapy or appropriately guide treatment decisions. The phase II IMvigor210 study demonstrated the efficacy and safety of atezolizumab, a programmed death-ligand 1-directed antibody, in patients with platinum-treated locally advanced or metastatic urothelial carcinoma. Patients could continue atezolizumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression at the investigator's discretion: this analysis assessed post-progression outcomes in these patients. PATIENTS AND METHODS: Patients were treated with atezolizumab 1200 mg i.v. every 3 weeks until loss of clinical benefit. Efficacy and safety outcomes in patients who experienced RECIST v1.1 progression and did, or did not, continue atezolizumab were analyzed descriptively. RESULTS: In total, 220 patients who experienced progression from the overall cohort (n = 310) were analyzed: 137 continued atezolizumab for ≥ 1 dose after progression, 19 received other systemic therapy, and 64 received no further systemic therapy. Compared with those who discontinued, patients continuing atezolizumab beyond progression were more likely to have had a baseline Eastern Cooperative Oncology Group performance status of 0 (43.1% versus 31.3%), less likely to have had baseline liver metastases (27.0% versus 41.0%), and more likely to have had an initial response to atezolizumab (responses in 11.7% versus 1.2%). Five patients (3.6%) continuing atezolizumab after progression had subsequent responses compared with baseline measurements. Median post-progression overall survival was 8.6 months in patients continuing atezolizumab, 6.8 months in those receiving another treatment, and 1.2 months in those receiving no further treatment. Atezolizumab exposure-adjusted adverse event frequencies were generally similar before and following progression. CONCLUSION: In this single-arm study, patients who continued atezolizumab beyond RECIST v1.1 progression derived prolonged clinical benefit without additional safety signals. Identification of patients most likely to benefit from atezolizumab beyond progression remains an important challenge in the management of metastatic urothelial carcinoma. CLINICALTRIALS.GOV ID: NCT02108652.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias Urológicas/patologia
6.
Clin Genitourin Cancer ; 13(1): 71-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24993933

RESUMO

BACKGROUND: The differential impact of the number of prior lines of therapy and the setting of prior therapy (perioperative or metastatic) is unclear in advanced urothelial carcinoma. PATIENTS AND METHODS: Ten phase II trials of salvage chemotherapy, biologic agent therapy, or both, enrolling 731 patients, were available. Data on the number of prior lines of therapy and the setting of prior therapy were required in addition to known previously recognized prognostic factors: time from prior chemotherapy, hemoglobin level, performance status, and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of the number of prior lines and prior perioperative therapy with overall survival (OS) as the primary clinical endpoint. Trial was a stratification factor. RESULTS: A total of 711 patients were evaluable. The overall median progression-free survival and OS were 2.7 and 6.8 months, respectively. The number of prior lines was 1 in 559 patients (78.6%), 2 in 111 (15.6%), 3 in 29 (4.1%), 4 in 10 (1.4%), and 5 in 2 (0.3%). Prior perioperative chemotherapy was given to 277 (39.1%) and chemotherapy for metastatic disease to 454 (64.1%). The number of prior lines was not independently associated with OS (hazard ratio, 0.99; 95% CI, 0.86-1.14). Prior perioperative chemotherapy was a favorable factor for OS on univariate but not multivariate analysis. CONCLUSION: The number of prior lines of therapy and prior perioperative chemotherapy were not independently prognostic in patients with urothelial carcinoma receiving salvage therapy. Adoption of these data in salvage therapy trials should enhance accrual, the interpretability of results, and drug development.


Assuntos
Tratamento Farmacológico/métodos , Terapia de Salvação/métodos , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/mortalidade , Idoso , Ensaios Clínicos Fase II como Assunto , Humanos , Pessoa de Meia-Idade , Assistência Perioperatória , Estudos Prospectivos , Análise de Regressão , Análise de Sobrevida , Resultado do Tratamento
7.
Br J Cancer ; 109(10): 2548-53, 2013 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-24129239

RESUMO

BACKGROUND: A phase III trial demonstrated an overall survival advantage with the addition of vinflunine to best supportive care (BSC) in platinum-refractory advanced urothelial cancer. We subsequently examined the impact of an additional 2 years of survival follow-up and evaluated the influence of first-line platinum therapy on survival. METHODS: The 357 eligible patients from the phase III study were categorised into two cohorts depending on prior cisplatin treatment: cisplatin or non-cisplatin. Survival was calculated using the Kaplan-Meier method. RESULTS: The majority had received prior cisplatin (70.3%). Survival was higher in the cisplatin group (HR: 0.76; CI 95% 0.58-0.99; P=0.04) irrespective of treatment arm. Multivariate analysis including known prognostic factors (liver involvement, haemoglobin, performance status) and prior platinum administration did not show an independent effect of cisplatin. Vinflunine reduced the risk of death by 24% in the cisplatin-group (HR: 0.76; CI 95% 0.58-0.99; P=0.04) and by 35% in non-cisplatin patients (HR: 0.65; CI 95% 0.41-1.04; P=0.07). INTERPRETATION: Differences in prognostic factors between patients who can receive prior cisplatin and those who cannot may explain the survival differences in patients who undergo second line therapy. Prior cisplatin administration did not diminish the subsequent benefit of vinflunine over BSC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/mortalidade , Cisplatino/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/mortalidade , Vimblastina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/patologia , Quimioterapia Adjuvante , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Vimblastina/uso terapêutico
8.
Ann Oncol ; 24(6): 1466-72, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23419284

RESUMO

BACKGROUND: To compare long-term, updated overall survival (OS) of patients with advanced transitional cell carcinoma of the urothelium (TCCU) treated with vinflunine plus best supportive care (BSC) or BSC alone, after failure of platinum-based chemotherapy. PATIENTS AND METHODS: Three hundred and seventy patients were randomly assigned in a phase III trial and allocated (2:1) to vinflunine (320 or 280 mg/m(2)) plus BSC or BSC alone. The first report (Bellmunt J, Theodore C, Demkov T et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinumcontaining regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009; 27(27): 4454-4461) had a median follow-up of 22.1 m and the current report has a follow-up of 45.4 m. RESULTS: Three hundred and fifty-two patients had died (censoring rate 5%). In the intention-to-treat (ITT) population, the median OS was 6.9 m and 4.6 m for vinflunine plus BSC versus BSC alone, respectively (n.s.). In multivariate Cox analysis, the addition of vinflunine was independently correlated with improved survival (HR: 0.719; 95% CI:0.570-0.906, P = 0.0052). In the eligible population, the median OS in both the arms was 6.9 and 4.3 m, respectively (HR: 0.78; 95% CI:0.61-0.96; P = 0.0227), indicating an estimated 22% reduction in the risk of death. CONCLUSIONS: The updated OS data confirm the positive treatment effect of vinflunine on survival that was previously reported. These results are consistent over time and confirm that vinflunine is a valuable option for second-line treatment in patients with advanced TCCU after failure of platinum-based regimens.


Assuntos
Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Vimblastina/análogos & derivados , Idoso , Carcinoma de Células de Transição/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Platina/uso terapêutico , Estudos Prospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Falha de Tratamento , Neoplasias da Bexiga Urinária/terapia , Urotélio/patologia , Vimblastina/uso terapêutico
11.
Ann Oncol ; 19(5): 946-50, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18272914

RESUMO

BACKGROUND: There is no standard second-line treatment for advanced urothelial carcinoma (UC). Response rates to second-line chemotherapy for advanced UC are low and response duration is short. Bortezomib is a proteasome inhibitor with preclinical activity against UC. PATIENTS AND METHODS: Treatment consisted of bortezomib 1.3 mg/m(2) i.v. twice weekly for two consecutive weeks, followed by a 1-week break. The primary end point was objective response rate (complete response + partial response) by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included safety, toxicity, and progression-free and overall survival. RESULTS: In all, 25 patients with advanced UC previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Only 29% of patients had node-only metastases. Grade 3/4 drug-related toxic effects included thrombocytopenia (4%), anemia (8%), lymphopenia (8%), sensory neuropathy (6%), hyperglycemia (4%), hypernatremia (4%), fatigue (4%), neuropathic pain (6%), dehydration (4%), and vomiting (4%). No objective responses were observed [95% confidence interval (CI) = 0-12]. The median time to progression was 1.4 months (95% CI = 1.1-2.0 months), and the median survival time was 5.7 months (95% CI = 3.6-8.4 months). There were no treatment-related deaths. CONCLUSION: Although bortezomib is well tolerated, it does not have antitumor activity as second-line therapy in UC.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Pirazinas/uso terapêutico , Terapia de Salvação , Neoplasias Urológicas/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Bortezomib , Carcinoma de Células de Transição/mortalidade , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/efeitos adversos , Pirazinas/efeitos adversos , Falha de Tratamento , Neoplasias Urológicas/mortalidade
12.
Oncogene ; 13(11): 2483-5, 1996 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-8957092

RESUMO

Allelic loss of chromsome 19q occurs frequently in malignant gliomas, suggesting the presence of a chromosome 19q glioma tumor suppressor gene. Deletion mapping studies have delineated a 3.5 Mb candidate region between D19S219 and HRC. Cloned sequences from the proximal 425 kb of this interval, however, have not shown tumor-specific alterations. To refine the location of the tumor suppressor gene further, we conducted loss of heterozygosity studies on 191 malignant gliomas using nine PCR-based polymorphisms. These included the previously identified and physically mapped markers D19S219, DM, D19S112, HRC and the recently physically mapped polymorphisms at D19S412, STD, D19S596 and GYS. In addition, we isolated a novel microsatellite polymorphism that maps 400 kb telomeric to D19S112. Oligodendroglial tumors showed frequent loss of heterozygosity in all grades, and typically displayed allelic loss at all studied markers. Astrocytomas, however, showed frequent loss primarily in anaplastic astrocytomas and displayed deletion breakpoints within the candidate region. Deletion mapping revealed a minimal region of overlap between D19S412 and STD, a distance of 900 kb. These data suggest that the D19S412-STD interval represents the most likely location for a chromsome 19q glioma tumor suppressor gene involved in astrocytoma, and perhaps oligodendroglioma, tumorigenesis.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 19/genética , Deleção de Genes , Genes Supressores de Tumor/genética , Glioma/genética , Alelos , Marcadores Genéticos , Humanos , Polimorfismo Genético
14.
Arch Surg ; 120(5): 573-7, 1985 May.
Artigo em Inglês | MEDLINE | ID: mdl-2985027

RESUMO

Of 12 women with carcinoma of the breast and coexistent silicone mastopathy, nine had had injections of liquid silicone for breast augmentation; three had leaking silicone-gel prostheses. The clinical findings indicated that early diagnosis was obscured by the silicone-induced mastopathy, which rendered the interpretation of physical findings and mammograms difficult. The pathologic findings were suggestive of a possible adverse effect of the presence of free silicone within the breast tissue, axillary nodes, and axillary fat. Although no causal relationship between silicone and breast carcinoma is implied, a heightened awareness of the possible coexistence of silicone mastopathy and breast carcinoma is necessary.


Assuntos
Neoplasias da Mama/induzido quimicamente , Próteses e Implantes/efeitos adversos , Silicones/efeitos adversos , Adulto , Idoso , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/induzido quimicamente , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Humanos , Mamografia , Pessoa de Meia-Idade
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