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1.
Br J Clin Pharmacol ; 85(6): 1357-1366, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30811063

RESUMO

AIMS: Cetuximab associated with cisplatin and 5-fluorouracil is used to treat patients with inoperable or metastatic head and neck squamous cell carcinomas (HNSCC) up until disease progression or unacceptable toxicities. To date, no biomarkers of efficacy are available to select patients who will benefit from treatment. METHODS: An ancillary pharmacokinetics (PK) exploration was performed in the context of a prospective study investigating circulating-tumour cells vs progression-free survival (PFS). Cetuximab plasma concentrations were analysed according to a population PK model. Individual exposure parameters were confronted with soluble epidermal growth factor receptor (sEGFR) concentrations, tumour response and PFS. RESULTS: PK data (28 patients, 203 observations) were best described by a two-compartment model with linear elimination. Performance status (PS) significantly correlated to both cetuximab clearance and central volume of distribution with both parameters increasing by 33.3% (95% CI 1-65.6) for each 1-point increase of PS compared to PS = 0. Univariate analysis showed that patients with higher trough cetuximab concentrations at Day 7 (Cmin,D7 ) had better tumour response (P = 0.03) and longer PFS (P = 0.035). However, multivariate analysis revealed that only PS and tumour size at baseline remained significantly associated with PFS. Levels of sEGFR increased during cetuximab treatment but were not associated with PFS in the multivariate analysis. CONCLUSIONS: Our study prospectively indicates that PS is likely a confounding factor in the relationship between cetuximab PK and PFS, patients with a poor PS having lower cetuximab plasma exposure and lower PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cetuximab/farmacocinética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Modelos Biológicos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Cetuximab/administração & dosagem , Cetuximab/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/farmacocinética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/sangue , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/patologia , Intervalo Livre de Progressão , Estudos Prospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Adulto Jovem
2.
Clin Cancer Res ; 16(17): 4434-45, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20660574

RESUMO

PURPOSE: There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography with computed tomography ((18)FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity. EXPERIMENTAL DESIGN: Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in (18)FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the (18)FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed. RESULTS: Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in (18)FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses. CONCLUSION: These results show that the (18)FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Quinazolinas/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Idoso , Animais , Western Blotting , Linhagem Celular Tumoral , Cloridrato de Erlotinib , Feminino , Imunofluorescência , Fluordesoxiglucose F18/farmacocinética , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Clin Cancer Res ; 16(4): 1264-71, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20145184

RESUMO

PURPOSE: Tipifarnib, a farnesyltransferase inhibitor, has antitumor activity in heavily pretreated metastatic breast cancer patients. Preclinical data suggest that FTIs could restore tamoxifen responsiveness in tamoxifen-resistant disease. Thus, combining FTIs and tamoxifen may be a promising clinical approach after relapse or progression on tamoxifen. EXPERIMENTAL DESIGN: Postmenopausal patients with measurable estrogen receptor- and/or progesterone receptor-expressing metastatic breast cancers were enrolled. Only patients with disease progression on tamoxifen were eligible, but there was no limitation regarding prior chemotherapy or hormone therapy regimens. Patients were immediately treated with 300 mg (n = 12) or 200 mg (n = 10) tipifarnib twice daily for 21 of 28-day cycles plus tamoxifen once daily. Serum was collected at baseline and after 8 weeks of treatment to enable proteomic comparison and identify possible predictive response markers. RESULTS: Twenty patients were enrolled and evaluated for efficacy: one patient had an objective response (liver metastasis) and nine had stable disease after 6 months for a clinical benefit rate of 50%; median duration of benefit was 10.3 (range, 7.4-20.2) months. The proteomic analysis by SELDI-TOF and LTQ-FT-Orbitrap identified a known peptide of fibrinogen alpha, the intensity of which was significantly increased in patients with progression compared with patients who benefited from the combined treatment after 8 weeks. CONCLUSIONS: Because the primary end point of efficacy (three objective responses) was not achieved, the study is negative. Nevertheless, the identified peptide could be of interest in discriminating, at 8 weeks of treatment, responders from nonresponders.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Quinolonas/administração & dosagem , Tamoxifeno/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Farnesiltranstransferase/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Pós-Menopausa , Análise Serial de Proteínas , Quinolonas/efeitos adversos , Quinolonas/farmacocinética
4.
Clin Cancer Res ; 13(23): 7086-92, 2007 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18056187

RESUMO

PURPOSE: To determine the safety and efficacy of erlotinib given as neoadjuvant treatment in patients with head and neck squamous cell carcinoma (HNSCC). Further objectives were to identify markers of response to erlotinib and to assess the pharmacodynamic effects of erlotinib in tumor cells. EXPERIMENTAL DESIGN: Patients with locally advanced nonmetastatic HNSCC were treated with erlotinib 150 mg daily pending surgical management. Tumor samples were collected before and after erlotinib treatment and were analyzed using immunohistochemistry. Epidermal growth factor receptor copy number was determined in tumors using CISH analysis. RESULTS: Between November 2003 and December 2005, 35 patients were included in the study. Neoadjuvant treatment with erlotinib in HNSCC patients was well tolerated and did not necessitate modification to routine surgical procedures. Among 31 evaluable patients, erlotinib was given for a median of 20 days. At the time of surgery, tumor shrinkage was observed in nine patients (29%). Immunohistochemistry analyses were done for 31 patients and showed a decrease in phosphorylated tyrosine residues and phosphorylated erk immunostaining after erlotinib treatment. In a retrospective analysis, baseline p21(waf) expression in the basal-like cell layer was statistically positively correlated with clinical response to treatment. Epidermal growth factor receptor copy number did not correlate with response to erlotinib. CONCLUSION: Neoadjuvant treatment of HNSCC with erlotinib was well tolerated. Baseline p21(waf) expression was associated with response to erlotinib and so might be useful as a tool to select patients for erlotinib therapy in this setting.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Inibidor de Quinase Dependente de Ciclina p21/genética , Receptores ErbB/genética , Cloridrato de Erlotinib , Feminino , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética
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