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1.
J Clin Oncol ; 33(5): 433-41, 2015 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-25559798

RESUMEN

PURPOSE: Linifanib, a potent, selective inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, has single-agent activity in non-small-cell lung cancer (NSCLC). We evaluated linifanib with carboplatin and paclitaxel as first-line therapy of advanced nonsquamous NSCLC. PATIENTS AND METHODS: Patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned to 3-week cycles of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) with daily placebo (arm A), linifanib 7.5 mg (arm B), or linifanib 12.5 mg (arm C). The primary end point was progression-free survival (PFS); secondary efficacy end points included overall survival (OS) and objective response rate. RESULTS: One hundred thirty-eight patients were randomly assigned (median age, 61 years; 57% men; 84% smokers). Median PFS times were 5.4 months (95% CI, 4.2 to 5.7 months) in arm A (n = 47), 8.3 months (95% CI, 4.2 to 10.8 months) in arm B (n = 44), and 7.3 months (95% CI, 4.6 to 10.8 months) in arm C (n = 47). Hazard ratios (HRs) for PFS were 0.51 for arm B versus A (P = .022) and 0.64 for arm C versus A (P = .118). Median OS times were 11.3, 11.4, and 13.0 months in arms A, B, and C, respectively. HRs for OS were 1.08 for arm B versus A (P = .779) and 0.88 for arm C versus A (P = .650). Both linifanib doses were associated with increased toxicity, including a higher incidence of adverse events known to be associated with VEGF/PDGF inhibition. Baseline plasma carcinoembryonic antigen/cytokeratin 19 fragments biomarker signature was associated with PFS improvement and a trend toward OS improvement with linifanib 12.5 mg. CONCLUSION: Addition of linifanib to chemotherapy significantly improved PFS (arm B), with a modest trend for survival benefit (arm C) and increased toxicity reflective of known VEGF/PDGF inhibitory effects.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Indazoles/administración & dosificación , Indazoles/efectos adversos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores
2.
Support Care Cancer ; 22(2): 513-8, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24122404

RESUMEN

BACKGROUND: Prolonged neurotoxicity after systemic chemotherapy has the potential to impact on quality of life. We explored the frequency of persistent peripheral neuropathy in patients who received oxaliplatin for colorectal cancer at two local centres. PATIENTS AND METHODS: Questionnaires were sent to patients who completed treatment with oxaliplatin for colorectal cancer at least 20 months prior to entering the study. Neuropathy questions were adapted from the FACT/GOG-Ntx (V.4) questionnaire. RESULTS: Of the 56 eligible patients, 27 returned the questionnaire. Twenty-five patients (93 %) experienced neuropathic symptoms during their treatment; 11 had grade-2, and two had grade-3 symptoms. At the time of completing the questionnaire, 17 patients (63.0 %; 95%CI 43.9-79.4 %) were still symptomatic with 12 patients (44.4 %; 95%CI 26.8-63.3) having grade-2 or grade-3 symptoms and three patients (11.1 %; 95%CI 2.9-27.3) having grade-3 neuropathic symptoms. Participants who received more than 900 mg/m2 oxaliplatin had a significantly higher risk of persistent grade-2 or grade-3 neuropathy (p = 0.031, RR = 8.3 95%CI = 1.2-57.4). There was a trend toward increased risk of persistent neuropathy of any grade among participants with a history of regular alcohol use (p = 0.051; RR = 1.7 95%CI 1.0-2.8). CONCLUSION: Persistent oxaliplatin-induced neuropathy is not as uncommon as previously suggested, and the rate of grade-2 and grade-3 symptoms could be considerably higher than previous reports.


Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Compuestos Organoplatinos/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Adulto , Anciano , Antineoplásicos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes de Neurotoxicidad/diagnóstico , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Encuestas y Cuestionarios
3.
J Clin Oncol ; 32(8): 760-7, 2014 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-24297950

RESUMEN

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.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/uso terapéutico , Sirolimus/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/enzimología , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Sirolimus/efectos adversos , Sirolimus/uso terapéutico , Sorafenib , Sunitinib , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Factores de Tiempo , Insuficiencia del Tratamiento , Adulto Joven
4.
J Hematol Oncol ; 2: 24, 2009 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-19500345

RESUMEN

INTRODUCTION: The ability to screen blood of early stage operable breast cancer patients for circulating tumour cells is of potential importance for identifying patients at risk of developing distant relapse. We present the results of a study of the efficacy of the immunobead RT-PCR method in identifying patients with circulating tumour cells. RESULTS: Immunomagnetic enrichment of circulating tumour cells followed by RT-PCR (immunobead RT-PCR) with a panel of five epithelial specific markers (ELF3, EPHB4, EGFR, MGB1 and TACSTD1) was used to screen for circulating tumour cells in the peripheral blood of 56 breast cancer patients. Twenty patients were positive for two or more RT-PCR markers, including seven patients who were node negative by conventional techniques. Significant increases in the frequency of marker positivity was seen in lymph node positive patients, in patients with high grade tumours and in patients with lymphovascular invasion. A strong trend towards improved disease free survival was seen for marker negative patients although it did not reach significance (p = 0.08). CONCLUSION: Multi-marker immunobead RT-PCR analysis of peripheral blood is a robust assay that is capable of detecting circulating tumour cells in early stage breast cancer patients.


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Células Neoplásicas Circulantes/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Línea Celular Tumoral , Separación Celular/métodos , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Técnicas de Inmunoadsorción , Magnetismo/métodos , Microesferas , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Células Neoplásicas Circulantes/química
5.
BMC Cancer ; 2: 14, 2002 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-12031094

RESUMEN

BACKGROUND: Immunomagnetic enrichment followed by RT-PCR (immunobead RT-PCR) is an efficient methodology to identify disseminated carcinoma cells in the blood and bone marrow. The RT-PCR assays must be both specific for the tumor cells and sufficiently sensitive to enable detection of single tumor cells. We have developed a method to test RT-PCR assays for any cancer. This has been investigated using a panel of RT-PCR markers suitable for the detection of breast cancer cells. METHODS: In the assay, a single cell line-derived tumor cell is added to 100 peripheral blood mononuclear cells (PBMNCs) after which mRNA is isolated and reverse transcribed for RT-PCR analysis. PBMNCs without added tumor cells are used as specificity controls. The previously studied markers epidermal growth factor receptor (EGFR), mammaglobin 1 (MGB1), epithelial cell adhesion molecule (EpCAM/TACSTD1), mucin 1 (MUC1), carcinoembryonic antigen (CEA) were tested. Two new epithelial-specific markers ELF3 and EphB4 were also tested. RESULTS: MUC1 was unsuitable as strong amplification was detected in 100 cell PBMNC controls. Expression of ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 was found to be both specific for the tumor cell, as demonstrated by the absence of a signal in most 100 cell PBMNC controls, and sensitive enough to detect a single tumor cell in 100 PBMNCs using a single round of RT-PCR. CONCLUSIONS: ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 are appropriate RT-PCR markers for use in a marker panel to detect disseminated breast cancer cells after immunomagnetic enrichment.


Asunto(s)
Neoplasias de la Mama/patología , Proteínas de Unión al ADN , Separación Inmunomagnética/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/genética , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/química , Neoplasias de la Mama/diagnóstico , Antígeno Carcinoembrionario/biosíntesis , Antígeno Carcinoembrionario/genética , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/genética , Efrina-B2 , Molécula de Adhesión Celular Epitelial , Receptores ErbB/biosíntesis , Genes erbB-1/genética , Humanos , Leucocitos Mononucleares , Mamoglobina A , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Técnicas de Amplificación de Ácido Nucleico , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normas , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Células Tumorales Cultivadas , Uteroglobina/biosíntesis , Uteroglobina/genética
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