RESUMEN
BACKGROUND: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. PATIENTS AND METHODS: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). RESULTS: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. CONCLUSION: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Quimioterapia Adyuvante , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Estadificación de Neoplasias , FarmacogenéticaAsunto(s)
Hemangioma , Melanoma , Neoplasias Cutáneas , Neoplasias de la Úvea , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hemangioma/diagnóstico , Humanos , Masculino , Melanoma/diagnóstico , Persona de Mediana Edad , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Cutáneas/diagnóstico , Neoplasias de la Úvea/diagnósticoRESUMEN
PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown. We describe outcomes of real-life patients according to the treatment strategy received. PATIENTS: We retrospectively collected 290 ALK rearranged advanced NSCLC diagnosed between 2011 and 2017 in 23 Italian institutions. RESULTS: After a median follow-up of 26 months, PFS for crizotinib and a new generation ALKis were 9.4 [CI 95% 7.9-11.2] and 11.1 months [CI 95% 9.2-13.8], respectively, while TTF were 10.2 [CI 95% 8.5-12.6] and 11.9 months [CI 95% 9.7-17.4], respectively, being consistent across the different settings. The composed outcomes (the sum of PFS or TTF) in patients treated with crizotinib followed by a new generation ALKis were 27.8 months [CI 95% 24.3-33.7] in PFS and 30.4 months [CI 95% 24.7-34.9] in TTF. The median OS from the diagnosis of advanced disease was 39 months [CI 95% 31.8-54.5]. Patients receiving crizotinib followed by a new generation ALKis showed a higher median OS [57 months (CI 95% 42.0-73.8)] compared to those that did not receive crizotinib [38 months (CI 95% 18.6-NR)] and those who performed only crizotinib as target agent [15 months (CI 95% 11.3-34.0)] (P < 0.0001). CONCLUSION: The sequential administration of crizotinib and a new generation ALKis provided a remarkable clinical benefit in this real-life population, being an interesting option to consider in selected patients.
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Quinasa de Linfoma Anaplásico/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib/uso terapéutico , Femenino , Reordenamiento Génico , Humanos , Italia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
ABCC2 (MRP2, cMOAT) expression has been implicated in cisplatin resistance in vitro. In mice, cisplatin disposition and toxicity were unaffected by Abcc2 knockout (Abcc2−/−). Moreover, in cancer patients (n = 237), cisplatin pharmacokinetics (P > 0.12) and efficacy (P > 0.41) were not associated with seven of the single-nucleotide polymorphisms (SNPs) in ABCC2. These SNPs were also not correlated with ABCC2 expression in the NCI60 panel (P > 0.26) or with cisplatin-induced cytotoxicity (P = 0.21). These findings highlight the importance of verifying drug-transporter interactions with in vitro tests in humans.
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Cisplatino/farmacocinética , Cisplatino/uso terapéutico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Animales , Antineoplásicos/efectos adversos , Línea Celular Tumoral , Cisplatino/efectos adversos , Estudios de Cohortes , ADN/genética , Variación Genética , Humanos , Enfermedades Renales/inducido químicamente , Ratones , Ratones Noqueados , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , ARN/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Población Blanca , Imagen de Cuerpo EnteroRESUMEN
AIM: The aim of this study was to analyze our experience with combined treatment of non-small cell lung cancer with synchronous brain metastases. METHODS: Between 1992 and 2008, 31 patients were treated by performing neurosurgery (or stereotactic radiosurgery) and lung surgery. Patients were divided into two groups according to their preoperative mediastinal work-up: group A (CT scan) and group B (FDG-PET scan). RESULTS: Twenty-six patients had one brain metastasis and five had two. Neurosurgery was performed in 10 patients, stereotactic radiosurgery in 20 and both approaches in 1. Seven patients underwent chemotherapy after cerebral procedure. Pulmonary resection was complete in 27 cases and incomplete in 4. Histological findings showed: adenocarcinoma in 19 cases, squamous cell carcinoma in 8 and large cell carcinoma in 4. All patients underwent adjuvant chemotherapy. Overall 1, 2 and 5-year survival rates were 83%, 47% and 21%, respectively. The median survival was 22 months. Univariate analysis showed a better prognosis for complete resection (P=0.008), adenocarcinomas (P=0.015), N0 disease (P=0.038), and Group B (P=0.045). Multivariate analysis showed that only the radicality of the resection (P=0.027) and Group B (P=0.047) were independent prognostic factors. CONCLUSION: Our experience confirms that selected patients with non-small cell lung cancer and synchronous brain metastases may be effectively treated by combined therapy. Complete resection, adenocarcinoma histology and N0 disease were prognostic factors. The incorporation of FDG-PET scan into the preoperative work-up may translate into a survival benefit.
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Neoplasias Encefálicas/terapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Procedimientos Neuroquirúrgicos , Neumonectomía , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/secundario , Quimioterapia Adyuvante , Femenino , Fluorodesoxiglucosa F18 , Humanos , Italia , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/efectos adversos , Procedimientos Neuroquirúrgicos/mortalidad , Oportunidad Relativa , Neumonectomía/efectos adversos , Neumonectomía/mortalidad , Tomografía de Emisión de Positrones , Modelos de Riesgos Proporcionales , Radiofármacos , Radioterapia Adyuvante , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: Asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF) is a vascular targeting agent exploiting a tumour-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13, overexpressed on tumour blood vessels. Significant preclinical synergy was shown between low doses of NGR-TNF and doxorubicin. METHODS: The primary aim of this phase I trial was to verify the safety of low-dose NGR-hTNF combined with doxorubicin in treating refractory/resistant solid tumours. Secondary objectives included pharmacokinetics (PKs), pharmacodynamics, and clinical activity. In all 15 patients received NGR-hTNF (0.2-0.4-0.8-1.6 microg m(-2)) and doxorubicin (60-75 mg m(-2)), both given intravenously every 3 weeks. RESULTS: No dose-limiting toxicity occurred and the combination was well tolerated. Around two cases of neutropenic fevers, lasting 2 days, and two cases of cardiac ejection-fraction drops, one asymptomatic and the other symptomatic, were registered. Only 11% of the adverse events were related to NGR-hTNF and were short-lasting and mild-to-moderate in severity. There was no apparent PK interaction and the shedding of soluble TNF-receptors did not increase to 0.8 microg m(-2). One partial response (7%), at dose level 0.8 microg m(-2), and 10 stable diseases (66%), lasting for a median duration of 5.6 months, were observed. CONCLUSIONS: NGR-hTNF plus doxorubicin was administered safely and showed promising activity in patients pre-treated with anthracyclines. The dose level of 0.8 microg m(-2) NGR-hTNF plus doxorubicin 75 mg m(-2) was selected for phase II development.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Factor de Necrosis Tumoral alfa/administración & dosificación , Factor de Necrosis Tumoral alfa/efectos adversos , Factor de Necrosis Tumoral alfa/farmacocinéticaRESUMEN
The purpose of this study was to evaluate associations between germline epidermal growth factor receptor (EGFR) variants involved in transcriptional regulation and overall survival in white patients with non-small-cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor, gefitinib. Of 175 consecutive patients treated with oral gefitinib (250 mg/day), 170 (median age: 67 years; 72% men) were evaluable for genotyping and survival. Fifty-five patients (33%) had stable disease and 17 (10%) had an objective response. The most common of four haplotypes was G-C (EGFR*1) at the EGFR -216G>T and -191C>A loci (frequency, 0.45). After adjusting for performance status, previous platinum-containing chemotherapy and occurrence of skin rash or diarrhea during the first treatment cycle in patients with performance status 0 or 1 (N=139), the absence of EGFR*1 was associated with significantly better survival (hazard ratio: 0.54; 95% confidence interval: 0.32-0.91; P=0.015). The results may help identify patients with NSCLC who can benefit from gefitinib treatment.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Receptores ErbB/genética , Mutación de Línea Germinal/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Polimorfismo Genético/genética , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Tasa de Supervivencia/tendenciasRESUMEN
AIM: To prospectively evaluate the impact of coregistered positron emission tomography (PET) and computed tomography (CT) in 3D conformal radiotherapy (3D-CRT) planning in patients with non-small lung cancer (NSCLC). METHODS: Twenty-one patients (median age: 57 years; range: 42-80 years) referred to 3D-CRT for NSCLC were recruited. Positron emission tomography with 18F-fluorodeoxyglucose ([18F]FDG-PET) and conventional CT images were coregistered (PET/CT images) using a commercial software package based on surface matching technique. Neoplastic areas were contoured on [18F]FDG-PET images with the aid of the correspondent CT image by a nuclear medicine physician. CT images and their relative PET contours were then transferred to treatment planning system. A radiation oncologist firstly contoured clinical target volumes (CTV) on CT scan alone (CTV-CT), and then on coregistered PET/CT images (CTV-PET/CT). CTV-CT and CTV-PET/CT were compared for each patient; a difference higher than 25% was considered of clinical relevance. RESULTS: Three patients were shifted to palliative radiotherapy for metastatic disease or very large tumor size, showed by [18F]FDG-PET. Of the remaining 18 patients a CTV change, after inclusion of PET/CT data, was observed in 10/18 cases (55%): larger in 7/18 (range 33-279%) and smaller in 3/18 patients (range 26-34%), mainly due to inclusion or exclusion of lymph-nodal disease and to better definition of tumor extent. CTV changes smaller than 25% occurred in the remaining 8/18 patients. CONCLUSIONS: [18F]FDG-PET and CT images co-registration in radiotherapy treatment planning led to a change in CTV definition in the majority of our patients, which may significantly modify management and radiation treatment modality in these patients.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Fluorodesoxiglucosa F18 , Aumento de la Imagen/métodos , Imagenología Tridimensional/métodos , Neoplasias Pulmonares/diagnóstico , Tomografía de Emisión de Positrones/métodos , Técnica de Sustracción , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Brain metastases are a common occurrence in patients with non-small-cell lung cancer (NSCLC). Whole-brain radiotherapy (WBRT) is the standard therapy; more aggressive approaches such as surgery or radiosurgery are indicated in a subset of patients only. The role of systemic treatments remains controversial. Gefitinib is an oral, highly tolerable, specific inhibitor of epidermal growth factor receptor-associated tyrosine kinase, which has shown activity in chemotherapy pre-treated NSCLC. The aim of this study was to evaluate the activity and safety of gefitinib in NSCLC patients with brain metastases. PATIENTS AND METHODS: From January 2001 to May 2003, 41 consecutive NSCLC patients with measurable brain metastases were treated with gefitinib, given orally at daily dose of 250 mg. Thirty-seven patients had received previous chemotherapy and 18 patients had been treated previously with WBRT, completed at least 3 months before entering the trial. RESULTS: A partial response (PR) was observed in four patients (10%), with stable disease (SD) in seven cases, for an overall disease control (DC) rate (DC=PR+SD) of 27% (95% confidence interval 13% to 40%). Median duration of PR was 13.5 months. Median progression-free survival (PFS) of the whole population was 3 months. DC rate was higher in patients pre-treated with WBRT (P=0.05) and with adenocarcinoma histological type (P=0.08); adenocarcinoma patients had also a longer PFS (P=0.04). Toxicity was mild and consisted of grade 1/2 skin toxicity and diarrhoea, occurring in 24% and 10% of patients, respectively. CONCLUSIONS: Gefitinib can be active on brain disease in NSCLC patients. Since the results of standard therapy for brain metastases in this clinical setting are particularly disappointing, gefitinib appears to be a possible new treatment option.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/patología , Diarrea/inducido químicamente , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Quinazolinas/efectos adversos , Radiografía , Enfermedades de la Piel/inducido químicamente , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The activity and toxicity profile of gefitinib in non-small cell lung cancer (NSCLC) patients aged 70 years or older has been only partially evaluated. The aim of this study was to evaluate the response rate and safety of gefitinib in elderly NSCLC patients. Elderly NSCLC patients pretreated with chemotherapy and with at least one measurable lesion received gefitinib at the daily dose of 250 mg until disease progression, unacceptable toxicity or refusal. From August 2001 to May 2003, 40 consecutive elderly patients have been enrolled onto the study in three Italian institutions. We observed one complete (2.5%) and one partial response (2.5%), 18 disease stabilisations (NC: 45%) lasting at least 2 months, including six patients (15%) who had disease stabilisation of 6 months or longer, for an overall disease control rate of 50% (95% CI: 34.5-65.5%). The median duration of response was 4.4 months (range 1.7-9.2). The side effects were generally mild and consisted of diarrhoea and skin toxicity. Grade 1-2 diarrhoea occurred in 23.6%, and one patient experienced grade 4 diarrhoea, requiring hospitalisation. Grade 1-2 skin toxicity, including rash, pruritus, dry skin, and acne, occurred in 20 patients (52.6%). Gefitinib is safe and well tolerated in elderly pretreated NSCLC patients. The disease-control rate achieved suggests that this drug could represent a valid option in the management of this unfavourable subgroup of patients.
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Envejecimiento , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/farmacología , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Diarrea/inducido químicamente , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/patología , Masculino , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Enfermedades de la Piel/inducido químicamenteRESUMEN
BACKGROUND AND OBJECTIVES: The different and unpredictable outcomes in early-stage non-small cell lung cancer patients requires urgent research concerning the biological pathway of this neoplasm. Our study investigated the frequency of expression and the clinicopathologic and prognostic significance of a series of biological markers in stage I and II resected non-small cell lung cancer. METHODS: A total of 99 cases of pathologic stage I and II were analyzed. The mean follow-up of surviving patients was 41 months. The expressions of the following biological markers were tested: bcl-2, p53, Ki-67, angiogenesis, and tumor vessel invasion. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biological markers using Cox's model for multivariate analysis. RESULTS: Tumoral vessel invasion was present in 22 (22%) pathologic samples, the angiogenesis mean value was 37 +/- 13, and median was 35; 13 (13%) patients showed positive immunostaining for bcl-2 oncoprotein. P53 oncoprotein expression was present in 48 patients (48.5%). All samples presented Ki-67 expression (mean value = 25.3 +/- 19.3, median = 20). The pathologic staging of the tumor was the most important independent prognostic factor for survival (P = 0.037) and for recurrence of disease (P = 0.040). Tumoral vessel invasion was the only marker with an independent predictive factor for survival and recurrence of disease in the group of patients without lymph node involvement (P = 0.02). CONCLUSION: Our data do not support a relevant prognostic role for p53, bcl-2, or Ki-67 immunohistochemical markers in non-small cell cancer. Tumor vessel invasion was an independent predictive factor of poor outcome in the group of patients without lymph node involvement. Pathological stage was confirmed as the most important independent prognostic factor.