Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
1.
Clin Cancer Res ; 18(16): 4406-14, 2012 Aug 15.
Article in English | MEDLINE | ID: mdl-22733536

ABSTRACT

PURPOSE: This retrospective study was undertaken to investigate the impact of initial gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) versus chemotherapy on the risk of central nervous system (CNS) progression in advanced non-small cell lung cancer (NSCLC) with EGFR mutations. EXPERIMENTAL DESIGN: Patients with stage IV or relapsed NSCLC with a sensitizing EGFR mutation initially treated with gefitinib, erlotinib, or chemotherapy were identified. The cumulative risk of CNS progression was calculated using death as a competing risk. RESULTS: One hundred and fifty-five patients were eligible (EGFR-TKI: 101, chemotherapy: 54). Twenty-four patients (24%) in the EGFR-TKI group and 12 patients (22%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC (P = 1.000); 32 of the 36 received CNS therapy before initiating systemic treatment. Thirty-three patients (33%) in the EGFR-TKI group and 26 patients (48%) in the chemotherapy group developed CNS progression after a median follow-up of 25 months. The 6-, 12-, and 24-month cumulative risk of CNS progression was 1%, 6%, and 21% in the EGFR-TKI group compared with corresponding rates of 7%, 19%, and 32% in the chemotherapy group (P = 0.026). The HR of CNS progression for upfront EGFR-TKI versus chemotherapy was 0.56 [95% confidence interval (CI), 0.34-0.94]. CONCLUSIONS: Our data show lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with an EGFR-TKI compared with upfront chemotherapy. If validated, our results suggest that gefitinib and erlotinib may have a role in the chemoprevention of CNS metastases from NSCLC.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Central Nervous System Neoplasms/secondary , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Mutation , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/epidemiology , Disease Progression , ErbB Receptors/antagonists & inhibitors , Erlotinib Hydrochloride , Female , Gefitinib , Humans , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Recurrence , Risk Factors
2.
J Thorac Cardiovasc Surg ; 144(3): S39-42, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22502967

ABSTRACT

Despite surgical resection, patients with early-stage (I to IIIA) non-small cell lung cancer (NSCLC) are at considerable risk of recurrence and death from their lung cancer. In recent years, multiple, large, randomized trials assessing the efficacy of adjuvant chemotherapy for resected NSCLC have been reported. Three of 6 trials with 300 or more patients with early-stage NSCLC have demonstrated that adjuvant cisplatin-based chemotherapy can significantly improve 5-year survival in carefully selected patients with resected NSCLC. These benefits have been confirmed in a meta-analysis of modern cisplatin-based adjuvant trials. The most consistent benefit has been reported in patients with resected stage II and IIIA NSCLC. The benefit of adjuvant chemotherapy in patients with resected stage IB NSCLC is less concrete. Herein, we review the results of the major adjuvant chemotherapy trials and their implications for the treatment of patients with completely resected NSCLC. A future challenge will be to identify the subsets of patients who will derive the greatest benefit from adjuvant chemotherapy. Current trials are also underway to define the role of novel targeted therapies, such as inhibitors of the epidermal growth factor receptor and monoclonal antibodies, in adjuvant treatment strategies.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/surgery , Lung Neoplasms/drug therapy , Lung Neoplasms/surgery , Pneumonectomy , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/secondary , Chemotherapy, Adjuvant , Disease-Free Survival , Evidence-Based Medicine , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Molecular Targeted Therapy , Neoplasm Recurrence, Local , Neoplasm Staging , Patient Selection , Risk Assessment , Risk Factors , Survival Analysis , Time Factors , Treatment Outcome
3.
Cancer Res ; 71(18): 6051-60, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21791641

ABSTRACT

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.


Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , ErbB Receptors/metabolism , Lung Neoplasms/metabolism , Mutation , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/genetics , Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Crizotinib , Drug Resistance, Neoplasm , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Models, Molecular , Oncogene Proteins, Fusion/biosynthesis , Oncogene Proteins, Fusion/genetics , Pyrazoles/pharmacology , Pyridines/pharmacology , Receptor Protein-Tyrosine Kinases/metabolism , Signal Transduction
4.
Clin Cancer Res ; 16(23): 5873-82, 2010 Dec 01.
Article in English | MEDLINE | ID: mdl-21030498

ABSTRACT

PURPOSE: Gefitinib and erlotinib can penetrate into the central nervous system (CNS) and elicit responses in patients with brain metastases (BM) from non-small cell lung cancer (NSCLC). However, there are incomplete data about their impact on the development and control of CNS metastases. EXPERIMENTAL DESIGN: Patients with stage IIIB/IV NSCLC with somatic EGFR mutations initially treated with gefitinib or erlotinib were identified. The cumulative risk of CNS progression was calculated using death as a competing risk. RESULTS: Of the 100 patients, 19 had BM at the time of diagnosis of advanced NSCLC; 17 of them received CNS therapy before initiating gefitinib or erlotinib. Eighty-four patients progressed after a median potential follow-up of 42.2 months. The median time to progression was 13.1 months. Twenty-eight patients developed CNS progression, 8 of whom had previously treated BM. The 1- and 2-year actuarial risk of CNS progression was 7% and 19%, respectively. Patient age and EGFR mutation genotype were significant predictors of the development of CNS progression. The median overall survival for the entire cohort was 33.1 months. CONCLUSIONS: Our data suggest a lower risk of CNS progression in patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib than published rates of 40% in historical series of advanced NSCLC patients. Further research is needed to distinguish between the underlying rates of developing CNS metastases between NSCLC with and without EGFR mutations and the impact of gefitinib and erlotinib versus chemotherapy on CNS failure patterns in these patients.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Central Nervous System Neoplasms/secondary , Genes, erbB-1/physiology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Quinazolines/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/mortality , Disease Progression , Erlotinib Hydrochloride , Female , Gefitinib , Genotype , Humans , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Middle Aged , Mutation/physiology , Neoplasm Staging , Quinazolines/adverse effects , Randomized Controlled Trials as Topic , Survival Analysis , Treatment Outcome
5.
Am J Physiol Heart Circ Physiol ; 285(2): H499-506, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12714334

ABSTRACT

Doxorubicin (DOX), an anticancer drug, causes a dose-dependent cardiotoxicity. Some evidence suggests that female children have an increased risk for DOX-mediated cardiac damage. To determine whether the iron chelator dexrazoxane (DXR) could reduce DOX-induced cardiotoxicity in the young, we injected day 10 neonate female and male rat pups with a single dose of saline or DOX, DXR, or DXR + DOX (20:1). We followed body weight gain with growth, measured cardiac hypertrophy after a 2-wk swim exercise program, markers of apoptosis (Bcl-2, BAX, BNIP1, caspase 3 activation), oxidative stress (heme oxygenase 1, protein carbonyl levels), the chaperone protein clusterin, and the transcriptional activator early growth response gene-1 (Egr-1) in hearts of nonexercised and exercised rats on neonate day 38. All DOX-alone and DXR + DOX-treated rats showed decreased weight gain, with female rats affected earlier than male rats. DXR-alone, DOX-alone, and DXR + DOX-treated rats had an increased heart weight-to-body weight (heart wt/body wt) ratio after the exercise program with female rats showing the largest increase in heart wt/body wt. Drug-treated females also showed increased cardiac apoptosis, as measured by the increased expression of the proapoptotic proteins BAX and BNIP1 and the appearance of caspase 3 activation products, and oxidative stress, as measured by increased heme oxygenase 1 expression, and reduced Egr-1 and clusterin expression when compared with the similarly treated male rats. We conclude that DXR preinjection did not reduce DOX-induced noncardiac and cardiac damage and that young female rats were more susceptible to DXR and DOX toxicities than age-matched male rats.


Subject(s)
Antineoplastic Agents/pharmacology , Doxorubicin/toxicity , Heart Diseases/chemically induced , Heart Diseases/drug therapy , Razoxane/pharmacology , Age Factors , Animals , Body Weight , Cell Differentiation , Female , Heart Diseases/pathology , Heme Oxygenase (Decyclizing)/metabolism , Heme Oxygenase-1 , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Organ Size , Oxidative Stress/drug effects , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Rats , Rats, Sprague-Dawley , Vesicular Transport Proteins , bcl-2-Associated X Protein
SELECTION OF CITATIONS
SEARCH DETAIL