Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 50
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Clin Cancer Res ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060099

RESUMO

PURPOSE: Our primary purpose is to explore safety and efficacy of high-dose icotinib in comparison with routine-dose icotinib in non-small cell lung cancer (NSCLC) patients harboring 21-L858R mutation. EXPERIMENTAL DESIGN: Treatment-naïve, EGFR-mutant (21-L858R or exon 19 deletion at 2:1) NSCLC patients were enrolled. Patients with 21-L858R mutation were randomized to receive routine-dose icotinib (125mg, thrice daily; L858R-RD) or high-dose icotinib (250mg, thrice daily; L858R-HD) , whereas patients with exon 19 deletion received only routine-dose icotinib (19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was median progression-free survival (mPFS), assessed by an independent review committee (IRC). RESULTS: From May, 2015 to November, 2017, 253 patients (86 in L858R-RD; 90 in L858R-HD; 77 in 19-Del-RD) were enrolled. The mPFS in L858R-HD group was similar to that in 19-Del-RD group (12.9 months and 12.5 months, respectively), and was significantly longer than that in L858R-RD group (12.9 months vs. 9.2 months, hazard ratio [HR]: 0.75; 95% confidence interval [CI]: 0.53 to 1.05). A longer but statistically non-significant mPFS was observed between 19-Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR: 0.80; 95% CI: 0.57 to 1.13). A higher objective response rate (ORR) was observed in L858R-HD group compared to L858R-RD group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar incidences of grade 3/4 toxicities were observed among the three treatment groups. CONCLUSIONS: High-dose icotinib improved mPFS and ORR in NSCLC patients harboring 21-L858R mutation with acceptable tolerability, which could be a new therapeutic option for this patient population.

2.
J Thorac Oncol ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007598

RESUMO

INTRODUCTION: Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor (TKI) selective for EGFR sensitizing and T790M resistant mutations. We assessed the safety, efficacy and pharmacokinetics (PK) of alflutinib in advanced NSCLC patients with confirmed T790M mutation, who progressed after the first- or second-generation EGFR-TKI therapy. METHODS: In the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. Primary endpoints were the safety, tolerability, and PK for the dose-escalation study, and the objective response rate (ORR, assessed by an independent radiological review committee) for the dose-expansion study. RESULTS: Between Nov 30, 2016, and Jul 24, 2018, 130 patients (14 in dose-escalation, 116 in dose-expansion) received alflutinib treatment (20, 40, 80, 160, or 240 mg once daily). By Oct 30, 2018, 79 (61%) patients remained on treatment. No dose limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40 - 240 mg), the overall ORR was 76.7% (89/116), and it was 70.6% (12/17) in patients with CNS metastases. 79% (103/130) of all patients had possibly treatment-related adverse events (AEs); 8% (11/130) had treatment-related grade ≥3 AEs. Serious adverse events (SAEs) were reported in 15% (20/130) of patients, and two SAEs were treatment related. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state. CONCLUSIONS: Alflutinib was clinically effective with an acceptable toxicity profile in advanced NSCLC patients (including those with CNS metastases) with EGFR T790M mutation. Further investigation is ongoing.

3.
J Hematol Oncol ; 13(1): 6, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31948451

RESUMO

BACKGROUND: BPI-9016M is a novel small-molecule inhibitor that simultaneously targets both c-Met and AXL tyrosine kinases. This phase I study aimed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of BPI-9016M in Chinese patients with advanced non-small cell lung cancer (NSCLC). METHODS: Over the dose range of 100 mg to 800 mg, eligible patients were administered with a single dose of 9016M tablet and received 7 days of pharmacokinetics evaluation, followed by continuous dose administration (QD dosing, 28 days). Standard "3 + 3" dose escalations were performed. RESULTS: Twenty NSCLC patients were treated. All patients experienced at least one adverse event (AE), of which treatment-related adverse events (TRAEs) were reported in 17 (85.0%) patients. The most common TRAEs were alanine transaminase (ALT) elevation (60%), bilirubin increased (40%), dysgeusia (40%), constipation (30%), hypertension (25%), and palmar-plantar erythrodysesthesia syndrome (15%). The TRAEs of grade 3 or higher during treatment were hypertension (15%), pulmonary embolism (5%), and laryngeal pain (5%). No dose-limiting toxicity (DLT) was observed, and the MTD was not reached. The median time to Cmax ranged from 2.0 to 3.5 h, and the plasma concentration of BPI-9016M declined rapidly after Tmax fitting a single-compartment model. The mean AUC0-72 h of M1 and M2-2, main metabolites of BPI-9016M, were 4.8-6.6 folds and 4.1-9.8 folds higher than that of BPI-9016M, respectively. Exposure to BPI-9016M, M1, and M2-2 reached moderate saturation at 600 mg. Among 19 evaluable patients, 1 had a partial response and 10 patients had stable disease. CONCLUSION: BPI-9016M showed favorable safety and pharmacokinetic profiles, and no DLT was observed at doses up to 800 mg once daily. The promising antitumor activity in Chinese NSCLC patients supports further development of this tyrosine kinase inhibitor. TRIAL REGISTRATION: Clinical Trial ID: NCT02478866, registered May 21, 2015.

4.
Chin J Cancer Res ; 31(5): 749-758, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31814679

RESUMO

Objective: To evaluate the efficacy and safety profile of first-line bevacizumab (Bev)-containing pemetrexed-platinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer (NS-NSCLC). Methods: A total of 415 eligible patients with NS-NSCLC who received first-line pemetrexed-platinum chemotherapy at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between February 2010 and September 2017 were reviewed retrospectively: 309 Bev(-) and 106 Bev(+) cases. Bev was administered at 7.5 mg/kg every 3 weeks in the Bev(+) group. To reduce the risk of a selection bias, a propensity score-matching (PSM) was conducted and 105 pairs of Bev(-) and Bev(+) cases were identified. Results: The median duration of follow-up was 15.8 months. The median progression-free survival (PFS) was prolonged significantly in the Bev(+) group than in the Bev(-) group in overall (9.8vs. 7.8 months, P=0.006) and PSM pairs (9.8 vs. 6.6 months, P<0.001). Moreover, patients receiving maintenance therapy with pemetrexed plus Bev had longer PFS than those interrupted after induction chemotherapy, or those receiving mono-maintenance with pemetrexed (12.3vs. 4.8 vs. 8.6 months; P<0.001). Multivariate analyses revealed Bev to be one of the favorable prognostic factors for PFS, along with the predictor of maintenance therapy. Conclusions: First-line induction and maintenance therapy with Bev (7.5 mg/kg every 3 weeks) combined with pemetrexed-platinum chemotherapy was efficacious and superior to non-Bev chemotherapy in Chinese patients with advanced NS-NSCLC.

5.
J Thorac Oncol ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31843683

RESUMO

INTRODUCTION: Blood-based tumor mutational burden (bTMB) has been studied to differentiate non-small cell lung cancer (NSCLC) patients who would benefit from anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. METHODS: Three independent cohorts of NSCLC patients treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N=211 and OAK, N=462) and further validated in the third National Cancer Center cohort (NCC, N=64). RESULTS: bTMB-H (bTMB≥cut-off point) was not associated with favorable OS following immunotherapy regardless of the cut-off points in either the POPLAR and OAK or the NCC cohorts (P>0.05) due to its correlation with the circulating tumor DNA (ctDNA) amount, which was associated with poor OS. In the POPLAR and OAK cohorts, upon allele frequency (AF) adjustment, a high allele frequency bTMB (HAF-bTMB, mutation counts with an AF>5%) was strongly correlated with the ctDNA amount (Pearson's r=0.65), while a low allele frequency bTMB (LAF-bTMB, mutation counts with an AF≤5%) was not (Pearson's r=0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [[HR], 0.70; 95% confidence interval [CI], 0.52-0.95; P=0.02), progression-free survival (PFS) (HR, 0.62; 95% CI, 0.47-0.80; P<0.001), and the objective response rate (ORR) (P<0.001) following immunotherapy but not chemotherapy, with a cut-off point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR, 0.20; 95% CI, 0.05-0.84; P=0.02), PFS (HR, 0.30; 95% CI, 0.13-0.70; P=0.003), and the ORR (P=0.001). CONCLUSIONS: We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and the ORR following anti-PD-1/PD-L1 therapies in NSCLC patients, which needs to be prospectively validated.

6.
Clin Lung Cancer ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31761448

RESUMO

BACKGROUND: Neurotrophin receptor kinase (NTRK) gene fusions (NTRK+) are rare but actionable oncogenic drivers present in a wide variety of solid tumors. However, the clinicopathologic characteristics of NTRK1 fusion-positive non-small-cell lung cancer are largely unknown. MATERIALS AND METHODS: Lung cancer tissue specimens and/or circulating cell-free DNA from patients with lung cancer who had undergone molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory in China were retrospectively reviewed. The laboratory performed NTRK1 fusion detection using hybridization-based targeted next-generation sequencing. The patients' clinical characteristics and treatment history were retrieved from the database for further evaluation. RESULTS: A total of 21,155 Chinese lung cancer cases had undergone molecular profiling from April 2016 to March 2019, including 13,630 adenocarcinoma cases. Of these cases, 12 were positive for NTRK1 fusion, including 10 cases of adenocarcinoma (0.073%), 1 primary sarcomatoid carcinoma, and 1 with an unknown histologic classification. Seven fusion partners (CD74, interferon regulatory factor 2 binding protein 2 [IRF2BP2], lamin A/C [LMNA], PHD finger protein 20 [PHF20], sequestosome 1 [SQSTM1], tropomyosin 3 [TPM3], TPR) were identified. Additionally, 1 unique rearrangement occurred upstream of the transcription start site of BCL9 fused to exon 12 of NTRK1 (intragenic region, BCL9-NTRK1). Of the 12 cases of NTRK1+ lung cancer, 6 had had concurrent activating EGFR mutations and/or had received previous treatment with EGFR tyrosine kinase inhibitors (TKIs), with 2 having concurrent EGFR T790M and 1 additional EGFR C797S. CONCLUSIONS: NTRK1+ lung cancer cases are extremely rare with multiple fusion partners. Additionally, emergence of NTRK1+ fusion might act as a resistance mechanism to EGFR TKIs. When performing comprehensive analysis of acquired resistance to EGFR TKIs, the ability to detect NTRK1 fusions will be important.

7.
Oncol Lett ; 18(5): 5085-5090, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31612019

RESUMO

Lynch syndrome (LS), as a result of the germline mutations in DNA mismatch repair genes, is characterized by the increased risk of endometrium, colon, and urinary tract cancer. Individuals with this disorder may occasionally have multiple primary carcinomas. Regardless of tumor type, pembrolizumab was approved for the treatment of patients with unresectable or metastatic mismatch repair deficient tumors, which may be an optional therapeutic method for patients with LS with multiple primary carcinomas. This case study is of a MSH2-deficient patient with LS with metachronous urothelial and colon cancer, who received pembrolizumab treatment for 8 months. The responses of the two primary sites to immunotherapy differed. Based on the changes of tumor markers and tumor size illustrated by imageological examinations, no response was observed in the sigmoid colon lesion, whereas an immune-associated phenomenon known as pseudoprogression was detected in the ureteral lesion. Immunotherapy was innovatively applied to the patient with multiple primary carcinomas. This case proposes a novel concept in which immunotherapy may potentially control the cancer growth in patients with LS and multiple primary carcinomas. However, further large-scale investigations are required. Furthermore, it raises a challenge to monitor the effectiveness of immunotherapy.

8.
J Cancer ; 10(21): 5108-5113, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602263

RESUMO

Background: Response Evaluation Criteria in Solid Tumors (RECIST) has been widely utilized to evaluate new therapeutic strategies in cancer. However, RECIST fails to assess the heterogeneity of response in highly active therapies. Depth of response (DepOR), defined as the maximum percentage change in tumor size compared with baseline, may provide a new strategy to evaluate disease response. In the present study, we studied the association between DepOR and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Methods: Advanced NSCLC patients harboring EGFR driver mutation (L858R or exon 19 deletion) treated with EGFR-TKI from August 2014 to July 2017 from two sites were retrospetively collected for analysis. Patients were divided into four groups by DepOR (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, Q4 = 76-100%). Kaplan-Meier curves were plotted for PFS against DepOR and the hazard ratio (HR) was determined through univariable and multivariable cox regression models. Results: In total, 265 patients were included for analysis. The number of patients in Group Q1-Q4 were 91 (34.3%), 73 (27.5%), 65 (24.5%) and 36 (13.6%), respectively. A greater DepOR was significantly associated with a longer PFS (Log-rank P<0.0001). The HRs (95% CI) for PFS comparing patients with different DepOR status were 0.58 (0.42-0.80) for Q2, 0.49 (0.35-0.69) for Q3, and 0.33 (0.22-0.50) for Q4, all compared with patients in Q1. DepOR as a continuous variable was also associated with prolonged PFS (HR, 0.20; 95% CI, 0.13-0.33; P<0.001). Additionally, in the multivariable cox regression model, abnormal LDH, brain metastasis and male were found to be associated with worse PFS outcomes (P<0.05). Conclusion: A greater DepOR is significantly associated with PFS benefit in advanced NSCLC treated with EGFR-TKI, suggesting that it may be a useful clinical outcome to evaluate the response of targeted therapy.

9.
Cancer Biol Med ; 16(3): 556-564, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31565484

RESUMO

Objective: Germline alterations in the breast cancer susceptibility genes type 1 and 2, BRCA1 and BRCA2, predispose individuals to hereditary cancers, including breast, ovarian, prostate, pancreatic, and stomach cancers. Accumulating evidence suggests inherited genetic susceptibility to lung cancer. The present study aimed to survey the prevalence of pathogenic germline BRCA mutations (gBRCAm) and explore the potential association between gBRCAm and disease onset in Chinese advanced non-small cell lung cancer (NSCLC) patients. Methods: A total of 6,220 NSCLC patients were screened using capture-based ultra-deep targeted sequencing to identify patients harboring germline BRCA1/2 mutations. Results: Out of the 6,220 patients screened, 1.03% (64/6,220) of the patients harbored the pathogenic g BRCA m , with BRCA2 mutations being the most pr edominant mutations (49/64, 76.5%). Patients who developed NSCLC before 50 years of age were more likely to carry g BRCA m (P = 0.036). Among the patients harboring classic lung cancer driver mutations, those with concurrent g BRCA m were significantly younger than those harboring the wild-type g BRCA (P = 0.029). By contrast, the age of patients with or without concurrent g BRCA m was comparable to those of patients without the driver mutations (P = 0.972). In addition, we identified EGFR-mutant patients with concurrent gBRCAm who showed comparable progression-free survival but significantly longer overall survival (P = 0.002) compared to EGFR-mutant patients with wild-type germline BRCA. Conclusions: Overall, our study is the largest survey of the prevalence of pathogenic g BRCA m in advanced Chinese NSCLC patients. Results suggested a lack of association between germline BRCA status and treatment outcome of EGFR-TKI. In addition, results showed a positive correlation between pathogenic g BRCA m and an early onset of NSCLC.

10.
Front Oncol ; 9: 556, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448219

RESUMO

Background: Lung adenocarcinoma (LUAD) possesses a poor prognosis with a low 5-year survival rate even for stages I-III resected patients, it is thus critical to understand the determinants that affect the survival and discover new potentially prognostic biomarkers. Somatic copy number alterations (CNAs) are major source of genomic variations driving tumor evolution, CNAs screening may identify prognostic biomarkers. Methods: Oncoscan MIP array was used to analyze the patterns of CNAs on formalin fixed paraffin embedded(FFPE) tumor specimens from 163 consecutive stage I-III resected LUAD patients, 145 out of which received platinum-based adjuvant chemotherapy. Results: Of the 163 patients, 91(55.8%) were recurred within 3 years after surgery. The most common aberrations in our cohort were 1q, 5p, 5q, 7p, 8q, 14p, 16p, 17q, 20q for copy number gains and 8p, 9p, 13p, 16q, 18q for losses. The GISTIC2 analysis produced 45 amplification peaks and 40 deletion peaks, involving some reported genes TERT, EGFR, MYC, CCND1, CDK4, MDM2, ERBB2, NKX2-1, CCNE1, and CDKN2A, most of which were consistent with TCGA database. The amplifications of 12p12.1 (CMAS, GOLT1B, YS2, LDHB, RECQL, ETNK1, IAPP, PYROXD1, KRAS) and KDM5A were correlated with worse prognosis in our cohort, this result was further validated in 506 LUAD patients from TCGA. In addition, 163 patients could be well-classified into five groups, and the clinical outcomes were significantly different based on threshold copy number at reoccurring alteration peaks. Among the 145 patients who received adjuvant chemotherapy, focal amplification of ERBB2 and deletion of 4q34.3 were found to be specific in relapsed patients, this result was validated in an independent group of Imielinski et al., demonstrating these two CNAs may contribute to resected LUAD recurrence after adjuvant chemotherapy. Conclusion: This study suggests that CNAs profiling may be a potential prognostic classifier in resected LAUD patients. Amplifications of 12p12.1 and KDM5A might be prognostic biomarkers for LUAD, and amplification of ERBB2 and deletion of 4q34.3 predicted early relapse after adjuvant chemotherapy. These novel findings may provide implication for better implementation of precision therapy for lung cancer patients.

11.
J Thorac Dis ; 11(5): 1779-1787, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31285870

RESUMO

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become important treatment options for non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutation. However, the detection of EGFR driver mutation is impeded by the lack of adequate tumor tissues, histopathological type, long detection period, and the heterogeneity of a tumor. Therefore, it is necessary to develop a more convenient method to guide the clinical use of EGFR-TKI. Circular RNAs (circRNAs) are characterized as a closed structure with covalently joined ends resistant to exonucleases may be a potential biomarker. In the present study, we aimed to screen circRNAs that may be associated with the efficacy of EGFR-TKI. Methods: The expression of circRNAs sequenced by circular microarray in plasma samples between gefitinib effective and ineffective groups were compared. RT-qPCR further validated the results in an independent cohort. Kaplan-Meier curves were used to analyze the association between circRNA and progression-free survival (PFS) of NSCLC patients treated with gefitinib. Results: In total, 52 NSCLC patients treated with gefitinib were included for analysis. 1,377 circRNAs were differentially expressed in gefitinib effective and ineffective groups, among which 989 circRNAs were up-regulated, and 388 circRNAs were down-regulated in the effective group. Furthermore, two differentially expressed circRNAs, hsa_circ_0109320 and hsa_circ_0134501, were validated by RT-qPCR in an independent cohort of 38 gefitinib-treated NSCLC patients. Elevated hsa_circ_0109320 was associated with longer PFS in gefitinib-treated NSCLC patients. Conclusions: Taken together, hsa_circ_0109320 may be a potential biomarker for the efficacy of EGFR-TKI in NSCLC patients. This provides a new molecular typing method for individualized precision treatment.

12.
Cancer Manag Res ; 11: 4449-4459, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191007

RESUMO

Purpose: The aim of this phase Ib study (clinicaltrials.gov: NCT01772732) was to assess safety, tolerability, and pharmacokinetics (PKs) of simotinib (a novel EGFR tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer (NSCLC) and EGFR gene mutation. Patients and methods: 41 patients with EGFR gene mutations were enrolled and received simotinib orally administered twice daily with dose escalating from 100 to 650 mg in 28 days cycle. Safety and tolerability were assessed through the study. Blood samples were collected for PK analysis on Days 1, 8, 9, 10, 15, 22 and 29. Tumor response was assessed at baseline, on Day 29 and every 8 weeks thereafter. Results: Simotinib was well tolerated, with no dose-limiting toxicities. Maximum tolerated dose (MTD) was not found. 95.1% of patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequently reported AEs. Simotinib was rapidly absorbed and eliminated with average T max ranging from 1 to 4 hrs and T 1/2 ranging between 6.2 and 13.0 hrs after multiple-dose administration. No dose-response relationship between dose and exposure was observed after multiple-dose administration. 39.3% of the enrolled patients achieved a partial response and 46.3% had stable disease. Median progression-free survival and overall survival were 9.9 (CI% 4.7; 12.1) months and 14.6 (95%CI 12.3; 22.5) months, respectively. Conclusion: Simotinib was well tolerated, with manageable AEs at doses of up to 650 mg and MTD was not reached. Further studies to explore higher doses are ongoing.

13.
Invest New Drugs ; 37(4): 731-737, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30706337

RESUMO

Background This phase I trial was primarily conducted to determine the maximum tolerated dose (MTD) of apatinib combined with docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR who have failed to first-line platinum-based chemotherapy, and to evaluate the safety and tolerability of apatinib plus docetaxel. Methods This was a single-center, open-label, dose-escalating phase I trial. The study used a standard 3 + 3 dose escalation design with the primary aim of determining the MTD. Twelve patients with advanced lung adenocarcinoma were enrolled, the primary endpoint was safety. Two doses of apatinib, 250 mg/day (level 1) and 500 mg/day (level 2), were evaluated in combination with 60 mg/m2 doxetacel every 3 weeks. Six patients have been treated at levels 1 and 2, respectively. Optimal dose of apatinib was determined by dose-limiting toxicity (DLT). Results Six patients have been treated at levels 1 and 2. At level 1, one of six patients experienced grade 3 acneiform rash as DLTs. At level 2, two patients experienced grade 3 hypertension and one experienced grade 3 nasal bleeding. MTD and recommended dose for phase II study was 250 mg/day. Most frequent adverse events of any grade were bilirubin elevation, hypertension, alanine aminotransferase elevation, transglutaminase elevation, hand foot syndrome and fatigue. The median progression-free survival was 2.76 month. Moreover, three patients had developed progressive disease and the mean duration of response was 2.79 months. Conclusion Apatinib plus docetaxel was well tolerated and showed promising efficacy in advanced lung adenocarcinoma. This combination therapy may represent a potent therapeutic option for advanced lung adenocarcinoma patients with wild-type EGFR.

14.
Clin Respir J ; 13(2): 98-104, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30586232

RESUMO

BACKGROUND: Patients with small cell lung cancer (SCLC) younger than 40 years are limited in number. Our research aimed to assess the characteristics, diagnosis and outcomes of this patient population. METHODS: Records of patients under the age of 40 with SCLC at the Chinese Academy of Medical Sciences between January 2006 and December 2015 were reviewed and evaluated. RESULTS: One hundred and three patients (67.0% limited stage, 33.0% extensive stage) were included, along with 54 (52.4%) never-smokers. The median diagnostic interval and the median survival time (MST) were 51.0 days and 24.0 months, respectively. A total of 41 (39.8%) patients claimed to have undergone antibiotic treatment before diagnosis, with a median duration of 2 weeks. In univariate analysis, survival was better for the limited stage group than the extensive stage group (MST, 28.0 vs. 13.0 months, P < 0.0001). Also, patients who received concurrent radiochemotherapy had better survival than those who received chemotherapy alone (MST, 29.0 vs. 18.0 months, P = 0.001). Patients with antibiotic treatment before SCLC diagnosis have worse prognosis than those without (MST, 21.0 vs. 27.0 months, P = 0.008). Moreover, a timely diagnosis (≤1 month) exerted a positive impact on the overall survival in limited stage patients (48.0 vs. 26.0 months, P = 0.047) and on progression-free survival in extensive stage patients (6.0 vs. 3.0 months, P = 0.030). Multivariate analysis suggested that disease stage, history of antibiotic treatment before SCLC diagnosis and performance status independently correlated with survival. CONCLUSION: Our study identified distinct characteristics and prognostic factors of SCLC patients under 40 years. More timely care may improve patient prognosis.


Assuntos
Quimiorradioterapia/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/epidemiologia , Adulto , Antibacterianos/uso terapêutico , Conscientização , China/epidemiologia , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Análise de Sobrevida , Fatores de Tempo , Adulto Jovem
15.
Asia Pac J Clin Oncol ; 15(3): 166-171, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30311393

RESUMO

AIM: Most epidermal growth factor receptor (EGFR) gene mutations affecting exon 19 (inframe deletions; 19 Del) and 21 (L858R), while the rest (referred as uncommon EGFR mutation) have not been fully described due to their rarity. Here we present a retrospective study that investigated clinical characteristics and outcome of patients with different EGFR mutations. METHODS: We retrospectively analyzed the EGFR mutation pattern and its association with clinical-pathological characteristics from 100 cases of nonsmall-cell lung cancer (NSCLC) harboring EGFR mutations, and compiled the genotype response data for NSCLC patients with common and uncommon EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs). Patients with advanced EGFR-mutated NSCLC were enrolled and treated with icotinib (oral administration, 125 mg, thrice per day). RESULTS: Among 100 patients, 85 and 15 had common and uncommon mutations, respectively. Four patients had a single mutation in 18 or 20 exon, and 11 had a complex mutation with del-19 or L858R. There was no significant association between the presence of different mutation type and the type of any clinical and pathological characteristics. Prolonged but not significant progression-free survival (PFS) was noted in patients with common EGFR mutations (18.07 [14.00-26.23] vs 12.9 [8.43-23.27], P = 0.056). Patients without brain metastases had increased PFS to icotinib than those with brain metastases (18.07 [95% confidence interval, CI 14.77-27.03] vs 13.17 [95% CI 8.63-22.63], P = 0.038). CONCLUSION: Uncommon EGFR mutations comprised 15% of all mutated patients, in which most were complex mutations. Compared with common EGFR mutation, uncommon EGFR mutations were associated with a modest sensitivity to EGFR TKIs. Our findings will be helpful to make clinical decision and select the appropriate therapy for EGFR-mutated NSCLC patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Éteres de Coroa/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos
16.
Thorac Cancer ; 9(12): 1716-1724, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30324773

RESUMO

BACKGROUND: Bevacizumab (Bev) plus platinum-based chemotherapy is a standard first-line treatment option for advanced non-squamous non-small cell lung cancer (NS-NSCLC). We evaluated the efficacy and safety of continuing Bev in Chinese patients with advanced NS-NSCLC progression after first-line treatment containing Bev in a real-world setting. METHODS: The data of 118 patients with advanced NS-NSCLC who received Bev between July 2009 and July 2017 were retrospectively collected. The patients were divided into groups: 15 in Bev first-line, 82 in Bev ≥ second-line, and 21 in Bev cross-lines. The primary endpoint was overall survival; secondary objectives were progression-free survival, objective response rate, disease control rate, and safety. RESULTS: The overall survival was 21.8, 32.5, and 18.9 months (P = 0.092) in the overall population and 39.3, 25.8, and 15.0 months (P = 0.347) in the wild-type population in the Bev first-line, Bev ≥ second-line, and Bev cross-lines groups, respectively. There were no significant differences in progression-free survival of second-line treatment between the groups in the overall population: 2.6, 3.7, and 3.2 months in the Bev first-line, Bev ≥ second-line, and Bev cross-lines groups, respectively (P = 0.796). No statistically significant improvement in objective response or disease control rates in the Bev cross-lines group was observed. No unexpected or severe adverse events were recorded. CONCLUSION: We found no benefit in continuing Bev treatment beyond progression after first-line treatment containing Bev for patients with advanced NS-NSCLC. Further research of validated predictive biomarkers of response to treatment after long-term antiangiogenic therapy is required.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Retratamento , Estudos Retrospectivos , Resultado do Tratamento
17.
Biochem Biophys Res Commun ; 503(3): 2173-2179, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30086882

RESUMO

The incidence and mortality of hepatocellular carcinoma (HCC) is high, but the mechanisms underlying the growth and progression of HCC have not been elucidated. Recently, the ZIC family member 5 (ZIC5) is emerging as an oncogene in various types of tumors. However, its expression and biological role in HCC have not been reported. This study first demonstrated that ZIC5 was up-regulated in HCC specimens, and high ZIC5 expression indicated poor prognosis of HCC patients. In addition, over-expressed ZIC5 promoted the proliferation, migration and invasion of HCC cell lines Huh7 and HepG2 in vitro and in vivo, while ZIC5 knockdown achieved the opposite effects. Actually, ZIC5 increased the expression of genes participating in Wnt/ß-catenin pathway such as ß-catenin and CyclinD1. ZIC5 also promoted ß-catenin to enter the nucleus of HCC cells. Furthermore, silencing ß-catenin abated the promoting role of ZIC5 in HCC. Overall, this study reveals a novel mechanism of ZIC5/ß-catenin that mediates the invasion and metastasis of HCC and ZIC5 serves as a novel indicator for prognosis of HCC patients.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas
18.
Thorac Cancer ; 9(7): 805-813, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29768721

RESUMO

BACKGROUND: Large scale randomized controlled trials have demonstrated that the use of bevacizumab in addition to chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) conveys significant survival benefits. We explored the clinical impact of a first-line regimen containing bevacizumab (B+) versus a non-bevacizumab regimen (non-B) in advanced non-squamous NSCLC (NS-NSCLC) patients in a real world setting. METHODS: The medical records of patients with advanced NS-NSCLC who received first-line therapy with or without bevacizumab were retrospectively collected. The primary outcome was progression-free survival (PFS), with secondary objectives of objective response rate (ORR), disease control rate (DCR), and safety. Exploratory analysis of EGFR and ALK status was conducted in subgroup. RESULTS: One hundred and forty-nine patients met the selection criteria: 62 in the B+ and 87 in the non-B group. The baseline characteristics were well balanced. In the overall population, the median PFS was significantly longer in the B+ than in the non-B group (9.7 vs. 7.0 months, hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.30-0.91; P = 0.0184). Improved trends in both ORR and DCR were observed in the B+ group. In wild-type patients, the median PFS of the B+ was 11.3 compared to 5.5 months in the non-B group (HR 0.43, 95% CI 0.20-0.91; P = 0.0234). In wild type and unknown populations, the median PFS was 11.3 (B+) compared to 6.0 months (non-B) (HR 0.53; 95% CI 0.28-1.02; P = 0.0520). The safety profile was acceptable in both groups and no unexpected findings were observed. CONCLUSION: Our analysis confirmed that a first-line regimen containing bevacizumab showed superior clinical benefits over a non-bevacizumab regimen in Chinese patients with advanced NS-NSCLC in a real world setting.


Assuntos
Quinase do Linfoma Anaplásico/genética , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos
19.
Thorac Cancer ; 9(6): 693-698, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29655198

RESUMO

BACKGROUND: EGFR-tyrosine kinase inhibitors (TKIs) combined with TS-1 might overcome EGFR-TKI resistance, which has been indicated by several preclinical studies. We investigated the synergistic efficacy and safety of the combination therapy of EGFR-TKIs and TS-1 in non-small cell lung cancer (NSCLC) patients with acquired resistance to previous EGFR-TKI therapy. METHODS: This was a phase II, single-arm and single-center prospective study. Stage IIIB-IV NSCLC patients with acquired resistance to prior EGFR-TKI treatment were enrolled. All patients were administered combination therapy of TS-1 and continuing EGFR-TKIs in this study. The primary endpoints were progression-free survival (PFS), while overall survival (OS), disease control rate (DCR), and safety were secondary endpoints. RESULTS: A total of 42 patients with acquired resistance to EGFR-TKIs were eligible for this study. The median PFS for all patients was five months (95% confidence interval [CI] 3.6-5.4). The OS and DCR were 31.9 (95% CI 17.8-46.0) months and 69.0% (29/42), respectively. No grade 4 toxicity or grade 3 hematologic toxicity was observed in this study. One patient (2%) experienced grade 3 elevated total serum bilirubin. CONCLUSION: The combination treatment of TS-1 and EGFR-TKIs was effective and well tolerated by patients who had experienced prior EGFR-TKI treatment failure. Our results need to be validated by larger prospective clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Resultado do Tratamento
20.
Thorac Cancer ; 9(4): 498-501, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29411527

RESUMO

Osimertinib is a novel, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting EGFR mutations and the EGFR T790 mutation. Here, we report a woman with EGFR-mutated lung adenocarcinoma who, after 23-month treatment with gefitinib, developed the EGFR T790M mutation, which converted the T790M status from positive to negative before osimertinib treatment and developed MET amplification, leading to rapid progression on osimertinib in two months. Subsequent treatment with crizotinib and c-Met inhibitor plus gefitinib also failed to improve the clinical outcome, suggesting the potential existence of another resistance mechanism. Our findings revealed the underlying multiple and heterogeneous mechanisms in resistance to osimertinib, suggesting combination strategies should be considered post-osimertinib progression.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Acrilamidas , Compostos de Anilina , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Mutação , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA