Objective To investigate the feasibility of detection of epidermal growth factor receptor ( EGFR) exon 19 deletions and exon 21 L858R mutations in pleural effusion fromnon-small-cell lung cancer ( NSCLC) patients by mutant enriched PCR assay. Methods The mutations of exon 19 and 21 of EGFR gene in pleural samples fromthirty NSCLC patients were analyzed using both the mutant-enriched PCR assay and the non-enriched PCR assay. Results Ten ( 33. 3% , 10/ 30) exon 19 deletions and five ( 16. 7% , 5/30) exon 21 L858R mutation were detected by the mutant-enriched PCR assay, while only 6 cases ( 20. 0% ) and 1 case ( 3. 3% ) were detected by the non-enriched PCR assay respectively. The difference of mutation detection rate of EGFR gene between the two methods was statistically significant ( P = 0. 032) . Mutations were detected in all of partial responders ( 2 /4) among the four patients who received gefitinib therapy. Conclusions Mutant-enriched PCR assay can detect EGFR exon 19 deletions and exon 21 L858R mutation in pleural effusion from NSCLC patients effectively, economically and accurately. It may be a valuable biomarker for gefitinib therapy in advanced NSCLC.
Objective To evaluate the effects of two different epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs) , Gefitinib and Erlotinib, on lung fibrosis induced by bleomycin.Methods Forty BALB/c female mice were randomly divided into four groups, ie. a control group( saline given orally and intratracheally) , a fibrosis group( saline given orally with bleomycin instillation) , a Gefitnib group( Gefitnib 20 mg/kg given orally with bleomycin instillation) , and an Erlotinib group ( Erlotinib25 mg/kg given orally with bleomycin instillation) . Bleomycin ( 3 mg/kg) was intratracheally instilled on the first day. Gefitinib or Erlotinib was given orally daily and normal saline as control. Then they were sacrificed by abdominal aortic bleeding 14 days after the bleomycin instillation. The left lung was stained with HE and Masson’s trichrome staining respectively for pathological examination. Total EGFR and phosphorylated EGFR were detected by immunohistochemistry. Hydroxyproline ( HYP) assay was performed in the right lung.Results Both Gefitinib and Erlotinib significantly reduced lung collagen accumulation and the content of HYP. Immunohistochemistry revealed that phosphorylation of EGFR in lung mesenchymal cells induced by bleomycin was inhibited. Furthermore, there was no difference between Gefitinib and Erlotinib in inhibiting lung fibrosis. Conclusion Our findings suggest that, in the preclinical setting, EGFR-TKIs may have aprotective effect on lung fibrosis induced by bleomycin.
Objective To investigate the effects of gefitinib in the treatment of sarcomatoid carcinoma. Methods Clinical data of a case of sarcomatoid carcinoma was analyzed and related literatures were reviewed.Results A patient with sarcomatoid carcinoma was admitted with progressive dry cough,chest pain and dyspnea for 3 months. The patient was diagnosed as lung sarcomatoid carcinoma by thoracoscopy and treated with gefitinib. After 2 weeks treatment, symptoms disappeared and tumor was stable for 4 months. Literatures review suggested that sarcomatoid carcinoma is a rare malignant tumor. Treatment of sarcomatoid carcinoma includes surgery, chemotherapy and radiotherapy, but these methods show little effect in advanced patients. In our case, the patient with sarcomatoid carcinoma in stage Ⅳ was treated by gefitinib and showed favourable effect. Conclusions Advanced sarcomatoid carcinoma patients have a short life span and poor life quality. Gefitinib may provide these patients a feasible therapeutic approach.
Objective To observe the effect of gefitinib on expression of epidermal growth factor receptor (EGFR) in bile duct epithelial cells, and the feasibility of inhibiting hyperplasia of bile duct epithelial cells with gefitinib. Methods Sixty-one patients with hepatolithiasis having to be in hospital for surgery from the First People’s Hospital of Shuangliu county were selected, with 25-65 years old, average 46.92 years. The patients were randomly divided into therapy group and control group. There were 30 cases in therapy group, in which fine duct was placed on lesion bile duct during operation, and through whom gefitinib solution was perfused after operation. There were 31 cases in control group with only T tube drainage after operation. The bile duct sample was obtained respectively during the operation and 6 weeks and 12 weeks after operation. The histology and expression change of EGFR were observed by HE staining, immunohistochemistry and RT-PCR method respectively. Results There were no significant differences in pathohistology changes of bile duct and the EGFR protein and mRNA expression between therapy group and control group during operation. The hyperplasia of epithelium mucosae and submucosal gland in the therapy group were obviously decreased as compared with those in control group, the EGFR mRNA and protein expression in therapy group were weaker than those of control group （Plt;0.05） 6 weeks and 12 weeks after gefitinib treatment. Conclusion EGFR is overexpressed in the chronic proliferative cholangitis, and continuously local application of gefitinib after operation can specifically interrupt the activation and expression of EFGR and then effectively inhibit the hyperplasia of bile duct epithelial cells.
ObjectiveTo systematically review the efficacy and safety of gefitinib versus pemetrexed as second-line treatment for advanced non-small cell lung cancer (NSCLC). MethodsDatabases including PubMed, The Cochrane Library (Issue 4, 2016), EMbase, CNKI, VIP and WanFang Data were searched to collect randomized controlled trials (RCTs) about gefitinib versus pemetrexed as second-line treatment for advanced NSCLC from inception to April 2016. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then meta-analysis was performed by using RevMan 5.3 software. ResultsA total of 11 RCTs involving 1 005 patients were finally included. The results of meta-analysis showed that: the rate of progression free survival (PFS) in the gefitinib group was superior to the pemetrexed group (HR=0.59, 95%CI 0.47 to 0.73, P<0.000 01). However, there were no significant differences between two groups in overall response rate (RR=1.28, 95%CI 0.86 to 1.90, P=0.22), disease control rate (RR=0.92, 95%CI 0.77 to 1.12, P=0.41) and the rate of overall survival (HR=0.75, 95%CI 0.56 to 1.01, P=0.05). The incidences of skin rash (RR=8.72, 95% CI 3.65 to 20.84, P<0.000 01) and diarrhea (RR=2.87, 95% CI 1.29 to 6.38, P=0.01) were significantly higher, but the incidences of neutropenia (RR=0.12, 95%CI 0.05 to 0.26, P<0.000 01) and fatigue (RR=0.46, 95%CI 0.30 to 0.72, P=0.000 6) were lower in the gefitinib group than those in the pemetrexed group. ConclusionGefitinib shows more superiority to pemetrexed, and it can be used as the second-line drug for advanced NSCLC． Due to the limited quality and quantity of included studies, more high quality studies are needed to verify the above conclusion.
Objective To evaluate the safety and efficacy of gefitinib in comparison with platinum-based doublets chemotherapy as a first-line precision treatment for advanced non-small cell lung cancer (NSCLC), and find the benefit population of gefitinib. Methods The Cochrane Library, PubMed, Embase, China National Knowledge Internet, VIP database and China Biology Medicine database were searched to collect the randomized contolled trials (RCTs) of gefitinib vs. platinum-based doublets chemotherapy for advanced NSCLC from inception to November, 2017. The data in the included RCTs were extracted, and the qualities were assessed in accordance with Cochrane Collaboration, and a Meta-analysis was conducted with RevMan 5.3 software. Results Four trials were included, including 968 subjects in the gefitinib group and 968 subjects in the chemotherapy group, and a majority of the subjects were diagnosed advanced adenocarcinoma, and all of the subjects were East Asians. The results of Meta-analysis showed that in all population or patients with epidermal growth factor receptor (EGFR) mutation-positive, gefitinib was better than chemotherapy in progression-free survival (PFS) [in all population: hazard ratio (HR)=0.76, 95% confidence interval (CI) (0.67, 0.85), P<0.000 01; in patients withEGFR mutation-positive: HR=0.42, 95%CI (0.35, 0.50), P<0.000 01] and objective response rate (ORR) [in all population: risk ratio (RR)=1.30, 95%CI (1.15, 1.47), P<0.000 1; in patients withEGFR mutation-positive: RR=1.92, 95%CI (1.46, 2.52), P<0.000 01], and there was no significant difference between the two groups in overall survival (OS) (P>0.05); but inEGFR mutation-negative, chemotherapy was better than gefitinib in PFS [HR=2.09, 95%CI (1.05, 4.13), P=0.03]. Subgroup analysis showed that in female patients, for patients with Performance Status (PS) score 0 or 1, and the ones who never smoked, gefitinib was better than chemotherapy in PFS (P<0.05); but there was no significant difference between the two groups in OS (P>0.05). The incidences of rash, itching, dry skin, paronychia, diarrhea, aminotransferase abnormality were higher in the gefitinib group (P<0.05), while the incidences of hair loss, vomiting, nausea, constipation, anorexia, leukopenia, thrombocytopenia, and neutropenia, anemia, fatigue, nerve toxicity reaction were higher in the chemotherapy group (P<0.05). Conclutions Based on the current evidence, in patients with adenocarcinoma of East Asians, the benefit population are those with the characteristics of EGFR mutation-positive, female, never smoking, and PS 0 or 1. In the aspect of safety, the common adverse drug events in subjects treated with gefitinib are the damage of skin mucous membrane, but the incidences of digestive system diseases and the blood system diseases are less in patients treated with gefitinib than those with chemotherapy.
Objective To systematically review the cost-effectiveness of gefitinib for advanced non-small cell lung cancer (NSCLC), in order to provide the economics values of gefitinib for clinical application. Method We electronically searched databases including PubMed, Ovid, Embase, Cochrane Library, Medline, China National Knowledge Internet, VIP, and Wanfang database for articles about the cost-effectiveness of gefitinib for advanced NSCLC patients from January 1946 to October 2017, and then performed a systematic literature review of economic evaluations of geftinib. Results A total of 20 independent studies were included in the present systematic review, in which 8 were the first-line treatment, 9 were the second-line treatment, 1 was the third-line treatment, and 2 were maintenance treatment. The most common comparison was gefitinib vs. chemotherapy (n=7), and other comparisons were gefitinib vs. erlotinib (n=4), gefitinib vs. docetaxel (n=3), gefitinib vs. placebo (n=2), gefitinib vs. icotinib (n=2), gefitinib vs. afatinib (n=1), and gefitinib vs. other treatments (n=1). For the advanced NSCLC patients, the first- or second-line treatment with gefitinib compared to chemotherapy was considered to be more cost-effective, especially in patients with mutated epidermal growth factor receptor gene. As the second-line treatment, gefitinib was considered to be more economical than erlotinib and docetaxel. Conclusion Gefitinib is considered to be a cost-effective strategy for the advanced NSCLC patients as the first- or second-line therapy.
ObjectivesTo systematically review the efficacy and safety of the first generation EGFR-TKIs versus pemetrexed as second-line treatment for advanced non-small cell lung cancer (NSCLC).MethodsDatabases including PubMed, EMbase, The Cochrane Library, CNKI, WanFang Data and CBM were searched to collect randomized controlled trials (RCTs) about the first generation EGFR-TKIs versus pemetrexed as second-line treatment for advanced NSCLC from inception to June 2017. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then meta-analysis was performed by using RevMan 5.3 software.ResultsA total of 20 RCTs involving 2 242 patients were finally included. The results of meta-analysis showed that: the rate of progression free survival (PFS) in the EGFR-TKI group was superior to the pemetrexed group (HR=0.78, 95%CI 0.58 to 0.99, P<0.000 1) with significant difference. However, there was no significant difference between two groups in complete remission rate (RR=1.81, 95%CI 0.65 to 5.07,P=0.26), partial remission rate (RR=0.93, 95%CI 0.78 to 1.11, P=0.44), stable disease rate (RR=0.92, 95%CI 0.82 to 1.03, P=0.16), progression disease rate (RR=1.09, 95%CI 0.99 to 1.20, P=0.09), overall response rate (RR=0.97, 95%CI 0.72 to 1.30, P=0.84), disease control rate (RR=0.93, 95%CI 0.87 to 1.01, P=0.07) and overall survival rate (HR=0.89, 95%CI 0.74 to 1.04, P<0.572). The incidences of skin rash (RR=12.43, 95%CI 3.98 to 38.84,P<0.01) and diarrhea (RR=3.94, 95%CI 2.32 to 6.70,P<0.01) were significantly higher in the EGFR-TKI group, but the incidences of leukopenia (RR=0.19, 95%CI 0.09 to 0.41,P<0.01 ), anemia (RR=0.40, 95%CI 0.17 to 0.92,P=0.03), thrombocytopenia (RR=0.37, 95%CI 0.14 to 0.97, P=0.04), nausea and vomiting (RR=0.50, 95%CI 0.28 to 0.87, P=0.01), constipation (RR=0.30, 95%CI 0.14 to 0.64, P=0.002) were significant lower in the EGFR-TKI group than that of the pemetrexed group.ConclusionGefitinib shows some superiority to pemetrexed in second-line treatment for NSCLC, and it can be used as the second-line drug for advanced NSCLC. Due to the limited quality and quantity of included studies, more high quality studies are needed to verify the above conclusion.
ObjectiveTo study effects of two kinds of epidermal growth factor receptor kinase inhibitors on bleomycin-induced pulmonary fibrosis in mice, and regulation mechanism on oncostatin M (OSM) and downstream signaling pathways.MethodsForty Kunming female mice were randomly divided into a control group, a fibrosis group, a gefitinib group, and an erlotinib group. The mice in the control group were administered with saline aerosol intratracheally. The mice in the fibrosis group were administered with bleomycin at a dose of 3 mg/kg aerosol intratracheally. The mice in the gefitinib group and the erlotinib group were administered with bleomycin at a dose of 3 mg/kg aerosol intratracheally and then gastrically perfused with gefitinib (20 mg·kg–1·d–1) or erlotinib (25 mg·kg–1·d–1). All mice accepted computer tomography examination 14 days after the treatment and then were sacrificed, and the lungs were collected for further detection. The lungs were stained with hematoxylin eosin and Masson’s trichrome, examined with Western blot for pathological examination and expressions of α-smooth muscle actin (α-SMA), OSM, Janus kinase 1 (JAK1), phospho-JAK1 (p-JAK1), signal transducers and activators of transcription 3 (STAT3), and phospho-STAT3 (p-STAT3) proteins.ResultsThe pathological injury of the lung in the gefitinib group and the erlotinib group was significantly relieved compared with that in the bleomycin group. The expressions of α-SMA, OSM, p-JAK1/JAK1, and p-STAT3/STAT3 proteins were also significantly reduced. There were no differences between the above-mentioned indexes between the gefitinib group and the erlotinib group.ConclusionsGefitinib and erlotinib can significantly relieve bleomycin-induced pulmonary fibrosis in mice. The underlying mechanism may be involved in inhibiting expression of OSM and downstream JAK/STAT pathways.
ObjectiveBy intervening with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, to explore the downstream signaling pathway of the transcription factor forkhead box O3a (Foxo3a) in C57BL/6 mice who are induced to pulmonary fibrosis with bleomycin, as so to illuminate the possible mechanism of Foxo3a in epithelial-mesenchymal transition (EMT) of pulmonary fibrosis.MethodsThirty C57BL/6 mice aged 6 weeks in half genders were randomly divided into a control group, a bleomycin group and a gefitinib group. The mice in the control group were injected with saline via trachea. The mice in the bleomycin group were injected with bleomycin at a dose of 3 mg/kg via trachea. The mice in the gefitinib group were injected with bleomycin at a dose of 3 mg/kg via trachea and then gastrically perfused with gefitinib (20 mg·kg–1·d–1). 14 days after the treatment, all mice were killed and lung tissue specimens were collected for further detection. Lung tissue sections were stained with hematoxylin eosin and Masson’s trichrome. The mRNA levels of α-smooth muscle actin (α-SMA), E-cadherin, high mobility group protein box 1 (HMGB1), Foxo3a, FoxM1 and Snail1 in the lung tissues were detected by RT-PCR. The protein expressions of α-SMA, E-cadherin, HMGB1, phospho-Foxo3a (p-Foxo3a), Foxo3a, FoxM1 and Snail1 in the lung tissues were determined by western blot.ResultsThe scores of lung inflammation and fibrosis were evidently decreased in the gefitinib group compared with that in the bleomycin group (P<0.01). Compared with bleomycin group, the mRNA level of α-SMA, Snail1 (P<0.01) and HMGB1 (P<0.05) were declined, but mRNA level of E-cadherin (P<0.01), Foxo3a and FoxM1 (P>0.05) were ascendant in the gefitinib group. Meanwhile, western blot analysis showed reduced protein expressions of α-SMA (P<0.05), Snail1(P<0.01), HMGB1 (P<0.05) and p-Foxo3a/Foxo3a (P<0.01) in lung tissues, while expressions of E-cadherin (P<0.05), Foxo3a and FoxM1 proteins (P>0.05) were increased in the gefitinib group.ConclusionsIncreased activity of Foxo3a can down-regulate Snail1, which decreases the expression of α-SMA and increases the expression of E-cadherin, thereby attenuating bleomycin-induced pulmonary fibrosis in mice.