Mei Hou

Results of randomized, multicenter, double-blind phase III trial of rh-endostatin (YH-16) in treatment of advanced non-small cell lung cancer patients

BACKGROUND Endostar™ (rh-endostatin, YH-16) is a new recombinant human endostatin developed by Medgenn Bioengineering Co. Ltd., Yantai, Shandong, P.R.China. Pre-clinical study indicated that YH-16 could inhibit tumor endothelial cell proliferation, angiogenesis and tumor growth. Phase I and phase II studies revealed that YH-16 was effective as single agent with good tolerance in clinical use.The current study was to compare the response rate , median ti me to progression (TTP) ,clinical benefit andsafety in patients with advanced non-small cell lung cancer ( NSCLC) , who were treated with YH-16 plus vi-norelbine and cisplatin (NP) or placebo plus NP. METHODS Four hundred and ninety-three histologically or cy-tologically confirmed stage IIIB and IV NSCLC patients , withlife expectancy > 3 months and ECOG perform-ance status 0-2 , were enrolledin a randomized ,double-blind ,placebo-controlled , multicenter trial ,either trialgroup : NP plus YH-16 (vinorelbine 25 mg/m² on day 1 and day 5 ,cisplatin 30mg/m² on days 2 to 4 , YH-167.5mg/m² on days 1 to 14) or control group : NP plus placebo (vinorelbine 25 mg/m² on day 1 and day 5 ,cis-platin 30 mg/m² on days 2 to 4 ,0.9% sodium-chloride 3 .75 ml on days 1 to 14) every 3 weeks for 2-6 cycles .The trial endpoints included response rate ,clinical benefit rate ,time to progression,quality of life and safety . RESULTS Of 486 assessable patients , overall response rate was 35.4% in trial group and 19.5% in controlgroup (P=0 .0003) . The median TTP was 6 .3 months and 3 .6 months for trial group and control group respectively (P < 0 .001) . The clinical benefit rate was 73 .3 %in trial group and 64.0% in control group (P=0 .035) .In untreated patients of trial group and control group ,the response rate was 40 .0% and 23.9%(P=0 .003) ,the clinical benefit rate was 76 .5 % and 65 .0 % (P=0 .023) ,the median TTP was 6 .6 and 3 .7months (P=0 .0000) ,respectively .In pretreated patients of trial group and control group ,the response ratewas 23.9% and 8.5%(P=0 .034) ,the clinical benefit rate was 65.2% and 61.7%(P=0 .68) ,the median TTP was 5 .7 and 3 .2 months (P=0 .0002) ,respectively . The relief rate of clinical symptoms in trial groupwas higher than that of those in control group ,but no significance existed (P > 0 .05) . The score of quality oflife in trial group was significantly higher than that in control group (P=0 .0155) after treatment . There were no significant differences in incidence of hematologic and non-hematologic toxicity , moderate and severe sideeffects betweentrial group and control group . CONCLUSIONS The addition of YH-16 to NP regimen results in significantly and clinically meaningful improvement in response rate , median time to tumor progression,and clinical benefit rate compared with NP alone in advanced NSCLC patients . YH-16 in combination with chemotherapy shows a synergic activity and a favorable toxic profile in advanced cancer patients .

A randomized clinical trial of preoperative neoadjuvant chemotherapy followed by surgery in the treatment of stage III non-small cell lung cancer

BACKGROUND To explore the feasibility and toxicity of preoperative neoadjuvant chemotherapy followed by surgery in the treatment of stage III NSCLC and to evaluate its effects on tumor response, resection rate, tumor downstaging, and survival rate. METHODS From Jan. 1990 to Jan. 2001, 624 patients were randomly devided into group A ( preoperative neoadjuvant chemotherapy group) and group B ( control group, without neoadjuvant chemotherapy) . Group A had 314 patients and group B had 310 cases. The patients in group A were give 2 cycles of neoadjuvant chemotherapy, and operations were performed in 4 weeks after finishing the last chemotherapy. Twenty-one patients were given bronchial artery intervensional chemotherapy. The other 293 cases were given intravenous chemotherapy. The regimens included MVP in 68 cases, CAP in 36 cases, EP in 67 cases, VIP in 20 cases, Gem+ DDP in 30 cases, NVB+ DDP in 32 cases, Taxol+ NVB in 30 cases, and Taxol+ DDP in 10 cases. The patients in group B were firstly operated. Thoracic radiation therapy of 50-55 Gy was g iven in the patients with N1 and N2 disease both in group A and group B. RESULTS The tumor response to induction chemotherapy was 73. 57%( 231/ 314) in group A. The tumor downstaging was 43. 63%( 137/ 314) . The histological complete response was 15. 92%( 50/ 314) . The resection rate was 97. 69% in group A, and 91. 94% in group B. No significant differences of blood loss, operative complications and mortality were observed between the group A and group B. The 1-, 3-, 5- and 10-year survival rates were 89. 35%, 67. 46% , 34. 39% and 29. 34% in group A, and 87. 53%, 51. 54%, 24. 19% and 21. 64% in group B respectively. The long-term survival rate in group A was remarkably higher than that in group B ( P < 0. 01) . CONCLUSIONS The results demonstrate that the preoperative neoadjuvant chemotherapy is safe and effective. It is helpful to decrease the tumor staging , to increase the resection rate of the tumor, and to improve the long-term survival rate and life qualities of patients with stage III NSCLC.

Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study

OBJECTIVES Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. MATERIALS AND METHODS EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. RESULTS Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, P<0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. CONCLUSIONS WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment.

Fibroblast Growth Factor Receptor 1 (FGFR1), Partly Related to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and Microvessel Density, is an Independent Prognostic Factor for Non-Small Cell Lung Cancer

Background This study aimed to explore the correlation between FGFR1 and clinical features, including survival analysis and the promotion of angiogenesis by fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2). FGFR1 gene amplification has been found in non-small cell lung cancer (NSCLC). However, the prognostic value of FGFR1 and the correlation between FGFR1 and clinical features are still controversial. Material/Methods A total of 92 patients with NSCLC who underwent R0 resection between July 2006 and July 2008 were enrolled in the study. The expression of FGFR1, VEGFR2, and CD34 was detected by immunohistochemistry. The correlations between the aforementioned markers and the patients’ clinical features were analyzed by the chi-square test. The impact factors of prognosis were evaluated by Cox regression analyses. Results The expression ratios of FGFR1 and VEGFR2 were 26.1% and 43.4%, respectively. The intensity of FGFR1 expression was related to VEGFR2 and histopathology. To some extent, the average microvessel density (MVD) had correlation to the expression of FGFR1 and VGEFR2. The pathological stages III–IV and high expression of FGFR1 were found to be independent prognostic factors. Conclusions The expression intensity of FGFR1 and VEGFR2 was associated with MVD, and the expression of FGFR1 is one of the independent prognostic indicators for NSCLC.

Polymorphisms in DNA repair genes of XRCC1, XPA, XPC, XPD and associations with lung cancer risk in Chinese people.

The carcinogenic chemicals and reactive oxygen species in tobacco can result in DNA damage. DNA repair genes play an important role in maintaining genome integrity. Genetic polymorphisms of DNA repair genes and smoking may contribute to susceptibility of lung cancer.

Salvage treatment with erlotinib after gefitinib failure in advanced non‐small‐cell lung cancer patients with poor performance status: A matched‐pair case–control study

Purpose:  Gefitinib plays an important role in non‐small‐cell lung cancer (NSCLC) treatment; however, progression of the disease occurs in most patients even after an initial response. The role of erlotinib after gefitinib failure has been investigated but continues to be debated, especially in heavily treated patients with poor performance status (PS). Therefore, a retrospective matched‐pair case–control study was carried out to evaluate the role of erlotinib after gefitinib failure in advanced NSCLC patients.

Screening and identification of lung cancer metastasis-related genes by suppression subtractive hybridization

Background and objective:  Lung cancer metastasis is a complicated process in which multiple stages and multiple genes are involved. There is an urgent need to use new molecular biology techniques to get more systematic information and have a general idea of the molecular events that take place in lung cancer metastasis. The object of this study was to construct the subtracted cDNA libraries of different metastatic potential lung cancer cell lines, NL9980 and L9981, which were established and screened from human lung large cell carcinoma cell line, WCQH‐9801.

A proteomic approach to elucidate the multiple targets of selenium-induced cell-growth inhibition in human lung cancer

Background:  Methylseleninic acid (MSA) has been implicated as a promising anticancer agent for lung cancer. However, the underlying molecular mechanism(s) responsible for MSAs action is not well understood. Our study aimed to examine the cellular effects of MSA on L9981 human high‐metastatic large cell lung cancer cells and gain insights into its possible molecular mechanism(s) through a proteomic approach.

Phase II study of oral etoposide maintenance for patients with extensive stage small cell lung cancer who have responded to the induction on an EP regimen

Maintenance therapy for extensive stage small cell lung cancer (ES‐SCLC) is still under debate. Many new agents fail during the maintenance course. As an active agent for SCLC, oral etoposide is worth being re‐evaluated.

A randomized study of small bore catheter thoracostomy closed drainage versus conventional pleural aspiration in the treatment of malignant pleural effusions

BACKGROUND Malignant pleural effusions commonly occur in patients with advanced cancer. Treatment is often palliative, such as pleural aspiration or tube thoracostomy with large bore chest tube. Tube thoracostomy with large bore chest tube can cause significant discomfort of patients. The aim of this study is to evaluate the efficacy of small bore catheter for drainage and administration of sclerosing agent in the treatment of malignant pleural effusions. METHODS Sixty patients with malignant pleural effusions were randomly assigned to small bore catheter thoracostomy closed drainage group or conventional pleural aspiration group. Cisplatin and interleukin-2 were infused into the thoracic cavity in eligible patients after drainage. Responses were evaluated 30 days later. RESULTS Overall response rate (complete response plus partial response) was 80.00% in small bore catheter thoracostomy closed drainage group and 36.67% in conventional pleural aspiration group respectively (P < 0.01). And the side effects in small bore catheter thoracostomy closed drainage group were obviously less than that in conventional pleural aspiration group. CONCLUSIONS Small bore intercostal catheter for drainage and administration of sclerosing agent is a valid and safe option for malignant pleural effusions.