A Meta-analysis of Ginsenoside Rg3 for Non-small Cell Lung Cancer

Similar documents
Cancer Cell Research 14 (2017)

Survival of patients with advanced lung adenocarcinoma before and after approved use of gefitinib in China

Kanglaite Injection Plus Chemotherapy Versus Chemotherapy Alone for Non-Small Cell Lung Cancer Patients: A Systematic Review and Meta-Analysis

Thoracic and head/neck oncology new developments

The efficacy of bevacizumab in Chinese patients with metastatic colorectal cancer and its effect in different line setting*

Is Bevacizumab (Avastin) Safe and Effective as Adjuvant Chemotherapy for Adult Patients With Stage IIIb or IV Non-Small Cell Lung Carcinoma (NSCLC)?

Small cell lung cancer (SCLC) accounts for approximately

Clinical progression of lobaplatin in combination chemotherapy for patients with recurrence or metastatic cancer*

Meta-Analysis of Trials Comparing Gemcitabine and Pegylated Liposomal Doxorubicin for Treatment in Women with Progressive or Recurrent Ovarian Cancer

Rong Biaoxue 1, Yang Shuanying 1*, Li Wei 1, Zhang Wei 2 and Ming Zongjuan 1 WORLD JOURNAL OF SURGICAL ONCOLOGY

LUNG CANCER TREATMENT: AN OVERVIEW

Combined Modality Therapy State of the Art. Everett E. Vokes The University of Chicago

trial update clinical

Virtual Journal Club: Front-Line Therapy and Beyond Recent Perspectives on ALK-Positive Non-Small Cell Lung Cancer.

Sponsor / Company: Sanofi Drug substance(s): Docetaxel (Taxotere )

National Horizon Scanning Centre. Erlotinib (Tarceva) in combination with bevacizumab for advanced or metastatic non-small cell lung cancer

Original Article Vascular endothelial growth factor polymorphisms and lung cancer risk

Hanrui Chen, Xuewu Huang, Shutang Wang, Xinting Zheng, Jietao Lin, Peng Li, Lizhu Lin

Systematic review of long-term Xingnao Kaiqiao needling efficacy in ischemic stroke treatment

Meta-Analysis of Randomized Controlled Trial in Treating Primary Liver Cancer by Fufang Kushen Injection Combined with TACE

Azithromycin enhances the favorable results of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer

Paclitaxel-etoposide-carboplatin/cisplatin versus etoposidecarboplatin/cisplatin. small-cell lung cancer: a retrospective analysis of 62 cases

Peking University People's Hospital, Peking University Institute of Hematology

Two Cycles of Chemoradiation: 2 Cycles is Enough. Concurrent Chemotherapy / RT Regimens

Management Guidelines and Targeted Therapies in Metastatic Non-Small Cell Lung Cancer: An Oncologist s Perspective

Targeted Agents as Maintenance Therapy. Karen Kelly, MD Professor of Medicine UC Davis Cancer Center

Heterogeneity of N2 disease

GASTRIC & PANCREATIC CANCER

EGFR inhibitors in NSCLC

PROSPERO International prospective register of systematic reviews

Erlotinib (Tarceva) for non small cell lung cancer advanced or metastatic maintenance monotherapy

Seasonal and geographical dispersal regularity of airborne pollens in China LI Quan-sheng, JIANG Sheng-xue, LI Xin-ze, ZHU Xiao-ming, WEI Qing-yu *

Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. Valle J et al. N Engl J Med 2010;362(14):

RESEARCH ARTICLE. Ying Fang, Li Wang, Guo-Hao Xia, Mei-Qi Shi* Abstract. Introduction. Materials and Methods

Department of Hematopoietic Stem Cell Transplantation, 307 Hospital of PLA, Academy of Military Medical Sciences, Beijing , China

GUODONG SHEN 1,2, GENG BIAN 2, HAIYING YU 2, MIN GAO 1, DONGMEI KANG 1, GAN SHEN 1,2 and SHILIAN HU 1,2

Lung Cancer Epidemiology. AJCC Staging 6 th edition

Angiogenesis and tumor growth

Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer

Addition of rituximab is not associated with survival benefit compared with CHOP alone for patients with stage I diffuse large B-cell lymphoma

Analysis of Prognosis and Prognostic Factors of Cervical Adenocarcinoma and Adenosqumous Carcinoma of the Cervix

Bevacizumab treatment for advanced non small cell lung cancer: A case report

MOLECULAR AND CLINICAL ONCOLOGY 1: , 2013

ORIGINAL ARTICLE. Oncology and Translational Medicine DOI /s Abstract

Cancer incidence and patient survival rates among the residents in the Pudong New Area of Shanghai between 2002 and 2006

Contemporary Chemotherapy-Based Strategies for First-Line Metastatic Breast Cancer

Supplementary Material

EXPERIMENTAL AND THERAPEUTIC MEDICINE 7: , 2014

TRANSPARENCY COMMITTEE OPINION. 29 April 2009

Original Article Association of osteopontin polymorphism with cancer risk: a meta-analysis

Choosing Optimal Therapy for Advanced Non-Squamous (NS) Non-Small Cell Lung Cancer

Maintenance therapy in advanced non-small cell lung cancer. Egbert F. Smit MD PhD Dept Thoracic Oncology Netherlands Cancer Institute

Yan Zhang 1*, Zheng Wang 2*, Xuezhi Hao 1, Xingsheng Hu 1, Hongyu Wang 1, Yan Wang 1, Jianming Ying 3. Original Article. Abstract

EGFR Tyrosine Kinase Inhibitors Prolong Overall Survival in EGFR Mutated Non-Small-Cell Lung Cancer Patients with Postsurgical Recurrence

Sergio Bracarda MD. Head, Medical Oncology Department of Oncology AUSL-8 Istituto Toscano Tumori (ITT) San Donato Hospital Arezzo, Italy

Media Release. Third phase III study of Avastin-based regimen met primary endpoint in ovarian cancer. Basel, 08 February 2011

It is estimated that 215,020 cases of lung cancer were newly

Management of advanced non small cell lung cancer

receive adjuvant chemotherapy

Advanced primary pulmonary lymphoepithelioma-like carcinoma: clinical manifestations, treatment, and outcome

FoROMe Lausanne 6 février Anita Wolfer MD-PhD Cheffe de clinique Département d Oncologie, CHUV

Non-small Cell Lung Cancer: Multidisciplinary Role: Role of Medical Oncologist

Exploring Personalized Therapy for First Line Treatment of Advanced Non-Small Cell Lung Cancer (NSCLC)

This article is downloaded from.

Evolving Paradigms in HER2+ MBC: Strategies for Individualizing Therapy with Available Agents

Novel EGFR TKI Theliatinib: An Open Label, Dose Escalation Phase I Clinical Trial

Correlation between expression and significance of δ-catenin, CD31, and VEGF of non-small cell lung cancer

CORRELATION BETWEEN SURVIVIN OVEREXPRESSION AND CLINICO-PATHOLOGICAL FEATURES OF INVASIVE CERVICAL CANCER: A META-ANALYSIS

Sorafenib for Advanced Hepatocellular Carcinoma

PERIOPERATIVE TREATMENT OF NON SMALL CELL LUNG CANCER. Virginie Westeel Chest Disease Department University Hospital Besançon, France

What is New in Geriatric Oncology: The Medical Oncology Perspective. Arti Hurria, MD Director, Cancer and Aging Research Program City of Hope

Original Article. Abstract

Plotting the course: optimizing treatment strategies in patients with advanced adenocarcinoma

Trabectedina + PLD nel trattamento del carcinoma ovarico. Nicoletta Colombo Universita Milano Bicocca Istituto Europeo Oncologia Milano

Maintenance paradigm in non-squamous NSCLC

This clinical study synopsis is provided in line with Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data.

RESEARCH COMMUNICATION

Association of mir-21 with esophageal cancer prognosis: a meta-analysis

Maintenance Therapy for Advanced NSCLC: When, What, Why & What s Left After Post-Maintenance Relapse?

Systemic Cytotoxic Therapy in advanced HCC

Recurrent response to advanced lung adenocarcinoma with erlotinib developing leptomeningeal metastases during gefitinib therapy and two case reports

Original Article CREPT expression correlates with esophageal squamous cell carcinoma histological grade and clinical outcome

Cutting Edge Treatment of Neuroendocrine Tumors

Cutting Edge Treatment of Neuroendocrine Tumors

1st line chemotherapy and contribution of targeted agents

Current state of upfront treatment for newly diagnosed advanced ovarian cancer

Chemo-radiotherapy in non-small cell lung cancer. HARMESH R NAIK, MD. September 25, 2002

Bevacizumab for the treatment of recurrent advanced ovarian cancer

Kai-chao Feng 1 *, Ye-lei Guo 2 *, Han-ren Dai 2 *, Yao Wang 2, Xiang Li 3, Wei-dong Han 2 *Contributed equally.

Table Selected Clinical Trials of Anti-Angiogenesis Therapy in Gynecologic Malignancies

Case 1 Metastatic Pancreatic Adenocarcinoma: What Therapy Should I Select First?

Phase I/II study of paclitaxel, gemcitabine and vinorelbine as first-line chemotherapy of non-small-cell lung cancer

Gemcitabine and Carboplatin in Patients with Refractory or Progressive Metastatic Breast Cancer after Treatment

1st-line Chemotherapy for Advanced disease

Bevacizumab rescue therapy extends the survival in patients with recurrent malignant glioma

Weekly Versus Triweekly Cisplatin-Based Chemotherapy Concurrent With Radiotherapy in the Treatment of Cervical Cancer

Lung cancer is the most common cause of cancer-related

Effect of FOLFOX4 combined with Brucea javanica emulsion on VEGF in patients with gastric cancer

Clinical efficacies of gemcitabine combined with docetaxel single or plus bevacizumab as second-line therapy for malignant pleural mesothelioma

ACRIN Gynecologic Committee

Transcription:

Clin Oncol Cancer Res (2011) 8: 175 180 175 DOI 10.1007/s11805-011-0578-4 A Meta-analysis of Ginsenoside Rg3 for Non-small Cell Lung Cancer Shan-shan HU Li-kun ZHOU Yi BA Hong-li LI Cai-hua ZHU Department of Digestive Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China Correspondence to: Yi BA Tel: 86-22-2334 0123 ext. 2101 E-mail: dryiba@gmail.com OBJECTIVE Ginsenoside Rg3 (Rg3) has shown anti-tumor effects on various tumor cells. It has been widely used in China for non-small cell lung cancer (NSCLC). However, there are only a few clinical trials to study the effectiveness of Rg3 on NSCLC, and almost them are smallsamples, so we performed a meta-analysis on the results of the studies we collected in order to investigate the effectiveness of Rg3 on NSCLC. METHODS A meta-analysis was conducted in all the selected randomized controlled trials evaluating the effectiveness of Rg3 on NSCLC patients. All on-line databases regarding Rg3 from 1950 to 2011 were searched. Supplemental hand searching of the references of retrieved articles was performed. RESULTS Six trials met the inclusion criteria. Four of them compared chemotherapy plus Rg3 with chemotherapy alone, and the other 2 compared chemotherapy plus Rg3 with chemotherapy plus placebo. These trials are homogeneous. Two of the trials report overall survival, but the data are not suitable for a meta-analysis. After meta-analysis was conducted in the included studies comparing the effects of chemotherapy plus Rg3 with that of chemotherapy alone or chemotherapy plus placebo, it was suggested that chemotherapy plus Rg3 increased the response rate [odds ratio: 2.64 (95% CI: 1.70 4.11), fixed effects model] and disease control rate [odds ratio: 3.34 (95% CI: 1.92 5.81); fixed effects model] of the patients at stage II IV, especially for the patients at stage III IV. CONCLUSION Meta-analysis of the available evidence suggests that Rg3 plus chemotherapy improves the response rate of NSCLC patients, and well-designed RCTs with large sample size are needed. KEY WORDS: Rg3, 20 (R)-GS-Rg3 (Rg3), non-small cell lung cancer, meta-analysis. Introduction Received May 25, 2011; accepted August 11, 2011 E-mail: editor@cocronline.org Tel (Fax): 86-22-2352 2919 Lung cancer is the leading cause of cancer death in China and the worldwide [1,2]. There has been a continuously increasing trend of lung cancer incidence in China,and China is anticipated to become the country with largest number of lung cancer patients by 2025 [3]. Nonsmall cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases and are divided into such subtypes as adenocarcinoma (the subset of bronchioloalveolar carcinoma), squamous cell carcinoma and large cell carcinoma. As far as 1983, it was found that extract of red ginseng reduced the incidence of lung adenoma [4]. Ginsenosides (GS) are the major active components of ginseng. Some researches have demonstrated that 20 (R)-

176 Clin Oncol Cancer Res (2011) 8: 175 180 GS-Rg3 (Rg3), an important component of GS, has antitumor effects on several kinds of cancer cells [5 8], especially on lung cancer cells [9,10]. In vitro studies have also revealed that Rg3 could increase the intracellular accumulation of drugs by means of binding to P-glycoprotein which is associated with multidrug resistance [11,12]. Based on the results of some randomized control trials (RCTs), Rg3 (trade name: Shengyi capsule) has been recommended in the Chinese edition of National Comprehensive Cancer Network (NCCN) guideline for relapse or metastasis of the NSCLC patients as an antiangiogenesis drug as well as a bevacizumab since 2006. However, the sample size in all the studies are small, therefore, it is necessary to perform a meta-analysis to evaluate the effectiveness and safety of Rg3 in NSCLC patients. Materials and Methods Search strategy Each of such keywords as Rg3, ginsenoside, ginseng or Shengyi capsule, along with lung cancer or non-small cell lung cancer and RCTs were entered when searching in the following electronic databases: (1) MEDLINE (August 1960 to February 2011); (2) EMBASE (Janurary 1966 to February 2011); (3) Chinese VIP database (Janurary 1989 to February 2011); (4) EBM review; (5) Current Controlled Trials (www.controlled-trials.com); (6) The National Research Register (www.updatesoftware.com/national/nrr-frame.html); (7) Clinicaltrials (clinicaltrials.gov). Outcomes evaluation The primary outcome was evaluated with response rate (RR) and the secondary outcomes evaluated with overall survival (OS), disease control rate (DCR, including the complete and partial response, plus stable disease and minor response if there is), time to progression (TTP), and progression-free survival time (PFS). Statistical analysis Meta-analysis was carried out by using review manager (RevMan 4.2) with fixed or random effects models, odds ratios (OR) and 95% confidence intervals (CI) were calculated. Weighted mean difference (WMD) was computed for continuous variable. Methodology of the included studies Based on the methods of randomization, allocation concealment, blinding and loss to follow up, the methodological quality of the included studies were assessed. Results Of the 403 articles identified in the literature search, only 8 articles related to RCTs were suitable to this analysis. After discussion, 2 articles were excluded, and one of them analyzed the effects of CTX plus Rg3 and Rg3 alone for postchemotherapy patients [13], and the other only presented randomization of study in its abstract without further descriptioninthemainbodyofthearticle [14]. Four out of 8 presented clinical trials which compared the effects of chemotherapy plus Rg3 with chemotherapy alone [15 18].The remaining 2 described clinical trials in which the effects of chemotherapy plus Rg3 and chemotherapy plus placebo were compared [19,20]. Details of the included studies presented in the 6 collected articles are summarized in Table 1. All the included studies had a total of 496 participants, and 3 of them included lung cancerpatients at stage II III while the other 3 included the patients at stage III IV. Primary and secondary outcomes Table 2 shows the results of the included studies. The duration of the studies varied from 6 weeks to 3 years and the longest one was 3 years [19] followed by another one of 1.6 years [20]. One of the studies listed Median TTP, median OS, 1 and 2 year survival rates, and one expressed median Table 1. The basic information of the collected studies. References Year Country of Origin N Sex ratio (F:M) Age (Year) KPS score Stage Intervention (n) Shi [19] 2006 China 41 10:31 37 75 > 60 II IV NP or MVP + Rg3(22) NP or MVP + placebo(19) Lin [15] 2002 China 151 109:42 53.8* > 60 II IV EP or MVP + Rg3(120) EP or MVP(31) Sun [20] 2006 China 115 79:36 20 75 > 60 III IV NP + Rg3(54) NP + placebo(61) Chen [16] 2005 China 60 46:14 35 69 > 60 II IV EP or MVP + Rg3(30) EP or MVP(30) Liu [17] 2007 China 70 43:27 35 70 > 60 IIIb IV NP + Rg3(35) NP(35) Liu [18] 2007 China 68 47:21 65 75 > 60 IIIb IV NP + Rg3 (35) NP(33) Duration of therapy 3 years 2 years N: number of the included patients in the studies; KPS: karnofsky performance status; n: number of the patients in groups; NP: chemotherapy regimen of vinorelbine plus cisplatin; MVP:mitomycin, vindesine and cisplatin; EP:etoposide and cisplatin; * mean age.

Clin Oncol Cancer Res (2011) 8: 175 180 177 Table 2. The results of the collected studies. Reference Year Intervention n CR PR MR SD Shi [19] 2006 NP or MVP + Rg3 22 2 8 2 7 NP or MVP + placebo 19 0 3 1 9 Lin [15] 2002 EP or MVP + Rg3 120 5 35 20 52 EP or MVP 31 0 4 2 18 Sun [20] 2006 NP + Rg3 54 1 16 19 12 NP + placebo 61 1 7 29 11 Chen [16] 2005 EP or MVP + Rg3 30 1 10 0 17 EP or MVP 30 0 5 0 16 Liu [17] 2007 NP + Rg3 35 0 13 0 19 NP 35 0 11 0 20 Liu [18] 2007 NP + Rg3 35 3 15 0 12 NP 33 1 8 0 12 n: number of the patients in groups; NP: chemotherapy regimen of vinorelbine plus cisplatin; MVP: mitomycin, vindesine and cisplatin; EP: etoposide and cisplatin Table 3. The quality of the main elements in collected studies. Reference Year Randomization Allocation concealment Blinding Loss to follow up Shi [19] 2006 A B A A Lin [15] 2002 A B D A Sun [20] 2006 B B A B Chen [16] 2005 B B B A Liu [17] 2007 B B B A Liu [18] 2007 C B B A Randomization: A, appropriate; B, unclear; C, quasi-randomization; D inappropriate. Allocation Concealment: A, concealed; B, unclear; C, not concealed. Blinding: A, double blind; B, blinding of participants or investigators; C blinding of analyst only; D, unclear; E, not blinded. Loss to follow up: A, 5% or less; B, 5.1% 10.0%; C, 10.1% 15%; D, more than 15%; E, unclear. OS and mean OS as mean SD. All the included studies showed CR, PR and SD, and 3 of them presentd MR which was regarded as SD in this analysis. Methodological quality of the studies Table 3 summarizes the quality of the 6 studies. All of the trials demonstrated the randomization and 2 of them were regarded appropriate. The method applied in one of the studies was quasi-randomization because the patients were distributed based upon the assigned date (even or odd). Allocation concealments were unclear in all the 6 included studies. Blinding was applied in 2 of the studies [19,20], and both were double-blind. One of the studied reported 9 patients drop-out [20]. Effects of chemotherapy plus Rg3 vs. chemotherapy alone or chemotherapy plus placebo Response rate and disease controlled rate All the response rates and disease control rates in all the included trials were evaluated with meta-analysis. These studies formed the basis for determining the effectiveness of chemotherapy+rg3. The results of the meta-analysis showed an OR of 2.64 (95% CI: 1.70 4.11) for RR in favor of chemotherapy+rg3 (P,0.001) and an OR of 3.34 (95% CI: 1.92 5.81) for DCR in favor of chemotherapy+rg3 (P,0.001) (Fig.1). Overall survival Overall survival was measured in the 2 long-term studies [18,19]. However, the meta-analysis was not applied to evaluate the OS in the 2 studies because of the limited data. Subgroup analysis Subgroup analysis for the patients at stage III IV were conducted. 3 of the included trials composed of the patients at stage II, one of them included 1 patient at stage II in chemotherapy plus placebo group, we excluded the patient regarding it as ineffective.thus, only the patients at stage III IV were remained in that trail and the data of the patients could be analyzed along with those in the other 3 trials which included the patients at stage III IV only. The results showed that there was no heterogeneity in the 4 studies (P50.76) with an OR of 2.41(95% CI 1.43 4.07) (P50.001) for RR in favors of chemotherapy+rg3. For DCR, there was no heterogeneity in the 4 studies (P50.51) with an OR of 2.69 (95%CI 1.34 5.04) in favors of chemotherapy +Rg3 (P50.005). Safety analysis One of the studies reported that 9 patients were of dropout (4 patients abandoned at the beginning of the study and 5 suffered from serious adverse effects), and no

178 Clin Oncol Cancer Res (2011) 8: 175 180 Fig.1. The effect of Rg3 in non-small cell lung cancer. RR: response rate, DCR: disease control rate, OR: odds ratios, n: number of incidence events of group. N: number of patients. Fig.2. III IV degree hematologic toxicity of chemotherapy + Rg3 vs. chemotherapy or plus placebo. n: number of incidence events of group. N: number of patients. further details were found [20]. Three of the trials reported that hematologic toxicity occurred in the patients. Thus, meta-analyses was conducted for analyzing hematologic toxicity at degree III IV. There were no statistical difference among anemia, leukopenia and thrombocytopenia. For anemia at degree III IV, the OR was 0.56 (95% CI: 0.18 1.78) (P50.33); for leukopenia at degree III IV, the OR was 1.55 (95%CI 0.73 3.27) (P50.25); for thrombocytopenia at degree III IV, the OR was 0.59 (95% CI 0.15 2.25) (P50.44) (Fig. 2).

Clin Oncol Cancer Res (2011) 8: 175 180 179 Discussion Angiogenesis is required in invasive growth and metastasis of tumor and regarded as a key point in cancer progression. Anti-angiogenic drugs may improve the effects of chemotherapy by causing vessel normalization and angiogenesis inhibitors normalize tumor endothelial cell s responsiveness to inflammatory cytokines in vivo [21]. Based on the result of ECOG 4559 [22], bevacizumab combined with paclitaxel and cisplatin has been recommended by Eastern Cooperative Oncology Group (ECOG) for recurrent or advanced non-squamous NSCLC patients. Rg3 has been recommended in Chinese edition of NCCN guideline as an anti-angiogenesis drug for advanced NSCLC patients. Our analysis suggests that NSCLC patients at stage III IV can get benefits when Rg3 combined with chemotherapy is applied. The patients at stage II IIIa, whose tumor are operable, may also be benefited with Rg3 too. One study including 133 patients observed life span of the post-operative patients at stage II IIIa, and showed that there were no statistical differences in 1-year, 2-year and 3- year survival among the patients receiving Rg3 or the patients receiving chemotherapy alone or the patients receiving Rg3 plus chemotherapy [23]. Although most studies are in short term, which makes meta-analysis for evaluating the long-term effects is unapplied, the 2 longterm studies both showed that the patients aquired benefits from the treatment of Rg3 plus chemotherapy on their long-term survival. Increased treatment-related deaths, neutropenia, possible bleeding and thrombocytopenia induced by bevacizumab are noticeable, while our analysis suggests that combination of chemotherapy and Rg3 does not increase hematological toxicity. In the included studies there were no descriptions about hypertension,which is regarded as a useful surrogate to predict the usability of bevacizumab. The cost of Rg3 in China is much less than that of bevacizumab. Cost effectiveness of Rg3 needs to be taken into consideration following the effect which has been proven. The anti-tumor mechanism of Rg3 is not very clear. Whether Rg3 can normalize vessels or overcome endothelial cell anergy and whether other anti-angiogenesis drugs, such as bevacizumab and endostatin can do the same are still unknown. All the included patients in the studies are Chinese. Considering the different effect of chemotherapy on NSCLC patients in different race groups, this modality of the treatment should be considered carefully when it is applied to different race of the patients.the methodological quality of the included studies is not high, and the sample size is small,so we conducted a meta-analysis to evaluate the effects of Rg3 in NSCLC patients.however,large-sample RCTs are necessary to conform the anti-tumor effects of Rg3. Conflict of interest statement No potential conflicts of interest were disclosed. References 1 Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. Cancer J Clin 2010; 60: 277 300. 2 http://www.moh.gov.cn/publicfiles/business/htmlfiles/ zwgkzt/ptjnj/year2009/t-9.htm 3 Yang GH. Prevalence levels, trends and distribution of death and its risk factors in Chinese population. Beijing: Peking Union Medical College Press 2005; 75. 4 Yun TK, Yun YS, Han IW. Anticarcinogenic effect of longterm oral administration of red ginseng on newborn mice exposed to various chemical carcinogens. Cancer Detect Prev 1983; 6: 515 525. 5 Liu WK, Xu SX, Che CT. Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci 2000; 67: 1297 1306. 6 Xu TM, Xin Y, Cui MH, et al. Inhibitory effect of ginsenoside Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian cancer. Chin med J 2007; 120: 584 588. 7 Iishi H, Tatsuta M, et al. Inhibition by ginsenoside Rg3 of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats. Clin EXP Metastasis 1997; 15: 603. 8 Jun X, Chen Hm, Peng SP, et al. Apoptosis Induced by Ginsenoside Rg3 in a Human Bladder Carcinoma Cell Line. Chin J Clin Oncol 2006; 3: 283 287. 9 Yun TK, Lee YS, Lee YH, et al. Anticarcinogenic effect of Panax ginseng C.A.Meyer and identification of active compounds. J Korean Med Sci. 2001; 16 Suppl: S6 18. 10 Zhang Q, Kang X, Zhao W. Antiangiogenic effect of lowdose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma. Biochem Biophys Res Commun 2006; 342: 824 828. 11 Choi CH, Kang G, Min YD. Reversal of P-glycoproteinmediated multidrug resistance by protopanaxatriol ginsenosides from Korean red ginseng. Planta Med 2003; 69: 235 240. 12 Seung-Whan Kim, Hyog-young Kwon, Dong-Whan Chi, et al. Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg3. Biochemical Pharmacology 2003; 65: 75 82. 13 Li HB, Liu WL, Zhang QY. The efficacy analysis of low- dose cyclophosphamide combined with ginsenoside Rg3 on advanced non-small cell lung cancer. Shiyong Zhongliu Zazhi 2006; 20: 18 20 (in Chinese). 14 Wang FL, Yang YM. The clinical observation of Rg3 combined particle knife to treat NSCLC in late period. Zhongguo Yiyao Daobao 2008; 5: 151 152 (in Chinese). 15 Lin HS, Piao BK, Li SQ. Phase II Clinical Trial Report of Treating Lung Cancer with Shen Yi Capsule. Zhongguo Zhongliu Linchuang 2002; 29: 276 279 (in Chinese). 16 Chen MW, Yao Y, Shi ZH. Observation of Curative Effect of Combined 20(R) Ginsenoside Rg3 with chemotherapy on nonsmall-cell Lung Cancers. Huanan Guofang Yixue Zazhi 2005; 19: 4 6. 17 Liu SQ, Sun LX, Ban LY, et al. Ginsenoside Rg3 capsules combined NP regimen in the treatment of advanced nonsmall cell lung cancer. Linchuang Zhongliuxue Zazhi 2007; 12: 847 849. 18 Liu Y, Liu S, Xu CA. Clinical observation of treating nonsmall-cell lung cancer by chemotherapy and shenyi capsule. Shanxi Yiyao Zazhi 2007; 36: 554 556 (in Chinese). 19 Shi MQ, Feng JF, PAN LX, et al. Clinical observation of treating non-small-cell lung cancer by chemotherapy and shenyi capsule. Linchuang Zhongliuxue Zazhi 2006; 11: 193 194. 20 Sun Y, Lin HS, Zhu YZ, et al. A randomized, prospective, multi-centre clinical trial of NP regimen (vinorelbine + cisplatin) plus Gensing Rg3 in the treatment of advanced

180 Clin Oncol Cancer Res (2011) 8: 175 180 non-small cell lung cancer patients. Chinese Journal of Lung Cancer 2006; 9: 254 257. 21 Dirkx AE, oude Egbrink MG, Castermans K, et al. Antiangiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and inflitration in tumors. FASEB J 2006; 20: 621 630. 22 Sandler A, Gray R, Perry MC, et al. Paclitaxel-Carboplatin Alone or with Bevacizumab for Non Small-Cell Lung Cancer. N Engl J Med 2006; 355: 2542 2550. 23 Lu P, Su W, Miao ZH, et al. Effect and Mechanism of Ginsenoside Rg3 on Postoperative Life Span of Patients with Non-Small Cell Lung Cancer. Chin J Intergr Med 2008; 14: 33 36.