Original Article
Kanglaite injection combined with chemotherapy versus chemotherapy alone in the treatment of advanced non‑small cell lung carcinoma ABSTRACT Objective: To evaluate the clinical efficacy of Kanglaite (KLT) injection combined with chemotherapy versus chemotherapy alone in the treatment of advanced non‑small cell lung carcinoma (NSCLC) by meta‑analysis. Materials and Methods: Electronic search of PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases was conducted to select studies about KLT injection combined with chemotherapy versus chemotherapy alone in the treatment of advanced NSCLC. The pooled risk ratio (RR) and its 95% confidence interval (95% CI) for objective response rate (ORR), Karnofsky (KPS) score improvement and nausea and vomiting were calculated by Stata11.0 statistical software. Result: Finally, we included 34 clinical trials in this meta‑analysis. The pooled results suggested that KLT injection combined with systematic chemotherapy can significantly increase the objective response rate (ORR) [RR = 1.35, 95% CI: 1.23–1.48, (Z = 6.43, P = 0.000)], the quality of patients’ life (KSP improvement) [RR = 2.04, 95% CI: 1.79–2.33, (Z = 10.57, P = 0.000)] and decrease the risk ratio of gastrointestinal reaction [RR = 0.53, 95% CI: 0.42–0.66, (Z = 5.53, P = 0.000)] compared with chemotherapy alone. Conclusion: KLT injection combined with chemotherapy can improve the short‑term efficacy, performance status and decrease the risk of gastrointestinal reaction compared with systematic chemotherapy alone. KEY WORDS: Chemotherapy, clinical efficacy, Kanglaite, meta‑analysis, non‑small cell lung carcinoma
INTRODUCTION Lung cancer is leading cause of cancer related death and most commonly diagnosed cancer globally in year 2008 according to the world cancer statistics.[1] Generally, lung cancer is divided non‑small lung cancer (NSCLC) and small cell lung carcinoma (SCLC) according to the pathology. The NSCLC accounting for 75%-80% lung cancer diagnosed is subdivided into squamous cell lung carcinoma, adenocarcinoma, and big cell lung carcinoma.[2,3] In China, NSCLC is the most commonly diagnosed solid carcinoma and the first leading cause of cancer-related death in male and second leading cause in female. Patients with early stage of NSCLC can be treated by surgery with relative acceptable prognosis and patients with advanced or metastasis stage of this disease could be only treaded with systematic chemoradiation. In advanced‑stage NSCLC, chemotherapy can prolong survival and improves patient quality of life, but its effectiveness is not completely satisfactory. And based on the cisplatin (DDP) and third generation C46
chemotherapy regimen, the objective response rate was only 20%-30%. Kanglaite (KLT) injection is a unique botanically sourced molecular targeted agent prepared as a micro‑emulsion for intravenous use. Several clinical studies indicated the KLT combined with systematic chemotherapy can improve the clinical efficacy in patients with several types of carcinoma. But with relatively small patients number included in each study, the statistical power is limited. Thus, we performed this meta‑analysis to further demonstrate the clinical efficacy of KLT in the treatment of NSCLC by meta‑analysis.
Xiaohong Liu, Qinghui Yang1, Yuling Xi, Kewei Yu2, Weizhen Wang3, Xiangmei Zhao4, Xiaoge Kou1 Departments of Pharmacy, 1Oncology and 3Emergency, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, 2 Department of Oncology, Shandong University Affiliated Jinan Central Hospital, Jinan 250013, 4Department of Epidemiology, Xinxiang Medical University, Xinxiang 453100, China For correspondence: Dr. Xiaoge Kou, Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, China. E‑mail: kouxiaogezlk@aliyun. com Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.139758
MATERIALS AND METHODS
PMID: *** Quick Response Code:
Literature source and search strategy We searched and extracted eligible studies about KLT injection assistant treatment of NSCLC by searching databases of PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wanfang Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 1- 2014
Liu, et al.: Kanglaite and advanced non-small lung carcinoma
databases. The combination of the following key words were used: “lung cancer”, “lung carcimoma”, “non‑small cell lung cancer”, “non‑small lung carcinoma”, “NSCLC”, “Kanglaite” and “KLT”. Inclusion and exclusion criteria The following criteria were used for the literature inclusion: (a): The study design was confined to prospective clinical controlled trials with or without blind; (b) The patients was pathologically confirmed non‑small lung carcinoma; (c) The intervention was KLT injection combined with systematic chemotherapy; (d) The control group was only given systematic chemotherapy; (f) The outcome should include the objective response rate, the KPS improvement and gastrointestinal reaction incidence rate. The major exclusion were: (a) Overlapping study populations; (b) Retrospectively studied; (c) patients without pathology confirmed; (d) Without detailed data about objective response rate, the KPS improvement and gastrointestinal reaction incidence rate.
Data extraction and quality evaluation The general characteristics of the included trials were extracted such as first author name, publication time, number of subjects in the treatment and control arms and detailed treatments regimen. The frequency for interested events in the combined treatment and control groups were extracted carefully. The general methodological quality of each included trials was evaluated by a six‑questionnaire according to the Cochrane protocol when evaluation of clinical randomized trials. The question questions are: (a) Adequate sequence gereration? (b) Allocation concealment? (c) Incomplete outcome data addressed? (d) Free of selective reporting? (f) Free of other bias? Response criteria According to the Response Evaluation Criteria in Solid Tumors (RECST) developed by the World Health Organization (WHO),[4] the tumor response were divided to complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The objective response
Table 1: The general characteristics of included studies Author Li SW
No (T/C) 34/30
Regimen T KLT+MVP
C MVP
KLT+NP KLT+NP KLT+HEP KLT+NP KLT+CAP/MVP KLT+CAP
NP NP HEP NP CAP/MVP CAP
Yang SJ Chen YZ Tang JH Xie XD Liu JX Lin YH
28/29 28/27 20/22 43/44 131/111 39/41
Lian ZP
50/50
KLT+GP
GP
Deng SG
21/22
KLT+GP
GP
Lu CD Lv XY Wu RL Wu XH Huang JY Li ZG Li ZH Liu YL Chen ZP Song JL Wang ZX An HJ Ju HB Zhong YH Wang YL Ren ZH Ren JP Hou EC Liu JQ Liu MS Sun SQ Liao GQ Zhu YZ Guan Y Lu CD
62/51 30/30 39/44 21/19 53/33 36/36 20/20 32/32 30/34 26/21 39/41 48/48 48/48 22/26 42/38 68/99 64/63 34/34 34/35 21/21 35/35 144/144 50/50 35/30 68/61
KLT+NP/GP KLT+NP KLT+NP KLT+EP KLT+EP KLT+NP KLT+NP KLT+CEP KLT+MVP KLT+CAP KLT+NP KLT+NP KLP+MVP KLT+NIC KLT+MVP/NP/TP KLT+EP/MVP/NP/GP KLT+NP KLT+NP KLT+GP KLT+EP KLT+GP KLT+NP KLT+DP KLT+GP KLT+NP
NP/GP NP NP EP EP NP NP CEP MVP CAP NP NP MVP NIC MVP/NP/TP EP/MVP/NP/GP NP NP GP EP GP NP DP GP NP
Outcomes
Duration
Year
CR, PR, KPS improvement, gastrointestion reaction, hepatic dysfunction CR, PR, KPS improvement CR, PR, KPS improvement CR, PR, KPS improvement, gastrointestion reaction, KPS improvement CR, PR, KPS improvement, symptom improvement CR, PR, KPS improvement, gastrointestion reaction, hepatic and renal dysfunction CR, PR, KPS improvement, gastrointestion reaction, hepatic and renal dysfunction CR, PR, KPS improvement, gastrointestion reaction, hepatic and renal dysfunction CR, PR, KPS improvement, gastrointestion reaction CR, PR, KPS improvement, CR, PR CR, PR, KPS improvement CR, PR, KPS improvement, gastrointestion reaction CR, PR, KPS improvement, gastrointestion reaction CR, PR, bone marrow suppression Bone marrow suppression CR, PR, KPS improvement KPS improvement CR, PR, KPS improvement CR, PR, symptom improvement CR, PR CR, PR, KPS improvement, symptom improvement KPS improvement CR, PR, symptom improvement CR, PR, KPS improvement CR, PR, KPS improvement CR, PR, CR, PR CR, PR, symptom improvement CR, PR, symptom improvement CR, PR CR, PR CR, PR
2 weeks
2002
2 weeks 2 weeks 2 weeks 60 days 6 weeks 6 weeks
2003 2003 2002 2003 1995 2004
10 days
2006
3 weeks
2006
20‑45 days 3 weeks 6 weeks 10 days 42‑63 days 21 days 6 weeks 8 weeks 20 days 6 weeks 6 weeks 10 days 6 weeks NA 10 days 3 weeks 3 weeks 10 days 10 days 3 weeks 20 days 20 days 3 weeks 3 weeks 45 days
2006 2004 2002 2001 2001 2003 2005 2003 1999 2002 2007 2005 2000 2001 2005 2007 2010 2008 2011 2006 2012 2009 2010 2010 2008
KLT=Kanglaite, CR=Complete response, PR=Partial response, GP=Gemcitabine and cisplatin, DP=Progressive disease, NP=Vinorelbine and cisplatin, EP=Etoposide and cisplatin, EVP=Etoposide vinblastine cisplatin, HEP=Hydroxycamptothecine etoposide cisplatin, MVP=Mitomycin vindesine cisplatin, NIC=catharanthine iphosphamide carboplatin
Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 1- 2014
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Liu, et al.: Kanglaite and advanced non-small lung carcinoma
rate was definite as CR + PR. And the exact definition for CR, PR, SD and PD was as follows: CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the Longest diameter (LD) of target lesions, taking as reference the baseline sum LD; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started; PD: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Statistical method All of the data was pooled and calculated by STATA11.0 software. The risk ratio was used to analyze dichotomous data. If heterogeneity was found across the trials the pooled results was calculated based on random effect model; otherwise, if there was no statistical heterogeneity was found across the included studies, the fixed effect model was used. Heterogeneity was tested using the Z score and χ2 in which P 0.05). But significant publication bias was found in the pooled results of KPS improvement [Figure 5]. DISCUSSION KLTanglaite injection, which had been confirmed with anti‑tumor activity, is one of Chinese herb preparations that is developed and manufactured by Zhejiang Kanglaite Pharmaceutical Co., Ltd in China.[39] It is mainly used for the treatment of several types of tumors such as NSCLCno‑small cell lung cancer, liver cancer, gastric cancer and etc., KLT is a unique botanically sourced molecular targeted agent prepared as a micro‑emulsion for intravenous use. It is manufactured by the state of art technology with active substance extracted from a natural herbal plant semen coicis. Clinical trials demonstrated that KLT has several advantages in treatment of carcinomas. Firstly, KLT can killing cancer cells directly and effectively while remarkably improving patient immune function; Secondly, synergistic in increasing efficacy and reducing toxicity when combined with chemotherapy regimens or radiation therapy; Thirdly, Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 1- 2014
Liu, et al.: Kanglaite and advanced non-small lung carcinoma
Figure 2: Forest plot for the objective response
Figure 3: Forest plot for the KPS Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 1- 2014
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Liu, et al.: Kanglaite and advanced non-small lung carcinoma
Figure 4: Forest plot for nausea and vomiting
0.42–0.66, (Z = 5.53, P = 0.000)] compared with chemotherapy alone. The pooled data indicated that KLT injection combined with chemotherapy can improve the short‑term efficacy, performance status and decrease the risk of gastrointestinal reaction compared with systematic chemotherapy alone.
Figure 5: Begg’s test for evaluation of the publication bia
providing high energy nutrition to treat cachexia; fourthly, controlling cancerous pain markedly; Fifthly, improving patients’ quality of life and notably prolonging survival. In this study, we include 34 trials comparing Kanglaite (KLD) injection combined with systematic chemotherapy versus chemotherapy alone in the treatment of NSCLC. Of the recruited 34 trails, the most common use chemotherapy regimens were NP, GP, EP and MVP. And the chemotherapy duration range from 10 days to 6 weeks. The pooled results showed that KLT injection combined with systematic chemotherapy can significant increase the objective response rate (ORR) [RR = 1.35, 95% CI: 1.23‑–1.48, (Z = 6.43, P = 0.000)], the quality of patients’ life (KPS improvement) [RR = 2.04, 95% CI: 1.79–2.33, (Z = 10.57, P = 0.000)] and decrease the risk ratio of gastrointestinal reaction [RR = 0.53, 95% CI: C50
Although the pooled results demonstrated good clinical efficacy for KLD injection assistant treatment NSCLC in this meta‑analysis, there still several limitation for this study. Firstly, in the procedure of relevant articles searching and inclusion, we found all the trails are come from Chinese mainland; Secondly, the quality of the included 34 trials are relative low according to the quality evaluation system provided by Cochrane hand book; Thirdly, significant heterogeneity for the pooled results of KPS improvement was found. Fourthly, there was obviously publication bias in the aspect of KPS improvement. In conclusion, the pooled data showed that KLT injection combined with chemotherapy can improve the short‑term efficacy, performance status and decrease the risk of gastrointestinal reaction compared with systematic chemotherapy alone. But considering the limitations, the conclusion should be interpreted with caution. REFERENCES 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69‑90. 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11‑30. 3. Hua F, Fang N, Li X, Zhu S, Zhang W, Gu J. A Meta‑analysis of the relationship between RARβ gene promoter methylation and non‑small cell lung cancer. PLoS One 2014;9:e96163. Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 1- 2014
Liu, et al.: Kanglaite and advanced non-small lung carcinoma
4. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: Immune‑related response criteria. Clin Cancer Res 2009;15:7412‑20. 5. Li SW, Wang Y. Clinical study of Kanglaite combined with chemotherapy for non‑small cell lung cancer patients. Tumor 2002;22:84. 6. Yang SJ, Yao YM, Li YF, Sun H, Ma BG. Clinical observation of Kanglaite injection combined with chemotherapy for non‑small cell lung cancer patients. Chin Integr Tradit West Med 2003;23:629. 7. Chen YZ, Li PP, Yan LF, Sun H, Zhang QH. Effective observation of Kanglaite injection plus NVB and DDP regimen for non‑small cell lung cancer patients. Chin Integr Tradit West Med 2003;23:629‑30. 8. Tang JH. Clinical study of Kanglaite injection combined with HEP regimen for advanced non small cell lung cancer patients. Tumour 2002;22:83. 9. Xie XD, Zheng ZD, Gao YL, Liu DW, Liui YY. A random control study: Effect of Kanglaite on life quality of patient with lung cancer in advanced stage. Chin Clin Rehabil 2003;7:672‑3. 10. Liu JX, Liao ML, Yan DJ, Zhou JY. Kanglaite injection for the treatment of primary lungcancer: A phase II clinical trial. Tradit Chin Drug Res Clin Pharmcol 1995;6:17‑22. 11. Lin YH, Wang F, Chen P, Zhang JL. Combination of Kanglaite injection and CAP regimen chemotherapy in treatment of late non‑small cell lung cancer. Qilu Oncol 2004;11:647‑9. 12. Lian Z, Lu Y, Hou E, Wang X. Combination of GP regimen and Kanglaite in the treatmentof advanced non‑small cell lung cancer. Zhongguo Fei Ai Za Zhi 2006;9:74‑7. 13. Deng SG, Wen SG, Wen SB, Chen AI. Clinical observation of Kanglaite injection combined with Gemzar and carboplatin for median and advanced non‑small cell lung cancer patients. Zhejiang Pract Med 2006;11:234‑6. 14. Lu CD. Kanglaite injection combined with chemotherapy for advanced non‑small cell lungcancer patients. Mod Oncol 2006;14:964‑5. 15. Lv XY, Zhang YQ, Li QS. Clinical study on quality of life for chemotherapy combined with kanglaite in non‑small cell lung cancer. Clin Pulm Med 2004;9:342‑3. 16. Wu RL, Ou DB, Pan X. Clinical observation of Kanglaite injection combined with NVB and DDP for median and advanced non‑small cell lung cancer patients. Shaanxi Oncol Med 2002;10:201. 17. Wu XH, Hua D, Sha LJ, Wu LL. Kanglaite injection combined with MVP regimen for non‑small cell lung cancer patients. Qilu Oncol 2001;8:657‑8. 18. Huang JY, Gao P, Wang XQ. Clinical observation of Kanglaite injection combined with EP regimen for advanced non‑small cell lung cancer patients. Tumour 2001;21:392. 19. Li ZG, Hu HY, Zhang JS. Observation on efficacy Kanglaite injection combined with chemotherapyin treating non‑small cell lung cancer in aged patients. Chin Cancer Prev Treat 2003;10:405‑6. 20. Li ZH, Lv JF, Zhou LZ. Clinical study of combined Kanglaite injection with chemotherapy in treatment of NSCLC. Chin Cancer Prev Treat 2005;12:1339‑40. 21. Liu YL, Sun XJ, Zhang J, Yang DC. Clinical observation of Kanglaite combined with CEP for non‑small cell lung cancer patients. Chin Cancer Prev Treat 2003;10:895. 22. Chen ZP. Clinical study of Kanglaite injection combined with chemotherapy for 30 advanced lung cancer patients. Zhejiang Coll TCM 1999;23:35.
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23. Song JL, Zhang LP, Liu ZW. Effect of combined therapy of Kanglaite on quality of life of middle‑old aged patients with advanced non‑small cell lung cancer. Chin Clin Rehabil 2002;6:1160‑1. 24. Wang ZX, Zhang ZG. Therapeutic effect of Kanglaite injection combined with chemotherapy on advanced non‑small cell lung cancer. Hebei Med J 2007;29:47‑8. 25. An HJ, Yuan JZ. Clinical observation of Kanglaite combined with NC improve NSCLC of agedness. Chin Pract Chin Mod Med 2005;18:1205‑6. 26. Ju HB, Chen XJ, Wang BQ, Song CS, Ren HQ, Zhang HY, et al. Clinical effect of Kanglaite plus PVM versus simple PVM for non‑small cell lung cancer patients. Pract Oncol 2000;15:56‑7. 27. Zhong YH, Liu H, Chen M. Clinical observation of Kanglaite combined with NIC for non‑small cell lung cancer patients. Shaanxi Oncol Med 2001;9:288. 28. Wang YL, Li DM, Xu H, Tao M, Wang QC. Combination of Kanglaite injection and chemotherapy for treatment of advanced non‑small cell lung cancer. Oncol Prog 2005;3:273‑5. 29. Ren ZH, Zhang CH. Kanglaite injection combined with chemotherapy for advanced non‑small cell lung cancer. Med Inf 2007;12:2138‑9. 30. Rem JP, Wang H, Liu LM, Li XH, Zhang FM, Zhang XQ, et al. Kanglaite injection combined with navelbine plus platinum protocol of chemotherapy for elder advanced non‑small cell lung cancer. Prog Mod Biomed 2010;10:3275‑8. 31. Hou EC. A clinical study on kanglaite injection combined with chemical therapy in the treatment of patients with advanced non‑small cell lung cancer. Tradit Chin Drug Res Clin Pharm 2008;19:504‑5. 32. Liu JQ, Shang LQ, Li XC, Wen F, Li J, Wang W. Effect of kanglaite combined with chemical therapy advanced non‑small cell lung cancer. J Mod Oncol 2011;10:1974‑6. 33. Liu MS, Wang CY. Kanglaite injection in the treatment of advanced non‑small cell lung cancer. Cancer Res Clin 2006;18:415. 34. Sun SQ, Zhu XL, Huang J, Xu T, Lin Y. Effect of Kanglaite injection combined with chemotherapy for improvement of quality of life in advanced stage NSCLC patients. J Pract Oncol 2012;5:506‑10. 35. Liao GQ, Wang GH, Liu PH, Wang HM, Qu YM, Xie GQ. Chemotherapy combined with Kanglaite in treatment of advanced non‑small cell lung cancer. J Pract Oncol 2009;6:595‑8. 36. Zhu YZ, Zhang HT. Kanglaite injection combined with TP regimen in the treatment of non‑small cell lung cancer with 100 case report. Mod Oncol 2010;8:1569‑71. 37. Guan Y, Guo QS, Song J. Kanglaite combined with GP regimen in the treatment of elderly patients with advanced non‑small cell lung carcinoma. Chin J Geriatr Care 2010;1:5‑7. 38. Lu CD. Kanglaite injection combined with chemotherapy in the treatment of non‑small cell lung cancer. Clin J Trandit Chin Med 2008;3:261‑2. 39. Zhan YP, Huang XE, Cao J, Lu YY, Wu XY, Liu J, et al. Clinical safety and efficacy of Kanglaite® (Coix Seed Oil) injection combined with chemotherapy in treating patients with gastric cancer. Asian Pac J Cancer Prev 2012;10:5319‑21. Cite this article as: Liu X, Yang Q, Xi Y, Yu K, Wang W, Zhao X, et al. Kanglaite injection combined with chemotherapy versus chemotherapy alone in the treatment of advanced non-small cell lung carcinoma. J Can Res Ther 2014;10:46-51. Source of Support: Nil, Conflict of Interest: None declared.
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Kanglaite injection combined with chemotherapy versus chemotherapy alone in the treatment of advanced non‑small cell lung carcinoma ABSTRACT Objective: To evaluate the clinical efficacy of Kanglaite (KLT) injection combined with chemotherapy versus chemotherapy alone in the treatment of advanced non‑small cell lung carcinoma (NSCLC) by meta‑analysis. Materials and Methods: Electronic search of PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases was conducted to select studies about KLT injection combined with chemotherapy versus chemotherapy alone in the treatment of advanced NSCLC. The pooled risk ratio (RR) and its 95% confidence interval (95% CI) for objective response rate (ORR), Karnofsky (KPS) score improvement and nausea and vomiting were calculated by Stata11.0 statistical software. Result: Finally, we included 34 clinical trials in this meta‑analysis. The pooled results suggested that KLT injection combined with systematic chemotherapy can significantly increase the objective response rate (ORR) [RR = 1.35, 95% CI: 1.23–1.48, (Z = 6.43, P = 0.000)], the quality of patients’ life (KSP improvement) [RR = 2.04, 95% CI: 1.79–2.33, (Z = 10.57, P = 0.000)] and decrease the risk ratio of gastrointestinal reaction [RR = 0.53, 95% CI: 0.42–0.66, (Z = 5.53, P = 0.000)] compared with chemotherapy alone. Conclusion: KLT injection combined with chemotherapy can improve the short‑term efficacy, performance status and decrease the risk of gastrointestinal reaction compared with systematic chemotherapy alone. KEY WORDS: Chemotherapy, clinical efficacy, Kanglaite, meta‑analysis, non‑small cell lung carcinoma
INTRODUCTION Lung cancer is leading cause of cancer related death and most commonly diagnosed cancer globally in year 2008 according to the world cancer statistics.[1] Generally, lung cancer is divided non‑small lung cancer (NSCLC) and small cell lung carcinoma (SCLC) according to the pathology. The NSCLC accounting for 75%-80% lung cancer diagnosed is subdivided into squamous cell lung carcinoma, adenocarcinoma, and big cell lung carcinoma.[2,3] In China, NSCLC is the most commonly diagnosed solid carcinoma and the first leading cause of cancer-related death in male and second leading cause in female. Patients with early stage of NSCLC can be treated by surgery with relative acceptable prognosis and patients with advanced or metastasis stage of this disease could be only treaded with systematic chemoradiation. In advanced‑stage NSCLC, chemotherapy can prolong survival and improves patient quality of life, but its effectiveness is not completely satisfactory. And based on the cisplatin (DDP) and third generation C46
chemotherapy regimen, the objective response rate was only 20%-30%. Kanglaite (KLT) injection is a unique botanically sourced molecular targeted agent prepared as a micro‑emulsion for intravenous use. Several clinical studies indicated the KLT combined with systematic chemotherapy can improve the clinical efficacy in patients with several types of carcinoma. But with relatively small patients number included in each study, the statistical power is limited. Thus, we performed this meta‑analysis to further demonstrate the clinical efficacy of KLT in the treatment of NSCLC by meta‑analysis.
Xiaohong Liu, Qinghui Yang1, Yuling Xi, Kewei Yu2, Weizhen Wang3, Xiangmei Zhao4, Xiaoge Kou1 Departments of Pharmacy, 1Oncology and 3Emergency, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, 2 Department of Oncology, Shandong University Affiliated Jinan Central Hospital, Jinan 250013, 4Department of Epidemiology, Xinxiang Medical University, Xinxiang 453100, China For correspondence: Dr. Xiaoge Kou, Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, China. E‑mail: kouxiaogezlk@aliyun. com Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.139758
MATERIALS AND METHODS
PMID: *** Quick Response Code:
Literature source and search strategy We searched and extracted eligible studies about KLT injection assistant treatment of NSCLC by searching databases of PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wanfang Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 1- 2014
Liu, et al.: Kanglaite and advanced non-small lung carcinoma
databases. The combination of the following key words were used: “lung cancer”, “lung carcimoma”, “non‑small cell lung cancer”, “non‑small lung carcinoma”, “NSCLC”, “Kanglaite” and “KLT”. Inclusion and exclusion criteria The following criteria were used for the literature inclusion: (a): The study design was confined to prospective clinical controlled trials with or without blind; (b) The patients was pathologically confirmed non‑small lung carcinoma; (c) The intervention was KLT injection combined with systematic chemotherapy; (d) The control group was only given systematic chemotherapy; (f) The outcome should include the objective response rate, the KPS improvement and gastrointestinal reaction incidence rate. The major exclusion were: (a) Overlapping study populations; (b) Retrospectively studied; (c) patients without pathology confirmed; (d) Without detailed data about objective response rate, the KPS improvement and gastrointestinal reaction incidence rate.
Data extraction and quality evaluation The general characteristics of the included trials were extracted such as first author name, publication time, number of subjects in the treatment and control arms and detailed treatments regimen. The frequency for interested events in the combined treatment and control groups were extracted carefully. The general methodological quality of each included trials was evaluated by a six‑questionnaire according to the Cochrane protocol when evaluation of clinical randomized trials. The question questions are: (a) Adequate sequence gereration? (b) Allocation concealment? (c) Incomplete outcome data addressed? (d) Free of selective reporting? (f) Free of other bias? Response criteria According to the Response Evaluation Criteria in Solid Tumors (RECST) developed by the World Health Organization (WHO),[4] the tumor response were divided to complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The objective response
Table 1: The general characteristics of included studies Author Li SW
No (T/C) 34/30
Regimen T KLT+MVP
C MVP
KLT+NP KLT+NP KLT+HEP KLT+NP KLT+CAP/MVP KLT+CAP
NP NP HEP NP CAP/MVP CAP
Yang SJ Chen YZ Tang JH Xie XD Liu JX Lin YH
28/29 28/27 20/22 43/44 131/111 39/41
Lian ZP
50/50
KLT+GP
GP
Deng SG
21/22
KLT+GP
GP
Lu CD Lv XY Wu RL Wu XH Huang JY Li ZG Li ZH Liu YL Chen ZP Song JL Wang ZX An HJ Ju HB Zhong YH Wang YL Ren ZH Ren JP Hou EC Liu JQ Liu MS Sun SQ Liao GQ Zhu YZ Guan Y Lu CD
62/51 30/30 39/44 21/19 53/33 36/36 20/20 32/32 30/34 26/21 39/41 48/48 48/48 22/26 42/38 68/99 64/63 34/34 34/35 21/21 35/35 144/144 50/50 35/30 68/61
KLT+NP/GP KLT+NP KLT+NP KLT+EP KLT+EP KLT+NP KLT+NP KLT+CEP KLT+MVP KLT+CAP KLT+NP KLT+NP KLP+MVP KLT+NIC KLT+MVP/NP/TP KLT+EP/MVP/NP/GP KLT+NP KLT+NP KLT+GP KLT+EP KLT+GP KLT+NP KLT+DP KLT+GP KLT+NP
NP/GP NP NP EP EP NP NP CEP MVP CAP NP NP MVP NIC MVP/NP/TP EP/MVP/NP/GP NP NP GP EP GP NP DP GP NP
Outcomes
Duration
Year
CR, PR, KPS improvement, gastrointestion reaction, hepatic dysfunction CR, PR, KPS improvement CR, PR, KPS improvement CR, PR, KPS improvement, gastrointestion reaction, KPS improvement CR, PR, KPS improvement, symptom improvement CR, PR, KPS improvement, gastrointestion reaction, hepatic and renal dysfunction CR, PR, KPS improvement, gastrointestion reaction, hepatic and renal dysfunction CR, PR, KPS improvement, gastrointestion reaction, hepatic and renal dysfunction CR, PR, KPS improvement, gastrointestion reaction CR, PR, KPS improvement, CR, PR CR, PR, KPS improvement CR, PR, KPS improvement, gastrointestion reaction CR, PR, KPS improvement, gastrointestion reaction CR, PR, bone marrow suppression Bone marrow suppression CR, PR, KPS improvement KPS improvement CR, PR, KPS improvement CR, PR, symptom improvement CR, PR CR, PR, KPS improvement, symptom improvement KPS improvement CR, PR, symptom improvement CR, PR, KPS improvement CR, PR, KPS improvement CR, PR, CR, PR CR, PR, symptom improvement CR, PR, symptom improvement CR, PR CR, PR CR, PR
2 weeks
2002
2 weeks 2 weeks 2 weeks 60 days 6 weeks 6 weeks
2003 2003 2002 2003 1995 2004
10 days
2006
3 weeks
2006
20‑45 days 3 weeks 6 weeks 10 days 42‑63 days 21 days 6 weeks 8 weeks 20 days 6 weeks 6 weeks 10 days 6 weeks NA 10 days 3 weeks 3 weeks 10 days 10 days 3 weeks 20 days 20 days 3 weeks 3 weeks 45 days
2006 2004 2002 2001 2001 2003 2005 2003 1999 2002 2007 2005 2000 2001 2005 2007 2010 2008 2011 2006 2012 2009 2010 2010 2008
KLT=Kanglaite, CR=Complete response, PR=Partial response, GP=Gemcitabine and cisplatin, DP=Progressive disease, NP=Vinorelbine and cisplatin, EP=Etoposide and cisplatin, EVP=Etoposide vinblastine cisplatin, HEP=Hydroxycamptothecine etoposide cisplatin, MVP=Mitomycin vindesine cisplatin, NIC=catharanthine iphosphamide carboplatin
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Liu, et al.: Kanglaite and advanced non-small lung carcinoma
rate was definite as CR + PR. And the exact definition for CR, PR, SD and PD was as follows: CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the Longest diameter (LD) of target lesions, taking as reference the baseline sum LD; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started; PD: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Statistical method All of the data was pooled and calculated by STATA11.0 software. The risk ratio was used to analyze dichotomous data. If heterogeneity was found across the trials the pooled results was calculated based on random effect model; otherwise, if there was no statistical heterogeneity was found across the included studies, the fixed effect model was used. Heterogeneity was tested using the Z score and χ2 in which P 0.05). But significant publication bias was found in the pooled results of KPS improvement [Figure 5]. DISCUSSION KLTanglaite injection, which had been confirmed with anti‑tumor activity, is one of Chinese herb preparations that is developed and manufactured by Zhejiang Kanglaite Pharmaceutical Co., Ltd in China.[39] It is mainly used for the treatment of several types of tumors such as NSCLCno‑small cell lung cancer, liver cancer, gastric cancer and etc., KLT is a unique botanically sourced molecular targeted agent prepared as a micro‑emulsion for intravenous use. It is manufactured by the state of art technology with active substance extracted from a natural herbal plant semen coicis. Clinical trials demonstrated that KLT has several advantages in treatment of carcinomas. Firstly, KLT can killing cancer cells directly and effectively while remarkably improving patient immune function; Secondly, synergistic in increasing efficacy and reducing toxicity when combined with chemotherapy regimens or radiation therapy; Thirdly, Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 1- 2014
Liu, et al.: Kanglaite and advanced non-small lung carcinoma
Figure 2: Forest plot for the objective response
Figure 3: Forest plot for the KPS Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 1- 2014
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Liu, et al.: Kanglaite and advanced non-small lung carcinoma
Figure 4: Forest plot for nausea and vomiting
0.42–0.66, (Z = 5.53, P = 0.000)] compared with chemotherapy alone. The pooled data indicated that KLT injection combined with chemotherapy can improve the short‑term efficacy, performance status and decrease the risk of gastrointestinal reaction compared with systematic chemotherapy alone.
Figure 5: Begg’s test for evaluation of the publication bia
providing high energy nutrition to treat cachexia; fourthly, controlling cancerous pain markedly; Fifthly, improving patients’ quality of life and notably prolonging survival. In this study, we include 34 trials comparing Kanglaite (KLD) injection combined with systematic chemotherapy versus chemotherapy alone in the treatment of NSCLC. Of the recruited 34 trails, the most common use chemotherapy regimens were NP, GP, EP and MVP. And the chemotherapy duration range from 10 days to 6 weeks. The pooled results showed that KLT injection combined with systematic chemotherapy can significant increase the objective response rate (ORR) [RR = 1.35, 95% CI: 1.23‑–1.48, (Z = 6.43, P = 0.000)], the quality of patients’ life (KPS improvement) [RR = 2.04, 95% CI: 1.79–2.33, (Z = 10.57, P = 0.000)] and decrease the risk ratio of gastrointestinal reaction [RR = 0.53, 95% CI: C50
Although the pooled results demonstrated good clinical efficacy for KLD injection assistant treatment NSCLC in this meta‑analysis, there still several limitation for this study. Firstly, in the procedure of relevant articles searching and inclusion, we found all the trails are come from Chinese mainland; Secondly, the quality of the included 34 trials are relative low according to the quality evaluation system provided by Cochrane hand book; Thirdly, significant heterogeneity for the pooled results of KPS improvement was found. Fourthly, there was obviously publication bias in the aspect of KPS improvement. In conclusion, the pooled data showed that KLT injection combined with chemotherapy can improve the short‑term efficacy, performance status and decrease the risk of gastrointestinal reaction compared with systematic chemotherapy alone. But considering the limitations, the conclusion should be interpreted with caution. REFERENCES 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69‑90. 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11‑30. 3. Hua F, Fang N, Li X, Zhu S, Zhang W, Gu J. A Meta‑analysis of the relationship between RARβ gene promoter methylation and non‑small cell lung cancer. PLoS One 2014;9:e96163. Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 1- 2014
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4. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: Immune‑related response criteria. Clin Cancer Res 2009;15:7412‑20. 5. Li SW, Wang Y. Clinical study of Kanglaite combined with chemotherapy for non‑small cell lung cancer patients. Tumor 2002;22:84. 6. Yang SJ, Yao YM, Li YF, Sun H, Ma BG. Clinical observation of Kanglaite injection combined with chemotherapy for non‑small cell lung cancer patients. Chin Integr Tradit West Med 2003;23:629. 7. Chen YZ, Li PP, Yan LF, Sun H, Zhang QH. Effective observation of Kanglaite injection plus NVB and DDP regimen for non‑small cell lung cancer patients. Chin Integr Tradit West Med 2003;23:629‑30. 8. Tang JH. Clinical study of Kanglaite injection combined with HEP regimen for advanced non small cell lung cancer patients. Tumour 2002;22:83. 9. Xie XD, Zheng ZD, Gao YL, Liu DW, Liui YY. A random control study: Effect of Kanglaite on life quality of patient with lung cancer in advanced stage. Chin Clin Rehabil 2003;7:672‑3. 10. Liu JX, Liao ML, Yan DJ, Zhou JY. Kanglaite injection for the treatment of primary lungcancer: A phase II clinical trial. Tradit Chin Drug Res Clin Pharmcol 1995;6:17‑22. 11. Lin YH, Wang F, Chen P, Zhang JL. Combination of Kanglaite injection and CAP regimen chemotherapy in treatment of late non‑small cell lung cancer. Qilu Oncol 2004;11:647‑9. 12. Lian Z, Lu Y, Hou E, Wang X. Combination of GP regimen and Kanglaite in the treatmentof advanced non‑small cell lung cancer. Zhongguo Fei Ai Za Zhi 2006;9:74‑7. 13. Deng SG, Wen SG, Wen SB, Chen AI. Clinical observation of Kanglaite injection combined with Gemzar and carboplatin for median and advanced non‑small cell lung cancer patients. Zhejiang Pract Med 2006;11:234‑6. 14. Lu CD. Kanglaite injection combined with chemotherapy for advanced non‑small cell lungcancer patients. Mod Oncol 2006;14:964‑5. 15. Lv XY, Zhang YQ, Li QS. Clinical study on quality of life for chemotherapy combined with kanglaite in non‑small cell lung cancer. Clin Pulm Med 2004;9:342‑3. 16. Wu RL, Ou DB, Pan X. Clinical observation of Kanglaite injection combined with NVB and DDP for median and advanced non‑small cell lung cancer patients. Shaanxi Oncol Med 2002;10:201. 17. Wu XH, Hua D, Sha LJ, Wu LL. Kanglaite injection combined with MVP regimen for non‑small cell lung cancer patients. Qilu Oncol 2001;8:657‑8. 18. Huang JY, Gao P, Wang XQ. Clinical observation of Kanglaite injection combined with EP regimen for advanced non‑small cell lung cancer patients. Tumour 2001;21:392. 19. Li ZG, Hu HY, Zhang JS. Observation on efficacy Kanglaite injection combined with chemotherapyin treating non‑small cell lung cancer in aged patients. Chin Cancer Prev Treat 2003;10:405‑6. 20. Li ZH, Lv JF, Zhou LZ. Clinical study of combined Kanglaite injection with chemotherapy in treatment of NSCLC. Chin Cancer Prev Treat 2005;12:1339‑40. 21. Liu YL, Sun XJ, Zhang J, Yang DC. Clinical observation of Kanglaite combined with CEP for non‑small cell lung cancer patients. Chin Cancer Prev Treat 2003;10:895. 22. Chen ZP. Clinical study of Kanglaite injection combined with chemotherapy for 30 advanced lung cancer patients. Zhejiang Coll TCM 1999;23:35.
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23. Song JL, Zhang LP, Liu ZW. Effect of combined therapy of Kanglaite on quality of life of middle‑old aged patients with advanced non‑small cell lung cancer. Chin Clin Rehabil 2002;6:1160‑1. 24. Wang ZX, Zhang ZG. Therapeutic effect of Kanglaite injection combined with chemotherapy on advanced non‑small cell lung cancer. Hebei Med J 2007;29:47‑8. 25. An HJ, Yuan JZ. Clinical observation of Kanglaite combined with NC improve NSCLC of agedness. Chin Pract Chin Mod Med 2005;18:1205‑6. 26. Ju HB, Chen XJ, Wang BQ, Song CS, Ren HQ, Zhang HY, et al. Clinical effect of Kanglaite plus PVM versus simple PVM for non‑small cell lung cancer patients. Pract Oncol 2000;15:56‑7. 27. Zhong YH, Liu H, Chen M. Clinical observation of Kanglaite combined with NIC for non‑small cell lung cancer patients. Shaanxi Oncol Med 2001;9:288. 28. Wang YL, Li DM, Xu H, Tao M, Wang QC. Combination of Kanglaite injection and chemotherapy for treatment of advanced non‑small cell lung cancer. Oncol Prog 2005;3:273‑5. 29. Ren ZH, Zhang CH. Kanglaite injection combined with chemotherapy for advanced non‑small cell lung cancer. Med Inf 2007;12:2138‑9. 30. Rem JP, Wang H, Liu LM, Li XH, Zhang FM, Zhang XQ, et al. Kanglaite injection combined with navelbine plus platinum protocol of chemotherapy for elder advanced non‑small cell lung cancer. Prog Mod Biomed 2010;10:3275‑8. 31. Hou EC. A clinical study on kanglaite injection combined with chemical therapy in the treatment of patients with advanced non‑small cell lung cancer. Tradit Chin Drug Res Clin Pharm 2008;19:504‑5. 32. Liu JQ, Shang LQ, Li XC, Wen F, Li J, Wang W. Effect of kanglaite combined with chemical therapy advanced non‑small cell lung cancer. J Mod Oncol 2011;10:1974‑6. 33. Liu MS, Wang CY. Kanglaite injection in the treatment of advanced non‑small cell lung cancer. Cancer Res Clin 2006;18:415. 34. Sun SQ, Zhu XL, Huang J, Xu T, Lin Y. Effect of Kanglaite injection combined with chemotherapy for improvement of quality of life in advanced stage NSCLC patients. J Pract Oncol 2012;5:506‑10. 35. Liao GQ, Wang GH, Liu PH, Wang HM, Qu YM, Xie GQ. Chemotherapy combined with Kanglaite in treatment of advanced non‑small cell lung cancer. J Pract Oncol 2009;6:595‑8. 36. Zhu YZ, Zhang HT. Kanglaite injection combined with TP regimen in the treatment of non‑small cell lung cancer with 100 case report. Mod Oncol 2010;8:1569‑71. 37. Guan Y, Guo QS, Song J. Kanglaite combined with GP regimen in the treatment of elderly patients with advanced non‑small cell lung carcinoma. Chin J Geriatr Care 2010;1:5‑7. 38. Lu CD. Kanglaite injection combined with chemotherapy in the treatment of non‑small cell lung cancer. Clin J Trandit Chin Med 2008;3:261‑2. 39. Zhan YP, Huang XE, Cao J, Lu YY, Wu XY, Liu J, et al. Clinical safety and efficacy of Kanglaite® (Coix Seed Oil) injection combined with chemotherapy in treating patients with gastric cancer. Asian Pac J Cancer Prev 2012;10:5319‑21. Cite this article as: Liu X, Yang Q, Xi Y, Yu K, Wang W, Zhao X, et al. Kanglaite injection combined with chemotherapy versus chemotherapy alone in the treatment of advanced non-small cell lung carcinoma. J Can Res Ther 2014;10:46-51. Source of Support: Nil, Conflict of Interest: None declared.
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