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| REVIEW ARTICLE |
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| Year : 2014 | Volume
: 10
| Issue : 4 | Page : 859-865 |
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Effect of statins on gastric cancer incidence: A meta-Analysis of case control studies
Zhiyuan Ma1, Wenjin Wang2, Guoyin Jin3, Pei Chu2, Haitao Li4
1 Geriatrics Department ward II, The First Hospital of Lanzhou University, Lanzhou, China
2 Department of Emergency, The First Hospital of Lanzhou University, Lanzhou, China
3 College of Traditional Chinese Medicine, Hebei North University, China
4 Department of General Surgery, Second Hospital of Zhangjiakou City, Zhangjiakou, China
| Date of Web Publication | 9-Jan-2015 |
Correspondence Address:
Wenjin Wang
The First Hospital of Lanzhou University. Lanzhou - 730000
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0973-1482.138218
Introduction: Gastric cancer is among the leading causes of cancer-related death worldwide, especially in Eastern Asia, Eastern Europe and South America. Statin is one of the most widely used medications for hypercholesterolemia. Several meta-analyses have failed to determine the relationship between statins and gastric cancer.
Aims: A meta-analysis of case control studies is conducted to evaluate the association of statin exposure and risk of gastric cancer.
Materials and Methods: Eight electronic databases (The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, 2012), PubMed, EMBASE, ISI Web of Knowledge, CNKI, CBM, CSJD and Wanfang Database) were searched for relevant publications through September 2013. Two reviewers determined the eligibility of articles and abstracted the data independently. RevMan 5.2 software was used for statistical analysis.
Results: 146 items were retrieved from the databases and 6 studies were identified in this meta-analysis, which included 5,993 cases and 54,800 matched controls. Results from the meta-analysis demonstrated that statins were inversely related to the risk of gastric cancer (RR = 0.56, 95% CI: 0.35-0.90). There was no significant difference for cumulative duration of statin exposure and gastric cancer, nor participants from Asia, Europe, or USA.
Conclusion: This meta-analysis suggests that statins have favorable effects on gastric cancer, rigorously designed and executed observational studies and randomized control trials with longer duration of follow-up are warranted to determine effects in clinical practice. 他汀类药物对胃癌发病影响：一个有对照病例研究的Meta分析
摘要 简介：在全球，尤其是亚洲东部，欧洲东部和美国南部，胃癌是癌症相关死亡的主要原因。他汀类药物是最广泛使用的药物治疗高胆固醇血症。几个荟萃分析未能确定他汀类药物与胃癌的关系。
目的：一个病例对照研究的Meta分析进行评估他汀类药物暴露与胃癌风险的关系。
材料和方法：从8个电子数据库（Cochrane对照试验注册中心（中央）（2012年12期），PubMed，EMBASE，ISI Web of Knowledge，CNKI，CBM，中文科技期刊数据库、万方数据库）中检索相关的出版物至2013年9月。两位专家确定了文章的合格性和数据独立性。采用RevMan 5.2软件进行统计分析。
结果：146个项目从数据库检索，6项研究参与Meta分析，其中包括5993病例和54800例对照。从荟萃分析表明他汀类药物对胃癌发生的危险性呈负相关（RR = 0.56，结果95%可信区间：0.35 0.90）。对他汀类药物的暴露与胃癌累积持续时间没有显著差异，与来自亚洲、欧洲和美国也没有显著差异。
结论：该荟萃分析表明，他汀类药物对胃癌无影响，在确定在临床实践的作用中，严格的设计和执行观察性研究与随机对照试验及较长时间的随访是必要的。
关键词：病例对照研究，胃癌，Meta分析，他汀类药物
Keywords: Case control study, gastric cancer, meta-analysis, statins
How to cite this article:
Ma Z, Wang W, Jin G, Chu P, Li H. Effect of statins on gastric cancer incidence: A meta-Analysis of case control studies. J Can Res Ther 2014;10:859-65 |
| > Introduction | |  |
Gastric cancer is among the leading causes of cancer-related death worldwide, especially in Eastern Asia, Eastern Europe, and South America. [1],[2],[3] Patients would benefit more if the disease can be diagnosed at an earlier stage. [4] Unfortunately, approximately two-thirds of patients are detected at an advanced stage. Survival rate is improved indeed after gastrectomy and perioperate chemotherapy, but the outcome has been disappointing. [5],[6],[7],[8] Therefore, preventive strategies to reduce morbidity are required.
Currently, chemoprevention strategies to decrease incidence of gastric cancer have become more and more attractive. Fukase et al. [9] demonstrated that H.pylori eradication therapies might reduce the risk of gastric cancer. In addition, several studies suggested that aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs) use were associated with a decreased risk of gastric cancer. [10],[11],[12],[13],[14] Recently, more and more researchers had begun to pay attention to the association of statin consumption and gastric cancer.
Statin (HMG CoA reductase inhibitors) is one of the most widely used medications for hypercholesterolemia. [15] Several studies have confirmed the benefits of statins for cardiovascular disease. [16],[17],[18] As more and more statins are being used, there has been an increasing interest in the preventive effect of statins in cancer. [19],[20],[21]
A meta-analysis of randomized control trials [22] by Shimoyama suggested that statins had no short-term effect on gastric cancer incidence, meanwhile, a population-based nested case control studies demonstrated that prolonged use of statins was not associated with a reducing risk of gastric cancer, [23] however, several case control studies indicated that statins might reduce the rate of gastric cancer recently, [24],[25] the effect of statins on gastric cancer risk is still topical and controversial. Thus, we conducted a meta-analysis to evaluate the association of statin exposure and gastric cancer risk.
| > Materials and methods | | |
Search strategy
We searched Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, 2012), PubMed, EMBASE, ISI Web of Knowledge, Chinese National Knowledge Infrastructure (CNKI), China BioMedical Literature (CBM), Chinese Scientific Journal Full-text Database (CSJD), and Wanfang Database. The following Medical Subject Headings and free text keywords were used: "Gastric cancer, gastric tumor, gastric carcinoma, stomach cancer, stomach carcinoma, cancer of the stomach, gastric neoplasm," "statin, statins, atorvastatin, lipitor, rosuvastatin, crestor, lovastatin, simvastatin, pravastatin." The reference lists of retrieved articles and previous meta-analysis [19],[20],[22] were also reviewed to search for additional trials. No language restrictions were set for the search and it was up-to-date on September 2013.
Study selection
The studies identified in the meta-analysis were either case control studies or nested case control studies that evaluated the association of statin exposure and gastric cancer risk. We excluded trials that evaluated statins and multi-site of cancers where the data of gastric cancer could not be isolated. Two reviewers determined the eligibility of each article independently. Disagreement was resolved by discussion.
Data collection
Two reviewers extracted the data independently. For each study, we extracted details on study design, study location, publication year, investigational therapy, number of events, total number of participants, and duration of statin exposure.
Statistical analysis
The summary RR (Risk Ratio) for exposure to statins vs. no exposure was the measure of interest. The heterogeneity assumption was assessed by Q statistic test [26] and I-square test. [27] When significant heterogeneity [P < 0.10, I 2 >50%] was found, random effects model was used. Otherwise, fixed effects model was used. Subgroup analysis by the duration of statin exposure or different regions of trials were conducted to reduce the impact of heterogeneity and achieve more accurate results. RevMan software (Version 5.2, Cochrane Collaboration) [28] was used for the statistical analysis. It was considered statistical significant when P values were less than 0.05.
| > Results | | |
Search results
[Figure 1] shows the process of study selection. 146 items were retrieved through eight electronic databases. We excluded 139 papers which did not satisfy the inclusion criteria. Seven case control studies [23],[24],[25],[29],[30],[31],[32] were considered to be eligible for this meta-analysis. One study [29] was excluded because data of gastric cancer could not be isolated. Finally, six case control studies [23],[24],[25],[30],[31],[32] were included in this meta-analysis.
Study characteristics
[Table 1] describes baseline characteristics for all six case control studies included. Three studies, [24],[25],[31] were carried out in Taiwan, one [30] in Korea, one [23] in UK, and one [32] in USA. A total of 5993 individuals participated in these trials, and 54,800 matched controls were included.
[Table 2] shows the number of cumulative duration of statin use. Cumulative duration of statin exposure was divided into: Less than 12 months, 13-24 months, 25-48 months, and more than 49 months, pooled RRs were also demonstrated in [Table 2].
Meta-analysis
[Figure 2] demonstrates results from the meta-analysis of statin exposure and gastric cancer. A total of 5993 cases and 54,800 matched controls were found in all six case control studies included. [23],[24],[25],[30],[31],[32] The pooled RR was significant at 0.56 with a 95% CI: 0.35-0.90.
[Figure 3] shows the meta-analysis of cumulative duration of statin use and gastric cancer. A total of four subgroups were conducted. There is no statistical significance for either subgroup. | Figure 3: Subgroup meta analysis of different type of statins use and gastric cancer
Click here to view |
[Figure 4] is the result from the meta-analysis of statin consumption and gastric cancer in different regions. There is no significant difference among participants from Asia, Europe and USA. | Figure 4: Subgroup meta analysis of different areas of statins use and gastric cancer
Click here to view |
| > Discussion | | |
The present meta-analysis suggests that statins are inversely related to the risk of gastric cancer, with a 44% decrease in gastric cancer risk among statin users. There was no significant difference for cumulative duration of statin exposure and gastric cancer, nor participants from Asia, Europe and USA.
The result of this meta-analysis of case control studies indicates a favorable effect for statin use and gastric cancer. The relationship between statins and gastric cancer has been evaluated in numerous meta-analyses of randomized control trials or observational studies, [19],[20],[21],[22] but there has been conflicts among these meta analyses, inverse, [20] neutral. [19],[21],[22] Similar controversial results have also been observed in the meta-analysis of statins and risk of colorectal cancer [21],[33],[34],[35],[36],[37] and liver cancer. [20],[21],[38],[39] Although unified conclusion was still not reached from these meta-analyses of statin exposure and gastric cancer, a modest protective effect cannot be excluded.
It has been indicated that participants benefitted more when statins were used for longer than 4 years, [29] but our meta analysis showed no such evidence for longer duration of statin exposure. Two studies [23],[30] contributed to this meta analysis, especially, for more than 25 months, however, only the data from Vinogradova Y ' s study [23] was available. Thus, data for present meta-analysis is not sufficient. In future, comprehensive report and a long time fellow-up of statin exposure are required.
In present meta-analysis, a comprehensive research was carried out, which ensured all the relevant publications were included. As a result, six case control studies [23],[24],[25],[30],[31],[32] were included, and five [23],[24],[25],[30],[31] of which were published in last 3 years. Thus, all the latest information about statins and gastric cancers was included in present meta-analysis.
There are some limitations to this meta-analysis. First, a lot of data specific for gastric cancer were not available. Only three studies [24],[30],[31] included were conducted to evaluate the relationship between statins and gastric cancer exclusively, while other trials [23],[25],[32] evaluated its association with multi-site cancer, and many data could not be isolated successfully. Thus, clinical trials about statins and gastric cancer should be reported more distinctively and prescriptively. Second, information of other confounding factor, such as H. pylori infection, use of other lipid lowering drugs, exposure of aspirin and other NSAIDs could not be adjusted. Although there is no definitive evidence demonstrating that H. pylori eradication therapy reduced gastric cancer risk, World Health Organization concluded in 1994 that H. pylori is carcinogenic to humans and plays a causal role in the development of gastric cancer. [40] Available evidence also demonstrated that there was an inversely association between aspirin and other NSAIDs use and gastric cancer. [14],[41] Third, there is significant heterogeneity between studies: P <0.00001, I2 = 97%. Significant difference of statin exposure ratio in case and control in studies of Leung HW (4.05 vs. 20.08%) and Lee J (10.07 vs. 37.33%) contributed to heterogeneity, and I2 dropped to 49% (P = 0.12) when studies of Leung HW[25] and Lee J[30] were excluded from this meta-analysis.
Chemoprevention for gastric cancer will be more attractive in future. There is few high quality evidences indicating that participants benefit from H. pylori eradication therapy, aspirin and other NSAIDs. Currently there are no sufficient further trials demonstrating the protective effect of statins in gastric cancer. [42] Therefore, we recommend that clinicians should make a greater effort to chemoprevention for gastric cancer.
In summary, results from present meta-analysis suggest that statins have favorable effects on gastric cancer, however, subtype evidence of statins and long term effects is lacking. Rigorously designed and executed observational studies and randomized control trials with long follow-up duration are warranted to determine its effects in clinical practice.
| > Acknowledgment | | |
We thank the library of Lanzhou University for database access and acquiring full texts.
| > 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. | Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006;12:354-62. |
| 3. | Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24:2137-50. |
| 4. | Degiuli M, Calvo F. Survival of early gastric cancer in a specialized European center. Which lymphadenectomy is necessary? World J Surg 2006;30:2193-203. |
| 5. | Pozzo C, Barone C. Is there an optimal chemotherapy regimen for the treatment of advanced gastric cancer that will provide a platform for the introduction of new biological agents? Oncologist 2008;13:794-806. |
| 6. | Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet 2009;374:477-90. |
| 7. | GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group, Paoletti X, Oba K, Burzykowski T, Michiels S, Ohashi Y, Pignon JP, et al. Benefit of adjuvant chemotherapy for resectable gastric cancer: A meta-analysis. JAMA 2010;303:1729-37. |
| 8. | Wagner Anna D, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, et al. Chemotherapy for advanced gastric cancer. Cochrane Database of Systematic Reviews 2010:CD004064. |
| 9. | Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, et al. Japan Gast Study Group. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: An open-label, randomised controlled trial. Lancet 2008;372:392-7. |
| 10. | Abnet CC, Freedman ND, Kamangar F, Leitzmann MF, Hollenbeck AR, Schatzkin A. Non-steroidal anti-inflammatory drugs and risk of gastric and oesophageal adenocarcinomas: Results from a cohort study and a meta-analysis. Br J Cancer 2009;100:551-7. |
| 11. | Epplein M, Nomura AM, Wilkens LR, Henderson BE, Kolonel LN. Nonsteroidal antiinflammatory drugs and risk of gastric adenocarcinoma: The multiethnic cohort study. Am J Epidemiol 2009;170:507-14. |
| 12. | Farrow DC, Vaughan TL, Hansten PD, Stanford JL, Risch HA, Gammon MD, et al. Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev 1998;7:97-102. |
| 13. | Wang WH, Huang JQ, Zheng GF, Lam SK, Karlberg J, Wong BC. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: A systematic review and meta-analysis. J Natl Cancer Inst 2003;95:1784-91. |
| 14. | Yang P, Zhou Y, Chen B, Wan HW, Jia GQ, Bai HL, et al. Aspirin use and the risk of gastric cancer: A meta-analysis. Dig Dis Sci 2010;55:1533-9. |
| 15. | Walley T, Folino-Gallo P, Schwabe U, van Ganse E; EuroMedStat Group. Variations and increase in use of statins across Europe: Data from administrative databases. BMJ 2004;328:385-6. |
| 16. | Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, et al. Cholesterol Treatment Trialists′ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90. |
| 17. | Zhou X, Du JL, Yuan J, Chen YQ. Statins therapy can reduce the risk of atrial fibrillation in patients with acute coronary syndrome: A meta-analysis. Int J Med Sci 2013;10:198-205. |
| 18. | Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2013: CD004816. |
| 19. | Browning DR, Martin RM. Statins and risk of cancer: A systematic review and metaanalysis. Int J Cancer 2007;120:833-43. |
| 20. | Kuoppala J, Lamminpää A, Pukkala E. Statins and cancer: A systematic review and meta-analysis. Eur J Cancer 2008;44:2122-32. |
| 21. | Emberson JR, Kearney PM, Blackwell L, Newman C, Reith C, Bhala N, et al. Cholesterol Treatment Trialists′ (CTT) Collaboration. Lack of effect of lowering LDL cholesterol on cancer: Meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 2012;7:e29849. |
| 22. | Shimoyama S. Statins and gastric cancer risk. Hepatogastroenterology 2011;58:1057-61. |
| 23. | Vinogradova Y, Coupland C, Hippisley-Cox J. Exposure to statins and risk of common cancers: A series of nested case-control studies. BMC Cancer 2011;11:409. |
| 24. | Chiu HF, Ho SC, Chang CC, Wu TN, Yang CY. Statins are associated with a reduced risk of gastric cancer: A population-based case-control study. Am J Gastroenterol 2011;106:2098-103. |
| 25. | Leung HW, Chan AL, Lo D, Leung JH, Chen HL. Common cancer risk and statins: A population-based case-control study in a Chinese population. Exp Opin Drug Saf 2013;12:19-27. |
| 26. | Cochran WG. The combination of estimate from different experiments. Biometrics 1954;10:101-29. |
| 27. | Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60. |
| 28. | Review Manager (RevMan) [Computer program]. Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012. Available from: http://ims.cochrane.org/revman/download. [Last accessed on 2012]. |
| 29. | Graaf MR, Beiderbeck AB, Egberts AC, Richel DJ, Guchelaar HJ. The risk of cancer in users of statins. J Clin Oncol 2004;22:2388-94. |
| 30. | Lee J, Lee SH, Hur KY, Woo SY, Kim SW, Kang WK. Statins and the risk of gastric cancer in diabetes patients. BMC Cancer 2012;12:596. |
| 31. | Lai SW, Liao KF, Lin CY, Lin CL, Sung FC. Statins on the risk of gastric cancer: A population-based observation in Taiwan. Am J Gastroenterol 2013;108:147-9. |
| 32. | Kaye JA, Jick H. Statin use and cancer risk in the General Practice Research Database. Br J Cancer 2004;90:635-7. |
| 33. | Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: A meta-analysis. JAMA 2006;295:74-80. |
| 34. | Bonovas S, Filioussi K, Flordellis CS, Sitaras NM. Statins and the risk of colorectal cancer: A meta-analysis of 18 studies involving more than 1.5 million patients. J Clin Oncol 2007;25:3462-8. |
| 35. | Bardou M, Barkun A, Martel M. Effect of statin therapy on colorectal cancer. Gut 2010;59:1572-85. |
| 36. | Taylor ML, Wells BJ, Smolak MJ. Statins and cancer: A meta-analysis of case-control studies. Eur J Cancer Prev 2008;17:259-68. |
| 37. | Cheng MH, Chiu HF, Ho SC, Tsai SS, Wu TN, Yang CY. Statin use and the risk of colorectal cancer: A population-based case-control study. World J Gastroenterol 2011;17:5197-202. |
| 38. | Pradelli D, Soranna D, Scotti L, Zambon A, Catapano A, Mancia G, et al. Statins and primary liver cancer: A meta-analysis of observational studies. Eur J Cancer Prev 2012;22:229-34. |
| 39. | Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: A systematic review and meta-analysis. Gastroenterology 2012;144:323-32. |
| 40. | Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum 1994;61:1-241. |
| 41. | Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: Analysis of individual patient data from randomised trials. Lancet 2011;377:31-41. |
| 42. | Ford AC. Chemoprevention for gastric cancer. Best Pract Res Clin Gastroenterol 2011;25:581-92. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]
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