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REVIEW ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 63-67
 

Metformin use and survival of lung cancer patients: Meta-analysis findings


1 Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing 210009, China
2 Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
3 Institute of Laboratory Medicine, Jinling Hospital of Nanjing University, Nanjing 210002, China
4 Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing 210009, China

Date of Web Publication1-Dec-2017

Correspondence Address:
Prof. J Zhao
Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing 210009
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.219582

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 » Abstract 

Previous studies on the association between metformin use and lung cancer survival have yielded mixed results. We aimed to perform a metaanalysis to assess the association with all available studies. Relevant studies were identified by searching PubMed and EMBASE to July 2016. We calculated the summary hazard ratios (HRs) and 95% confidence intervals (CIs) using randomeffects models. Twelve cohort studies involving 124,533 participants were included in this study. The results showed that metformin use was not associated with the overall survival of lung cancer patients (HR = 0.79, 95% CI: 0.62–1.02). In the subgroup analyses by country or subtype of lung cancer, although a beneficial effect of metformin use on overall survival was found in patients with smallcell lung cancer or in lung patients from China, it may be inappropriate draw a final conclusion considering small sample size, low study quality, and the limited number of studies in the subgroups. Further analyses found that metformin use after diagnosis showed a beneficial effect on both over survival (HR = 0.79, 95% CI: 0.72–0.87) and progressionfree survival (PFS; HR = 0.62, 95% CI: 0.39–0.96) of lung cancer patients. In conclusion, metformin use after diagnosis is associated with improved overall survival and PFS of lung cancer patients. Nevertheless, this effect of metformin use is needed for further assessment.


Keywords: Neoplasm, outcome, prognosis, survival, tumor


How to cite this article:
Zhong S, Wu Y, Yan X, Tang J, Zhao J. Metformin use and survival of lung cancer patients: Meta-analysis findings. Indian J Cancer 2017;54:63-7

How to cite this URL:
Zhong S, Wu Y, Yan X, Tang J, Zhao J. Metformin use and survival of lung cancer patients: Meta-analysis findings. Indian J Cancer [serial online] 2017 [cited 2020 Mar 31];54:63-7. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/63/219582



 » Introduction Top


Lung cancer is the leading cause of cancer-related death in the worldwide and one of the most incurable cancers due to late presentation, disease relapse, and low rate of curative therapy.[1] Despite clinical treatments for lung cancer have greatly improved in recent years, the improvement for long-term survival is very limited. It, therefore, appears important to develop novel therapies that may improve survival in patients with lung cancer.

Recently, the potential anticancer properties of metformin have attracted more interest. Metformin, a biguanide commonly prescribed to treat type 2 diabetes, may exert its anticancer effect through activating AMP-activated protein kinase and inhibiting the mTOR signaling pathway.[2] Emerging evidence suggests that metformin could reduce cancer risk and improve survival in certain cancers, including breast, colorectal, and prostate.[3],[4],[5] A number of observational studies have tried to examine the effect of metformin use on the outcome of lung cancer;[2],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] some have suggested that metformin use was associated with increased risk of death, while others reported beneficial effect or no effect. Two meta-analyses [19],[20] have examined the association between metformin use and survival of lung cancer patients. Both showed a favorable survival outcome for lung cancer patients who used metformin. However, we found that the two meta-analyses did not correctly extract data from the original articles. In addition, they combined risk estimates for progression-free survival (PFS) with those for disease-free survival (DFS) and then obtained a summary estimate for DFS. From then on, several cohort studies were published. Therefore, we systematically conducted a meta-analysis by combining all available studies to derive a more precise estimation of the association between metformin use and lung cancer survival.


 » Materials and Methods Top


Literature search

We searched PubMed (from 2005 to present) and EMBASE (from 2002 to present) using the following terms “metformin,” “lung,” “cancer,” and (“mortality” OR “survival”). The latest date of this search was July 2016. All cohort or case–control studies evaluating the association between metformin use and lung cancer survival were eligible, without language restriction. Reference lists of every article were retrieved, and relevant reviews were examined manually to further identify potentially relevant studies. All searches were conducted independently by two investigators; differences were checked by the two and resolved by discussion. When two or more studies presented possible overlap, the one with largest populations was included.

Inclusion criteria

All the studies were included in this meta-analysis if they met the following criteria: (a) The exposure of interest was metformin use; (b) the study design was case–control or cohort; (c) the outcomes of interest were over survival or PFS of patients with lung cancer; and (d) risk estimates and 95% confidence intervals (CIs) were reported (or information to calculate them).

Data extraction

Data were extracted from the eligible articles by two independent investigators. The extracted data included the last name of first author, year of publication, origin of the study, follow-up period, subtype of lung cancer, sample size, metformin exposure, risk estimates and corresponding 95% CIs, and covariates adjusted for in the multivariable analysis. For studies provided more than one risk estimate, we extracted the one that was adjusted for the greatest number of confounding factors. Discrepancies were resolved by consensus, involving a third investigator.

Study quality assessment

The methodological quality of the studies was independently assessed by two investigators using the nine-star Newcastle–Ottawa Scale (NOS).[21] Each study was evaluated based on eight items, categorized into three broad perspectives including selection, comparability, and outcome for cohort studies or exposure for case–control studies. We considered studies with a score of 7 or greater as high quality. Discrepancies were resolved by discussion or through consultation with a third investigator.

Statistical methods

The potential relation between metformin use and lung cancer survival was investigated as described previously.[22] Briefly, summary estimates of hazard ratios (HRs) and 95% CIs were obtained using a random-effects model where the restricted maximum likelihood estimator was used to evaluate the inter-study heterogeneity.[23],[24] Prediction interval (PI) of summary estimate for the random effects model was calculated to depict the uncertainty of the average treatment effect.[25] If a study provided separate risk estimates by data source,[12] we treated them as different studies. Inter-study heterogeneity was estimated using a Chi-square-based Q-test,[26] with a P < 0.10 considered statistically significant.[27] We explored the source of heterogeneity by country (categorical moderator), publication year (continuous moderator), sample size (continuous moderator), study quality (continuous moderator), and the score of each item in NOS assessment (0 and 1) using meta-regression. Sensitivity analyses were performed to reflect the influence of individual data on summary HR. Finally, the potential for publication bias was examined using Begg's and Egger's regression test.[28] All of the statistical analyses were done with R software, (version 3.1.1; The R foundation for Statistical Computing, Vienna, Austria), using the packages metafor.[29] All statistical tests were two-sided.


 » Results Top


Characteristics of the studies

The flow chart summarizing the process of study selection is shown in [Figure 1]. Three hundred and twenty-eight abstracts and titles were identified and assessed, and fourteen studies were evaluated in detail with regard to their fulfillment of the inclusion criteria. One article was excluded as no usable data reported.[17] Another study evaluating lung cancer-specific mortality was also excluded.[2] Finally, 12 cohort studies [6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[18] involving 124,533 participants were selected for meta-analysis. [Table 1] shows the characteristics of the included studies. Among these 12 studies, 12 studies reported on the association between metformin use and all-cause mortality, and four studies reported on the association between metformin use and PFS [Table 1]. [Table S1] [Additional file 1] presents the methodological quality of studies included in the final analysis. The NOS results showed that the average score was 4.67, ranging from 2 to 8.
Figure 1: Flow chart of the selection of publications included in the meta-analysis

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Table 1: Characteristic of the included studies

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Association of metformin use with over survival

Risk estimates of the association between metformin use and over survival are shown in [Figure 2]. The overall results showed that metformin use was not associated with the risk of dying from any cause (HR = 0.79, 95% CI: 0.62–1.02, P = 0.07; 95% PI: 0.36–1.75). In the subgroup analysis by study quality (high quality, NOS score ≥6; and low quality, NOS score <6), no effect was observed in high quality studies (HR = 0.84, 95% CI: 0.62–1.14, P = 0.28; 95% PI: 0.43–1.68) or in low quality studies (HR = 0.73, 95% CI: 0.48–1.11, P = 0.14; 95% PI: 0.25–2.11). Stratifying by country, metformin use was associated with improved over survival of lung cancer patients in China studies (HR = 0.47, 95% CI: 0.32–0.70, P < 0.01; 95% PI: 0.32–0.70) but not in the USA studies (HR = 0.90, 95% CI: 0.64–1.28, P = 0.57; 95% PI: 0.36–2.28). In stratified by subtype of lung cancer, metformin use only decreased risk of dying from small-cell lung cancer (SCLC, HR = 0.52, 95% CI: 0.29–0.91, P = 0.02; 95% PI: 0.29–0.91) but not from non-SCLC (NSCLC, HR = 0.72, 95% CI: 0.48–1.07, P = 0.11; 95% PI: 0.30–1.71). When restricting to the studies evaluating metformin use after diagnosis, metformin use showed a beneficial effect on over survival of lung cancer patients (HR = 0.79, 95% CI: 0.72–0.87, P < 0.01; 95% PI: 0.72–0.87).
Figure 2: Pooled analysis and subgroup analyses by country or subtype of lung cancer for the association between metformin use and overall survival of lung cancer patients. SCLC = Small-cell lung cancer; NSCLC = Non-small cell lung cancer

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There was significant heterogeneity between studies (P for heterogeneity <0.01). After exploring by meta-regression, however, we failed to find the source of the heterogeneity. From the results of the leave-one-out sensitivity analysis, all the results above were not materially altered (data not shown). We found no evidence of publication bias using Begg's (P = 0.86) and Egger's (P = 0.82) tests.

Association of metformin use with progression-free survival

[Figure 3] presents the estimated HR of PFS in patients with metformin use. The overall results showed that metformin use was associated with improved PFS in patients with lung cancer (HR = 0.62, 95% CI: 0.39–0.96, P = 0.03; 95% PI: 0.27–1.38).
Figure 3: Pooled analyses of the association between metformin use and progression-free survival of lung cancer patients

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There was significant heterogeneity between studies (P for heterogeneity = 0.08). In the sensitivity analysis, the heterogeneity disappeared after removing the study by Ahmed et al.[9] (HR = 0.53, 95% CI: 0.39–0.71 P < 0.01; 95% PI: 0.39–0.71; P for heterogeneity = 0.49, I2 = 0%).


 » Discussion Top


We investigated the effect of metformin use on lung cancer survival involving 124,533 participants. After combining the results from 12 cohort studies, we found that metformin use was not associated with overall survival of patients with lung cancer. In the subgroup analysis by country, the beneficial effect of metformin use on lung cancer overall survival was only found in China studies but not in the USA studies. Stratifying by subtype of lung cancer, a similar association was also found in patients with SCLC. However, we noted that the sample size of the three studies [10],[13],[18] from China was relatively smaller than other studies and had lowest NOS score [Table S1]. Both studies [10],[13] evaluating metformin use in SCLC patients were from China. Taking above mentioned into account, therefore, it seems unable to draw a final conclusion about the effect of metformin use on patients with SCLC or lung patients from China. When restricting to the studies evaluating metformin use after diagnosis, metformin use showed a beneficial effect on over survival of lung cancer patients, without significant heterogeneity. We further analyzed the effect of metformin use on PFS of lung cancer patients by combining result from four studies [7],[8],[9],[18] in which we noted that metformin use after diagnosis was evaluated. The results indicated that metformin use after diagnosis was associated with improved PFS in patients with lung cancer. Therefore, it is reasonable to assume that only taking metformin after diagnosis has an effect on survival of lung cancer patients. Two studies [2],[15] reported separate risk estimates for metformin use before and after diagnosis. The study by Currie et al.[15] showed that patients who used metformin after diagnosis had an HR of 0.767 (95% CI: 0.590–0.997) for overall survival, and those who used metformin before diagnosis had an HR of 0.834 (95% CI: 0.665–1.045). In another study by Menamin et al.,[2] metformin use after diagnosis (HR = 0.86, 95% CI: 0.68–1.09) showed more beneficial effects on lung cancer-specific mortality than metformin use before diagnosis (HR = 0.97, 95% CI: 0.86–1.11), although both did not reach statistical significance. Considering above mentioned, we conclude that metformin use after diagnosis is associated with improved overall survival and PFS in lung cancer patients.

The potential limitations of our study should be considered when interpreting the results. First, there was statistically significant heterogeneity in the analysis of overall survival. Although we explored the heterogeneity using meta-regression, we failed to find the source of the heterogeneity. Second, although many of the studies had adjusted for important risk factors, residual confounding factors related to metformin use may also have influenced results of individual studies. Third, in the subgroup analysis, the sample size of each subgroup was relatively small not having enough statistical power to explore the real association. Fourth, several studies did not evaluate metformin use before and after diagnosis separately. Fifth, the NOS score of most studies were lower than 7; therefore, the results should be interpreted with caution.


 » Conclusion Top


Metformin use after diagnosis is associated with improved overall survival and PFS in lung cancer patients. Nevertheless, the effect of metformin use on breast cancer survival is needed for further assessment. Future trials should examine the role of metformin in patients with lung cancer in a randomized controlled trial with larger sample size, well-controlled confounding factors, long enough follow-up time, and more accurate assessment of metformin exposure levels.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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