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The role of metformin on lung cancer survival: the first systematic review and meta-analysis of observational studies and randomized clinical trials

  • Review – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

To assess the effects of metformin use on lung cancer (LC) survival according to summarized results from observational studies (OBs) and randomized clinical trials (RCTs).

Methods

We systematically searched electronic databases and, to our knowledge, for the first time, RCTs were included in a systematic review and meta-analysis about the role of metformin on LC survival. We carried out meta-analyses separately for OBs and RCTs. Analyses for overall survival (OS) concerning OBs were stratified by studies with and without time-dependent approach. Subgroup analyses were adopted for OBs to identify the sources of heterogeneity. Included studies were assessed for quality.

Results

We identified ten OBs and four RCTs. For OBs, metformin use was associated with improved OS for LC patients. Only two studies used time-dependent approach in which a higher ratio was found when compared to the non-use of the time-dependent analysis in eight studies. OBs were classified as high quality but the risk of bias was “unclear” in eight OBs due to absence of the time-dependent analysis. For RCTs, metformin use was not beneficial for OS and neither for progression-free survival. Heterogeneous quality was found among RCTs. Sources of bias that could alter significantly the results or raise doubts were identified in RCTs.

Conclusion

Time-dependent analysis should be considered an appropriate strategy for OBs focused on the metformin use for LC patients’ survival, and further studies applying this approach are required. More well-designed RCTs are needed to provide consistent results for the association between metformin use and LC survival.

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Availability of data and material

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Code availability

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Abbreviations

AMPK:

Adenosine monophosphate-active protein kinase

DM:

Diabetes mellitus

HR:

Hazard ratio

LC:

Lung cancer

LCSS:

Lung cancer-specific survival

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PFS:

Progression-free survival

RCT:

Randomized clinical trial

RR:

Relative risk

SCC:

Squamous cell carcinoma

SCLC:

Small cell lung carcinoma

T2D:

Type 2 diabetes mellitus

95% CI:

95% Confidence interval

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Funding

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Author information

Author notes

  1. Tatiana Natasha Toporcov and Elisabete Weiderpass jointly supervised this work.

Authors and Affiliations

  1. Department of Epidemiology, School of Public Health, University of São Paulo, Av. Dr. Arnaldo 715, Cerqueira César, São Paulo, SP, CEP 01246-904, Brazil

    Suzan Brancher & Tatiana Natasha Toporcov

  2. Department of Dentistry, State University of Ponta Grossa, Ponta Grossa, Brazil

    Ana Elisa Ribeiro

  3. International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France

    Elisabete Weiderpass

Authors
  1. Suzan Brancher
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  2. Ana Elisa Ribeiro
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  3. Tatiana Natasha Toporcov
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  4. Elisabete Weiderpass
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Contributions

TNT, SB and EW were responsible for the conception of the study. SB and AER contributed to the data collection and extracted the data. SB and TNT assessed the eligibility of each article, independently. SB conducted the analysis and produced the results, figures and tables. AER and TNT provided statistical support. TNT and EW contributed to data interpretation. SB wrote the manuscript. TNT, AER and EW revised the manuscript. AER contributed to manuscript editing at the moment of submission. All authors were involved in the manuscript review.

Corresponding author

Correspondence to Suzan Brancher.

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Brancher, S., Ribeiro, A.E., Toporcov, T.N. et al. The role of metformin on lung cancer survival: the first systematic review and meta-analysis of observational studies and randomized clinical trials. J Cancer Res Clin Oncol 147, 2819–2836 (2021). https://doi.org/10.1007/s00432-021-03728-x

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  • DOI: https://doi.org/10.1007/s00432-021-03728-x

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