Metformin Adjunct With Antineoplastic Agents for the Treatment of Lung Cancer: A Meta-Analysis of Randomized Controlled Trials and Observational Cohort Studies

Abstract

Objective: Resistance to anticancer agents ensures a poor prognosis in patients with lung cancer. Metformin could enhance the anticancer effects of standard antineoplastic agents [traditional chemotherapy drugs, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), or immune checkpoint inhibitors (ICIs)]; however, it is unclear whether metformin can be combined with antineoplastic agents in the treatment of lung cancer. To explore the efficacy of combinational strategies, we performed a systematic review and meta-analysis for diabetic and non-diabetic patients with lung cancer.Method: An electronic literature search was performed to obtain relevant randomized controlled trials (RCTs) and observational cohort studies. Hazard ratios (HR) with 95% confidence intervals (CI) of overall survival (OS) and progression-free survival (PFS) outcomes were extracted. Subgroup analysis by antineoplastic agents, study type, histology and clinical stage were investigated.Results: 14 studies (three RCTs and eleven observational cohort studies) consisting 3,856 patients were included in the meta-analysis. Compared to standard antineoplastic agents alone (traditional chemotherapy drugs, EGFR-TKIs or ICIs), the antineoplastic agents combined with metformin significantly improved OS (HR 0.73, 95% CI 0.66–0.81, p < 0.00001) and PFS (HR 0.72, 95% CI 0.59–0.88, p = 0.001); a similar association was found in observational evidence. Limited data from RCTs showed no differences in OS or PFS.Conclusion: Metformin plus antineoplastic agents may improve survival outcomes of patients with lung cancer. Further investigation is needed.

Insulin Resistance and Cancer: In Search for a Causal Link

“…Although conflicting results exist in the literature with regard to metformin and endometrial cancer, and heterogeneity across studies is substantial, it has been estimated that there is a significant lower incidence and better prognosis of gynecological cancers in patients with metformin therapy. Moreover, several recent meta-analyses indicate that metformin may also reduce the incidence of lung cancer [ 310 , 311 ] and increase lung cancer survival in metformin-treated type 2 diabetic patients [ 311 , 312 ]. Finally, limited data from inconclusive meta-analyses suggest that metformin might improve all-cause mortality in certain cancer types [ 313 ], including gastric [ 314 ], pancreatic [ 315 ], and colorectal cancer [ 316 ], and reduce breast cancer-specific mortality [ 313 ].…”

Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress

“…However, recent clinical trials failed to support the administration of adjuvant metformin in breast cancer [ 60 , 61 , 62 , 63 ]. By contrast, a meta-analysis found that metformin adjunct with standard cancer therapies significantly improved lung cancer patient survival [ 64 ]. It remains unclear if the difference may be attributed to differential metformin transporter expression in the two cancer types.…”

Advances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review)

“…A number of preclinical studies have reported good results of metformin acting concurrently with radiotherapy, tyrosine kinase inhibitors (TKIs) and ICIs in NSCLC ( 104 – 107 ), which has encouraged the use of combination therapies. In a meta-analysis of 14 clinical studies comprising 3,856 patients, the combination of metformin with standard antineoplastic drugs significantly improved OS in patients with lung cancer ( 108 ). These results suggest that metformin combined with radiotherapy may be an effective regimen for the treatment of patients with NSCLC.…”