Table 1:
Best evidence papers
| Author, date, journal and country Study type (level of evidence) | Patient group | Outcomes | Key results (metformin vs control) | Comments |
|---|---|---|---|---|
|
Arrieta et al. (2019), JAMA Oncol, Mexico [2] RCT (level 2) |
Trial information Study period: 2016–2017 Sample size: n = 139 Metformin group: n = 69 Control group: n = 70 Median follow-up: 16.9 months (95% CI, 7.0–24.9) Patients Stage IIIB or IV LUAD EGFRm: positive Previous anti-cancer treatment: NA History of diabetes: none Intervention Metformin group: erlotinib, afatinib or gefitinib at standard dosage, plus metformin 500 mg, p.o., b.i.d. Control group: erlotinib, afatinib or gefitinib at standard dosage |
Median PFS |
13.1 months (95% CI 9.8–16.3) vs 9.9 months, (95% CI 7.5–12.2) HR 0.60, 95% CI 0.40–0.94, P = 0.03 |
This RCT was open labelled and only enrolled non-diabetic NSCLC patients. The allocation in this study was not masked All patients in this study were EGFR-TKI naive. However, prior anti-cancer treatments were unavailable among the entire population In the metformin group, the discontinuation rate of metformin usage was 23.2% The intention-to-treat analysis was not performed |
| Median OS |
31.7 months (95% CI 20.5–42.8) vs 17.5 months (95% CI 11.4–23.7) HR 0.52, 95% CI 0.30–0.90, P = 0.04 |
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| ORR |
71.0% vs 54.3% OR 0.48, 95% CI 0.24–0.97, P = 0.04 |
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| DCR |
98.6% vs 92.9% OR 0.19, 95% CI 0.02–1.68, P = 0.14 |
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Li et al. (2019), Clin Cancer Res, China [3] RCT (level 2) |
Trial information Study period: 2013–2015 Sample size: n = 202 Metformin group: n = 97 Control group: n = 105 Median follow-up: 19.15 months (IQR 12.99–28.44) Patients Stage IIIB or IV NSCLC EGFRm: positive Previous anti-cancer treatment: none History of diabetes: none Intervention Metformin group: gefitinib, 250mg, p.o., q.d., plus metformin, from 500 to 1000 mg, p.o., b.i.d. Control group: gefitinib, 250 mg, p.o., q.d., plus placebo, from 500 to 1000 mg, p.o., b.i.d. |
Median PFS |
10.3 months (95% CI 8.4–13.0) vs 11.4 months (95% CI 10.0–12.2) HR 1.04, 95% CI 0.75–1.45, P = 0.8087 |
This RCT only studied non-diabetic NSCLC patients All the enrolled patients were EGFR-TKI naive and never received any previous anti-cancer treatment The status of LKB1 expression was not detected The discontinuation rate of metformin usage was 3.1% The statistical analysis was based on the intention-to-treat population |
| 1-year PFS | 41.2% (95% CI 30.0–52.2) vs 42.9% (95% CI 32.6–52.7), P = 0.6268 | |||
| Median OS |
22.0 months (95% CI 19.0–31.5) vs 27.5 months (95% CI 22.8–31.5) HR 1.15, 95% CI 0.79–1.68, P = 0.4571 |
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| ORR |
66.0% (95% CI 55.7–75.3) vs 66.7% (95% CI 56.8–75.6) OR 0.97, 95% CI 0.52–1.81, P = 1.000 |
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| DCR |
97.9% (95% CI 92.7–99.7) vs 97.1% (95% CI 91.9–99.4) OR 1.40, 95% CI 0.16–17.04, P = 1.000 |
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| AE incidence | 91.89% vs 82.88%a | |||
| Grade 3–4 AEb | 23.42% vs 18.92%a | |||
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Chen et al. (2015), Cancer Lett, China [4] Retrospective observational study (level 3) |
Study information Study period: 2006–2014 Sample size: n = 90 Metformin group: n = 44 Control group: n = 46 Patients Stage IIIA, IIIB or IV NSCLC EGFRm: positive Previous anti-cancer treatment: none History of diabetes Type of diabetes: T2DM Severity: each patient’s diabetes was well treated Exposure b Metformin group: erlotinib, gefitinib or icotinib, plus metformin Control group: erlotinib, gefitinib or icotinib, plus non-metformin hypoglycemic agents |
Median PFS |
19.0 months (95% CI 16.4–21.6) vs 8.0 months (95% CI 5.2–10.8) HR 0.46, 95% CI 0.28–0.75, P = 0.005 |
This study focused on NSCLC patients with T2DM The sample size (90 patients) was relatively small Bias from the comparison should be considered because some patients used insulin in the control group. Previous studies have indicated that insulin might increase the risk of tumour growth [5] |
| Median OS |
32.0 months (95% CI 26.5–37.5) vs 23.0 months (95% CI 9.6–36.4) HR 0.44, 95% CI 0.26–0.76, P = 0.002 |
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| ORR | 70.5% (95% CI 55–83) vs 45.7% (95% CI 31–61), P = 0.017 | |||
| DCR | 97.7% (95% CI 88–100) vs 80.4% (95% CI 66–91), P = 0.009 | |||
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Hung et al. (2019), Integr Cancer Ther, China [6] Retrospective observational study, (level 3) |
Study information Study period: 2004–2012 Sample size: n = 1633 Metformin group: n = 373 Control group: n = 1260 Patients Stage IIIB or IV NSCLC EGFRm: positive Anti-cancer treatment (non-EGFR-TKI): chemotherapy, radiotherapy, concurrent chemoradiotherapy or none History of diabetes Type of diabetes: T2DM History of hypoglycemic agents’ usage: patients who received insulin were excluded. Severity: NA Exposure Metformin group: erlotinib, gefitinib or both, plus metformin Control group: erlotinib, gefitinib or both |
Median PFS | 9.2 months (95% CI 8.6–11.7) vs 6.4 months (95% CI 5.9–7.2), P < 0.001 |
This study only focused on NSCLC patients with T2DM The distribution of comorbidities was a significantly different in the 2 groups Anti-cancer treatment was heterogeneous between and within the groups |
| Median OS | 33.4 months (95% CI 29.4–40.2) vs 25.4 months (95% CI 23.7–27.2), P < 0.001 | |||
| Comorbidity | ||||
| Hypertension | 78.3% vs 71.4%, P = 0.0088 | |||
| COPD | 29.8% vs 39.8%, P = 0.0005 | |||
| RI | 2.1% vs 5.2%, P = 0.0116 | |||
| SRD | 17.2% vs 26.3%, P = 0.0003 | |||
AE: adverse events; b.i.d.: twice a day; CI: confidence interval; COPD: chronic obstructive pulmonary disease; DCR: disease control rate; EGFR: epidermal growth factor receptor; EGFRm: EGFR mutation; HR: hazard ratio; IQR: interquartile range; LUAD: lung adenocarcinoma; NA: not available; NSCLC: non-small-cell lung cancer; ORR: objective response rate; OR: odd ratio; OS: overall survival; PFS: progression-free survival; p.o.: take orally; q.d.: once a day; RCT: randomized controlled trial; RI: renal insufficiency; SRD: smoking-related disorder; T2DM: diabetes mellitus type 2; TKI: tyrosine kinase inhibitor; TNM: tumour–node–metastasis.
n = 111 in each group for safety analysis.
Adverse effects were graded according to Common Terminology Criteria for Adverse Events (V.4.0) [7].