The Effect of Metformin on Chemotherapy-Induced Toxicities in Non-diabetic Breast Cancer Patients: A Randomised Controlled Study

Abstract

Background and objective: Breast cancer patients treated with adriamycin-cyclophosphamide plus paclitaxel (AC-T) are often challenged with serious adverse effects for which no effective therapies are available. Here, we investigated whether metformin, an antidiabetic drug with additional pleiotropic effects could favourably offset AC-T induced toxicities.

Patients and methods: Seventy non-diabetic breast cancer patients were randomised to receive either AC-T (adriamycin 60 mg/m² + cyclophosphamide 600 mg/m² × 4 cycles Q21 days, followed by weekly paclitaxel 80 mg/m² × 12 cycles) alone or AC-T plus metformin (1700 mg/day). Patients were assessed regularly after each cycle to record the incidence and severity of adverse events based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. Moreover, baseline echocardiography and ultrasonography were done and repeated after the end of neoadjuvant therapy.

Results: Addition of metformin to AC-T resulted in significantly less incidence and severity of peripheral neuropathy, oral mucositis, and fatigue (p < 0.05) compared to control arm. Moreover, the left ventricular ejection fraction (LVEF%) in the control arm dropped from a mean of 66.69 ± 4.57 to 62.2 ± 5.22% (p = 0.0004) versus a preserved cardiac function in the metformin arm (64.87 ± 4.84 to 65.94 ± 3.44%, p = 0.2667). Furthermore, fatty liver incidence was significantly lower in metformin compared with control arm (8.33% vs 51.85%, p = 0.001). By contrast, haematological disturbances caused by AC-T were preserved after concurrent metformin administration (p > 0.05).

Conclusion: Metformin offers a therapeutic opportunity for controlling toxicities caused by neoadjuvant chemotherapy in non-diabetic breast cancer patients.

Trial registration: This randomised controlled trial was registered on November 20, 2019 in ClinicalTrials.gov under registration number: NCT04170465.

Fig. 1

The Consolidated Standards of Reporting Trials (CONSORT) diagram

Fig. 2

Incidence of different Common Terminology Criteria for Adverse Events (CTCAE) grades of peripheral neuropathy by cycle between metformin and control arms experienced during neoadjuvant therapy. Data are expressed as percentages of frequencies of incident events of 35 observations in each arm. AC adriamycin-cyclophosphamide cycle, CI confidence interval, G grade of severity, OR odds ratio, Tw paclitaxel weekly cycle. *p value < 0.05 versus control values

Fig. 3

Incidence of different Common Terminology Criteria for Adverse Events (CTCAE) grades of oral mucositis by cycle between metformin and control arms experienced during neoadjuvant therapy. Data are expressed as percentages of frequencies of incident events of 35 observations in each arm. AC adriamycin-cyclophosphamide cycle, CI confidence interval, G grade of severity, OR odds ratio, Tw paclitaxel weekly cycle. *p value < 0.05 versus control values

Fig. 4

Incidence of different Common Terminology Criteria for Adverse Events (CTCAE) grades of fatigue by cycle between metformin and control arms experienced during neoadjuvant therapy. Data are expressed as percentages of frequencies of incident events of 35 observations in each arm. AC adriamycin-cyclophosphamide cycle, CI confidence interval, G grade of severity, OR odds ratio, Tw paclitaxel weekly cycle. *p value < 0.05 versus control values