September 29, 2021

Metformin Studied for Impact on Tumor Response in Patients With HCC Treated With Y-90 Radiation Segmentectomy

September 29, 2021—A recent analysis aimed to understand the role of metformin on improved tumor response in patients undergoing yttrium-90 (Y-90) radiation segmentectomy for hepatocellular carcinoma (HCC).

In the study by Mohammad Elsayed, MD, et al, 106 patients with HCC undergoing Y-90 radiation segmentectomy were evaluated. Among all patients, 40 (37.7%) had reported diabetes, of which 19 (18.4%) were taking metformin.

Key Findings

Patients with HCC who were taking metformin and treated with Y-90 radiation segmentectomy showed a reduction in viable lesions and TTD as well as a greater proportion of complete response based on mRECIST criteria.
Overall survival was not statistically significant between patients taking metformin and those not taking metformin.

Patients on metformin had a greater mean reduction of viable lesions compared to those not on metformin (1.05 vs 0.49; P = .001). There was a greater reduction in mean total tumor diameter (TTD) for the metformin group (reduction of 40.4 mm) compared with the nonmetformin group (reduction of 17.1 mm; P = .018).

A larger proportion of patients within the metformin cohort with complete response by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria (65.6% vs 89.5% treatments; P = .039) compared with patients not taking metformin was observed. Overall survival was not shown to be statistically significant between those taking metformin and those who did not.

Investigators concluded that metformin may be associated with increased tumor response in patients with HCC undergoing Y-90 radiation segmentectomy. However, further studies are needed to understand the effects of metformin more fully in optimizing therapy.

ENDOVASCULAR TODAY ASKS…

We spoke with coauthor Dr. Elsayed of Emory University School of Medicine, in Atlanta, Georgia, to provide additional context to this study and its possible impact on future research related to this topic.

What first led the authors to evaluate metformin in this setting?

Metformin is gaining massive attention as an antiaging and anticancer agent. This is warranted, as growing evidence demonstrates that metformin may improve outcomes in various cancers. This includes HCC, with research suggesting that metformin may protect against the formation of HCC in cirrhosis as well as improve tumor response to external beam radiotherapy.^1-6 Given the potential antitumor and sensitizing effects of metformin in HCC, we were prompted to examine the potential role of this medication in improving outcomes after Y-90 radioembolization.

To further study the potential role of metformin in HCC tumor response, what would your hypothetical study design be? What key question would you aim to answer?

A compelling clinical question generated by this study is whether all patients (including nondiabetics) with HCC who are eligible for Y-90 radiation segmentectomy should take metformin. A well-controlled, blinded, prospective clinical trial would be useful to elucidate the role of metformin for improving tumor response in HCC after Y-90 radioembolization.

This study notes that overall survival for patients on metformin not being statistically significant may have been impacted by the short-term follow-up period observed. What follow-up period should be targeted in later research to better evaluate overall survival? Why?

Overall survival is challenging to study as small sample sizes, short-term follow-up periods, and heterogeneity in long-term management may obscure differences between treatment groups. Although this study included patients with a range of tumor involvement, the majority had early stage disease as defined by the Barcelona Liver Clinic Staging System. Patients with early stage disease tend to have a relatively good prognosis, so a follow-up period of at least a few years would be needed to ensure substantial follow-up and inclusion of patients in overall survival analyses.

1. Tseng C-H. Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes. Liver Int. 2018;38:2018-2027. doi: 10.1111/liv.13872

2. Nkontchou G, Cosson E, Aout M, et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab. 2011;96:2601-2608. doi: 10.1210/jc.2010-2415

3. Jang WI, Kim MS, Lim JS, et al. Survival advantage associated with metformin usage in hepatocellular carcinoma patients receiving radiotherapy: a propensity score matching analysis. Anticancer Res. 2015;35:5047-5054.

4. Seo YS, Kim YJ, Kim MS, et al. Association of metformin use with cancer-specific mortality in hepatocellular carcinoma after curative resection: a nationwide population-based study. Medicine (Baltimore). 2016;95:e3527. doi: 10.1097/MD.0000000000003527

5. Harris K, Smith L. Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother. 2013;47:1348-1352. doi: 10.1177/1060028013503108

6. Li J, Hernanda PY, Bramer WM, et al. Anti-tumor effects of metformin in animal models of hepatocellular carcinoma: a systematic review and meta-analysis. PLoS One. 2015;10:e0127967. doi: 10.1371/journal.pone.0127967

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