Role of vitamin K2 in preventing the recurrence of hepatocellular carcinoma after curative treatment: A meta-analysis of randomized controlled trials

Abstract

BackgroundHepatocellular cancer is notorious for recurrence even after curative therapy. High recurrence determines the long term prognosis of the patients. Vitamin K2 has been tested in trials for its effect on prevention of recurrence and improving survival. The results are inconclusive from individual trials and in our knowledge no systematic review which entirely focuses on Vitamin K2 as a chemo preventive agent is available to date. This review is an attempt to pool all the existing trials together and update the existing knowledge on the topic.MethodsMedline, Embase and Cochrane Register of Controlled trials were searched for randomized controlled trials where vitamin K2 or its analogues, in any dosage were compared to placebo or No vitamin K2, for participants of any age or sex. Reference lists and abstracts of conference proceedings were searched by hand. Additional papers were identified by a manual search of the references from the key articles. Attempt was made to contact the authors of primary studies for missing data and with the experts in the field.Trials were assessed for inclusion by two independent reviewers. Primary outcomes were recurrence rates and survival rates. There were no secondary outcomes. Data was synthesized using a random effects model and results presented as relative risk with 95% Confidence Intervals.ResultFor recurrence of hepatocellular cancer after hepatic resection or local ablative therapy, compared with controls, participants receiving Vitamin K2, pooled relative risks for hepatocellular cancer were 0.60; 95% CI: 0.28–1.28, p = 0.64) at 1 yr 0.66; 95% CI: 0.47–0.91), p = 0.01) at 2 yr; 0.71; 95% CI: 0.58–0.85, p = 0.004) at 3 yr respectively. The results were combined using the random analysis model.ConclusionFive RCTs evaluated the preventive efficacy of menatetrenone on HCC recurrence after hepatic resection or local ablative therapy. The meta-analysis of all five studies, failed to confirm significantly better tumor recurrence- free survival at 1 year. Improved tumor recurrence at 2nd and 3rd year may be just due to insufficient data. There was no beneficial effect on the overall survival. However, to confirm the beneficial effect or lack of it, large, higher quality randomized controlled trials are still required.

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

“…However in a double‐blind, randomized, placebo‐controlled study of 548 patients, efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed 41. Meta‐analysis of five randomized controlled trials failed to confirm significantly higher disease‐free survival at 1 year, and the reduced tumor recurrence at later years may be just due to insufficient data 42. Setoguchi et al43 demonstrated that effective delivery of menahydroquinoe‐4 (MKH), the active form of menaquinoe‐4 (vitamin K2 homolog), was critical for regulating HCC growth.…”

Vitamin K2 (menaquinone) Supplementation and its Benefits in Cardiovascular Disease, Osteoporosis, and Cancer

“…47 A level 2 meta-analysis of 5 RCTs observed significantly reduced HCC recurrence at two and three years, but not one year; there was no benefit to survival. 56 Another level 2 meta-analysis of 6 RCTs and one cohort study also found no significant reduction in recurrence at one year, but a significant reduction at two and three years; this study found a significant improvement in overall survival. 57 However, due to the small sample sizes and relatively short follow-up times of the available clinical trials, more research is needed to definitively understand the benefit of menaquinone in the prevention and treatment of HCC.…”

Adjuvant Intrahepatic Injection Iodine-131-Lipiodol Improves Prognosis of Patients with Hepatocellular Carcinoma After Resection: a Meta-Analysis

“…Vitamin K (VK) is a fat-soluble vitamin that regulates clotting factor production by acting as a coenzyme for a VK-dependent carboxylase that catalyzes carboxylation of glutamic acid residues into gamma-carboxyglutamic acid. The findings in vitro have indicated that VK2 has an antiproliferative effects against hepatoma cell lines, but its efficacy in suppressing HCC recurrence was not confirmed in human studies [22]. Interferon has a variety of biologic properties, including antiviral, immunomodulatory, antiproliferative, antiangiogenic, and tumouricidal effects.…”