Supplementing sorafenib treatment with vitamin K could augment sorafenib anticancer action for patients with hepatocellular carcinoma


Sorafenib is an oral multikinase inhibitor that has been in use in the past decade as the only first-line anticancer treatment for hepatocellular carcinoma. It functions by suppressing cancer cell proliferation and tumor angiogenesis by restraining c-Raf and B-Raf in cancer cells and the vascular endothelial growth factor receptors of vascular endothelium cells. Unfortunately, the less than 5% objective response rate of sorafenib for advanced hepatocellular carcinoma has continued to hamper its effective use.

Previous studies reported that combination treatment with vitamin K and sorafenib induce growth restriction as well as apoptosis of liver cancer cells. Moreover, researchers found increased efficacy in preclinical studies of transplanted tumors in rats when treated with vitamin K and sorafenib compared to rats treated with only sorafenib. The superior outcome of combined treatment of sorafenib with vitamin K possibly because of suppression of the des-γ-carboxy prothrombin production of cancer cells.

To verify if vitamin K actually improves sorafenib anticancer action, researchers Dr. Yoshimichi Haruna, Dr. Takayuki Yakushijin, and Dr. Seiichi Kawamoto from the Osaka General Medical Center in Japan performed a phase II, randomized, open-label trial study of a previous retrospective study by the authors suggesting that supplementing sorafenib treatment with vitamin K improves sorafenib anticancer action against hepatocellular carcinoma. The study was anchored on the fact that many cirrhotic patients in Japan with hepatocellular carcinoma are dosed with vitamin K for osteoporosis because vitamin K replenishes bone mineral density thereby preventing osteoporosis fracture. Their research work is published in the journal, Cancer Medicine.

Patients with progressed hepatocellular carcinoma who hadn’t received any previous systematic therapy were considered for the study. The authors randomized the patients assigned at a 1:1 ratio to receive sorafenib supplemented with vitamin K2 or sorafenib only. The researchers continued the treatment until radiological disease progression, adverse events occurrence, a decline in performance status, or death. Locoregional treatment or systematic chemotherapy in place of sorafenib treatment was allowed after the patients ceased sorafenib only or sorafenib with vitamin K treatment.

The research team observed that the response rate of the vitamin K candidates was much higher than that of the sorafenib only candidates. Also, the median time of progression-free survival was largely extended in the vitamin K group than in the sorafenib only group. However, the authors didn’t observe any significant difference in the median time of overall survival between the two groups. However, the vitamin K group with a partial response or complete response reported a significantly extended median time of overall survival compared with other candidates in the sorafenib only group and vitamin K group.

To this end, this was the first prospective study showing the safety and efficacy of vitamin K supplementation during sorafenib treatment of hepatocellular carcinoma. Although further research is still needed to verify the benefit of sorafenib and vitamin K combination, in view of potential options in the future hepatocellular carcinoma treatment, along with other tyrosine-kinase inhibitors and immune checkpoint inhibitors, the findings of the study are sufficient to confirm that supplementing sorafenib treatment with vitamin K could augment sorafenib anticancer action against hepatocellular carcinoma.


Yoshimichi Haruna, Takayuki Yakushijin, and Seiichi Kawamoto. Efficacy and safety of sorafenib plus vitamin K treatment for hepatocellular carcinoma: A phase II, randomized study. Cancer Medicine, 2021, issues 10, pages 914–922.

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