Abstract

Background: We have previously reported that vitamin K dosing augments the anticancer effects of sorafenib by suppressing levels of des-γ-carboxy prothrombin (DCP), a known tumor growth and angiogenesis factor produced in HCC under sorafenib-induced ischemia. Herein, we aimed to establish whether vitamin K dosing could afford a similar anticancer effect when combined with transarterial chemoembolization (TACE), known to induce ischemic tumor necrosis in HCC.

Methods: We performed a prospective, randomized, open-label trial, randomly assigning patients with unresectable HCC (1:1) to TACE + vitamin K or TACE alone groups. In the TACE + vitamin K group, patients received 45 mg of oral vitamin K2 daily from the day of TACE until day 28. Co-primary endpoints were objective response rate and progression-free survival (PFS); the secondary endpoint was safety.

Results: No significant differences in baseline characteristics were observed between the TACE + vitamin K group (n=50) and TACE alone group (n=51). The TACE + vitamin K group exhibited a significantly higher objective response rate than the TACE alone group (96.0% vs. 82.4%, p=0.028). The PFS was significantly longer in the TACE + vitamin K group than that in the TACE alone group (median time: 262 days [95% confidence interval (CI), 35.8–488.2 days] vs. 146 days [95% CI, 111.6–180.4 days]; p=0.013, hazard ratio (HR): 0.55 [95% CI, 0.34–0.89]). Subgroup analysis revealed that vitamin K dosing prolonged PFS, particularly in females (HR of female and male: 0.25 vs. 0.72), patients within up-to-7 criteria (HR of within up-to-7 criteria and beyond: 0.44 vs. 1.21), or those with high baseline serum DCP levels (HR of DCP≧100 and <100 mAU/mL: 0.38 vs. 0.65). The PFS was markedly prolonged in patients; male with their baseline DCP≧100 mAU/mL or female, and within up-to-7 criteria; who seem to be most favorable for TACE + vitamin K (median [95% CI] days: 712 [290.1–1133.9] vs. 141 [89.3–192.7], HR 0.11 [0.04–0.30], P<0.001). Furthermore, we focused on the incidence of rapid and crucial recurrence defined as emergence of macroscopic vascular invasion (Vp4 or Vp3), multicentric intrahepatic recurrence (an increase>10 nodules compared with the latest radiological image), massive infiltrative tumor growth, extrahepatic spread, or abrupt death due to rapid tumor progression, within 120 days after TACE. In the TACE + vitamin K group, 4 patients (8%) had 4 events of rapid and crucial recurrence, whereas 11 patients (22%) of the TACE alone group experienced 14 events of rapid and crucial recurrence. The rapid and crucial recurrence was observed more frequently in the TACE alone group than in the TACE + vitamin K group (P=0.049). Regarding safety, there were no significant differences in the incidence of adverse events between the two groups.

Conclusion: Compared with TACE alone, vitamin K dosing combined with TACE improved anticancer outcomes.