Stronger Neo-Minophagen C (SNMC): A stronger adjuvant for TACE?

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer in the world.¹ Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are the major causes of HCC in Taiwan.² Among the current available treatment modalities, transarterial chemoembolization (TACE) is recommended for patients with the Barcelona Clinics Liver Cancer (BCLC) stage B HCC, which include patients who have Child-Pugh grade A or B liver functional reserve and have large, multifocal tumors, but without extra-hepatic spread, vascular invasion, nor cancer-related symptoms.³ Nevertheless, the application of TACE is not limited to BCLC stage B HCC in the clinical practice.⁴ Hence, the outcomes of patients with HCC who undergo TACE are quite diverse due to the heterogenous demographic characteristics, tumor burden, as well as liver functional reserve. It has been reported that the overall survival (OS) of patients with HCC after TACE varied from 2.5 years up to 4 years in the different studies with different inclusion criteria.⁵

However, TACE is regarded as a non-curative treatment modality for HCC.⁶ Tumor progression or recurrence after TACE are common and several courses of TACE might be needed to achieve a better tumor control.⁷ Nevertheless, each TACE procedure not only induces extensive tumor necrosis but also causes deterioration of liver function. Consequently, HCC patients who have an underlying impaired liver function or clinically significant portal hypertension bear a higher risk of developing liver failure or mortality after TACE.^{4, 8} Moreover, Sieghart et al. proposed an Assessment for Retreatment with TACE (ART) score which enrolled an increase of serum aspartate aminotransferase (AST) level >25%, an increase of Child-Pugh score from baseline, and absence of radiological response after the initial TACE treatment, could predict the prognoses of HCC patients after the second course of TACE.⁹ Adhoute and colleagues further constructed an ABCR score which was composed of BCLC stage and serum alpha-fetoprotein levels at baseline, change in Child-Pugh score from baseline, and the radiological response after the initial course of TACE.¹⁰ In this study, HCC patients who had an ABCR score ≥4 prior to the second TACE had a median OS of only 4.6 months in the training cohort and 7.5 months in the validation cohort, respectively, if they underwent subsequent TACE treatment. Taken together, it indicates that ongoing hepatic necroinflammation and the deterioration of liver functional reserve after TACE is critical in determining the outcomes of HCC patients. Patients who have impaired liver function after initial TACE are not recommended to undergo further TACE.

Stronger Neo-Minophagen C (SNMC; Minophagen Pharmaceutical, Tokyo, Japan) has been widely prescribed intravenously for patients with various forms of hepatitis, especially viral hepatitis. Its active ingredient, glycyrrhizin, has been reported to have anti-inflammatory, antihepatotoxic, antiallergic, antitumor, and antiviral effects.^11-13 Takahara revealed that glycyrrhizin could suppress the secretion of hepatitis B surface antigen and interfered its intracellular transport.¹¹ Matsumoto also showed that glycyrrhizin could suppress of the release of HCV by the inhibitory effect on phospholipase A2 in vitro.¹² In the clinical aspects, Hung et al. conducted a prospective randomized trial to investigate the efficacy and safety of glycyrrhizin plus tenofovir versus tenofovir for patients with chronic hepatitis B with severe acute exacerbation.¹⁴ Compared to patients who treated with tenofovir alone, those who received glycyrrhizin and tenofovir combination therapy had a more rapid decline of serum AST and alanine aminotransferase (ALT) levels and an improvement in the model for end-stage liver disease score. However, the virological responses (HBV DNA reduction and hepatitis B e antigen seroclearance, etc.) and clinical outcomes (such as overall mortality or receipt of liver transplantation), were comparable between the two groups of patients. It suggested that glycyrrhizin could ameliorate hepatic necroinflammation and reduce serum ALT and AST levels for patients who suffered from acute liver damage.

In this issue of Advances in Digestive Medicine, Huang et al. conducted a prospective, randomized study to investigate the therapeutic effects of SNMC for patients with BCLC stage B HCC and underwent TACE.¹⁵ The results showed that patients who received SNMC after TACE had a significantly lower serum bilirubin levels and shorter prothrombin time (PT) compared to those without SNMC therapy. They also had a lower rate of fever and nausea than their counterparts. Moreover, although the differences were not significant, patients who received SNMC therapy had a lower serum ALT and AST levels. Regarding the potential adverse effects of SNMC, the rates of hypertension and hyperkalemia were comparable between these two groups of patients. It suggested the SNMC therapy was safe and seemed to have a hepatoprotective effect to restore liver function for patients with HCC after TACE.

However, several concerns need to be addressed. First, in this study, the prescription of SNMC and the follow-up period after TACE was only 3 days. The true therapeutic impact of SNMC on the clinical outcomes of patients with HCC after TACE, such as the risk of hepatic decompensation and mortality, could not be investigated in this study. Moreover, whether SNMC could restore liver functional reserve after TACE and increase the opportunity to receive subsequent TACE or systemic therapy for patients with viable HCC is obscure. Second, patients who received SNMC after TACE had a significantly lower serum total bilirubin levels and shorter PT than their counterparts. It suggested that SNMC could restore liver function shortly after TACE. However, the dynamic changes of serum ALT and AST levels after TACE were not different significantly between patients with and those without SNMC therapy. It might be due to the relatively small number of patients in this study.

In conclusion, the prescription of SNMC for HCC patients who undergo TACE is safe. Moreover, it could reduce serum total bilirubin levels and PT immediately after TACE. However, it is warranted to conduct more prospective studies to elucidate the long-term survival benefit of SNMC as an adjuvant therapy of TACE for patients with HCC.

Chien-Wei Su: Speakers' bureau: Gilead Sciences, Bristol-Myers Squibb, AbbVie, Bayer, and Roche. Advisory arrangements: Gilead Sciences. Grants: Bristol-Myers Squibb.