J Liver Cancer.  2021 Sep;21(2):155-162. 10.17998/jlc.2021.09.22.

The effect of nucleos(t)ide analogues on clinical outcomes of patients treated with transarterial chemoembolization and radiofrequency ablation for hepatitis B virus-related hepatocellular carcinoma

• Park JM
• Choe WH
• Kim JH
• Kwon SY
• Yoo BC

• KMID: 2520902
• DOI: http://doi.org/10.17998/jlc.2021.09.22

Abstract

Background/Aims
Because hepatitis B virus (HBV) replication has been known to play an important role in cancer recurrence after curative treatment of HBV-related hepatocellular carcinoma (HCC), we examined whether treatment based on nucleos(t)ide analogues (NAs) might decrease the recurrence rate and improve patient survival.
Methods
The retrospective cohort study enrolled 73 patients with chronic hepatitis B who were treated with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) with curative intent for HCC. Among those, 30 and 43 patients were treated with tenofovir disoproxil fumarate (TDF) and entecavir (ETV), respectively.
Results
Of the 73 patients, 51 experienced HCC recurrence, and 14 patients were dead during a follow-up of 73±34 months. Multivariate analyses showed that tumor size (hazard ratio [HR], 1.590; 95% confidence-interval [CI], 1.106-2.285; P=0.012) and Child-Pugh class B (vs. class A/non cirrhosis; HR, 5.794; 95% CI, 2.311-14.523; P=0.001) was significantly associated with HCC recurrence, and Child-Pugh class B (HR, 7.357; 95% CI, 2.100-25.777; P=0.002) was an independent unfavorable prognostic factor for survival. During NAs therapy, TDF was superior to ETV for complete viral response at 1 year after the date of combination of TACE and RFA (P=0.016). However, the risks of HCC recurrence and survival were not significantly different between those treated with TDF versus ETV.
Conclusions
TDF was superior to ETV for achieving complete viral response. However, the recurrence and mortality after TACE and RFA for HBV-related HCC were not significantly different between patients treated with TDF versus ETV.

Keyword

Hepatitis B; Hepatocellular carcinoma; Nucleos(t)ide analogues; Radiofrequency ablation; Transarterial chemoembolization

Figure

• 

  Figure 1 Changes in mean log values of the serum hepatitis B virus (HBV)-DNA levels from the date of combination treatment of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) during nucleos(t)ide analogue (NA) therapy. The decrease in HBV-DNA was significant in patients treated with tenofovir disoproxil fumarate (TDF) than in patients treated with entecavir (ETV) at 3, 6, and 9 months after the combination treatment of TACE and RFA (P<0.05).

• 

  Figure 2 Cumulative recurrence-free survival after combination therapy with transarterial chemoembolization and radiofrequency ablation is shown. Kaplan-Meier curves reveal no significant difference in recurrence-free survival among patients treated with tenofovir disoproxil fumarate (TDF) compared with entecavir (ETV).

• 

  Figure 3 Cumulative overall survival after combination therapy with transarterial chemoembolization and radiofrequency ablation is shown. Kaplan-Meier curves reveal no significant difference in overall survival among patients treated with tenofovir disoproxil fumarate (TDF) compared with entecavir (ETV).

Reference

References

1. Liang LY, Wong GL. Unmet need in chronic hepatitis B management. Clin Mol Hepatol. 2019; 25:172–180.

2. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015; 386:1546–1555.

3. Kim BK, Park JY, Kim DY, Kim JK, Kim KS, Choi JS, et al. Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection. Liver Int. 2008; 28:393–401.

4. Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, Wu MS, et al. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA. 2012; 308:1906–1914.

5. Yin J, Li N, Han Y, Xue J, Deng Y, Shi J, et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol. 2013; 31:3647–3655.

6. European Association for the Study of the Liver. EASL 2017 Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017; 67:370–398.

7. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016; 10:1–98.

8. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018; 67:1560–1599.

9. Lee JH, Kim BK, Park SY, Tak WY, Park JY, Kim DY, et al. The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma. Eur J Intern Med. 2021; 89:48–55.

10. Choi J, Jo C, Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. Hepatology. 2021; 73:661–673.

11. Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019; 380:1450–1462.

12. Kim YS, Lim HK, Rhim H, Lee MW, Choi D, Lee WJ, et al. Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular carcinoma: analysis of prognostic factors. J Hepatol. 2013; 58:89–97.

13. Kim JW, Kim JH, Won HJ, Shin YM, Yoon HK, Sung KB, et al. Hepatocellular carcinomas 2–3 cm in diameter: transarterial chemoembolization plus radiofrequency ablation vs. radiofrequency ablation alone. Eur J Radiol. 2012; 81:e189–e193.

14. Morimoto M, Numata K, Kondou M, Nozaki A, Morita S, Tanaka K. Midterm outcomes in patients with intermediate-sized hepatocellular carcinoma: a randomized controlled trial for determining the efficacy of radiofrequency ablation combined with transcatheter arterial chemoembolization. Cancer. 2010; 116:5452–5460.

15. Choe WH, Kim YJ, Park HS, Park SW, Kim JH, Kwon SY. Short-term interval combined chemoembolization and radiofrequency ablation for hepatocellular carcinoma. World J Gastroenterol. 2014; 20:12588–12594.

16. Kang SG, Yoon CJ, Jeong SH, Kim JW, Lee SH, Lee KH, et al. Single- session combined therapy with chemoembolization and radiofrequency ablation in hepatocellular carcinoma less than or equal to 5 cm: a preliminary study. J Vasc Interv Radiol. 2009; 20:1570–1577.

17. Li W, Ni CF. Current status of the combination therapy of transarterial chemoembolization and local ablation for hepatocellular carcinoma. Abdom Radiol (NY). 2019; 44:2268–2275.

18. Xiao G, Yang J, Yan L. Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis. Hepatology. 2015; 61:292–302.

19. Kim AR, Park E, Kwon SY, Park SJ, Kim YJ, Yoo BC, et al. Efficacy and safety of combined radiofrequency ablation with transarterial chemoembolization in patients with Barcelona Clinic Liver Cancer Stage A hepatocellular carcinoma ineligible for curative treatment. Korean J Gastroenterol. 2019; 73:167–176.

20. Fujimori M, Takaki H, Nakatsuka A, Uraki J, Yamanaka T, Hasegawa T, et al. Survival with up to 10-year follow-up after combination therapy of chemoembolization and radiofrequency ablation for the treatment of hepatocellular carcinoma: single-center experience. J Vasc Interv Radiol. 2013; 24:655–666.

21. Kim JW, Kim JH, Sung KB, Ko HK, Shin JH, Kim PN, et al. Transarterial chemoembolization vs. radiofrequency ablation for the treatment of single hepatocellular carcinoma 2 cm or smaller. Am J Gastroenterol. 2014; 109:1234–1240.

22. Lim YS. Management of antiviral resistance in chronic hepatitis B. Gut Liver. 2017; 11:189–195.

23. Ghany MG, Doo EC. Antiviral resistance and hepatitis B therapy. Hepatology. 2009; 49(5 Suppl):S174–84.

24. Wong JS, Wong GL, Tsoi KK, Wong VW, Cheung SY, Chong CN, et al. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther. 2011; 33:1104–1112.

25. Murata K, Tsukuda S, Suizu F, Kimura A, Sugiyama M, Watashi K, et al. Immunomodulatory mechanism of acyclic nucleoside phosphates in treatment of hepatitis B virus infection. Hepatology. 2020; 71:1533–1545.