Adjuvant therapy options following curative treatment of hepatocellular carcinoma: A systematic review of randomized trials

https://doi.org/10.1016/j.ejso.2012.01.006Get rights and content

Abstract

Aims

Numerous postoperative therapies for preventing recurrence of hepatocellular carcinoma (HCC) have been reported, but their efficacy remains controversial and knowledge about adverse effects is limited. A systematic review of randomized controlled trials (RCTs) was performed to gain a comprehensive picture of the efficacy and risks of these therapies.

Methods

MEDLINE, EMBASE and the Cochrane Library were systematically searched through July 2011. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated.

Results

A total of 2989 patients from 28 RCTs involving 10 postoperative therapies were included. For interferon therapy, the estimated RR for the 2-year recurrence rate was 0.84 (95% CI 0.73–0.97, P = 0.02) and the overall survival (OS) was 1.15 (95% CI 1.07–1.22, P < 0.001). Postoperative therapy with the vitamin K2 analog did not lead to a significant reduction in the 1-year recurrence rate, with a pooled RR of 0.60 (95% CI 0.28–1.27, P = 0.18). However, it did slightly improve the 1-year OS, with a pooled RR of 1.03 (95% CI 1.00–1.05, P = 0.03). Transarterial chemotherapy with or without embolization, adoptive immunotherapy and heparanase inhibitor PI-88 therapy may delay tumor recurrence. The effects of acyclic retinoid, lipiodol-iodine-131 and tumor vaccine treatment were promising but require further study. All postoperative therapies except interferon administered intramuscularly were well tolerated by the majority of patients.

Conclusions

Use of adjuvant interferon is definitely associated with an increase in OS. Postoperative therapies involving acyclic retinoid, lipidol-iodine-131, or tumor vaccine may improve the OS of patients with HCC after curative treatment.

Introduction

Hepatocellular carcinoma (HCC), a malignancy with poor prognosis, has a heterogeneous composition with multiple variables that vary from region to region.1 The incidence of HCC is increasing in many countries.2, 3 Resection and ablation remain the primary treatments for HCC. However, even after curative resection or ablation, recurrence is common and is, in fact, the main cause of patient deaths. Consequently, adequate adjuvant and/or chemopreventive therapy is needed to improve survival.

Various types of postoperative therapies have been reported for HCC patients following curative treatment. However, benefits of adjuvant or chemopreventive therapy have not been definitively demonstrated.4 Several randomized controlled trials (RCTs) have reported inconsistent or even contradictory data, and available systematic reviews have included only a few RCTs or have explored only one form of adjuvant therapy. In addition, most of the systematic reviews on this topic have not assessed the adverse effects of adjuvant or chemopreventive therapies. Here we describe a large-scale systematic review intended to provide a more comprehensive analysis to help identify the most suitable postoperative therapy for patients with HCC after curative treatments.

Section snippets

Identification of trials

The electronic databases of MEDLINE, EMBASE and the Cochrane Library were systematically searched through July 2011. Studies comparing curative treatment alone with curative treatment followed by postoperative therapy were identified using the following key words: hepatocellular carcinoma, hepatic tumor, liver tumor, postoperative, adjuvant, chemopreventive. In order to include all possible studies, the search was not limited to controlled or randomized trials. Manual search of relevant

Selection of studies

Our search yielded 676 clinical studies relevant to adjuvant or chemopreventive therapy for HCC. Fourteen studies were excluded because some patients had received neoadjuvant therapies, resection may not have been curative, or a real control group (no adjuvant therapy) was not included. In the end, 28 RCTs involving 2989 patients were included6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 (Fig. 1). In 15 of the studies,

Discussion

The current study systematically reviewed the published RCTs of postoperative therapies for patients with HCC after curative treatments and sought to evaluate their efficacy using meta-analysis or a descriptive approach. The cumulative evidence indicates that adjuvant IFN reduces the 2-year recurrence rate and improves the 2-year OS, and that chemopreventive VK2 analog therapy improves 1-year OS. Systemic and loco-regional chemotherapy as well as chemotherapy combined with embolization were not

Limitations

This systematic review included only patients with HCC treated by curative resection or local ablation, and it included studies involving no adjuvant or chemopreventive treatment arm. Second, four of the included studies were of low methodological quality. Third, some studies failed to report the proportion of patients lost to follow-up or reported proportions greater than 15%, which can lead to incomplete outcome bias.52 Fourth, the proportion of patients who adhered to the protocol completely

Conclusion

The present analysis demonstrates that adjuvant acyclic retinoid, lipiodol-iodine-131 and tumor vaccination may improve the OS of patients with HCC after curative treatments. The effect of IFN on OS is the most definite. On the other hand, IFN therapy is frequently associated with adverse effects. Since acyclic retinoid enhances the sensitivity of HCC cells to IFN,54 further work is needed to investigate combinations of postoperative therapies, such as IFN with acyclic retinoid.

Acknowledgments

The authors thank Dr Armando Chapin Rodríguez and Dr Liu-Cheng Wu for their language editing, which substantially improved the quality of the manuscript. This work was supported by a grant from the National Natural Science Foundation of China (Project No. 81160262/H1602 to L-Q L), which did not play any role in the design of the study, in the collection or analysis of data, or in the writing of the manuscript.

References (54)

  • H.C. Sun et al.

    Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma

    J Hepatol

    (2007)
  • A.L. Cheng et al.

    Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

    Lancet Oncol

    (2009)
  • J.A. Marrero et al.

    The challenge of prognosis and staging for hepatocellular carcinoma

    Oncologist

    (2010)
  • C. Bosetti et al.

    Trends in mortality from hepatocellular carcinoma in Europe, 1980–2004

    Hepatology

    (2008)
  • A. Tan et al.

    Is there a role for adjuvant treatment after hepatic resection for hepatocellular carcinoma?

    Oncology

    (2010)
  • M. Egger et al.

    Bias in meta-analysis detected by a simple, graphical test

    BMJ

    (1997)
  • L.T. Chen et al.

    Randomized phase III study of adjuvant interferon alfa-2b in hepatocellular carcinoma with curative resection–the Taiwan Cooperative Oncology Group (TCOG) T1297 study

    Hepatology

    (2005)
  • C.M. Lo et al.

    A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma

    Ann Surg

    (2007)
  • V. Mazzaferro et al.

    Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis

    Hepatology

    (2006)
  • H.C. Sun et al.

    Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial

    J Cancer Res Clin Oncol

    (2006)
  • S.M. Lin et al.

    Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors

    Cancer

    (2003)
  • Y. Shiratori et al.

    Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus

    Ann Intern Med

    (2003)
  • S. Kubo et al.

    Randomized clinical trial of long-term outcome after resection of hepatitis C virus-related hepatocellular carcinoma by postoperative interferon therapy

    Br J Surg

    (2002)
  • H. Yoshida et al.

    Effect of vitamin K2 on the recurrence of hepatocellular carcinoma

    Hepatology

    (2011)
  • S. Kakizaki et al.

    Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection

    J Gastroenterol Hepatol

    (2007)
  • T. Mizuta et al.

    The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study

    Cancer

    (2006)
  • N. Hotta et al.

    Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma

    Hepatogastroenterology

    (2007)
  • Cited by (59)

    • Adjuvant transarterial chemoembolization for patients with hepatocellular carcinoma involving microvascular invasion

      2019, American Journal of Surgery
      Citation Excerpt :

      However, the long term prognosis after resection remains far from satisfactory due to the high incidence of tumor recurrence.5,6 Many postoperative therapies and/or adjuvant treatments after curative resection have been reported,7,8 but none of them is recommended by official guidelines.9–12 Nevertheless, adjuvant transarterial chemoembolization (A-TACE) has been reported to be beneficial for patients with risk factors of recurrence after resection, such as multiple nodules of >5 cm or macrovascular invasion.3

    • Postoperative adjuvant transcatheter arterial chemoembolization should be considered selectively in patients who have hepatocellular carcinoma with microvascular invasion

      2019, HPB
      Citation Excerpt :

      MVI has been confirmed to be associated with intrahepatic micrometastasis and is an important risk factor for the recurrence and long-term survival of patients with HCC after curative liver resection.6,8–10 To reduce tumor recurrence in patients undergoing liver resection for HCC, postoperative adjuvant treatments are regarded as effective measures.11–13 Currently, transarterial chemoembolization (TACE) is an important adjuvant strategy to prevent HCC recurrence.

    • Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis

      2016, Digestive and Liver Disease
      Citation Excerpt :

      So, many neo-adjuvant and adjuvant therapies have been advocated to improve the outcomes of patient after curative treatment in the past decades. These adjuvant therapies include interferon therapy, immunotherapy, radiation therapy, chemotherapy and so on, however, they have limited effect and need to be further investigated [6–9]. Nowadays, immunotherapy is becoming a promising treatment option for HCC by eliminating micrometastatic residual disease after curative resection to reduce the risk of relapse [10,11].

    View all citing articles on Scopus
    c

    Both authors contributed equally to this work.

    View full text