Adjuvant therapy options following curative treatment of hepatocellular carcinoma: A systematic review of randomized trials
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.
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Both authors contributed equally to this work.