Review article: overview of medical treatments in unresectable hepatocellular carcinoma—an impossible meta‐analysis?

Abstract

Background: Controversies surrounding medical treatment in patients with unresectable hepatocellular carcinoma continue to persist. Aim: To perform a meta‐analysis of therapeutic modalities which had been evaluated in two or more randomized trials. Methods: Fifty‐two randomized trials were studied; only 30 were included. This overview identified seven therapeutic modalities which had been evaluated in two or more trials: adriamycin, 5‐fluorouracil, interferon, percutaneous ethanol injection, transarterial chemotherapy, the combination of lipiodol with transarterial chemotherapy, and tamoxifen. Results: Comparisons of survival between control groups showed substantial heterogeneity. There was no survival benefit at 1 year with adriamycin (mean difference 4%), 5‐fluorouracil (mean difference −3%), percutaneous ethanol injection (mean difference 6%) or transarterial chemotherapy (mean difference −2%). For interferon, the survival benefit was significant with the Der Simonian & Laird method (mean difference 9%, 95% CI = 1–18%, P = 0.04) but not with the Peto et al. method (2.4 mean odds ratio, 95% CI = O.9–6.8). The meta‐analysis of tamoxifen showed a borderline survival benefit (mean difference 25%, 95% CI = 0–49%, P = 0.05). However, in sensitivity analyses, the survival benefit of tamoxifen was no longer significant. Conclusions: No treatment has clearly proven efficacy in survival. 5‐Fluorouracil, adriamycin and transarterial chemotherapy were not associated with survival benefit at 1 year. The number of randomized controlled trials was insufficient to enable a conclusion to be reached for interferon and percutaneous ethanol injection. Controversy persists concerning tamoxifen efficacy. Interferon and tamoxifen require new randomized controlled trials on a larger population of patients.

Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival

“…Two previous systematic reviews reported controversial results. 11,12 A more recent meta-analysis suggested small benefits favoring chemoembolization, but this study had several flaws. 83 Chemoembolization and arterial chemotherapy are analyzed as a single treatment approach, the handling of 3-arm trials is controversial, Fig.…”

“…This raises the need for a systematic meta-analysis assessment, with a major role to integrate valid information and provide estimates of treatment effects when RCTs themselves are not of sufficient size. 9,10 Two systematic reviews published years ago 11,12 suggested a potential benefit for at least 3 therapies (embolization, tamoxifen, and interferon) but emphasized that the amount of data was limited to achieve valid conclusions. Several RCTs have been published since then; thus, an up-to-date analysis may provide new and more consistent insight on the estimates of treatment efficacy.…”

Radiation therapy for hepatocellular carcinoma

“…[31][32][33] Newer targeted biologic therapies, such as those that target epidermal growth factor receptor, vascular endothelial growth factor, Raf kinase, and other targeted approaches, are being investigated in clinical trials and may show evidence of efficacy in the future. In summary, there is a need for novel therapies for unresectable HCC, especially for tumors that measure Ͼ 5 cm in greatest dimension.…”

Pilot study with pegylated liposomal doxorubicin for advanced or unresectable hepatocellular carcinoma

“…Third, from our small trial it remains unclear as to whether the survival length of our patients achieving SD is due to the specific antitumour treatment or might have been achieved with best supportive care alone. Whereas the superiority of a specific antitumour treatment over best supportive care has been demonstrated for other highly aggressive tumours (Ahlgren, 1996;Scheithauer et al, 1999;Hoffman and Glimelius, 1998;Burris et al, 1997), meta-analyses from randomized trials using doxorubicin for HCC did not reveal any survival benefit (Mathurin et al, 1998;Simonetti et al, 1997). However, these data were generated from the treatment with the free drug doxorubicin.…”

“…However, considering both, the modest response rates of less than 20% and the pronounced treatment related toxicities, doxorubicin is not considered a major breakthrough in the treatment of HCC (Mathurin et al, 1998).…”