Alternative treatment strategies to sorafenib in patients with advanced hepatocellular carcinoma: a meta-analysis of randomized Phase III trials

Abstract

IntroductionThis meta-analysis was conducted to evaluate efficacy and safety in patients treated with sorafenib vs other tyrosine-kinase inhibitors (TKIs) or selective internal radiotherapy (SIRT) for advanced hepatocellular carcinoma (HCC).MethodsElectronic databases were systematically reviewed for randomized Phase III trials comparing sorafenib with other TKIs or SIRT in advanced HCC. Sorafenib was defined as the control arm. Other TKIs or SIRT was defined as the experimental arm. Overall survival (OS), time to progression (TTP), objective response rate (ORR), disease-control rate (DCR), and adverse events (AEs) were reviewed. Four trials in the other-TKI group (n=4,218) and two in the SIRT group (n=819) were eligible.ResultsCompared with sorafenib, other TKIs showed similar benefit on OS (HR 1.08, 95% CI 0.93–1.24; P=0.31) and TTP (HR 0.86, 95% CI 0.66–1.12; P=0.26) for advanced HCC. A significant increase in ORR (RR 1.67, 95% CI 1.15–2.43; P=0.008) was found with other TKIs, but no increase in DCR (RR 1.11, 95% CI 0.98–1.26; P=0.11) was observed. Other TKIs were associated with more frequent grade 3/4 AEs than sorafenib, including hypertension (P<0.00001), thrombocytopenia (P=0.002), fatigue (P<0.00001), decreased appetite (P<0.00001), and vomiting (P<0.0001). For locally advanced HCC, neither OS (HR 1.14, 95% CI 0.98–1.32; P=0.09) nor TTP (HR 0.87, 95% CI 0.74–1.02; P=0.10) differed significantly in SIRT and sorafenib. There was an increase in ORR (RR 2.60, 95% CI 1.69–4.00; P<0.0001), but no improvement in DCR (RR 0.91, 95% CI 0.81–1.02; P=0.11) in the SIRT group. Fewer patients treated with SIRT had grade 3/4 AEs than those treated with sorafenib, including diarrhea (P<0.0001), fatigue (P=0.0006), and hand–foot syndrome (P=0.0002). Other TKIs were noninferior to sorafenib in OS and TTP in advanced HCC, but with increased risk of toxicities.ConclusionPatients with locally advanced HCC treated with SIRT got similar efficacy with less toxicity to those treated with sorafenib.

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“…A suspension of 1 × 10 7 HepG2 cells (0.5 ml) was subcutaneously injected into the left back of 6-week old female BALB/c nude mice. When the tumor volume reached 100 mm 3 , the mice were randomly assigned to different groups (5 mice/group). Control group received 25 mg/kg PBS once daily for ten consecutive days; for the NP-BEZ235-Ab group, NP-BEZ235-Ab (equivalent 25 mg/kg body weight BEZ235) was administered once daily via the tail vein for 10 days, respectively; for the γ-ray group, where 2 Gy γ-ray radiation was administered on days 1 (D1), 4 (D4), 7 (D7), and 10 (D10), total 8.0 Gy of γ-ray irradiation was received; for the γ-ray +NP-BEZ235-Ab treatment group, NP-BEZ235-Ab (equivalent 25 mg/kg body weight BEZ235) was administered once daily via the tail vein for 10 days, 2 Gy radiation was administered on D1, D4, D7, and D10, and total 8.0 Gy of γ-ray irradiation was received.…”

“…9). After the tumor volume reached about 100 mm 3 , it was randomly divided into four groups, control group, γ-ray group, NP-BEZ235-Ab group, and NP-BEZ235-Ab+γ-ray group, and the corresponding process was carried out as shown in Fig. 10a.…”

“…Hepatocellular carcinoma (HCC), a malignant tumor that occurs from liver cells, is the most common primary liver cancer, which is a serious hazard to human health and is one of the few cancers with rising incidence in recent decades [1,2]. Radiotherapy is effective in the treatment of many malignant tumors, but HCC is resistant to radiation [3][4][5], and a strategy to increase its radiation sensitivity is needed.…”

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“…11 Representative Phase III trials have shown that sorafenib significantly improved overall survival in patients with advanced HCC. 12 Furthermore, sorafenib has been shown to activate autophagy and apoptosis. 13,14 Interactions between non-coding RNA and autophagy have received increased attention with regard to hepatocellular carcinoma.…”

The clinical efficacy and safety of kanglaite adjuvant therapy in the treatment of advanced hepatocellular carcinoma: A PRISMA-compliant meta-analysis

“…HCC is a fatal disease with a poor prognosis. Despite the development of diagnostic methods, early detection of HCC remains difficult [3,4]. In most patients, HCC progresses to an advanced stage, with a 5-year survival rate of less than 20% [3].…”