Transarterial Chemoembolization ± Intravenous Bevacizumab in the Treatment of Hepatocellular Cancer
Transarterial Chemoembolization ± Intravenous Bevacizumab in the Treatment of Hepatocellular Cancer
Abstract & Commentary
Synopsis: In this single-institute pilot study, 30 subjects with hepatocellular cancer were randomized to transarterial chemoembolization with or without bevacizumab. Bevacizumab use significantly improved progression-free survival at 16 weeks but no significant difference was seen with respect to the primary outcome (vessel count) or in the overall survival.
Source: Britten CD, et al. Transarterial chemoembolization plus or minus intravenous bevacizumab in the treatment of hepatocellular cancer: A pilot study. BMC Cancer 2012;12:16.
Hepatocellular cancer (HCC) is the third most common cause of cancer mortality in the world with rising incidence rates in the United States. Survival trends reveal an increase in the percentage of patients diagnosed with localized and regional disease than distant disease from 1992-1993 to 2003-2004.1 Liver transplantation is the standard treatment in patients with localized disease who meet the Milan criteria (single tumors ≤ 5 cm or 3 nodules ≤ 3 cm), and in carefully selected cases, 5-year survival can be as high as 70%. However, the paucity of donor livers as well as strict criteria for resection and percutaneous ablation therapies exclude many patients from these therapies. Transarterial chemoembolization (TACE) can be employed in patients with preserved liver function for the treatment of large (> 3 cm) or multifocal HCC confined to the liver as neoadjuvant therapy prior to liver transplant or for primary unresectable tumors with survival benefit.2 However, the results are not permanent and the procedure fails due to neovascularization regulated by vascular endothelial growth factor (VEGF). Not only are VEGF levels higher in hepatocellular cancer, but they are also up-regulated by the TACE due to tumor hypoxia.3 Because of the direct effect of bevacizumab on VEGF and on microvessel density, this study tested the hypothesis that the use of bevacizumab with TACE may improve upon the results observed with TACE alone.
This was a single institution pilot study in which 30 subjects with HCC were randomized with a computer-generated allocation in a one-to-one ratio to either bevacizumab at a dose of 10 mg/kg IV every 14 days beginning 1 week prior to TACE (TACE-BEV arm) or observation (TACE-O arm). TACE of all lesions was done using doxorubicin 25 mg/m2 (emulsified with lipiodol, 10-12 mL), cisplatin 50 mg/ m2, and mitomycin-C 5 mg/m2, with Embosphere® microspheres (Biosphere Medical, Rockland, MA) at day 8. Repeat TACE was performed at week 14 if there were evidence for recanalization, residual tumor blush, or new lesions that could be targeted. TACE-BEV subjects were allowed to continue bevacizumab beyond week 16. The primary outcome measure was neovessel formation by angiography at weeks 10 and 14. Angiography was performed on day 8, and again at weeks 10 and 14. TACE-O subjects were allowed to crossover to bevacizumab at week 16 in the setting of progressive disease. Secondary outcome measures were progression-free survival (PFS) at 16 weeks, overall survival (OS), bevacizumab safety, and an analysis of VEGF levels before and after TACE with and without bevacizumab. Subjects had at least one lesion > 3 cm and no lesion > 15 cm, and no more than three lesions total. Subjects were excluded if they had Child's class C liver dysfunction, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) > 2, bilirubin > 2.5 mg/ dL, INR > 1.5, extra hepatic disease, thrombosis of the main portal vein, or contraindications to bevacizumab.
Nine of 15 randomized to the TACE-O arm and 14 of 15 randomized to the TACE-BEV arm completed all three angiograms. At week 10, new vessel formation was seen in four of 11 (36%) TACE-O and 4 of 14 (29%) TACE-BEV subjects. Three of nine (33%) TACE-O and two of 14 (14%) TACE-BEV subjects demonstrated neovascularity at week 14. Four of nine (44%) TACE-O subjects and six of 15 (40%) TACE-BEV subjects underwent TACE at week 14. Three of 11 (27%) TACE-O subjects and three of 14 (21%) TACE-BEV, and one of nine (11%) TACE-O subjects and two of 14 (14%) TACE-BEV subjects had evidence of collaterization at weeks 10 and 14, respectively. The PFS at 16 weeks was significantly lower in the TACE-O arm than in the TACE-BEV arm (0.19 vs 0.79; P = 0.021), but despite that, the median OS in the TACE-BEV arm was lower (49 months) than the TACE-O arm (61 months) (P = 0.21). No life-threatening bevacizumab-related toxicities were observed. Bevacizumab pharmacokinetics did not differ significantly from historical controls. TACE-BEV patients had a lower fold change in the serum VEGF levels than TACE-O arm.
Commentary
The authors are to be congratulated on their attempt to improve the results of TACE by targeting the VEGF pathway, which has been shown to be a useful marker for tumor progression, vascular invasion, as well as poor prognosis in HCC. Although sorafenib is associated with improved survival in advanced HCC patients, liver transplantation and resection still remain the only options for cure. Increasing the success of TACE procedures by targeting VEGF may increase the number of patients who will be eligible for transplantation. In this population with no or minimal liver dysfunction, the authors demonstrated that bevacizumab can be safely administered along with TACE with benefit in reducing neovascularization, serum VEGF levels, and improving PFS. Although this was a single institution study, it was a randomized trial with clearly defined endpoints and detailed assessments. It also is interesting to note that the incidence of grade 3-4 side effects, including hypertension, did not significantly differ between the two groups and bevacizumab was safely administered through the TACE procedures. This is in contrast to other surgical procedures where the incidence of vascular events increased with bevacizumab and a minimum of 6 weeks off therapy is recommended prior to surgery.
However, despite showing that TACE-BEV was associated with decreased percentage of new vessels there was no significant difference between the treatment groups in the mean (± standard deviation) percent change from baseline of the vessel count at time points. Similarly, there was no difference in the recanalization. The small sample size also precludes evaluation of the significant PFS results and the non-significant overall survival results. Although vascular events were comparable between the two groups, almost 90% of the subjects had Child-Pugh class A and the generalizability of safety to other risk groups, particularly those with more advanced disease, cannot be made.
In this well-conducted pilot trial of the use of anti-angiogenesis inhibitor bevacizumab in combination with TACE, the added treatment was found to be safe and effective in reducing VEGF levels in patients with minimal hepatic dysfunction. This was an exploratory study that will, no doubt, be expanded upon as investigators focus upon anti-angiogenesis pathways to improve outcomes with TACE.
References
1. Altekruse SF, et al. Hepatology 2012;55:476-82. doi: 10.1002/hep.24710.
2. Lo CM, et al. Hepatology 2002;35:1164-1171.
3. Sergio A, et al. Am J Gastroenterol 2008;103:914-921.
4. Li X, et al. World J Gastroenterol 2004;10:2878-2882.
In this single-institute pilot study, 30 subjects with hepatocellular cancer were randomized to transarterial chemoembolization with or without bevacizumab. Bevacizumab use significantly improved progression-free survival at 16 weeks but no significant difference was seen with respect to the primary outcome (vessel count) or in the overall survival.Subscribe Now for Access
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