Combination Interventional Therapy for Hepatocellular Carcinoma

Many interventional oncologists are exploring combined therapies for solitary hepatocellular cancer (HCC). The outcome of combining transarterial chemoembolization (TACE) and ablation has been reported, including two randomized, controlled trials; a small trial from 2010¹ in which the rate of local progression-free survival (PFS) was found to be significantly better in the combined treatment group, and a study of 189 patients from 2013² in which TACE plus radiofrequency ablation (RFA) was found superior to RFA alone in patients with solitary HCC <7.0 cm in diameter, both with regard to overall survival (OS) and recurrence-free survival. Similar findings were reported in a large retrospective study by Kim et al, with treatment allocation (TACE vs TACE + ablation) a significant predictor of survival, favoring the combined treatment group.³ A retrospective study of patients with tumor burden meeting Milan criteria found no difference in survival whether treatment was surgical resection or TACE + RFA.⁴ Our group found no significant difference in overall survival for patients with solitary tumors up to 7 cm in size comparing treatment with transarterial embolization (TAE) + ablation to surgical resection in an exploratory, retrospective review in 2005.⁵ This prompted a change in our method of treatment and was followed by a report on long-term outcome (median follow-up 11 years) in 2013 that supported the earlier findings of equivalence.⁶ Median OS was 66 months in the resection group and 58 months in the TAE-ablation group (P=.39).

Combining embolization with ablation has several advantages, whether for small tumors or those larger than 3 cm. Smaller primary liver tumors can be difficult to accurately target with either computed tomography (CT) or ultrasound (US) within the background of cirrhosis, present in the majority of patients (Figure 1). 

Although this can potentially be overcome using either CEUS or fusion imaging, not all practitioners are experienced with these techniques. When ablation is used alone, accurate targeting is critical if a complete ablation is to be achieved. Embolizing the tumor first allows for very accurate targeting since the tumor will be stained with either lipiodol, if TACE is used, or with contrast when TAE or DEB-TACE is performed. This is secondary to the embolization agent trapping contrast within the tumor when intra-tumoral stasis is achieved (Figure 2).

In the case of tumors larger than 3 cm, the risk of recurrence is known to be higher when treated with ablation alone. Embolizing the tumor first may enhance the ablation zone by two mechanisms. First, flow within the regional vessels is reduced, or in some cases eliminated, by the embolization, resulting in less flow-related cooling. Second, in the case of HCC, the “oven effect” (in which the energy deposition results in higher heating of the soft tumor within the “harder” shell of surrounding liver) may be enhanced and can be exploited. For these reasons, combination treatment allows for treatment of lesions that might otherwise be considered too large for ablation alone (Figure 3). The combination might also improve upon recurrence rate following embolization alone, although this has not been proven.

Finally, if part of the tumor is undertreated by the embolization, for example, if a feeder from the phrenic artery has been missed, this is quite clear on a CT obtained within 24 hours that will demonstrate a “defect” in uptake of contrast or lipiodol in the undertreated region. This area can be specifically targeted during the subsequent ablation. Given understanding of the blood supply to “watershed tumors,” as well as the widespread use of cone-beam CT and other methods for accurately determining the blood supply to a tumor at the time of treatment, this may be less important than the combined therapeutic effect of embolization and ablation.

I certainly consider it “best practice” to combine hepatic transarterial embolization with ablation for solitary HCC of virtually any size up to 7 cm in diameter, knowing that I am much less likely to have to come back and treat a local recurrence after the use of either method alone. The fact that not just the PFS but also the OS has been shown to be better with combined therapy also informs my decision. This evidence should be seriously considered by those treating patients with HCC.

Figure 1. Pretreatment magnetic resonance in patient with history of renal cell carcinoma status post nephrectomy 5 years earlier with solitary 1.3 cm enhancing lesion in right liver (A). Non-contrast computed tomography day of attempted ablation 2 months later (B).

Figure 2. Same patient as in Figure 1. Selective angiogram demonstrating tumor (A). Computed tomography immediately following embolization where tumor is clearly visible, allowing for accurate targeting (B).

Figure 3. Non-contrast scan demonstrating two right-sided lesions, one in segment 5/1, the other in segment 5/6 (A, B). Contrast retention after embolization in 5/1 lesion (C). Radiofrequency applicator in 5/6 lesion without much contrast retention (D). Follow-up venous phase scan 1 month post treatment (E). Follow-up venous phase scan 2 years post embolization/ablation (F).

References 

1. Morimoto M, Numata K, Kondou M, Nozaki A, Morita S, Tanaka K. Midterm outcomes in patients with intermediate-sized hepatocellular carcinoma: a randomized controlled trial for determining the efficacy of radiofrequency ablation combined with transcatheter arterial chemoembolization. Cancer. 2010;116:5452-5460.
2. Peng ZW, Zhang YJ, Chen MS, et al. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial. J Clin Oncol. 2013;31:426-432.
3. Kim JH, Won HJ, Shin YM, et al. Medium-sized (3.1-5.0 cm) hepatocellular carcinoma: transarterial chemoembolization plus radiofrequency ablation versus radiofrequency ablation alone. Ann Surg Oncol. 2011;18:1624-1629.
4. Kagawa T, Koizumi J, Kojima S, et al. Transcatheter arterial chemoembolization plus radiofrequency ablation therapy for early stage hepatocellular carcinoma: comparison with surgical resection. Cancer. 2010;116:3638-3644.
5. Maluccio M, Covey AM, Gandhi R, et al. Comparison of survival rates after bland arterial embolization and ablation versus surgical resection for treating solitary hepatocellular carcinoma up to 7 cm. J Vasc Interv Radiol. 2005;16:955-961.
6. Elnekave E, Erinjeri JP, Brown KT, et al. Long-term outcomes comparing surgery to embolization-ablation for treatment of solitary HCC <7 cm. Ann Surg Oncol. 2013;20:2881-2886.