Hepatocellular carcinoma (HCC) is one of the ten most common neoplasms affecting people worldwide, and the third most common cause of cancer-related deaths. Surgery remains the gold standard for the treatment of HCC, however, such treatments are suitable in only 25-30% because of the tumour stage or severity of underlying cirrhosis. Transarterial chemoembolisation (TACE) is now generally accepted as an effective palliative treatment for patients with unresectable HCC and adequate preservation of liver function.
Enhancing treatment for HCC
Also at the CIRSE meeting, Professor Lencioni, University of Pisa, Pisa, Italy, presented ’Drug-Eluting Bead enhanced RFA in hepatocellular carcinoma’, in which he discussed the results of a prospective, single-arm pilot clinical study.
Currently, radiofrequency ablation (RFA) is accepted as a first-line treatment for non-resectable HCC and a comprehensive spectrum of devices are now available, such as the UniBlate and StarBurst (RITA Medical Systems/AngioDynamics), single and multi-probe devices (respectively). Such devices allow for the successful treatment of tumours up to 5cm in size, with an ablation zone of up to 7cm.
However, as Lencioni explained, there are some limitations in the use of RFA to treat HCC. HCC is a highly vascularised tumour and perfusion mediated tissue-cooling negatively affects the outcome of the procedure.
In 2000, Lencioni and colleagues demonstrated that RFA can be significantly enhanced by performing balloon catheter occlusion of the hepatic artery or chemoembolisation prior to RFA. Although subsequently adopted by several other institutions, this approach has the limitation that it does not take into account the heat sink effect caused by peri-tumoural vessels, which may be a cause of treatment failure.
Recent data obtained in patients who received RFA as a bridge treatment before transplantation has shown that the peri-vascular location is the most important predictor of treatment failure for RFA.
Another limitation is due to the propensity of HCC to penetrate the capsule and produce microsatellites. Referring to a study by Sasaki et al, 2005, Lencioni explained that microsatellites were found on histology in 50% of patients carrying tumours of intermediate size, that is, tumours of 5cm. Interestingly, he pointed out that most of the microsatellites are located in close proximity to the main tumour, at a distance of 1cm or less. "Because of the ’oven’ effect caused by the different tissue conductivity of the tumour interior with respect to surrounding tissue, there is a dramatic drop in the temperatures that can be achieved with RFA when administered from the tumour interior to the extra-capsular zone." (Figure 1).
Typically, sub-lethal heating is obtained in the extra-capsular zone and this sub-lethal heating (45-50ºC) is currently not achieving a sustained treatment effect. However, in experimental animal studies, it has been shown that the administration of an additional cytotoxic drug, for example, doxorubicin, results in increased necrosis, in which the peri-tumoural area exposed to sub-lethal heating will die (Figure 2).
Pilot clinical trial
In a prospective study entitled ’Radiofrequency ablation combined with doxorubicin eluting beads arterial chemoembolisation in the treatment of hepatocellular carcinoma: a pilot clinical trial’, Lencioni and colleagues investigated the feasibility, safety and effectiveness of RFA combined with doxorubicin-eluting beads in the treatment of HCC. The study included 20 (14 male and six female) adult patients (63-83 years old, mean 70±6) with single HCC 3.0-7.0cm in diameter (mean 5.0±1.4cm) showing evidence of residual viable tumour by computed tomography (CT)/magnetic resonance imaging (MRI) obtained one-two hours after RFA.
DC Bead (100-300µm and 300-500µm) were prepared at 25 mg/mL doxorubicin and delivered as required via a mocrocatheter. Crucially, DC Bead administration was performed within 24 hours of RFA treatment. This is necessary to take advantage of the hyperemia induced by the ablation to facilitate delivery and entrapment of the beads in the peri-tumoural area.
The follow-up period was 6-20 months (mean 12 months ± 5), and tumour response was measured by the RECIST (Response Evaluation Criteria in Solid Tumors) criteria - EASL (European Association for the Study of the Liver) amendment, which includes:
Complete response of the target lesion (disappearance of enhancement at one month);
Confirmed complete response of target lesions (complete response lasting no less than six months); and
Overall response (confirmed complete response of target lesion, no new lesions).
Results
The results demonstrated that the treatment protocol was successfully completed in all patients. One patient developed hepatic infarction that resolved spontaneously during the follow-up. The volume of coagulation necrosis increased from 48.1±35.7% after RFA alone to 75.5±52.4% after DEB administration, with an increase of 60.9±39.0%, resulting in complete ablation of 14 (70%) of 20 tumours. Overall, in terms of safety, there were no major complications reported. Patients were discharged 2-4 days after the procedure. When the ablation volume was measured after RFA alone and DEB-enhanced RFA, there was a substantial increase, (on average, 61%), with DEB-enhanced-RFA (Figure 3).
Partial response with minimum persistence of tumour areas occurred in six patients. Of interest, only two out of 14 patients with complete response at initial imaging assessment had progression due to a relapse of the target lesion. Therefore, 12 out of 20 had confirmed complete response of target lesion. New lesions were detected in three patients and responsible for progression, but nevertheless, objective overall response was confirmed in 75% of patients including ten (50%) with complete overall response at the time of study end (Figure 4).
Summary
This pilot study provides the first evidence of synergy between RFA and controlled and sustained local delivery of a chemotherapeutic agent as allowed by the DC Bead. Intra-arterial DEB administration did enhance the effect of RFA, leading to a high rate of complete response in HCC tumours resistant to standard RFA treatment. No major complications were observed and DEB-enhanced-RFA was found to be extremely well-tolerated.
Lencioni explained that it is crucial that a randomised controlled trial comparing DEB-enhanced RFA versus standard RFA treatment should take place to prove the clinical benefit of this new therapeutic approach, and to confirm that it opens new prospects in interventional oncology.
