Reply

We thank Metussin et al. for their interest and comments regarding our study on the impact of multiple transarterial chemoembolization (TACE) treatments on hepatocellular carcinoma in patients awaiting liver transplant.

First, they suggest including patients listed for liver transplant who subsequently progressed beyond listing criteria and dropped off the transplant wait list. In our study, we decided to exclude from the analysis a total of 19 patients who dropped off the wait list (namely, 10 patients died, 8 patients were too sick, and 1 patient had an inactive tumor at imaging and as a result did not proceed to transplant). The main reason of the exclusion was that the primary aims of the study were to evaluate the efficacy of multiple TACE treatments on tumor necrosis (evaluated on histological analysis), on tumor recurrence after liver transplant, and on overall posttransplant survival. It is obvious that in order to perform the analysis, we needed the transplant to be performed. As Metussin et al. correctly reported, many studies in the literature have previously reported that TACE performed before liver transplant might reduce the drop-out rate; therefore, we chose not to include this as an aim of the present study.

Regarding the second point on the frequency of treatment, TACE was repeated when technically and clinically feasible if a local and/or distant intrahepatic recurrence was documented. In the study, we demonstrated that the number of TACE does not correlate with the histological necrosis in the explant suggesting that the tumor biology behavior has a pivotal role in the TACE-related necrosis and that repeating TACE is not useful in some patients (likely those with a more aggressive tumor). Although it is possible that patients who received a single treatment and then waited <6 months could be considered under-treated, recurrence was not detected on follow-up imaging, or a subsequent treatment would have been provided. Patients submitted to a single TACE cycle versus those submitted to multiple cycles were at an increased risk of recurrence on the univariate analysis; however, this finding was not confirmed by multivariate analysis, suggesting that this finding may be more likely to be related to waiting time, as patients submitted to a single TACE treatment also had a shorter waiting time (P = 0.002). Furthermore, multiple TACE treatments were not found to be associated with survival.

As regards the schedule and timing for retreatment, patients underwent imaging (chest radiography and computed tomography scans of the chest and abdomen or contrast-enhanced magnetic resonance imaging) at approximately 3 months after the TACE procedure according to our protocol in order to assess the radiological response in treated lesions and to exclude disease recurrences. Given that organ allocation policy in the United States requires that imaging be repeated every 3 months, this interval works well from a practical standpoint; however, we also believe that the time interval between TACE cycles is not too long, but it allows recurrence to be seen (and then treated). In cases where only one side was treated and existing untreated lesions remained in the other lobe, this interval was reduced.

Finally, different cirrhosis etiologies were not reported in the manuscript but were collected in subgroups in order to lighten the tables and make the statistical analysis more reliable. As expected, hepatitis C virus (HCV) was the most common diagnosis at 28/104 (27%); HCV combined with alcohol was 22/104 (21%); alcohol alone was 15/104 (14%); hepatitis B virus was 9/104 (9%), followed by progressively smaller numbers of other diagnoses, including nonalcoholic steatohepatitis, cryptogenic, primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune hepatitis, and hemochromatosis.