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Original Research |
1 Department of Radiology, Hospital de Bellvitge, Feixa Llarga s/n, 08907
L'Hospitalet de Llobregat, Barcelona, Spain.
2 Department of Surgery, Hospital de Bellvitge, Barcelona, Spain.
3 Department of Pathology, Hospital de Bellvitge, Barcelona, Spain.
Received August 3, 2007;
accepted after revision November 23, 2007.
Address correspondencen to E. Alba
(estheralba{at}csub.scs.es).
Abstract
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SUBJECTS AND METHODS. From January 2000 to August 2005, 56 patients with HCC underwent TACE before orthotopic liver transplantation (OLT). Radiologic findings before and after TACE were assessed and correlated with histologic findings after OLT. The area of induced necrosis was pathologically evaluated in each HCC nodule.
RESULTS. One hundred thirty-one HCC nodules were detected at histologic study. One hundred seventeen HCC nodules (91.4%) were hyperenhancing in the arterial phase on the preoperative imaging studies. The percentage of tumor necrosis was greater than 90% in 48 nodules (38%), between 50% and 90% in 19 nodules (15%), and less than 50% in 61 nodules (48%); tumor necrosis data were not recorded for the remaining three nodules. The size of the preoperatively detected lesions ranged from 0.2 to 9 cm (mean, 2.58 cm). The mean percentage of tumor necrosis was 67.8% in this group, but it rose to 79.2% in the hypervascular lesions. The size of the nodules that were not detected preoperatively ranged from 0.1 to 1.9 cm (mean, 0.68 cm), and the mean percentage of tumor necrosis was only 1.57%.
CONCLUSION. TACE is a safe treatment in well-selected patients. Its antitumoral effect is high in hypervascular lesions (mean necrosis, 79.2%). It provides good local control in preoperatively diagnosed HCC (mean necrosis, 67.8%), but its impact is limited in lesions not detected preoperatively (mean necrosis, 1.57%).
Keywords: cirrhosis • hepatitis • hepatocellular carcinoma • liver disease • liver transplantation • transcatheter arterial chemoembolization
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Regional ablative therapies (percutaneous ethanol injection, thermal ablation, and transcatheter arterial chemoembolization [TACE]) are performed frequently in patients with HCC who are not candidates for either resection or orthotopic liver transplantation (OLT) [7, 8].
Although locoregional therapies are associated with a significant risk of recurrence or tumor progression with a longer duration of follow-up, the effectiveness of these treatments in inducing tumor necrosis and providing temporary control of tumor spread makes them ideal procedures as a bridge to OLT [9–11]. This is an important consideration because the waiting time for OLT has increased progressively over the past few years [12], leading to an increased risk of tumor progression and therefore of dropout from the waiting list [13, 14]. Preliminary data have suggested a possible benefit of locoregional treatments in reducing the risk of dropout due to tumor progression when the waiting time exceeds 6 months [14–16], but solid evidence supporting this practice is lacking. Ideally, confirmatory evidence would be provided by randomized controlled studies [17]. However, given the risk of tumor progression, many physicians are reluctant to offer no treatment to patients with HCC who are on the waiting list for OLT.
There are basically two therapeutic alternatives in patients with HCC on the waiting list for OLT: TACE or thermal ablation procedures, such as radiofrequency ablation, laser ablation, and cryoablation.
Radiofrequency ablation is the thermal procedure that is most widely used for treating HCC. Radiofrequency ablation is a thermal treatment technique that produces coagulation necrosis of tumor cells by heating tumor tissues with temperatures exceeding 55°C. Radiofrequency ablation can be effectively applied in small lesions (< 4 cm), either hypervascular or hypovascular, and the overall necrosis induced is higher than that achieved using TACE. However, radiofrequency ablation can be applied only locally in a limited number of nodules and tumor recurrence is frequent, reaching 59% after 1-year follow-up [18].
TACE is based on the mechanical occlusion of the arteries feeding hypervascular HCC nodules coupled with the antitumoral effect of cytostatics. TACE is particularly effective in hypervascular lesions. It allows a regional treatment including large and multinodular lesions. TACE may also be potentially effective in small HCC nodules not depicted on preoperative studies, but confirmatory studies are lacking. However, the overall tumor necrosis induced by TACE seems to be inferior to that induced by radiofrequency ablation. In addition, investigators recently reported that TACE performed before liver transplantation has no impact on patient survival [19].
The primary objective of the present study was to assess the treatment efficacy of TACE in patients with HCC on the waiting list for OLT. We also assessed the results of TACE in small HCC nodules detected histologically after OLT that had not been detected on preoperative imaging to assess the efficacy of chemoembolization as a regional therapy in the liver.
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Preoperative diagnosis of HCC was performed according to the guidelines established by the European Association for the Study of the Liver (EASL) [17]. Patients with HCC were selected for OLT on the basis of the Milan criteria [5]: a solitary tumor < 5 cm or three or fewer lesions—none > 3 cm—without extrahepatic or vascular spread.
Because of an estimated waiting time exceeding 6 months, chemoembolization was indicated before OLT in 62 patients (54.9%). The mean waiting time before OLT was 201 days (range, 3–464 days).
Chemoembolization was not possible in four cases because of technical factors or medical contraindications. Two patients were excluded from the study because they had received another preoperative therapy along with chemo embolization (radiofrequency ablation [n = 1] or surgical re section [n = 1] before chemoembolization).
Our final study group included 56 patients: 10 women and 46 men ranging in age from 42 to 73 years (mean age, 58 years).
Viral hepatitis was the most common cause of liver disease, accounting for 67.9% of the cases (n = 38), followed by alcoholic liver disease (23.2%, n = 13). The cause in the remaining five patients (8.9%) was mixed (viral and alcoholic).
CT Technique
Preoperative diagnosis of HCC was based on EASL criteria: hypervascular
lesions on CT with washout in tumors larger than 2 cm or hypervascular tumors
on CT and MRI larger than 2 cm.
Helical CT was performed with single- or double-slice CT (ProSpeed Plus and Nxi, GE Healthcare). Patients underwent biphasic study at 25 and 70 seconds after injection of 150 mL of nonionic contrast medium at 3–5 mL/s. We routinely obtained equilibrium phase images 2–3 minutes after the administration of contrast material.
CT was performed 1 month after the embolization procedure with the same protocol. Follow-up CT was repeated every 3 months until transplantation.
TACE Procedure
All patients had adequate hepatic function to undergo TACE. More than half
of the cohort (64.3%, n = 36) had Child-Pugh class A cirrhosis and
33.9% (n = 19), class B; Child-Pugh class C cirrhosis was seen in
only one patient. An informed consent form was obtained from all patients.
Celiac and superior mesenteric arteriography was performed to map the arterial anatomy and to assess portal flow. Chemoembolizations were per formed with a mixture of 50 g of doxorubicin hydrochloride (Adriamycin, Adria) and 15 mg of iodized oil (Lipiodol Ultrafluide, Andre Guerbet) given before mechanical obstruction with absorb able gelatin sponge particles (Spongostan, Johnson & Johnson). The mixture of chemotherapy and iodized oil was equally distributed among the affected lobes. When the tumor was localized in only one lobe, a large dose of the mixture was ad ministered to the affected lobe (usually two thirds to the affected lobe and one third to the unaffected lobe), in terms of treating potentially undetected lesions.
The procedure was non-tumor-selective and was done in a single session, except in one patient who underwent two sessions. Patients were under conscious sedation for the procedure.
TACE was well tolerated by most of the patients. Most patients experienced abdominal pain, fever, nausea, and vomiting, consistent with postembolization syndrome, which was controlled with medical treatment. Only one patient experienced hepatic insufficiency that required emergency transplantation a few days after TACE. That patient had wide portosystemic anastomoses and hepatofugal flow that were overlooked during the TACE procedure. None of the patients died in association with TACE. The mean time between chemoembolization and OLT was 201 days (range, 3–464 days).
Pathologic Evaluation
Radiologic findings before and after TACE were assessed and correlated with
the histologic findings after OLT.
The liver explants were sliced and examined by the same pathologist. In the analysis of the HCC characteristics in the liver explant, tumor size, number of lesions, tumor stage (pT1–pT4) according to the United Network for Organ Sharing (UNOS) classification, and the presence or absence of vascular invasion were recorded. The degree of treatment-induced necrosis in each nodule was categorized as greater than 90%, between 50% and 90%, or less than 50%.
Tumor nodules found at histologic examination that had not been detected before OLT were specifically recorded and measured, and the degree of tumor necrosis was recorded.
Actuarial survival was estimated by the Kaplan-Meier method.
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Radiologic–Pathologic Correlation
On the explanted livers, 131 HCC nodules were detected at histologic study.
The size of the lesions ranged from 0.1 to 9 cm (mean, 1.8 cm). Preoperative
radiologic studies correctly detected 92 HCC lesions. The sensitivity of the
radiologic studies was 70.2%. The false-negative rate was 29.8%.
There was a false-positive lesion in our series (Fig. 1A, 1B, 1C, 1D, 1E). The nodule had transient brisk hyperenhancement on arterial phase imaging, isodensity relative to the normal liver parenchyma on portal phase imaging, and hypodensity relative to normal liver parenchyma on delayed imaging. This lesion was depicted on selective proper hepatic arterio graphy. Complete iodized oil retention inside the nodule was present on CT 1 month after TACE. On histopathologic examination, the nodule was not identified.
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On preoperative imaging studies, 91.4% of the HCCs were hyperenhancing in the arterial phase. After TACE, 90.4% of these tumors had nodular retention of iodized oil. The mean percentage of necrosis was 79.2% in this group of hypervascular lesions (Fig. 2A, 2B, 2C, 2D).
Although all patients included in the study met the Milan criteria before liver transplantation, pathologic data on the explanted liver showed that 11 patients (19.6%) did not meet those criteria. Eight of these patients had more than three nodules; two had three nodules, but some were more than 3 cm (one 9-cm large lesion); and one patient had a solitary 6.5-cm tumor. Two of the 11 patients (18%) that exceed Milan criteria showed HCC recurrence. These two patients were the only ones with vascular invasion in this subgroup. In one of the patients with HCC recurrence, there was a great discrepancy between the radiologic tumor size and pathologic tumor size. The lesion was a unique 4.8-cm nodule that showed an infiltrative pattern on pretransplantation CT. On explanted liver, 3 months after TACE, the lesion was 9 cm, was not encapsulated, and showed no quantitative necrosis. In addition, there was microvascular and biliary invasion, and two satellite nodules were also found. The patient experienced prompt intrahepatic and extrahepatic tumor recurrence and died 12 months after OLT. Vascular invasion was observed in six patients, including microvascular invasion in three patients and macrovascular invasion in three patients.
Follow-Up and Survival
The average follow-up for all patients in this study was 31.5 months, with
a minimum follow-up period of 3 months. The overall median survival of all 56
patients was 53.3 months from the date of OLT. The recurrence-free survival at
5 years is shown in Table 1.
The 1- and 5-year recurrence-free survival rate was 82.9% and 60.4%,
respectively, for the 56 patients. Only six patients (10.7%) developed HCC
recurrence.
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At the end of the study, 16 patients (28.6%) had died and six patients (10.7%) had developed HCC recurrence. Three of the patients with HCC recurrence showed microvascular invasion, one showed lymphatic invasion, and two exceeded the Milan criteria for liver transplantation. However, two patients with tumor recurrence did not present vascular or lymphatic invasion at histologic examination and were within the established Milan criteria. Only one of the six patients who developed HCC recurrence is still alive. For the study population, the median cumulative survival value was 53.33 months (95% CI, 44.99–61.67 months) (Fig. 4). The overall actuarial survival rate at 5 years was 60.4% (Table 1). Non-tumor-related mortality occurred in 11 patients.
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The main advantages of thermal ablation are that greater necrosis can be induced and liver function is less affected by the procedure than by TACE. However, thermal ablation can only treat localized lesions, seen on CT or sonography, and cannot treat the whole liver during a single session as we can with TACE.
In our study, total hepatectomy after OLT offered us a unique chance to investigate the entire parenchyma, to assess the therapeutic effect of TACE on preoperatively visible and nonvisible tumors, and to determine the real extent and spread of HCC.
As we expected, preoperative staging underestimated the number of nodules. Preoperative radiologic studies correctly detected 70.2% of the HCC nodules (92/131). The sensitivity of preoperative radiologic studies was therefore similar to previous series reported in the literature [21, 22].
The extent of tumor necrosis after chemoembolization has been reported to range from 60% to 100% [20, 23–29]. In our study, the percentage of tumor necrosis in the nodules detected at histologic study was greater than 90% in 38% of the nodules, between 50% and 90% in 15% of the nodules, and less than 50% in 48% of the nodules. Overall, 53% of the nodules had tumor necrosis greater than 50%. The results in terms of procedure-induced necrosis are similar to those of previous studies. Decaens et al. [19] found that only 30% of patients had tumor necrosis of greater than 80%.
As has been previously reported in other series [30, 31], our series showed great correlation between hypervascularity of the nodules in the presurgical studies, nodular retention of iodized oil after TACE, and percentage of necrosis. In 90.4% of the hypervascular tumors, there was nodular retention of iodized oil after TACE with a mean percentage of necrosis of 79.2% of necrosis at histopathologic examination.
Technical details of the TACE method vary considerably among centers. Because there is no consensus on how selective chemoembolization should be, in our series TACE was always performed nonselectively to treat the whole liver. Although some authors recommend avoiding whole-liver chemoembolization because of potential serious injury to the liver [10], other authors advocate bilobar embolization and global treatment of the whole liver [6, 32]. In well-selected patients, chemoembolization is a safe treatment. Only one patient in our series experienced a serious complication, rapid liver failure, after TACE that resulted in an urgent liver transplantation. In fact, that patient had large portosystemic anastomoses and hepatofugal flow that had been overlooked during the TACE procedure. Our results are probably related to the fact that, in our institution, poor liver function is considered a relative contraindication for pretransplantation TACE. In fact, more than half of the cohort had cirrhosis assessed as Child-Pugh class A (64.3%). The single patient with Child-Pugh class C cirrhosis who underwent this treatment before OLT was thought to have a long waiting time before transplantation and the benefit of TACE in an attempt to prevent dropout was considered to be higher than the risk of severe impairment of liver function in that particular case.
Another argument to perform embolization of the whole liver is that it may allow reaching any possible HCC nodule that may not have been detected during the previous staging [6] and therefore a regional tumoral treatment would be performed. However, our results show that tumors that were preoperatively detected had more necrosis (mean necrosis, 67.8%) than those not detected preoperatively (mean necrosis, 1.57%), although the former were substantially larger (mean diameter, 2.58 vs 0.68 cm). Therefore, the antitumoral effect of chemoembolization in HCC nodules not detected radiologically is limited probably because the nondetected nodules are small and lack arterial hypervascularization.
Previous reports have established that TACE achieves maximal tumor response when repeated multiple times [33]. In our series, the aim of the procedure was to reduce the rate of tumor progression to avoid dropout from the transplantation waiting list, not to achieve a complete response in terms of necrosis; therefore, we did not consider performing multiple TACE sessions. Only one patient underwent a second TACE treatment because follow-up CT showed tumoral progression (a new, third, HCC nodule had appeared). This approach is supported by the relatively short waiting time before liver transplantation in our series (mean time, 201 days). Therefore, another schedule may be needed in centers with longer waiting periods.
Previous studies involving patients receiving preoperative radiologic treatment of HCC before liver transplantation have conflicting results in terms of patient survival and tumor recurrence [19, 20, 34, 35]. In terms of survival, a study from Taiwan compared the outcomes of 29 patients with HCC undergoing transplantation with and without prior transarterial embolization (TAE). The TAE group had a better survival (84% at 5 years) than the non-TAE group (75% at 4 years) [29]. However, Decaens et al. [19] reported a series of 200 patients and concluded that, with a mean waiting period of 4.2 months and one TACE procedure, TACE performed before transplantation did not influence overall survival and disease-free survival after transplantation.
In terms of postoperative recurrence, Majno and coworkers [35] reported that HCC recurrence was infrequent (7%) in patients in whom TACE induced complete necrosis of the tumor. Disease-free survival was also significantly higher in these patients than in those patients who did not show complete necrosis or those who did not undergo TACE [35]. These results are different from the results in our series. Two of the six patients (33.3%) who developed HCC recurrence had mainly total necrosis. Unfortunately, we do not have an explanation for this fact.
Although all patients included in the study met the Milan criteria before liver transplantation, pathologic data on the explanted liver showed that 11 patients (19.6%) did not meet these criteria. However, only two of those 11 patients (18%) showed HCC recurrence. Interestingly, these patients were the only ones with vascular invasion in this subgroup. Obviously, our study is limited because it is a retrospective and observational study and not a randomized controlled trial. However, the widely held premise that locoregional therapy may slow tumor progression and thus also reduce the risk of dropout from the waiting list for OLT [15, 16] makes it unlikely to perform randomized controlled trials because of ethical considerations.
In conclusion, our results suggest that chemoembolization is a safe treatment in well-selected patients. Its antitumoral effect is high in hypervascular lesions (median necrosis, 79.2%), and it provides good local control in preoperatively diagnosed HCC (median necrosis, 67.8%). However, in lesions not visible on imaging before transplantation, the efficacy of TACE decreases (median necrosis, 1.57%). Chemoembolization in patients who are candidates for OLT should, therefore, be as selective as possible to maximize necrosis of the targeted tumors because its effect in small, nondetected lesions in the rest of the liver is limited.
However, under the current HCC-adjusted MELD (model for end-stage liver disease) scheme of organs allocation, patients with an HCC larger than 3 cm or with more than two nodules will benefit from a fast-track transplantation in less than 3 months and preoperative treatment will probably not be necessary. On the other hand, our results show that chemoembolization has minimal antitumoral effect in HCC nodules not detected preoperatively. Therefore, chemoembolization will probably not be the first option as a bridge to transplantation. In that setting, patients on the waiting list for OLT with HCC who will need treatment will have small solitary nodules that are probably best treated with thermal ablation.
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