Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fifth most common cancer worldwide. The incidence of HCC is increasing in conjunction with the prevalence of major risk factors for its development, such as cirrhosis caused by hepatitis C or nonalcoholic fatty liver disease. It is the third leading cause of cancer-related mortality (1
Significant progress has been made during recent years in the management of HCC. Treatments are generally classified as either curative or palliative; choice of therapy depends on tumor characteristics, presence of metastasis or vascular invasion, and liver function. Recommended curative treatments for HCC include liver transplantation, surgical resection, and radiofrequency ablation; however, the majority of patients are not candidates for these treatments (2
Transarterial chemoembolization (TACE) is the most commonly implemented palliative treatment for HCC, particularly for patients with unresectable HCC who are ineligible for transplantation (1 3, 4 5–12
TACE with drug-eluting beads (DEB-TACE ) is a novel drug delivery system that results in a slow and sustained release of chemotherapeutic agent. In many centers, DEB-TACE treatment has replaced the use of cTACE in recent years. Two initial studies established DEB-TACE to be a safe and effective palliative treatment of HCC (13, 14 15–17 DEB-TACE has been proposed to have an improved pharmacokinetic profile with fewer systemic adverse effects compared with cTACE (17–19
Although studies comparing cTACE and DEB-TACE are beginning to appear in the literature (20–24 DEB-TACE .
RESULTS
A total of 176 patients were listed for OLT and included in the initial analysis of dropout. One hundred eleven consecutive patients who underwent cTACE (n=76) or DEB-TACE (n=35) before OLT and had explant pathology available were included in the subsequent analysis of explant pathology. There were no differences between groups in terms of age, sex, stage of cirrhosis, or stage of HCC (Table 1 ). The most common etiology of HCC was hepatitis C (62% and 58% of cTACE and DEB-TACE patients, respectively). The vast majority of patients in both groups had early or intermediate (stage A or B) HCC classification at baseline as defined by the Barcelona Liver Cancer Clinic staging criteria; almost 90% had Child-Pugh scores of A or B. All patients were determined to be non-resectable by an experienced hepatobiliary surgeon based on location or extent of cirrhosis.
TABLE 1: Baseline clinical characteristics of patients with HCC undergoing OLT
Wait time to transplant was longer in the DEB-TACE patients, but this did not reach statistical significance (mean wait time 300±157 days and 399±211 days for cTACE and DEB-TACE patients, respectively; P =0.10). In the cTACE group, the average time from last treatment to transplant was 161 days (range 3–546, median 147). In the DEB-TACE group, the average time from last treatment to transplant was 220 days (range 15–1,008, median 161). There was no statistical difference between the two groups with regard to average time from last treatment to transplant.
There was no difference in the number of treatments needed to control HCC in patients treated with cTACE versus DEB-TACE , or patients who proceeded to OLT were delisted. In the cTACE group, 34.2% only required one treatment, 40.7% had two treatments, 15.7% had three treatments, and 10.8% had four or more treatments. In the DEB-TACE group, 23.5% only required one treatment, 35.3% had two treatments, 20.5% had three treatments, and 20.5% had four or more treatments (P =NS).
Overall, tolerability of the procedure was similar in both groups. In the cTACE group, there were 14 major complications requiring prolonged hospital stay out of 141 procedures (10%): eight hepatic decompensation, two severe abdominal pain, one cytopenia, one premature ventricular contractions, one acute renal failure, and one gastrointestinal bleed. In the DEB-TACE group, there were 14 major complications requiring prolonged hospital stay out of 128 procedures (10.9%): six hepatic decompensation, two severe abdominal pain, one gastrointestinal bleed, one spontaneous bacterial peritonitis, one acalculous cholecystitis, one hemorrhagic mucositis, and one hepatic abscess. No patients were removed from the transplant list or died while waiting because of complications of the TACE procedure.
Explant pathology information was available for all patients who underwent OLT (Table 2 ). There were no significant differences between groups in explant pathology characteristics. Approximately two thirds of patients in both groups had a single lesion; very few patients had four or more lesions. Tumors were located in the right lobe in 66% and 77% of cTACE and DEB-TACE patients, respectively. Most patients (76%–80%) in both groups met the criteria for Milan, and over 90% of patients met Region 5 criteria.
TABLE 2: Pathologic explant data of OLT patients after cTACE or DEB-TACE
Necrosis details on explant pathology were available for 66 patients who underwent cTACE and all patients who underwent DEB-TACE . cTACE resulted in complete necrosis in 50.9% of cases, greater than or equal to 50% necrosis in 24.5%, less than 50% necrosis in 3.7%, and no necrosis in 20.8% (Fig. 1 ). DEB-TACE resulted in complete necrosis in 57.1% of cases, greater than or equal to 50% necrosis in 17.1%, less than 50% necrosis in 2.8%, and no necrosis in 22.9%. Differences in rates of necrosis between groups were nonsignificant. Microvascular invasion was present in seven (9.2%) and in three (8.6%) of cTACE and DEB-TACE cases, respectively (P =0.23). Response to locoregional therapy did not correlate with tumor grade, time since last treatment, or number of treatments.
FIGURE 1: Percent necrosis seen on liver transplant explant after treatment with cTACE versus DEB-TACE .
Numerically more patients who received DEB-TACE were delisted before transplantation compared with those who received cTACE, but this difference did not reach statistical significance. (42% vs. 29%; P =0.08). Because of the retrospective nature of this database, the reason for delisting could not reliably be elucidated. All patients were followed after delisting for ongoing cancer treatments and survival. The rate of delisting and dropout in patients treated with cTACE was higher in patients beyond Milan criteria (47% beyond vs. 24.6% within, P =0.02). In contrast, patients treated with DEB-TACE had an equivalent rate of dropout whether they were within Milan criteria or outside of Milan criteria (45.1% within vs. 50% outside, P =0.77). The known risk factors for dropout of longer wait time, higher Child–Turcotte–Pugh (CTP) class, and higher Barcelona Clinic Liver Cancer (BCLC) stage had a significant effect in patients treated with cTACE. When patients were treated with DEB-TACE , these risk factors were no longer significant (Table 3 ).
TABLE 3: Characteristics of patients experiencing dropout from OLT list versus those who underwent OLT
There was no difference between groups in the proportion of patients with tumor recurrence. 12 (15.7%) patients within the cTACE group and 4 (11.4%) patients within the DEB-TACE group had recurrence of HCC after OLT (P =0.54). In the 12 patients in the cTACE group with recurrence, 9 patients were within Milan criteria, and 8 of 12 had no microvascular invasion on explant. In the four patients in the DEB-TACE group, three were within Milan criteria, and one of four had microvascular invasion on explant. More patients in the recurrence group had microvascular invasion on explant compared to the overall group (31% vs. 9%, P =0.02). Complete necrosis on explant was seen in 18% of recurrence patients, compared to the overall group of 53.4%. Greater than or equal to 50% necrosis was seen in a higher proportion of recurrence patients, compared to the overall group of 54.5% versus 21.5%. No necrosis was seen in 27.2% of recurrence patients compared to the overall group of 21.5%. In patients with recurrence, tumors were well differentiated in 31.2%, moderate in 56.2%, and poorly differentiated in 12.5% (Table 4 ).
TABLE 4: Comparison of explant pathology of patients with recurrence of HCC after OLT compared to entire treatment group
Total median follow-up time in the cTACE group was 3.8 years (range 0.1–9.8 years), and in the DEB-TACE group was 3.35 years (range 0.7–8.7 years). Overall survival was calculated based on intention-to-treat recurrence-free survival from date of diagnosis and was not statistically different between the groups (Fig. 2 ).
FIGURE 2: Recurrence free intention-to-treat survival from date of diagnosis of HCC in patients treated with cTACE versus DEB-TACE while waiting for OLT.
DISCUSSION
This study documented excellent necrosis rates in the majority of patients treated with either TACE modality. To our knowledge, this is the first comparison of pathologic response rates between cTACE and DEB-TACE in patients with HCC who underwent OLT.
The presence of partial necrosis has been shown to be significantly associated with a risk for HCC recurrence. A study by Ravaioli et al. (25
A recent small, retrospective study evaluating DEB-TACE (n=8) and bland embolization (n=8) before OLT in patients with HCC reported that 77% of DEB-TACE patients achieved complete necrosis compared with 27% of bland embolization patients (P =0.04). The authors recommended that further studies with larger sample sizes be conducted to confirm these findings. They concluded that the high rate of necrosis associated with DEB-TACE is likely a direct effect of drug action in hypervascular and peripheral areas of HCC nodules (26 DEB-TACE in our larger cohort, but this rate was still acceptable with nearly 60% of patients having complete necrosis on explant.
Although no statistical differences were seen between TACE modalities in this study, pharmacokinetic data specific to DEB-TACE suggest the possibility of higher rates of necrosis for DEB-TACE compared with cTACE. A 2006 study of DEB-TACE in a rabbit model established that, during times of greatest tumor necrosis (7–14 days post-treatment), the rate approached 100% (19 DEB-TACE treatment achieved localized concentrations across this time period sufficient to cause widespread cancer cell death. The necrosis rates in animals that received cTACE approached 90% at day 3 after administration but were lower at day 7. Although this toxic effect of cTACE appears beneficial, the authors noted that it may actually be detrimental secondary to occlusion or stasis of the main vessel feeding the tumor, an effect not found in DEB-TACE study animals. They concluded that there is clear supportive evidence for the TACE concept, and that DEB-TACE produced higher tumor drug levels and maintained a greater degree of necrosis through day 7 compared with cTACE in this animal study (19
In the current study, both cTACE and DEB-TACE resulted in complete necrosis in more than half of patients (50.9% and 57.1% for cTACE and DEB-TACE , respectively); approximately three fourths of patients in both groups experienced tumor necrosis rates of greater than or equal to 50%. The rates of tumor recurrence after transplantation did not differ between groups; this appears to be reflective of the overall excellent and similar rates of necrosis between cTACE and DEB-TACE that were observed.
Prolonged waiting times at many centers are associated with an increased risk of tumor progression and dropout or delisting of patients from the waiting list. There is currently a tendency to expand the Milan criteria to increase the number of patients who receive OLT (27 DEB-TACE patients were delisted compared with cTACE patients, although this number did not reach statistical significance. This likely is a result of the numerically longer wait time for patients who received DEB-TACE related to increased demand for organs during the time period that DEB-TACE was utilized.
When these data were stratified according to Milan criteria, a significant treatment group difference was evident in pattern of dropouts between patients meeting and exceeding Milan criteria. Specifically, the dropout rate in patients receiving DEB-TACE did not differ between patients within versus outside of Milan criteria. In contrast, there was a significantly higher rate of dropout among patients receiving cTACE who were outside of Milan criteria compared to those within criteria. This suggests that perhaps in patients with disease beyond Milan criteria requiring downstaging, DEB-TACE may be a more useful treatment modality than cTACE. In addition, patients with more advanced disease, CTP class B/C or BCLC stage B/C, seem to have a better chance of proceeding to OLT if they are treated with DEB-TACE rather than cTACE. This confirms what was seen in the Precision V study, where patients with more advanced disease had better response rates when treated with DEB-TACE rather than cTACE (21
More recent studies directly comparing cTACE with DEB-TACE in terms of clinical parameters offer encouraging results. A small retrospective study published in 2010 showed improved survival with DEB-TACE versus cTACE in patients with unresectable HCC (20 DEB-TACE versus cTACE for treatment of HCC reported a numerically better disease control rate with DEB-TACE , including improved disease control in the subset of patients with more advanced disease (21 DEB-TACE compared with those who received cTACE (28 DEB-TACE compared to cTACE (29 DEB-TACE is equivalent to cTACE in terms of tumor response, although safety equivalence was more difficult to determine (30
Randomized, controlled trials are underway to further evaluate clinical outcome parameters as well as pathologic response rates to TACE modalities for treatment of HCC and in patients awaiting OLT.
Potential limitations of this study include its single-center and nonrandomized study design. This study represents a real-world experience of conventional TACE and DEB-TACE , which is important information to determine which modality is better. The excellent pathologic response rates documented in the majority of patients for both TACE modalities suggest that either is an acceptable treatment to achieve tumor control for patients awaiting OLT. Larger studies employing a prospective randomized design should be undertaken to provide further information on potential differences between the two treatment options.
MATERIALS AND METHODS
Consecutive patients who underwent cTACE or DEB-TACE for HCC between January 2005 and December 2010 at California Pacific Medical Center were included in the analysis. The following data were obtained from medical records: demographics (age, gender, race or ethnicity), clinical characteristics (underlying disease, presence or absence of diabetes mellitus, body mass index, pretransplant alpha-fetoprotein, BCLC stage, pretransplant MELD score, Child-Pugh score, Eastern Cooperative Oncology Group performance status score), and survival. Patients who underwent OLT and had explant pathology were reviewed for response rate to TACE. Pathology information included lesions (number, location, size), tumor differentiation, Milan criteria, microvascular invasion, and tumor recurrence. One hundred seventy-six patients were included in this retrospective, nonrandomized study.
At our center, conventional TACE was used exclusively for transarterial therapy until January 1, 2008. At this time, a programmatic decision was made to change to TACE with drug-eluting beads. Patients were grouped based on which transarterial therapy they received, which was based on at what time point they were treated. All procedures were performed by the same interventional radiology team. Each patient underwent cross-sectional imaging with computed tomography or magnetic resonance imaging 4 weeks after TACE procedure, and then on an every 3-month basis. Any evidence of ongoing enhancement was re-treated with transarterial therapy.
cTACE was performed using lipiodol mixed with three chemotherapeutic agents: doxorubicin 50 mg, cisplatin 50 mg, and mitomycin C 10 mg. Standard hepatic angiography was performed, and the mixture was infused into the feeding arteries of tumors until arterial stasis was achieved. Gelfoam was used on a case-by-case basis to obtain stasis of the arterial feeding supply of the tumors.
DEB-TACE was performed using LC Bead. The size of the bead used was determined by interventional radiology based on the size of tumor to be treated. All patients were treated using 100- to 300-µm-size beads or 300- to 500-µm-size beads. The beads were loaded with 75 mg of doxorubicin per vial, with a maximum of 150 mg of doxorubicin infused per treatment. If necessary, unloaded beads were subsequently infused to achieve adequate decrease of arterial flow. Because LC Beads are non-radio-opaque, the vials were mixed with non-iodinated contrast. The number of vials used for each patient was variable depending on the number and size of tumors. Multiple, larger tumors were treated with two vials of LC beads loaded with doxorubicin, and smaller, solitary tumors were generally treated with a single vial. Early in the treatment experience, beads were infused until full stasis was achieved. After 1 year of experience, it was determined that sluggish flow was adequate to achieve tumor kill, and the treatment protocol was modified to achieve sluggish flow.
Patients were listed for OLT if they met listing criteria at California Pacific Medical Center. This center lists patients within Milan criteria (one lesion up to 5 cm in size, or up to three lesions, all less than 3 cm in size) (31
All explanted livers were processed according to a routine clinical protocol; the freshly explanted livers were serially sliced at 1-cm intervals, and any macroscopically visible nodules underwent hematoxylin and eosin staining and microscopic evaluation. The percentage of necrosis was defined as the volume of necrosis as compared to the total tumor volume and categorized as complete necrosis (no viable tumor), greater than or equal to 50% necrosis, less than 50% necrosis, or no evidence of necrosis. In the case of multiple tumors, the percentage of necrosis was determined by correlation of transarterial therapy with pathologic explant nodule, and the worst percentage necrosis for all treated lesions was determined. All lesions that had viable tumor present for evaluation was graded by differentiation (well, moderate, poor). Each tumor nodule was sectioned, stained, and carefully examined for microvascular invasion.
Overall survival was calculated from date of diagnosis to date of death as intention-to-treat. Death dates of all patients were verified through the Social Security Death Index. Recurrence-free survival was calculated from the date of diagnosis to the date of recurrence after OLT or, in the instance of no recurrence, at the date of death.
The study was approved by the Institutional Review Board of California Pacific Medical Center with a waiver of informed consent. Patients gave written informed consent before all procedures.
Statistical Analysis
Demographic features and study variables were analyzed using STATA software package, version 11. Categorical variables, which are presented as ratios and percentage, were compared using the chi-square or Fisher exacts test as appropriate. Continuous variables such as age, BMI, and MELD score were compared using the Student t test. The percentage of necrosis on explant tumors were calculated and plotted on a bar graph. A P value of less than 0.05 was considered statistically significant.
ACKNOWLEDGMENTS
Emma Hitt, Hitt Medical Writing, LLC.
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