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Original Research |
1 Department of Radiology, David Geffen School of Medicine at UCLA, 10833 Le
Conte Ave., Los Angeles, CA 90095-1721.
2 Present address: Department of Radiology, Konkuk University Hospital, Seoul
143-729, Korea.
3 Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles,
CA.
4 Department of Digestive Diseases, David Geffen School of Medicine at UCLA, Los
Angeles, CA.
Received March 21, 2007;
accepted after revision October 19, 2007.
Address correspondence to D. S. K. Lu
(dlu{at}mednet.ucla.edu).
Abstract
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MATERIALS AND METHODS. A total of 42 patients (23 men and 18 women; age range, 22–83 years) with unifocal HCC underwent percutaneous radiofrequency ablation as their sole interventional treatment between May 1998 and August 2003. Subcapsular tumors were selected for ablation if there was no large exophytic component, and they were ablated through an indirect puncture, a gradual increase in radiofrequency power output, and needle track ablation. Technical effectiveness after single-session radiofrequency ablation, complications, local tumor progression, overall survival, and event-free survival rates were compared between the two groups.
RESULTS. There were 15 patients with subcapsular HCC and 27 patients with nonsubcapsular HCC. The technical effectiveness was 93% (14/15) in the subcapsular HCC group and 96% (26/27) in the nonsubcapsular group (p > 0.99), complication rates were 0% (0/15) and 7.4% (2/27) (p = 0.53), and rates of local tumor progression were 21% (3/14) and 15% (4/26) (p = 0.68), respectively. No needle track or peritoneal seeding was found in either group. No significant differences were found in overall survival (3 years: 60% vs 56%; p = 0.78) and event-free survival rates (3 years: 59% vs 48%; p > 0.99) between the two groups.
CONCLUSION. Radiofrequency ablation of subcapsular HCC can be comparable to that of nonsubcapsular HCC with regard to the technical and clinical outcomes when there is proper patient selection and an optimized technique is used.
Keywords: hepatocellular carcinoma • interventional radiology • liver • radiofrequency ablation
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Radiofrequency ablation for centrally located tumors close to major bile ducts can cause bile duct injury, leading to abscess or biloma associated with bile duct strictures [1, 2]. Also, radiofrequency ablation for tumors adjacent to blood vessels larger than 3 mm may result in incomplete necrosis as a result of blood flow–related "heat-sink" effect [3].
Llovet et al. [4] reported that percutaneous radiofrequency ablation of subcapsular HCC increased the risk of neoplastic seeding (36%, four neoplastic seeding of 11 subcapsular cases) along the percutaneous needle track, one of the most serious complications in any cancer treatment. However, their results were not consistent with anecdotal experiences from many other radiofrequency ablation groups, thus initiating a debate over whether the subcapsular location of tumor is a contraindication for radiofrequency ablation [5–8]. Several subsequent studies have yielded conflicting results, so the safety controversy continues [9–12]. In addition, some authors have reported that a subcapsular location was associated with a high rate of local recurrence in radio frequency ablation of HCC [13, 14], whereas recent studies have not supported such an association [10, 12]. Therefore, it remains controversial whether the subcapsular location of HCC is an unfavorable factor for percutaneous radiofrequency ablation of HCC.
In this retrospective study, our hypothesis was that percutaneous radiofrequency ablation of subcapsular HCC is comparable to that of nonsubcapsular HCC with regard to complications, local efficacy, and overall survival when cases are properly selected, direct puncture is avoided, gradual power deposition is used, and thermocoagulation of the needle track is performed.
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-fetoprotein levels (> 200 µg/L) or tumor growth during follow-up
(n = 21). All patients were deemed to have unresectable HCC on the
basis of tumor size, location, or underlying liver function, or they had
refused surgical resection. The study population consisted of 23 men and 18
women with a mean age of 61.7 years (range, 22–83 years; median age, 63
years). The mean size of the index tumor was 2.9 cm (SD, 1.1 cm) in diameter
(range, 1.0–5.5 cm).
Radiofrequency Ablation
All radiofrequency ablation procedures were performed percutaneously by one
of two radiologists whose radiofrequency ablation experiences were 7 and 5
years, respectively. Radiofrequency ablation was performed with the patient
under conscious sedation (34 patients) or general anesthesia (eight patients).
Radiofrequency ablation devices used in this study included both multitined
expandable electrodes (2.0-, 3.0-, or 3.5-cm electrodes [LeVeen,
Radiotherapeutics, now Boston Scientific] or 2- to 3-cm model 30/3-cm
Starburst XL electrodes [Rita Medical]) and internally cooled electrodes (2.0-
or 3.0-cm single electrode or 2.5-cm cluster electrode [Cool-Tip, Radionics,
now Valleylab]). The selection of device was based on availability and
evolution of the devices over the time period of the study and on operators'
subjective preference. The algorithm of energy deposition was according to the
manufacturer's recommended protocols for each device. For the Boston
Scientific device, power output was increased manually until impedance started
to rise. First-cycle radiofrequency energy was then applied, with the peak
power setting kept constant for 15 minutes or until a rapid uncontrolled rise
in impedance automatically shut off the power. For the Valleylab device,
chilled water was circulated through the internal lumen of the electrode to
maintain the electrode tip temperature under 25°C, thus preventing
charring around the electrode tip during active heat deposition. The power
output was automatically controlled with the standard impedance control
algorithm during each ablation cycle of up to 12 minutes. For the Rita device,
radiofrequency energy delivery was based on a temperature control algorithm,
with a target temperature typically set between 95°C and 110°C.
Regardless of the device type, the needle track was carefully thermocoagulated by applying continuing radiofrequency energy at the end of each ablation, with the electrode being withdrawn slowly. For the Valleylab device, the track thermocoagulation was performed in a manual mode by applying 20- to 50-W power, or in the track ablation mode (depending on device vintage) to keep the electrode tip temperature above 80°C. The pump for the internal circulation of chilled water was turned off during thermocoagulation. For the Rita device, the track ablation mode was used, and the electrode tip temperature was similarly maintained above 80°C. For the Boston Scientific device, 10-W power was applied until automatic power termination occurred due to rapid rise in impedance.
For subcapsular tumors, special attention was given to avoiding puncture of the tumor along the exposed liver surface. Therefore, indirect access through the intervening nontumorous liver parenchyma was used in all cases. Power output was slowly increased for the ablation itself for both types of tumors. When multitined devices were used, the gradual power ramp-up was inherent in the manufacturer's algorithm. For the internally cooled devices, power output was manually ramped up over several minutes.
Ablation was performed by guiding and monitoring with either sonography (HDI 3000 or 5000, ATL) or CT (HighSpeed, GE Healthcare; or Somatom, Siemens Medical Solutions). Single or overlapping ablations were performed on the basis of index tumor size, geometry, and imaging feedback from sonography or CT during the ablation procedure. The goal of ablation was not only complete coverage of the index tumor but also achieving a safety margin of 5–10 mm around the tumor if feasible.
Postablation Follow-Up
Posttreatment CT (n = 38) or MRI (n = 4) was performed
within 1 month (usually within 2 days) of radiofrequency ablation. After
initial post-treatment imaging, follow-up imaging consisting of CT or MRI was
performed every 3 months. CT was performed with single-detector or MDCT (CTi
or LightSpeed, GE Healthcare; or Sensation 16, Siemens Medical Solutions) and
consisted of a dual-phase liver protocol that included unenhanced, hepatic
arterial dominant, and portal dominant phases (collimation, 5–7 mm;
pitch, 1–1.5). MRI was performed using 1.5-T clinical imagers (Horizon,
GE Healthcare; or Vision, Siemens Medical Solutions) and a liver protocol
consisting of unenhanced T2-weighted spin-echo imaging, unenhanced T1-weighted
gradient-echo imaging, and contrast-enhanced dynamic fat-saturated T1-weighted
gradient-echo imaging. For 42 patients, the median follow-up after
radiofrequency ablation was 23 months (range, 4–74 months; 95% CI,
18–27 months).
Comparison of Subcapsular and Nonsubcapsular HCC
Subcapsular HCC was defined as a tumor abutting the liver capsule. All 42
HCC nodules were retrospectively classified as either subcapsular or
nonsubcapsular by one author with 6 years of experience in abdominal imaging
who was unaware of other clinical and radiologic follow-up data. The following
items were compared between the two groups:
First, technical effectiveness, based on postablation images after single-session radio frequency ablation. When a preexisting tumor region was not fully covered by the new coagulation zone, even though distinct nodular enhancement was not clearly noted, the nodule was deemed incompletely treated.
Second, major complications, defined as those prompting further treatment or hospitalization, including hemorrhage requiring transfusion, ab scess requiring drainage, bile duct stricture re quiring biliary drainage, pleural effusion requir ing thoracentesis, tumor seeding, and hepatic insufficiency.
Third, local tumor progression, defined on follow-up imaging. In the case of liver transplantation, the last follow-up imaging studies before transplantation were used.
Fourth, overall survival, which was determined by the time from the initial radiofrequency ablation until the last clinical or imaging follow-up, or death.
Fifth, event-free survival, which was deter mined by the time from the initial radio frequency ablation until local tumor progression, emergence of intrahepatic new lesions, distant metastasis, or death.
Sixth, for patients who underwent orthotopic liver transplantation, survival was determined by the time from the initial radiofrequency ablation until the last clinical or imaging follow-up or death.
Data of patients' Child-Pugh classification, nodule size, technical effectiveness of ablation, local tumor progression, intrahepatic distant recurrence, extrahepatic metastasis, and complications were obtained from a prospectively collected computerized database. This data collection, as a matter of routine feedback for the ablation treatment in order to improve patient care, was approved by the institutional review board with waiver of informed consent.
Statistical Analysis
The variables in the subcapsular HCC and nonsubcapsular HCC groups were
compared. Patient age and tumor size were compared using the Mann-Whitney
test. Patient sex, Child-Pugh class, hepatitis C virus positivity, hepatitis B
surface antigen positivity, previous hepatic resection, needle biopsy, and
serum -fetoprotein level greater than 200 µg/L were evaluated using
the Fisher's exact test. Technical effectiveness rates, major complication
rates, and emerging rates of local tumor progression during follow-up were
also compared using the Fisher's exact test. Survival rates and event-free
survival rates were evaluated using the Kaplan-Meier method. Comparison of
these survival data were performed using the log-rank test. Median follow-up
periods were compared using the Mann-Whitney test. A p value of 0.05
was considered to be indicative of a statistically significant difference.
Statistical analysis was performed with commercially available software
programs (SPSS 10.0 for Windows, SPSS; and Graphpad Prism, version 3.00 for
Windows, Graphpad Software). All reported p values are
two-tailed.
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Median follow-up periods after initial radiofrequency ablation were 26 months (range, 4–62 months; 95% CI, 13–31 months) for the subcapsular group and 22 months (range, 8–74 months; 16–27 months) for the nonsubcapsular group (p = 0.60, Mann-Whitney test).
Technical Effectiveness
Technical effectiveness was achieved in 14 (93%) of 15 subcapsular HCCs
(Figs. 1A,
1B,
1C, and
1D) and 26 (96%) of 27
nonsubcapsular HCCs after single-session radiofrequency ablation. No
statistically significant difference was found between the two groups
(p > 0.99, Fisher's exact test). Patients with residual tumor were
further treated with either second-session radiofrequency ablation (one
patient with 5.0-cm nonsubcapsular HCC) or transarterial chemoembolization
(one patient with 3.8-cm subcapsular HCC). Thereafter, the two patients showed
complete local control based on follow-up CT or MRI studies.
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Local Tumor Progression Rates
Local tumor progression developed in three (21%) nodules of the 14
subcapsular HCCs in which complete technical effectiveness was achieved by
single-session radiofrequency ablation and in four (15%) of 26 nonsubcapsular
HCCs with complete technical effectiveness during the follow-up period. No
significant difference was seen between the two groups (p = 0.68,
Fisher's exact test).
Overall Survival Rates
A total of 12 patients, including four patients with subcapsular HCC and
eight patients with nonsubcapsular HCC, died during follow-up. Among them, the
death of one patient in each group was attributed to postoperative
complications after orthotopic liver transplantation. Overall survival rates
at 1, 2, and 3 years were 80%, 80%, and 60% in the subcapsular HCC group and
89%, 74%, and 57% in the nonsubcapsular HCC group (p = 0.78, log-rank
test) (Fig. 2).
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Survival Rates in the Patients with Orthotopic Liver Transplantation
Of the total 42 patients included in this study, 23 (55%) patients
underwent orthotopic liver transplantation during follow-up. The proportions
of patients who underwent liver transplantation were not significantly
different between the two groups (9/15 [60%] in the subcapsular HCC group vs
14/27 [52%] in the nonsubcapsular HCC group; p = 0.75, Fisher's exact
test). For those patients who underwent liver transplantation, overall
survival rates at 1, 2, and 3 years were 96%, 91%, and 71%, respectively. The
median tumor size of the subcapsular HCC group tended to be larger than that
of the nonsubcapsular HCC group, but this difference was not statistically
significant (3.8 vs 2.5 cm; p = 0.07). Complete tumor necrosis based
on histologic examination of the explanted liver was achieved in six (67%) of
nine subcapsular HCCs and in 10 (71%) of 14 nonsubcapsular HCCs (p
> 0.99, Fisher's exact test). Survival rates at 1, 2, and 3 years were
100%, 100%, and 67% in the subcapsular HCC group (n = 9) and 93%,
85%, and 71% in the nonsubcapsular HCC group (n = 14) (p =
0.59, log-rank test). No patient developed HCC recurrence after
transplantation.
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Regarding the safety of percutaneous radiofrequency ablation of subcapsular HCC, a major concern is neoplastic seeding into the needle track or peritoneal cavity. Reported rates of neoplastic seeding after radiofrequency ablation of hepatic tumors in general range from 0% to 4% [5–7, 9, 11, 15, 16]. Most of these studies did not specifically analyze the tumor location. To date, several articles have studied the relationship between subcapsular location of HCC and neoplastic seeding (Table 2). Llovet et al. [4] and Jaskolka et al. [9] showed that needle track seedings were associated with subcapsular location of tumor, whereas other investigators did not find such an association [10–12]. In the former groups, direct puncture of the subcapsular tumor was performed and thermocoagulation of the needle track was not routinely performed. In contrast, in the latter groups, authors tried to avoid direct puncture of subcapsular HCCs—albeit some cases with direct puncture were included in the study by Livraghi et al. [11]— and performed thermocoagulation of the needle track.
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At our institution, we think that multiple factors likely contribute to potential problems in the ablation of subcapsular tumors. We theorize that bleeding and peritoneal tumor seeding likely occur because of puncture or rupture of the subcapsular tumor and the liver capsule. This risk is expected to correlate with the extent of tumor abutting the liver surface. Even if indirect puncture is used and there is no transgression of the subcapsular tumor surface by the ablation electrode, tumors that are largely exophytic or that have a large subcapsular surface area may rupture due to any rapid heating of the tumor. Therefore, if such risk is recognized, cases are properly selected, and careful attention is given to technique, we believe that many subcapsular tumors can be safely ablated. Those tumors that are significantly exophytic or have large surface contact with the liver capsule should be avoided. On the basis of the authors' subjective experience and recommendations, maximum tolerance for an exophytic component would be approximately one third of the tumor volume, and maximum tolerance for surface area contact would be approximately one third of the tumor surface. Depending on the case and the operator's level of comfort, however, tumors with lesser degrees of surface contact or protrusion should also be carefully considered for exclusion. For cases selected for ablation, the technique should be optimized by using indirect puncture of the tumor through the nontumorous liver, a slow and gradual increase in radiofrequency power output, and needle track coagulation to minimize bleeding when appropriate.
Another concern of radiofrequency ablation of subcapsular HCCs is a high risk for local recurrence. Two studies have suggested that subcapsular location is a risk factor for local tumor recurrence [13, 14]. However, our results indicated that there is no significant difference with regard to the rate of local tumor progression between subcapsular and nonsubcapsular HCCs, even though tumor size was significantly larger in the subcapsular HCCs than in the nonsubcapsular HCCs. Our findings are consistent with studies by Poon et al. [10] and Cho et al. [12], who also found no difference in local tumor control rates between the two groups. The hypothesis behind the potential low efficacy of radiofrequency ablation for subcapsular HCCs was the increased technical difficulty of placing the radiofrequency electrode adequately for a subcapsular tumor as compared with a nonsubcapsular tumor, thus leading to incomplete ablation. Although this may be true for some subcapsular tumors, we believe that such technical difficulty could be overcome in most cases with increasing operator experience because there is a significant learning curve for radiofrequency ablation of hepatic tumors [17].
Our results indicated no significant difference in technical effectiveness between the sub capsular and nonsubcapsular HCC groups, even though the subcapsular HCC tumors were larger than the nonsubcapsular HCC tumors (3.3 vs 2.5 cm). This was in accordance with the two previous reports by Poon et al. [10]—in which subcapsular HCCs were larger than nonsubcapsular HCCs (3.4 vs 2.2 cm), and a percutaneous approach was implemented in only 25% of subcapsular HCCs—and by Cho et al. [12]—in which the tumor size of the two groups was not different (1.8 vs 1.8 cm) and a percutaneous approach was used in all cases.
Radiofrequency ablation has recently emerged as an effective and safe bridge to liver transplantation for patients with HCC who are awaiting transplantation [18, 19]. In our study population, nine patients with subcapsular HCC and 14 patients with nonsubcapsular HCC underwent orthotopic liver transplantation after undergoing radiofrequency ablation as a bridge therapy. Our results showed no difference with regard to clinical outcome between these two groups. Therefore, in a potential liver transplantation candidate with HCC, subject to considerations based on guidelines proposed in this article, percutaneous radiofrequency ablation may still be a viable option for treatment.
A limitation of this study was the relatively small number of cases, which is largely attributed to the inclusion of only patients with single HCC at the time of treatment in order to avoid the potential bias of data clustering. A further large-scale study might be required to verify the safety and efficacy issue of radiofrequency ablation of subcapsular HCC.
In conclusion, our results show that percutaneous radiofrequency ablation of subcapsular HCC can be comparable to that of nonsubcapsular HCC with regard to complications, local control, and survival rates, when proper case selection, indirect puncture of the index tumor, a gradual increase in power deposition, and thermocoagulation of the needle track are performed.
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