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ORIGINAL ARTICLES |
From the Centre for the Study of Liver Disease and the Departments of Surgery (RT-PP, KK-CN, C-ML, S-TF) and Radiology (VA, JY), The University of Hong Kong, Pokfulam, Hong Kong, China.
Correspondence: Address correspondence and reprint requests to: Ronnie Tung-Ping Poon, MS, FRCS (Edin), FACS, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China; Fax: 852-28-17-5475; E-mail: poontp{at}hkucc.hku.hk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Between May 2001 and October 2002, 80 patients underwent RFA of 104 HCC nodules. Forty-eight patients had subcapsular HCC (group I), whereas the other 32 patients did not have subcapsular HCC (group II). RFA was performed via celiotomy, laparoscopy, or a percutaneous approach. Subcapsular HCCs were ablated by indirect puncture through nontumorous liver, and the needle track was thermocoagulated.
Results: There were no significant differences between groups in treatment morbidity (14.6% vs. 15.6%; P = .898), mortality (2.1% vs. 0%; P = 1.000), complete ablation rate after a single session (89.4% vs. 96.9%; P = .392), local recurrence rate (4.3% vs. 12.5%; P = .216), recurrence-free survival (1 year: 60.9% vs. 49.2%; P = .258), or overall survival (1 year: 88.3% vs. 79.4%; P = .441). After a median follow-up of 13 months, no needle-track seeding or intraperitoneal metastasis was observed.
Conclusions: This study shows that the results of RFA for subcapsular HCCs are comparable to those of RFA for nonsubcapsular HCCs. Subcapsular HCC should not be considered a contraindication for RFA treatment.
Key Words: Hepatocellular carcinoma • Radiofrequency ablation • Complications • Subcapsular carcinoma
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Radiofrequency ablation (RFA) is a recently developed technique for ablation of liver tumors. It has attracted great interest in recent years because of the promising results reported in earlier studies.9–11 Compared with other local ablative modalities, it has been shown to be more effective than percutaneous ethanol injection in inducing complete tumor necrosis12 and safer than cryoablation of liver tumors.13,14 Although RFA is now a widely used treatment for unresectable HCC in many centers,9–16 the indications of RFA for HCC have not been clearly established and need to be refined by clinicians who treat HCC.17
Recently, Llovet et al.18 reported a high incidence (12.5%) of tumor seeding in the needle track after a median follow-up of 10 months among 32 patients who underwent RFA for HCCs. All four cases of needle-track seeding in that series occurred in patients with subcapsular HCC, which was identified to be a significant risk factor for needle-track seeding. Hence, the authors concluded that RFA should not be recommended for patients with a subcapsular HCC. A French group reported three major treatment-related complications after RFA for subcapsular HCC, namely, subcapsular hematoma, sustained severe pain, and peritoneal dissemination.19 This group of authors also suggested that subcapsular HCC has to be excluded from RFA. A more recent study by a Japanese group reported that patients with subcapsular HCC had a significantly higher incidence of local recurrence after percutaneous RFA than those with nonsubcapsular HCC. Thus, the authors suggested that subcapsular HCCs may be less suitable for RFA.20 Although a subcapsular tumor location is considered a contraindication to RFA for HCC by some groups, other centers do not exclude subcapsular HCC from RFA.21,22 So far, there are limited data on the results of RFA for subcapsular HCCs, and the existing data were mainly derived from the few aforementioned studies.18–20 The role of RFA for subcapsular HCCs remains a controversial issue to be resolved with further studies. We conducted a study to elucidate the role of RFA for subcapsular HCCs by comparing the treatment results of patients with subcapsular HCCs and those with nonsubcapsular HCCs.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Technique of RFA
RFA treatment was performed by a team consisting of hepatobiliary surgeons and interventional radiologists. All RFA treatments were performed with a standard protocol by using the Cool-Tip radiofrequency system (Radionics Inc., Burlington, MA). A single electrode with a 2- or 3-cm exposed tip was used for tumors smaller than 3 cm in diameter, and a clustered probe consisting of three parallel electrodes was used for tumors >3 cm in diameter. The temperature at the tip of the electrode was maintained at <20°C by continuous infusion of the lumen of the needle electrode with cold saline to prevent charring around the needle tip. The ablation was performed in an automatic impedance control mode in which the radiofrequency current was automatically adjusted according to the impedance measured at the needle tip. Depending on the size and site of the tumor, each ablation cycle lasted 8 to 12 minutes. Multiple overlapping ablations were performed for large tumors. After ablation of the tumor, the needle track was thermocoagulated by continuing radiofrequency current in a manual mode when the needle was withdrawn slowly. For patients who had subcapsular HCC, defined as a tumor abutting the capsular surface of the liver (Fig. 1),19 we avoided direct perpendicular puncture of the tumor through the capsular surface of the tumor if possible. Instead, we punctured the tumor obliquely through a layer of nontumorous liver, and the needle track was also thermocoagulated. We aimed at ablation of all tumors with a curative intent, with a margin of 1 cm, in a single session of RFA.
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Data Collection and Outcome Measures
Clinical data of all patients were prospectively collected in a computerized database. The treatment protocol and data collection were approved by the institutional review board of our hospital. Patients were classified into those with one or more subcapsular HCCs (group I) and those who did not have a subcapsular HCC (group II). The clinical data and treatment outcomes of the two groups of patients were compared. The outcome measures that were compared included the post-RFA complication rate, treatment mortality, complete ablation rate, needle-track tumor seeding, local recurrence, distant intrahepatic recurrence, extrahepatic recurrence, and survival after RFA. A complication was defined as any adverse event after RFA, excluding pain or a transient febrile response after the procedure. Treatment mortality was defined as any death within 30 days of the RFA treatment. Response to ablation was assessed by a helical computed tomography (CT) scan 1 month after ablation. Complete ablation was defined as the absence of any contrast-enhancing lesion indicating residual tumor at the ablation site in the postablation CT scan. Patients who had residual tumor in the postablation scan were offered a repeated percutaneous ablation if feasible; otherwise they were treated with transarterial chemoembolization. All patients had monitoring of serum alfa fetoprotein (AFP) level, chest x-ray, and CT scan every 3 months to detect intrahepatic recurrence or distant metastasis. Local recurrence was defined as tumor recurrence within or at the periphery of the ablated lesion in the subsequent CT scans after complete ablation was documented in the first postablation CT scan. Distant intrahepatic recurrence was defined as a new tumor that appeared in the liver separate from the ablated area. Extrahepatic recurrence referred to any recurrence outside the liver.
Statistical Analysis
Continuous data were expressed as median and range and were compared between groups by using the Mann-Whitney U-test. Categorical variables were compared by using the 
2 test (or Fisher’s exact test where appropriate). Recurrence-free survival and overall survival after RFA were computed by using the Kaplan-Meier method and were compared between the two groups by using the log-rank test. Treatment mortality was excluded in the recurrence-free survival analysis and included in the overall survival analysis. All statistical analyses were performed with the SPSS statistical package (SPSS 10.0 for Windows; SPSS, Inc., Chicago, IL). A P value <.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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3 cm and those with tumors >3 cm in diameter in group I (91.3% vs. 87.5%; P = 1.000). Incomplete ablation was observed in one patient in group II after percutaneous RFA of a 3.0-cm tumor. When only patients who underwent percutaneous RFA were analyzed, there was no significant difference in the complete ablation rate after a single session of RFA between group I and group II (83.3% vs. 95.0%; P = .540). Three of the patients with incomplete ablation after the first session of RFA in group I, including two with percutaneous RFA and one with open RFA, were treated with a repeated session of percutaneous RFA, and complete ablation was subsequently achieved. The other three patients in group I and group II who had incomplete ablation were treated with transarterial chemoembolization. There was no significant difference in the overall complete ablation rate between group I and group II after repeated ablation (95.7% vs. 96.9%; P = 1.000).
Follow-Up Results
All patients have been followed up for at least 8 months after RFA. The patient who died of multiorgan failure after RFA was excluded from the follow-up analysis of recurrence. The median follow-up of the other 79 patients was 13 months (range, 8–25 months). The follow-up period was similar between group I and group II (median, 13 months in both groups). By the time of data analysis, 16 patients (34.0%) in group I and 15 patients (46.9%) in group II had developed recurrence. There were no significant differences in the incidences of local recurrence, distant intrahepatic recurrence, and extrahepatic recurrence (Table 3). None of the patients developed needle-track tumor seeding or peritoneal metastasis. The overall local recurrence among the 79 patients was 7.6%. When the number of tumor nodules ablated was considered instead, the overall local recurrence rate in this series was 6.0%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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One explanation offered by Llovet et al.18 regarding the high rate of needle-track seeding that they observed was the larger size (17 gauge) of the RFA needle compared with the fine needle used for ethanol-injection therapy, which used to be the standard modality for ablation of HCC before the availability of RFA or other newer thermal ablative techniques. The study by Llovet et al.18 has invited several criticisms on potential flaws in their technique of RFA, because needle-track seeding was rarely observed in previous studies of hundreds of cases of ablation of HCC with the same RFA needle.21,22,24,25 In a multicenter Italian study of 1766 patients (including 1176 patients with HCC) who received RFA for liver tumors using the same Cool-Tip RFA system, only 4 patients (.2%) had needle-track seeding.26 This rate of needle-track seeding is comparable to that of ethanol-injection therapy.27 Some authors speculated that the high rate of needle-track seeding after RFA for subcapsular HCC in the series of Llovet et al.18 might be related to two technical problems: (1) the needle track was not thermocoagulated in patients with subcapsular HCCs or (2) subcapsular HCCs were punctured directly without going through a layer of nontumoral liver tissue.22,24 In our center, RFA treatment was initiated in May 2001, when the report of Llovet et al.18 had just been published. We used the same Cool-Tip RFA system as Llovet et al.18 We did not, however, regard subcapsular HCC as a contraindication for RFA, because a high rate of needle-track seeding had not been observed by other studies. Instead, we paid particular attention to the two technical measures suggested by other authors to avoid tumor dissemination in RFA.22,24 In this study, we have demonstrated that with careful attention to the technique of RFA for subcapsular HCC, specific complications of RFA related to a subcapsular location of HCC could be avoided. The results after ablation of subcapsular HCC were comparable to those after ablation of nonsubcapsular HCC.
In this study, group I had more severe cirrhosis than group II, as reflected by a significantly lower platelet count and a trend toward worse indocyanine green retention at 15 minutes in the former group. Tumor size was significantly larger in group I. The higher serum AFP level in group I was probably related to the larger tumor size in this group. These differences between groups were most likely attributable to patient selection. Patients with a small subcapsular HCC and underlying cirrhosis are more amenable to surgical resection than those with a nonsubcapsular HCC because wedge excision may be possible for a small subcapsular HCC, whereas resection of a nonsubcapsular HCC may require a more extensive hepatic resection and, thus, a sacrifice of more nontumorous liver even for a small tumor. Hence, we tended to offer RFA to patients with larger subcapsular HCC or more severe underlying cirrhosis when hepatic resection was considered unsafe, whereas RFA was offered to patients with smaller nonsubcapsular HCC and less severe cirrhosis. The larger tumor size in group I also explained the higher frequency of open RFA in this group, because we usually ablated tumors >3 cm in diameter by an open approach. For small subcapsular HCCs that are amenable to a percutaneous approach, our usual choice is still percutaneous RFA.
Despite the larger tumor size and worse liver function in group I compared with group II, there were no significant differences in post-RFA morbidity or mortality. Notably, subcapsular hematoma or intraperitoneal hemorrhage was not observed in any patient. Subcapsular HCC was reported previously to give a higher incidence of hemorrhagic complications after ultrasound-guided needle biopsy of liver focal lesions.28 Both intraperitoneal hemorrhage and subcapsular hematoma are known complications of ethanol-injection therapy for HCC, with an incidence of .6% reported in a multicenter study of 1066 patients.27 There has been some concern of an increased risk of intraperitoneal bleeding or subcapsular hematoma after RFA of a subcapsular liver tumor; this has been reported with both Cool-Tip needle and hook electrode systems.18–20,29 We did not observe any case of bleeding complications in our patients. RFA induces thrombosis of small vessels. Careful thermocoagulation of the needle track by continuing power during slow withdrawal of the electrode after cooling is stopped could prevent bleeding after RFA.30 In fact, we have successfully used RFA for hemostasis of ruptured subcapsular HCCs.31 In a recent literature review, no bleeding complication occurred in 214 patients who had cauterization of the track, compared with 10 cases (1.0%) of bleeding among 1036 patients who did not have cauterization.32 Overall, the reported incidence of intraperitoneal hemorrhage or subcapsular hematoma after RFA was approximately .6% in the literature. This does not seem to be higher than that after ethanol-injection therapy.27,32 Llovet et al.18 reported 4 cases (12.5%) of subcapsular hematoma and 1 case (3.1%) of intraperitoneal hemorrhage in their series of RFA for HCC in 32 patients. The high incidence of bleeding complications may be related to the failure to cauterize the needle track in patients with subcapsular HCC. In our experience, the track could be satisfactorily cauterized if the needle was placed into the tumor obliquely through a layer of nontumorous liver. Track cauterization in the case of a perpendicular direct approach to a subcapsular tumor is more likely to result in burns of the abdominal wall and skin.32
Severe pain is another potential problem with percutaneous RFA of subcapsular HCC.19 We have also observed more severe pain in patients undergoing percutaneous RFA of a subcapsular HCC than in those undergoing percutaneous RFA of nonsubcapsular HCCs. However, the pain was tolerable by our patients with more analgesics and sedation, and we never had to terminate the procedure because of pain. Some authors have suggested that general anesthesia may be preferable in the coagulation of lesions close to the liver capsule.32
The complete ablation rate after the first session of RFA was slightly lower in group I than in group II (89.4% vs. 96.9%), but the difference was not statistically different. In the case of percutaneous ablation of a subcapsular HCC, the ribs may restrict the angle of needle insertion, and it may sometimes be difficult to insert the needle into the desired position within the tumor, especially if the needle is inserted obliquely through a layer of nontumorous liver. This could have accounted for the slightly lower complete ablation rate (83.3%) among patients with percutaneous RFA in group I. However, after a second session of percutaneous ablation, the complete ablation rate was comparable between group I and group II (95.7% vs. 96.9%). Our complete ablation rate in the entire series, even after a single session of RFA (92.4%), was substantially higher than that of 65% reported by Llovet et al.18 Other centers with a large experience in RFA of HCC have also reported a complete ablation rate of 90% to 95%.10,11 In cases in which accurate puncture of a subcapsular HCC is hindered by the ribs, a laparoscopic or open approach may be preferable.
A more serious concern of RFA for subcapsular HCC is the risk of needle-track tumor seeding, which, if it occurs, may convert a potentially curable case to a noncurable one. This is a particularly important issue because RFA is increasingly used as a bridging therapy for tumor control before liver transplantation.18,23,33,34 Needle-track seeding may manifest as a recurrent tumor in the abdominal wall in the case of percutaneous RFA or as an intraperitoneal deposit in patients who have undergone open or laparoscopic RFA. In contrast to the high incidence of needle-track seeding reported by Llovet et al.,18 we have not observed any needle-track seeding or peritoneal recurrence in either group of patients after a median follow-up of 13 months. All patients have been observed for at least 8 months after RFA, which should allow most cases of needle-track tumor seeding to be detected, if there are any.18,32 The follow-up duration in our study was longer than that of the study by Llovet et al.18 Some studies10,22 with long follow-up duration also reported no needle-track seeding after RFA of HCC. Most other authors21,24–26,32 have reported a low rate of needle-track seeding, from .2% to 2.8%, which was not significantly different from the rate of needle-track seeding after ethanol-injection therapy.27 Needle-track seeding was not a specific complication of RFA for subcapsular HCC. Shirato et al.35 have reported a case of needle-track seeding after ablation of a nonsubcapsular HCC by using a hook electrode. We believe that avoiding the direct puncture of subcapsular HCC and thermocoagulating the needle track are important technical factors that have helped prevent needle-track tumor seeding or tumor cell dissemination into the peritoneal cavity in our patients.
Other authors21,25 have speculated that the needle biopsy performed before RFA might have contributed to the high incidence of needle-track tumor seeding in the series by Llovet et al.18 In that study, needle biopsy was performed in 27 of the 32 patients undergoing RFA. Some centers refrained from needle biopsy in patients with HCC undergoing RFA except in doubtful cases.21 We agree that in patients with typical radiological features of HCC in combination with a diagnostic level of serum AFP, a needle biopsy is probably not necessary before RFA. In this study, we performed needle biopsy for histological confirmation of the diagnosis of HCC in all cases for the purpose of a prospective study, and we have not observed any needle-track seeding or peritoneal dissemination. Hence, we believe that the high incidence of needle-track seeding in the study of Llovet et al.18 was unlikely to be related to the needle biopsy, although details regarding the type of biopsy needle used were not provided in that study. In the literature, the risk of needle-track seeding after needle biopsy of liver malignancies ranged from .003% to 2%, depending on the type of biopsy needle used.36,37
There was no significant difference in the local recurrence rate between group I and group II in this study, in contrast to a previous report of a higher local recurrence rate after RFA of subcapsular HCCs.20 There were also no significant differences in the distant intrahepatic and extrahepatic recurrence rates. Similar to the case of hepatic resection for HCC, distant intrahepatic recurrence was the most common type of recurrence observed; this could be related to multicentric hepatocarcinogenesis or intrahepatic metastasis.38 The short-term recurrence-free and overall survival results were also comparable between groups. The overall local recurrence rate of 6% among all tumor nodules ablated in this study was much lower than that of 26% reported after RFA of 65 tumors in the previous study by Komorizono et al.20 The median follow-up (16 months) of the latter study was slightly longer than that of this study, and local recurrence was defined more loosely as recurrence in the same segment of the liver.20 Nonetheless, the local recurrence rate in that study seems to be much higher compared with previous studies.9,10 Using the same definition of local recurrence as in our study, Curley et al.10 reported a low local recurrence rate of 3.6% after a median follow-up of 19 months among 110 HCC patients treated with RFA. Rossi et al.9 reported a 5% local recurrence rate among 39 HCC patients treated with RFA after a mean follow-up of 22.6 months. The reason for the high local recurrence rate in the study by Komorizono et al.20 was not clear. The authors stated that it was difficult to obtain a tumor-free margin along the capsule for a subcapsular tumor. It is obvious that there will not be a tumor-free margin on the capsular side if the tumor is abutting the liver capsule. The authors did not further elaborate how this could have affected the local recurrence rate. To our knowledge, a subcapsular location of the tumor has never been reported as a risk factor of recurrence after resection of HCC.39 It is rather unlikely that the absence of a margin on the capsular side of a subcapsular HCC would increase the risk of local recurrence after RFA. In our experience, subcapsular location did not increase the risk of local recurrence after RFA for HCC.
In conclusion, this study showed that the results of RFA for subcapsular HCCs were comparable to those of RFA for nonsubcapsular HCCs. With careful attention to the technique of RFA, complications such as subcapsular hematoma and needle-track tumor seeding, which may be associated with ablation of subcapsular HCCs, could be avoided or minimized. Our findings suggest that subcapsular HCC should not be considered a contraindication for RFA.
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ACKNOWLEDGMENTS |
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Supported by the Outstanding Young Researcher Award of the University of Hong Kong.
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FOOTNOTES |
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Received for publication August 27, 2003. Accepted for publication November 17, 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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