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Original Research |
1 Department of Radiology, University of Brescia, Piazzale Spedali Civili 1,
Brescia 25100, Italy.
2 Department of Clinical Epidemiology, University of Brescia, Brescia,
Italy.
Received February 12, 2005;
accepted after revision May 19, 2005.
Address correspondence to P. Cabassa
(paolocab{at}libero.it).
Abstract
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SUBJECTS AND METHODS. In a 5-year period (1998-2003), 68 HCCs in 59 patients (age range, 47-88 years) were treated percutaneously with radiofrequency ablation using expandable needle electrodes. The mean lesion diameter was 3.1 cm (range, 1-12 cm). Fifty-one of 59 patients were in Child-Pugh class A, and eight were in class B. Follow-up was performed by helical CT at 1, 4, and 6 months and every 6 months after that. The mean follow-up was 24.1 months (range, 6-60 months). Survival and disease-free survival rates were evaluated separately by statistical analysis. Any complications were reported during follow-up.
RESULTS. Cumulative survival rates were 94.4%, 65%, and 43.1% at 1, 3, and 5 years, respectively. Median survival time was 23.6 months (range, 4-62 months). Maximum tumor diameter was associated with the probability of survival: 73% among patients with lesion diameters of 3 cm or less, 76.5% among patients with lesion diameters of 3-5 cm, and only 40% among patients with lesion diameters of more than 5 cm (p = 0.05, log-rank test; p = 0.07, Tarone-Ware test). In 34 (57.6%) of 59 patients during follow-up, new nodules noncontiguous with the treated nodule developed in the liver (tumor recurrences). Median disease-free survival rates were 32.1%, 28.1%, and 17.5% at 1, 2, and 3 years, respectively. One major complication occurred (hemoperitoneum that required transfusion).
CONCLUSION. Radiofrequency ablation with expandable electrodes is safe and effective in the treatment of HCC.
Keywords: abdomen • liver disease • oncology • radiofrequency ablation
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HCC was diagnosed using sonographically guided biopsy in 53 patients and
using a combination of appropriate imaging findings and raised levels of serum
-fetoprotein (> 400 µg/L) in six patients. All patients enrolled
in the study were considered to be unsuitable for surgical resection because
of severe cirrhosis according to Child-Pugh classification, the location of
the tumor, proximity of the tumor to major vessels or biliary ducts,
coexistent morbidities, or refusal of the patient to undergo resection.
The eligibility criteria for radiofrequency ablation included the presence
of a single tumor, independently of its diameter; the presence of no more than
three nodules, each being less than 3 cm in maximum diameter; the absence of
extrahepatic disease; the absence of main trunk portal vein thrombosis; a
Child-Pugh class of A or B (Child-Pugh C patients were excluded); prothrombin
activity of no less than 50%; and a platelet count of no less than
60,000/mm3. No previous chemoembolization or other minimally
invasive treatments for HCC had been performed. Importantly, nodules larger
than 5 cm were excluded; this criterion for patient exclusion has been in use
at our institution since January 2001. Nodules adjacent to the liver surface
or gallbladder were not considered an exclusion criterion. All patients had
undergone baseline preprocedural evaluation, including serum blood laboratory
tests (blood count, platelets, coagulation profile, renal panel, electrolytes,
albumin, alanine aminotransferase, aspartate aminotransferase,
-glutamyl transferase, total bilirubin, and -fetoprotein tumor
marker), color Doppler sonography of the abdomen, triple-phase helical CT or
contrast-enhanced MRI of the abdomen, and chest radiography.
Table 1 summarizes the demographic, clinical, laboratory findings, and sonographic findings. All patients gave informed consent to be treated. The study was conducted in accordance with the principles of the Helsinki Declaration [14].
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Radiofrequency Ablation
Patients were admitted to the hospital early on the morning of treatment.
They had fasted for at least 6 hr before the procedure. All procedures were
performed by one radiologist in the afternoon in the interventional radiology
unit. Conscious sedation (fentanyl [Fentanest, Pharmacia, 50-100 µg] and
propofol [Diprivan, Astra Zeneca, 10-20 mg in a bolus according to patient
weight]) was administered by an anesthesiologist, who followed all patients
during the ablation procedure, monitoring vital signs and assisting with
ventilation.
In addition to the conscious sedation, a local anesthetic was administered along the planned puncture line (10 mL of 2% lidocaine hydrochloride [Lidrian, Bieffe Medical]).
All patients in the series were treated using the RF2000 radiofrequency ablation system. This monopolar system consists of a 100-W radiofrequency generator to which LeVeen needle electrodes are connected. In addition, the generator requires placement of two patient-grounding pads on the patient thighs to complete the electrical circuit.
The LeVeen needle electrodes consist of 15-gauge cannulae with lengths of 12, 15, or 25 cm, and a 2.0-, 3.0-, or 3.5-cm-diameter umbrella can be chosen. The 2.0-cm device has eight individual tines to form the umbrella, whereas the 3.0- and 3.5-cm devices have 10 tines. This difference helps to ensure full coverage of the ablation zone.
All procedures were performed percutaneously using sonographic guidance with a Sequoia unit (Acuson-Siemens) with a 4V2 or 4C1 multifrequency probe. For lesions in the right lobe, an intercostal approach was used most often, whereas lesions in the left lobe were treated with an epigastric approach.
Initially, the 15-cm cannula was chosen, and the diameter of the LeVeen needle selected depended on the maximum tumor diameter. However, since January 2001, we have used the 3.5-cm needle exclusively to achieve a larger margin of safety when treating smaller tumors. The LeVeen needle electrode was connected to the RF2000 generator, and the circuit was completed using the patient-grounding pads. The baseline power output was set at 50 W (when using the 3.5-cm needle), and the protocol recommended by the manufacturer was followed (Fig. 1).
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Since January 2002, we have adopted a new approach for those patients in whom impedance roll-off did not occur within 10 min. The tines of the needles were retracted slightly to reduce the diameter of the ablation. After retraction and progressive ablation of the center of the tumor, the power decreased (with a parallel rise in impedance signifying that a central zone of necrosis was being formed) and was increased manually back to 90 W. Once this rise in impedance began, the tines were redeployed into the tumor and the procedure was continued until full roll-off occurred. As indicated, the net effect was first to ablate the center of the tumor and then to ablate the periphery of the tumor.
The number of insertions and treatments depended on the maximum tumor diameter. Tumors that had a maximum diameter of 3 cm or less were treated with one ablation. Tumors that had a maximum diameter of more than 3 cm were treated with multiple insertions and overlapping ablations (compound ablations). Postprocedural protocols required that a blood count and clinical evaluation be performed the evening after ablation and the following morning. Patients were discharged the next day if no complications had occurred.
Assessment of Treatment Effectiveness and Follow-Up
Helical CT was performed before and after every treatment (Somatom plus 4,
Siemens Medical Solutions) at 250 mA and 120 kV with a 5-mm collimation and
pitch of 1.5. Images were obtained during the hepatic arterial (25-30 sec),
portal (80-90 sec), and equilibrium (240-300 sec) phases after injection of a
nonionic contrast medium. The injection rate was 4.0 mL/sec using a power
injector.
Patients who have been treated with radiofrequency ablation at our institution undergo a control CT examination at 1 month and subsequent CT examinations at 4 and 6 months. They are followed every 6 months after this initial follow-up. Images were examined by three radiologists with experience in liver imaging. Reviewers were aware of the clinical history of the patient. They compared the morphology and enhancement pattern of the treated lesion with those of the lesion before treatment.
Ablation was considered to be complete when no enhancement was seen within the treated lesion. Any nodular or irregular enhancement during the arterial phase (corresponding to the target lesion) was considered to be vital tumor (local tumor progression). A surrounding peripheral enhancement seen on the 1-month control images during the arterial phase was considered to be perilesional hyperemia (benign periablational enhancement) and not tumor foci. New lesions in different segments with respect to the treated lesions (tumor recurrences) also were assessed.
Suspected local tumor progression was confirmed on the basis of an
enlargement (increase in maximum diameter) during follow-up. Patients with
either local tumor progression or intrahepatic recurrence were considered
candidates for treatment with radiofrequency ablation or, if radiofrequency
ablation was not appropriate, chemoembolization, according to clinical and
imaging characteristics. Clinical evaluation, including an -fetoprotein
assay, was performed every 3 months for the first year and subsequently every
6 months. No patients were lost during follow-up.
Statistical Analysis
We evaluated survival and disease-free survival separately. Disease-free
survival was considered to be the time from treatment until the first
recurrence or, if the patient died without evidence of recurrence, until
death. Survival and disease-free survival were estimated in all patients
according to their age and sex, their maximum tumor diameter, and whether they
had tumor recurrence. The maximum diameter of the tumor was classified into
one of three categories according to survival analysis for HCC cases: 3 cm or
less, 3-5 cm, or more than 5 cm. Cumulative survival curves for different
variables were modeled using the Kaplan-Meier method, and the significance of
differences between the curves was tested using the log-rank test and
alternatives such as the Tarone-Ware and the Peto-Peto-Prentice tests
[15]. Furthermore, some
characteristics and demographic variables were entered as predictors in Cox
proportional hazards models. All tests were two-sided and were performed using
a p value of 0.05 for rejecting the null hypothesis, although
p values of less than 0.1 also were considered. Because of the low
number of patients with abnormal bilirubin levels (3/59) and with Child-Pugh
class B (8/59), these clinical variables were not statistically analyzed. The
software used for the analyses was the Stata statistical package (release 7.0,
Stata).
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Among the 18 incompletely treated nodules, five (27.8%) were re-treated;
three of these five were subsequently found to be completely ablated on
follow-up CT at 4 months. At 4 months, six nodules that had been considered
completely ablated at 1 month showed local tumor progression; one of these six
was re-treated with success, as depicted by no enhancement at the 12-month
follow-up. At 6 months, an additional local failure was observed. Because of
the morphology (ill-defined margins of multiple recurrence nodules), this was
not re-treated. After that time, no other nodules considered completely
ablated showed tumor persistence. Thus, local tumor control was achieved in 49
of 68 nodules—that is, 72.1%. All patients who had increased
-fetoprotein levels before the procedure showed a decrease at their
first clinical examination after radiofrequency ablation. Bilirubin levels did
not change in the three patients who had abnormal levels before the procedure.
Five patients had a mild rise in bilirubin levels after the procedure, but the
levels normalized within 1 month.
The follow-up period ranged from 6 to 60 months (mean, 24.1 months). At the end of the study 42 (71.2%) of 59 patients were alive.
The cumulative survival rates were 94.4%, 65%, and 43.1% at 1, 3, and 5 years, respectively. Median survival time was 23.6 months (range, 4-62 months). The Kaplan-Meier survival rate for all patients is shown in Figure 2.
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Recurrences were found in 29 patients at 1-12 months, in two patients at the 12-month control examination, and in three patients at the 24-month control examination. Eighteen patients with local tumor progression or intrahepatic tumor recurrences underwent chemoembolization during follow-up. Patients undergoing chemoembolization had a survival similar to that of untreated patients (p > 0.1 with the Cox model analysis).
Sixteen patients had no recurrence or local tumor progression; one patient died without evidence of disease recurrence 35 months after treatment, and all the others are alive. Median disease-free survival was 6 months (range, 1-53.8 months), with survival rates of 32.1%, 28.1%, and 17.5% at 1, 2, and 3 years, respectively. The Kaplan-Meier curve for disease-free survival in all patients is shown in Figure 4. Most cases of recurrence or death were in the first 12 months after treatment. No variable investigated was associated with disease-free survival time.
We encountered one major complication during our investigations. One man with a small lesion (2.2 cm) in segment IV sustained an intraperitoneal hemorrhage. He required a transfusion, but in 72 hr the hematocrit values stabilized and the fluid collection was no longer evident on sonography.
Minor complications such as abdominal pain and fever (the so-called postablation syndrome) were common, especially for patients with lesions adjacent to the liver surface, but all patients were discharged without event on the second or third day after ablation. No complications related to the radiofrequency devices (skin burns) were noted. No case of tumor seeding was noted during follow-up.
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Our results indicate that radiofrequency ablation with expandable electrodes is a safe procedure and is effective in local tumor control, considering that 21 (30.9%) of 68 lesions were at least 3.5 cm in diameter and eight of 21 at least 5 cm. Local tumor control was achieved in 72.1% of tumors overall (data from 1-year follow-up) and in 88.6% of tumors 3 cm or less in diameter. Tumor size remains the most critical factor for successful in situ ablation. We obtained only one complete ablation in lesions larger than 5 cm, and 52.6% of lesions 3-5 cm in maximum diameter were completely ablated. The use of minimally invasive therapies, such as chemoembolization, before radiofrequency ablation could be an option in these patients, as reported in the literature [23, 24]. Nevertheless, survival rates did not differ between patients with tumors 3 cm or less in diameter and patients with tumors 3-5 cm in diameter. Therefore, one can conclude that the upper limit for effective radiofrequency ablation is 5 cm.
Our results have been skewed by our use, in the early stages of the protocol, of a 3.0-cm-diameter electrode for lesions with a maximum diameter of 3 cm. The use of this needle for lesions this large limited our ability to obtain a curative response. The overall survival rates are satisfactory if we consider that inclusion criteria were not limited by lesion diameters in early cases and that eight patients were Child-Pugh class B. Furthermore, the results are similar to those of Buscarini et al. [22], who treated 101 lesions 3.5 cm or less in diameter with three types of devices, and to those of Rossi et al. [21], who treated 41 HCCs using a multiple-probe technique. Buscarini et al. reported overall 1-, 3-, and 5-year survival rates of 89%, 62%, and 33%, respectively. Rossi et al. reported 1-, 3-, and 5-year survival rates of 94%, 68%, and 40%, respectively.
The high number of intrahepatic tumor recurrences is not surprising given that HCC is a multifocal disease and that improved survival permits longer-term follow-up. This longer-term follow-up combined with the probability that new nodules will develop within the liver or that previously undetected synchronous lesions will be detected would lead to increased rates of intrahepatic recurrence. In the largest reported series—149 cases—of HCC treated with the LeVeen probe, Curley et al. [9] found a 45.5% rate of intra- or extrahepatic tumor recurrences, with a median follow-up of 19 months.
This study had some limitations. First, we considered CT (and obviously time) as a gold standard. CT is the imaging technique of choice in these patients but can miss small local recurrences, particularly in early control examinations. Second, the survival curves also include the 18 patients with recurrence who underwent chemoembolization; this procedure did not modify patient survival but was a treatment additional to radiofrequency. Third, during our early experience we included patients with lesions too large to undergo thermal ablation with the intention to cure. As a result, the clinical practice within our institution was changed in January 2001 such that the maximum lesion diameter considered suitable for radiofrequency ablation was 5 cm. Patients with lesions larger than 5 cm were no longer considered candidates for radiofrequency ablation in the absence of adjunctive treatments.
In conclusion, radiofrequency ablation with LeVeen expandable needle electrodes is a safe and effective technique in the treatment of HCC. Our results suggest that treatment of large lesions (3-5 cm) requires combined therapy or improved needles that can ablate a larger volume. With the advent of technical improvements and standardized combined therapies, radiofrequency ablation could assume a primary role in the treatment of HCC.
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3 cm.