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1 All authors: Interventional Ultrasound Service, D. Cotugno Hospital, Viale Colli Aminei 491, Naples 80131, Italy.
Received December 30, 2002;
accepted after revision February 27, 2003.
Address correspondence to A. Giorgio.
Abstract
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SUBJECTS AND METHODS. Between September 2000 and June 2002, 84 patients (55 men and 29 women) with cirrhosis who ranged in age from 48 to 74 years (mean age, 64 years) and who had 95 hepatocellular carcinomas (seven patients had two tumors and two patients had three tumors) were treated with high frequency–induced thermotherapy. The diameters of the tumors ranged from 1.5 to 8.5 cm (mean, 3.6 cm). The efficacy of radiofrequency ablation was evaluated with triphasic contrast-enhanced CT performed 4 weeks after the procedure.
RESULTS. Posttreatment CT showed complete necrosis in 73 (77%) of 95 hepatocellular carcinomas in 62 patients. Complete necrosis based on tumor size was seen in 40 (95%) of 42 tumors with diameters equal to or smaller than 3 cm, 32 (71%) of 45 tumors with diameters between 3.1 and 5.0 cm, and one (12%) of eight tumors with diameters larger than 5.0 cm. Twenty-two hepatocellular carcinomas showed incomplete necrosis. None of the patients experienced major complications. Four patients were lost to follow-up. The length of the follow-up period ranged from 4 to 22 months (mean, 10 months). One patient died 8 months after the radiofrequency ablation treatment. All the remaining patients are still alive. During the follow-up period, eight (10%) of 80 patients showed a local recurrence on sonography and CT.
CONCLUSION. Our experience suggests that percutaneous radiofrequency ablation of hepatocellular carcinoma with high frequency–induced thermotherapy is safe and effective in the treatment of hepatocellular carcinomas equal to or smaller than 3 cm, fairly effective for hepatocellular carcinomas between 3 and 5 cm, and ineffective for tumors larger than 5 cm.
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Recently, we tested a new radiofrequency system using a cannulated needle electrode with multiple side holes connected to a pump filled with saline solution. Coagulation of the targeted lesion is obtained with a high-frequency alternating current produced by a radiofrequency generator. During the exposure of the lesion to the radiofrequency current, saline solution can be injected into the tumor through the needle electrode, perfusing the neoplastic tissue around the needle tip. This action increases the electrical conductivity of the radiofrequency fields in the targeted tissue and prevents tissue vaporization and charring, thus increasing the volume of coagulation necrosis.
Up to now, experiences with saline-enhanced radiofrequency treatment of the liver have been reported in ex vivo calf livers [12, 13], in vivo animal livers [13, 14], and in vivo liver metastases in humans [13]. To our knowledge, no previous report has described this treatment in patients with hepatocellular carcinoma. We report the results (volume of necrosis, side effects, short-term complications, and follow-up findings) achieved in a series of patients with cirrhosis and hepatocellular carcinoma who were treated with a saline-enhanced radiofrequency technique.
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Before treatment, all patients underwent abdominal sonography on a
commercially available scanner (AU-5, Esaote Biomedica, Genoa, Italy) with
3.5- and 5.0-MHz convex electronic probes and a triphasic helical CT (Somatom
Plus 4, Siemens, Erlangen, Germany or Synergy Power, General Electric Medical
Systems, Milwaukee, WI) using a contrast medium. Serum 
-fetoprotein
levels were obtained, and serum tests for liver function and hemocoagulation
were performed. We also obtained an ECG and a chest radiograph for each
patient.
We selected patients to be treated with radiofrequency ablation on the
basis of the following criteria: presence of either a single tumor of any size
or no more than three tumors, none of which exceeded 3.0 cm in diameter; an
international normalized ratio less than or equal to 1.5; platelet count
greater than or equal to 60 x 109L; absence of ascites,
portal vein thrombosis, or extrahepatic hepatocellular carcinoma metastases;
and liver function impairment not more severe than Child-Pugh classification B
(nine points). In our series of patients, international normalized ratio
values ranged from 0.8 to 1.5; platelet count ranged from 65 to 185 x
109L. We categorized the patients into three groups according to
their serum level of -fetoprotein: 38 patients had a level at or below
20 µg/L; 39 patients had a level between 21 and 150 µg/L (range,
28–96 µg/L), and seven patients had a level of more than 150 µg/L
(range, 174–460 µg/L).
The diagnosis of hepatocellular carcinoma was confirmed in all patients by sonographically guided percutaneous liver biopsy. The treatment was approved by our institutional review board, and informed consent was obtained from all patients before the procedure.
Equipment
All patients were treated with a new generation of radiofrequency equipment
(Elektrotom 106, HITT, Berchtold, Germany) that includes a computer-supported
high-frequency generator of sinusoidal, unmodulated high-frequency voltages
and currents of 375 KHz, with a maximum power output of 60 W. High-frequency
voltage is delivered through output terminals to the 15-gauge needle
electrodes (Fig. 1A). Each
needle electrode has an exposed 2.5-cm-long active tip with eight side holes
and no terminal hole (Fig. 1B); large self-sticking dispersive nickel plaque electrodes; and an infusion pump
for injecting saline solution through the electrode holes.
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The radiofrequency unit is supplied with software for feedback control and
regulation of the impedance in the treated tumoral tissue. A power curve is
generated in the lower impedance range of 100–350 
. As a result,
the high-frequency power supply is automatically and constantly regulated,
irrespective of the actual impedances of the circuit in the patient. This
feature should guarantee a microarc-free low-voltage tissue coagulation in the
targeted area treated by the needle electrode. In impedance greater than 350
, automatic regulation occurs in accordance with a constant voltage
curve, with increasing reduction of the high-frequency power. If the current
impedance exceeds the programmed upper threshold value of 700 ± 50
, the high-frequency output is automatically reduced to 5 W until the
current impedance has fallen below the lower threshold value of 400 ±
50 . The higher frequency power is then switched on again.
This threshold control, with a total switching hysteresis of 300 ±
100 , provides automatic heat regulation in the targeted area during a
constant flow of the 0.9% saline solution (approximately 20–40
drops/min) through the radiofrequency needle electrode to the treated area. If
the upper impedance is exceeded for a short time at 900 ± 50 ,
the automatic remote control of the syringe pump releases a bolus five times
the value of the nominal flow for 1.2 sec. This bolus is only permitted at
5-sec intervals in the case of increased impedance. Detrimental desiccation in
the targeted area is thus prevented. The reduced impedance advantageously
increases the high-frequency power turnover.
A digital display appears in the information display in real time and keeps
the user informed during the thermotherapy. Current and voltage sensors enable
permanent monitoring of the actual impedance of the electrical circuit in the
patient during high-frequency activation. The actual impedance level is
signaled visually and acoustically. A lighted bar graph visually displays the
impedance as 10 defined levels (100 each) up to 900–1000
.
Procedure
Eleven patients with tumors deeply situated in the right lobe of the liver
were treated after subcutaneously receiving 10 mL of a local anesthetic (2%
solution of lidocaine), and 73 patients were treated while under general
anesthesia without tracheal intubation, by means of premedication with IV
atropine (0.5 mg) and induction with propofol (9–12 mg/kg of body weight
per hour) and IV fentanyl (50 mg)
[15] because of one or more of
the following reasons: subcapsular tumors (19 patients); large (> 4 cm)
tumors requiring multiple needle insertions and therefore long exposure to
thermoablation (15 patients); or refusal of patient to undergo percutaneous
treatment while awake (39 patients).
After sonographically determining the most favorable percutaneous approach (Fig. 2A), we inserted a needle electrode into the tumor under sonographic guidance, advanced the tip to reach the distal margin of the targeted lesion (Fig. 2B), and then activated the current generator and the pump for the saline injection for 10–15 min. Sonographic real-time monitoring of the treatment showed progressive enlargement of a hyperechoic area of thermolesion in the tumor resulting from the injection of saline and the vaporizing effect of the heat (Figs. 2C, 2D, 2E). To ensure the complete hyperechogenicity of the tumor, we obtained multiple sonograms using both the intercostal and subcostal approaches.
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Because preliminary clinical studies have proven that a single insertion of the radiofrequency electrode can produce a thermolesion exceeding 4.0 cm in diameter [15], we planned to use a single insertion for tumors with diameters up to 4.0 cm. In the case of tumors with larger diameters, we planned multiple needle insertions to obtain the complete hyperechogenicity of the tumor at the end of the treatment (Fig. 3A). In a previous study, we stated that the hyperechoic spots generated in large lesions during the thermoablation can obscure the still untreated portions of the tumor and hamper the repositioning of the needle in the lesion [16]. For this reason, we preferred to treat lesions with diameters larger than 5 cm in two sessions to allow a correct positioning of the electrodes in the viable tumor as shown on a CT scan scheduled 1 week after the first session. The second session was always carried out within 2 weeks of the first session.
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At the end of each insertion, the current generator was switched off only after the needle electrode had been retrieved to heat the needle path and prevent seeding of tumoral cells. Each procedure lasted not less than 0.5 hr and not more than 2 hr. All the patients were discharged from the hospital the day after the procedure. A sonographic follow-up examination was performed 24 hr after the treatment.
The efficacy of radiofrequency ablation therapy was evaluated by means of triphasic contrast-enhanced CT performed 4 weeks after the treatment by scanning all the liver with helical CT (slice thickness, 10 mm and pitch, 1:1/1:1.2, depending on the volume of the liver) after administering 150 mL of iodinated contrast medium (Iopamiro 370 [iopromide], Bracco, Milan, Italy) at a flow rate of 3 mL/sec. Acquisition of arterial and portal phase images was initiated 20 and 60 sec, respectively, after the beginning of the contrast medium injection, whereas late-phase images were obtained with cluster scanning initiated 70 sec after the end of contrast medium injection. Tumoral necrosis was considered complete when no intralesional enhancement area was evident during the early arterial phase and throughout the portal and late-contrast phases (Fig. 2F). Otherwise, the tumor response was rated as incomplete [17] (Fig. 3B).
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Follow-up of patients was conducted using abdominal sonography and
assessment of serum -fetoprotein every 2 months. Sonography was
performed to evaluate changes in the volume of the treated lesions and to
detect new tumors (recurrence) and portal vein thrombosis. If sonography
showed a local or distant recurrence, helical CT was performed.
Fever and pain were classified as minor complications. Events requiring prolonged hospitalization, blood transfusion, or surgery were considered major complications (i.e., hemoperitoneum, pleural effusion, portal vein thrombosis, decompensation of liver cirrhosis, renal insufficiency, marked jaundice, or abscess).
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CT performed after treatment showed a complete necrosis in 73 (77%) of 95 hepatocellular carcinomas in 62 patients. Twenty-two hepatocellular carcinomas in 22 patients showed incomplete necrosis after radiofrequency ablation; however, necrosis always involved more than 50% of tumor volume.
In 16 (73%) of 22 tumors with incomplete necrosis, the residual vital tumor tissue was always located along the wall of a major hepatic vessel (hepatic veins or portal veins).
Eighteen of 22 patients with incomplete necrosis underwent percutaneous ethanol injection performed under sonographic guidance for completion of the treatment, whereas four patients refused further treatments and were lost to follow-up. Twelve patients were treated with conventional multisession percutaneous ethanol injection (without anesthesia), and six were treated under general anesthesia with a single-session percutaneous ethanol injection. The amount of ethanol injected per patient to achieve complete necrosis of the residual viable tumor in the hepatocellular carcinomas previously treated with radiofrequency ablation ranged from 5 to 25 mL (mean, 14.5 mL). Subsequent CT performed 1 month after percutaneous ethanol injection showed complete necrosis in all 18 tumors treated.
Follow-Up
The length of follow-up ranged from 4 to 22 months (mean, 10 months). One
patient died 8 months after the radiofrequency ablation treatment. All the
remaining patients are still alive. Postprocedural sonography and follow-up CT
showed a local recurrence of tumor in eight (10%) of 80 patients as follows:
at 4 months in two patients; at 6 months in one; at 8 months in two; at 12
months in one; at 14 months in one; and at 20 months in one. Intrahepatic
recurrences in different segments were observed in five patients (6%). Local
recurrences and new lesions were all treated by additional radiofrequency
ablation sessions or by percutaneous ethanol injection.
Complications
None of the patients experienced a major complication. Fever lasting
1–3 days was observed in 26% (22/84), and pain lasting 12–24 hr
after treatment was reported by 21% (18/84) of patients. Administration of
painkiller was necessary in 14% (12/84) of patients. During follow-up, we
observed no cutaneous or abdominal-wall tumor implantations (seeding) along
the needle tract either clinically or on sonography or CT.
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Percutaneous ethanol injection, introduced by Livraghi et al. in 1986 [20], has been the most frequently used technique for the local treatment of hepatocellular carcinoma [18, 20–27]. The difficulty of predicting the volume of necrosis achievable and the possible serious collateral effects of ethanol diffusion into the non-tumorous liver tissue are important limitations of percutaneous ethanol injection treatment. For these reasons, alternative percutaneous ablative procedures (ablation produced by radiofrequency, interstitial laser photocoagulation, or microwave) have been proposed for the treatment of liver tumors [18]. Radiofrequency ablation has been proven in several studies to be a reliable method with which to treat hepatocellular carcinoma [3–10, 28].
Originally, a single electrode insertion with conventional radiofrequency ablation produced only a 1.6-cm-diameter spherical or elliptical area of necrosis [3–7]. The difficulty in achieving greater dimensions with conventional radiofrequency ablation is due to carbonization of the tissue, which, because carbonized tissue is a poor conductor, increases impedance and limits propagation of the current; therefore, tumors of greater volumes required more insertions [2, 5].
Larger volumes of necrosis have subsequently been obtained with radiofrequency ablation using expandable, large-caliber (12- to 14-gauge) needle electrodes [6–8]. Once positioned in the tumor, the needle electrode opens like an umbrella into seven to 10 retractable curved electrodes around the target. The technique produces a reproducible area of necrosis approximately 3–4 cm in diameter.
Obtaining volumes of necrosis larger than 1.6 cm while simultaneously preventing carbonization around the tip of the electrode tip became achieveable with the introduction of an internally cooled 1.2-mm-diameter (18-gauge) needle electrode [8–11]. Circulation of saline solution with a temperature of 2–5°C in two coaxial lumens situated in the electrode prevents carbonization around the needle tip and allows a reproducible area of necrosis of 2.4 cm. A greater volume of necrosis with a diameter of more than 4.5 cm has been obtained with a device consisting of three cooled electrodes (electrode "cluster") that can be simultaneously and percutaneously inserted into the liver [7]. Even so, this approach can be unsafe in patients with cirrhosis who have impaired coagulation.
Some investigators have attempted to increase the volume of coagulation necrosis by injecting saline into the tumor through side holes of a cannulated needle electrode before or during radiofrequency application [12, 13]. They hypothesize that this technique could support the radiofrequency effect by keeping a high ion concentration in the tissue around the electrode tip (a crucial point for heat generation by radiofrequency) and by decreasing the impedance and thereby preventing carbonization.
Using saline-enhanced radiofrequency ablation, Miao et al. [12] reported necrosis of lesions larger than 5.5 cm. Livraghi et al. [13] conducted several experiments using thin 18-gauge needle electrodes and continuous saline infusion (1 mL/min) during radiofrequency application in ex vivo models and in vivo animals and humans. Clinical studies in 15 patients with liver metastases proved the efficacy of saline-enhanced radiofrequency ablation in producing large volumes of necrosis with diameters up to 3.9 cm. Livraghi et al. postulated several potential effects related to saline injection. These included enlargement of the effective surface area of the radiofrequency electrode because of the high local ion concentration from saline injection, improved tolerance of increased generator output because of tissue cooling or decreased tissue impedance, and direct contact of the tissue with boiling saline diffusing into the tumor (the same effect has been previously reported with direct injection of hot water into the hepatocellular carcinoma [29]).
In spite of these encouraging preliminary results, this technique was abandoned in favor of other forms of radiofrequency ablation because of the irregular shape of the area of tissue necrosis and the difficulty in predicting the size of necrosis [13]. However, similar problems are encountered occasionally with other thermoablation techniques. For instance, incomplete and irregular necrosis due to the cooling effect of large vessels located near the margins of the treated tumor have been described with all the radiofrequency ablation devices and with interstitial laser photocoagulation [5, 20–32].
To our knowledge, no report has described saline-enhanced radiofrequency treatment of hepatocellular carcinoma in patients with cirrhosis. The equipment used in our study is fairly similar to that used by Livraghi et al. [13]. Nonetheless, there are some remarkable differences: larger (15-gauge) needle electrodes; feedback control of the impedance in the tissue, which allows the regulation of the power output to keep the impedance below a threshold value and provide automatic heat regulation in the targeted area; and automatic modification of the flow rate of continuous saline infusion during radiofrequency application to keep a low impedance in the tissue, thus avoiding desiccation and subsequent carbonization in the targeted area.
Although the biologic peculiarity of metastatic hepatocellular carcinoma
may make comparison between our results and those reported by Livraghi el al.
[13] inappropriate, we think
that the differences in the devices used in each study could partially explain
the differences in the efficacy of saline-enhanced radiofrequency ablation in
our patients and theirs. In fact, we observed a high rate of complete necrosis
(95%) in tumors smaller than or equal to 3.0 cm in diameter and a fairly good
efficacy (71%) in tumors larger than 3.1 but smaller than or equal to 5.0 cm.
In the group studied by Livraghi et al., the success rate was 75% for tumors
smaller than 3.0 cm, and the complete necrosis rate was only 11% for tumors
between 3.0 and 4.5 cm. Nevertheless, our results are similar to those
reported by Rossi et al. [8] in
the treatment of hepatocellular carcinoma using radiofrequency ablation with
an expandable needle electrode (100% rate of complete necrosis in 26
hepatocellular carcinomas < 3.5 cm) and by Livraghi et al.
[33] in a study using
radiofrequency ablation with a cooled-tip needle electrode (90% rate of
complete necrosis in tumors 
3.0 cm and 71% rate of complete necrosis in
tumors 3.1–5.0 cm).
The low rate of complete necrosis in large (> 5.0 cm) hepatocellular carcinomas in our series confirms the lack of efficacy of radiofrequency ablation as the sole treatment in these tumors [33]. Combination with other therapies (i.e., transarterial chemoembolization or percutaneous ethanol injection) should be considered [34]. In five of our patients, we achieved complete necrosis of large (5.0–8.5 cm) hepatocellular carcinomas with several sessions of percutaneous ethanol injections. Percutaneous ethanol injection seems to be useful in treating portions of the tumor located near large hepatic vessels that often survive radiofrequency ablation treatment because of the cooling effect of the blood flow.
A recent work [35] compared saline enhancement and internally cooled needle electrode radiofrequency ablation for the treatment of small carcinomas of the breast in an animal model. The authors found the two methods to be equally efficacious but encountered a significantly greater complication rate with the saline technique, leading them to conclude that the cooled-tip needle electrode technique was preferable. However, in patients with cirrhosis who had medium and large hepatocellular carcinomas treated with the internally cooled needle electrode, Livraghi et al. [24, 33] reported severe complications (i.e., fatal septic shock due to peritonitis, hemorrhage requiring laparotomy, hemothorax requiring percutaneous drainage, long-lasting pain, and several cases of pleural effusions).
We did not encounter any deaths or major complications in the patients in our series. In particular, we never observed pleural effusion, ascites, or decompensation of liver cirrhosis, and only 21% of our patients experienced pain that required administration of analgesics. Furthermore, during follow-up, we have not observed any case of seeding, a finding that is in contrast with the high rate (12%) recently reported by Llovet et al. [36] after the treatment of hepatocellular carcinoma with internally cooled needles, especially in cases of superficially located lesions. The mean follow-up period of our study and that of the study by Llovet et al. are similar. In addition, as in their study, 20% of the lesions in our series were superficially located.
In conclusion, our experience suggests that percutaneous radiofrequency ablation of hepatocellular carcinoma by high frequency–induced thermotherapy with saline injection is as effective as other radiofrequency techniques and can be a simple and safe treatment in patients with cirrhosis that is highly effective for small hepatocellular carcinomas and fairly effective for hepatocellular carcinomas of middling size (3–5 cm). The treatment has a poor efficacy for large tumors (> 5 cm).
The radiofrequency device that has been used in our study delivers 60 W of power, which is quite low compared with the power delivered by other commercially available generators. It is likely that with a more powerful radiofrequency device, larger and more completely treated areas of ablation could have been achieved.
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