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1 Department of Gastroenterology, Hiroshima Prefectural Hospital, 1-5-54
Ujina-Kanda, Minami-ku, Hiroshima 734-8530, Japan.
2 Department of Radiology, Hiroshima Prefectural Hospital, Minami-ku, Hiroshima
734-8530, Japan.
3 Department of Surgery, Hiroshima Prefectural Hospital, Minami-ku, Hiroshima
734-8530, Japan.
Received February 10, 2003;
accepted after revision April 17, 2003.
Address correspondence to M. Kitamoto.
Abstract
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SUBJECTS AND METHODS. Twenty-one patients with 26 nodules smaller than 3 cm in diameter were treated with radiofrequency ablation. Of these, 10 nodules were treated with a combination of radiofrequency ablation and chemoembolization using doxorubicin. All nodules were evaluated for size of induced coagulation, local recurrence, and complication.
RESULTS. The therapeutic areas averaged 27.6 x 22.3 mm using an electrode with a 2-cm tip and 37.2 x 29.1 mm using an electrode with a 3-cm tip. With respect to the results for 14 nodules treated using an electrode with a 3-cm tip with or without chemoembolization, the greatest dimension of the area coagulated by combined therapy was significantly larger (longest axis dimension, 39.9 ± 4.4 mm; shortest axis dimension, 32.3 ± 5.2 mm; n = 7 nodules) than areas without chemoembolization (longest axis dimension, 34.6 ± 2.6 mm; shortest axis dimension, 26.0 ± 3.3 mm; n = 7 nodules) (longest and shortest axis dimensions, p < 0.05). No recurrence occurred in the nodules smaller than 2 cm in diameter. Among the nodules larger than 2 cm in diameter, one local recurrence was observed in seven nodules treated by combined therapy, while two local recurrences were observed in seven nodules treated by radiofrequency alone. Minor complications developed in three patients, two with persistent high fever and one with biliary stenosis.
CONCLUSION. The combination of radiofrequency ablation and transcatheter arterial chemoembolization using doxorubicin markedly increased the extent of induced coagulation compared with radiofrequency alone, despite a small number of patients and the preliminary nature of this study.
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To obtain a large therapeutic area in the treatment for hepatic tumor with radiofrequency ablation, multiple overlapping treatments in a contiguous fashion [7, 16], temporary occlusion of the tumor blood supply [14, 17, 18], and injection of a saline solution around the electrode to lower tissue impedance [8] are performed. However, although the rate of complete necrosis of ablated tumors is high, about a third of patients develop recurrent tumor [16], and incomplete treatment is sometimes found adjacent to vessel walls [7, 9]. These results show that the perivascular zone and the periphery of the tumor are poorly treated by radiofrequency alone. Thus, multidisciplinary approaches such as chemotherapy or intraarterial treatment combined with radiofrequency ablation are required rather than radiofrequency alone. Some authors have shown that such combination therapy, including thermal ablation, is a better approach [12, 14, 20].
The effect of anticancer agents on cancer cells is enhanced by hyperthermia [21–24]. Goldberg et al. [25–27] show that the preadministration of doxorubicin enhanced the efficacy of radiofrequency ablation in the treatment of liver tumors. We postulate that combining radiofrequency ablation with transcatheter arterial chemoembolization using doxorubicin may be beneficial in increasing the amount of focal tumor destruction. The purpose of this study was to determine whether a combination of radiofrequency ablation and transcatheter arterial chemoembolization using doxorubicin increases the area of coagulation necrosis compared with radiofrequency alone. In addition, local recurrences and complications were also evaluated to compare the two therapeutic groups.
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CT studies were performed on a HiSpeed Advantage scanner (General Electric Medical Systems, Milwaukee, WI) during and after the injection of 100 mL of contrast medium (Iopamiron [iopamidol], Nihon Schering, Osaka, Japan) at a rate of 3 mL/sec. Triple-phase CT of the liver was performed during the arterial phase, the portal venous phase, and the equilibrium phase for 30 sec, 60 sec, and 180 sec, respectively, after the beginning of the injection of the contrast medium. Each acquisition through the liver was accomplished in a single breath-hold. In 24 nodules, the diagnosis of hepatocellular carcinoma was based on classic imaging manifestations of this tumor on CT: early enhancement at the arterial phase and hypoattenuation at the portal venous phase or at the equilibrium phase. In two nodules with no classic imaging manifestations, fine-needle biopsy revealed well-differentiated hepatocellular carcinoma.
Serum levels of 
-fetoprotein (normal value, < 20 ng/mL) and
des-gamma-carboxy prothrombin (PIVKA-II [protein induced by vitamin K absence
or antagonism]: normal value, < 40 arbitrary U/mL) were assayed before
treatment in all patients. Levels of -fetoprotein were normal in five
patients, in the range of 20–200 ng/mL in 14 patients, and more than 200
ng/mL in two patients. Elevated levels of PIVKA-II were found in 10 patients.
Both tumor markers were found to be positive in eight patients. Either marker
was positive in 10 patients (-fetoprotein, in eight; PIVKA-II, in two).
Both markers showed normal findings in three patients.
The study was approved by the ethics committee of our hospital. The procedure of the treatment was explained to patients, and written informed consent was obtained from each. Of these patients, transcatheter arterial chemoembolization was performed in 10 nodules (three nodules < 2 cm in diameter, seven of 2–3 cm in diameter) before radiofrequency ablation. Sixteen patients did not receive chemoembolization because informed consent for angiography was not obtained, although assigning the patients to receive chemoembolization was not randomized. Figure 1 shows the algorithm of patient treatment in our study. In patients who received chemoembolization, the nodules were treated by radiofrequency ablation after the procedure at the same hospital stay. The duration between chemoembolization and radiofrequency ablation was 9–30 days (average, 18.2 days).
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Procedure for Radiofrequency Ablation
Four nodules were treated with intraoperative radiofrequency ablation
without the Pringle maneuver (clumping the hepatic vascular pedicle).
Twenty-two nodules were treated with percutaneous radiofrequency ablation. A
20- or 15-cm-long, 17-gauge, Cool-Tip electrode with a 3- or 2-cm-long exposed
metallic tip (Radionics, Burlington, MA) was used to deliver radiofrequency
energy. Nodules larger than 2 cm in diameter were treated using an electrode
with a 3-cm tip, and nodules smaller than 2 cm were treated using an electrode
with a 2 cm-tip. A 200-W, 480-kHz monopolar radiofrequency generator (CC-1,
Radionics) was used as the energy source. A standard grounding pad (Radionics)
was placed on each of the patient's thighs. All patients were treated with
general anesthetic. Just before electrode insertion, analgesics such as
fentanyl citrate (Fentanest, Sankyo, Tokyo, Japan) and propofol (Diprivan 1%,
AstraZeneca, Osaka, Japan) were administered IV by an anesthesiologist while
the cardiovascular and respiratory systems were continuously monitored. A
single electrode was directly inserted through the skin and positioned at the
center of the nodule under sonographic guidance using a 3.75-MHz convex probe
with lateral biopsy apparatus. At the time of treatment, the most appropriate
approach with no large vessels near the targeted nodule was selected. The tip
of the electrode was advanced until it reached the deepest margin of the
tumor. Radiofrequency energy was applied for 8–12 min (one treatment
session). Multiple needle punctures were performed for relatively large
tumors. At the end of treatment, radiofrequency ablation application and
cooling circuits were simultaneously interrupted, and the heated tissues were
allowed to heat the electrode by diffusion until the maximum temperature had
been attained. The maximum tip temperature was then recorded. To prevent
bleeding, bile leakage, and malignant seeding, the intrahepatic needle track
was treated with thermocoagulation and the electrode was removed. We
administered an antibiotic prophylaxis of 2 g/day of cefotiam dihydrochloride
(Pansporin, Takeda, Osaka, Japan) for 3 days to all patients.
Intercostal sonography with the patient in the supine position was selected for 18 nodules, subcostal sonography for three nodules, and posteroanterior sonography below the right twelfth rib with the patient in the left lateral decubitus position was used for one nodule. Twenty-three nodules were treated in one treatment session, and three nodules were treated in two sessions.
Procedure for Chemoembolization
The Seldinger technique with local anesthesia was used to access the
femoral artery. An angiographic catheter was inserted into the right or left
hepatic artery where the targeted nodule was located. Anticancer agents mixed
with iodized oil (Lipiodol, Nihon Schering) were injected through the right or
left hepatic artery.
We used a doxorubicin (Adriacin, Kyowa Hakkou, Tokyo, Japan)–Lipiodol emulsion as the chemoembolization agent [29]. One patient who had a nodule smaller than 2 cm was treated with a high-molecular-weight anticancer agent [30] early in the study period. The doxorubicin–Lipiodol emulsion was prepared as follows: doxorubicin was dissolved in 2.5–3.5 mL of contrast medium (Iopamiron) and then mixed with 2.5–3.5 mL of Lipiodol in a 1:1 ratio by shaking. The average dose of doxorubicin used was 29.4 mg. Gelatin sponge embolization was not performed in any patient.
Efficacy and Follow-Up
The size and location of the nodules, the size of ablated area, and local
recurrence were assessed by consensus between two radiologists. In all
patients, the following serum test results were checked before treatment and 1
day, 4–7 days, and 1 month after treatment: transaminase, bilirubin,
albumin, creatinine, and a complete blood cell count.
Efficacy was assessed using CT studies within 4–7 days after the procedure and using hepatocellular carcinoma–related tumor marker assays within 7–10 days. Follow-up studies included serum marker assays every 1–2 months, sonography every 2–3 months, and CT studies every 3–6 months.
Statistical Analysis
The minimum and maximum lengths for the treated lesions were recorded and
are reported as means plus or minus standard deviations. The statistical
significance of the difference between the means of the two groups was
evaluated using a nonpaired Student's t test. The differences in
percentage data were evaluated using Fisher's exact test or the chi-square
test.Values for p of less than 0.05 were considered significant.
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At the 3-month follow-up, abnormal -fetoprotein levels normalized
(< 20 ng/mL) in six of 16 patients, decreased in five patients, and
increased in five patients. PIVKA-II levels normalized in seven of 10
patients, decreased in one patient, and increased in two patients.
Efficacy With and Without Chemoembolization
We compared the coagulation diameters for radiofrequency ablation using an
electrode with a 3-cm tip with and without transcatheter arterial
chemoembolization before radiofrequency ablation on CT scans obtained within 1
week after treatment. With respect to 14 nodules of 2–3 cm in diameter
with and without chemoembolization, the background of patients, ablation
conditions, and results are summarized in
Table 1. With respect to
background characteristics, including tumor size and functional hepatic
reserve, no differences were seen in the two therapeutic groups except sex and
age of patients. No significant differences were seen in ablation conditions,
such as the number of needle insertions or the treatment time, between the two
therapeutic groups. The clinical course of combination therapy is shown in
Figure 2A,
2B,
2C,
2D. The longest axis of the
area coagulated by radiofrequency ablation with chemoembolization was
significantly larger (39.9 ± 4.4 mm; n = 7 nodules) than the
long axis of the area without it (34.6 ± 2.6 mm; n = 7
nodules) (p < 0.05). The shortest axis of the area coagulated by
radiofrequency ablation with chemoembolization was significantly larger (32.3
± 5.2 mm; n = 7 nodules) than the shortest axis of the area
without it (26.0 ± 3.3 mm; n = 7 nodules) (p <
0.05).
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With respect to the results from 12 nodules using an electrode with a 2-cm tip in relation to chemoembolization before radiofrequency ablation, the greatest dimension of the treated area in the combination group was 31.7 ± 4.0 x 25.0 ± 3.6 mm, and in the radiofrequency-alone group was 26.2 ± 4.1 x 21.4 ± 2.6 mm. No significant differences were observed in the two therapeutic groups.
Clinical Outcome
All patients had follow-up for a minimum of 6 months. Local recurrence was
found in three nodules (11.5%) and confirmed with CT at the 3-, 9-, and
11-month follow-ups. Two were retreated: one with percutaneous radiofrequency
ablation, another with percutaneous ethanol injection guided by
CO2-enhanced sonography
[31]. No local recurrence was
seen in the nodules smaller than 2 cm in diameter. Among the nodules larger
than 2 cm in diameter, the rate of local recurrence was 14.3% (1/7) in the
nodules treated by radiofrequency ablation with chemoembolization and 28.6%
(2/7) in the nodules treated by radiofrequency alone, a result that was not
significant. During follow-up, two patients in the radiofrequency-alone group
died because of cancer progression.
Complications
No deaths occurred in the 90 days after radiofrequency ablation in these 21
patients. No treatment-related major complications developed. Fever greater
than 38°C was observed in five (50%) of 10 cases treated with
radiofrequency ablation with chemoembolization and in six (37.5%) of 16
patients treated with radiofrequency alone, a result considered not
significant. No difference in duration of high fever was seen between the two
therapeutic groups. Two patients (one from each therapeutic group) had
persistent high fever for longer than 5 days with no clinical signs of
infection. Although their hospital discharge was delayed, those patients
required no additional antibiotics except an antipyretic. Transient increases
in serum transaminase concentration were observed in all patients. In the
patients receiving combination therapy, serum alanine aminotransferase levels
(baseline, 71 ± 40.7 U/L; 1 day after radiofrequency ablation, 112
± 59.5 U/L) were higher than in the radiofrequency-alone group
(baseline, 51 ± 32.7 U/L; 1 day after radiofrequency ablation, 76
± 38.0 U/L). No significant difference was seen between the two
therapeutic groups in the rates of elevated serum alanine aminotransferase
levels compared with baseline rates. These results suggest that a relatively
high increase in serum alanine aminotransferase might be caused by the effect
of chemoembolization in the combination therapy group. However, the serum
transaminase level returned to the baseline values within a week in almost all
patients with or without transcatheter arterial chemoembolization.
One late complication was observed. Biliary stenosis was seen in one
patient whose tumor was located in liver segment VIII close to large vessels
such as the right portal trunk and the roots of right hepatic and middle
hepatic veins. The therapeutic area covered the tumor, but moderate dilatation
of the bile duct at the right lobe was seen on CT performed 3 months after
treatment. MR cholangiopancreatography revealed biliary stenosis at the
treated site and moderate dilatation of the bile duct at the right lobe.
Twenty-three months after treatment, no sign of local recurrence was seen,
with normal values for -fetoprotein and PIVKA-II, and no marked change
of liver function test results was observed (Fig.
3A,
3B,
3C,
3D,
3E). In summary, three minor
complications (11.5%) were experienced in our study (two persistent high
fever; one biliary stenosis). The difference in the incidence of minor
complications between the combination group and the radiofrequency ablation
group was significant (p < 0.05).
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-fetoprotein or PIVKA-II, and
local recurrence, not for survival rate. No significant differences were seen
in functional hepatic reserve, tumor size, and the prevalence of hepatitis
virus infection that may represent the nature of hepatocellular carcinoma.
Moreover, ablation conditions were equivalent in the two therapeutic groups.
Thus, it is true that a relatively large coagulation area was induced in our
combination group at fewer treatment sessions. Combinations of transarterial treatment and thermal ablation for the treatment of hepatocellular carcinoma have been widely reported, including microwave coagulation and transarterial embolization for medium-sized carcinomas [5, 6], radiofrequency ablation and transarterial embolization for hepatic tumor [12, 14], and laser ablation and transcatheter arterial chemoembolization [20]. Those combined therapies were able to treat large nodules. A reduction in blood flow can increase the extent of tumor ablation [5, 14, 17, 18]. Thus, a reduction of blood flow after chemoembolization likely caused, at least in part, the increase in the area of coagulation in our study. Although substantial retention of Lipiodol occurs, it remains unclear whether reduced blood flow is present at ablation in the combination group. We did not perform arterial embolization using gelatin sponges. Moreover, the average duration between chemoembolization and radiofrequency ablation was 18.2 days. MR studies showed rapidly enhancing portions in the tumor after chemoembolization, irrespective of the accumulation of Lipiodol [33]. If substantial blood flow is present, a relatively large area of induced coagulation in the combination group might be explained by the following speculation. Recently, Goldberg et al. [25] showed that a combination of radiofrequency ablation and direct intratumoral doxorubicin injection markedly increases the extent of induced coagulation in an animal model, and that IV liposomal doxorubicin enhances the effectiveness of radiofrequency ablation in an animal model [26] and in human hepatic tumors [27]. Indeed, the effect of doxorubicin on malignant cells is enhanced by hyperthermia [21–24]. Although the mechanism is not well understood, it has been clearly shown that hyperthermia increases the doxorubicin concentration in cells [21, 23]. The alterations in membrane permeability and fluidity may be present under hyperthermic conditions [21–24]. With rising temperature, passive intake of small molecules across the cell membrane increases, and active energy-dependent extrusion of doxorubicin is inhibited [21–22, 24]. Thus, the threshold to induce tumor destruction might decrease below 50°C, which is the key temperature to induce coagulation [16, 21–24]. After chemoembolization using doxorubicin, the concentration of doxorubicin is reported to be relatively high in liver tissue [34]. It is also reported that radiofrequency ablation increases doxorubicin accumulation in the periphery of tumors adjacent to the zone of coagulation [35]. Increased effectiveness in our study might be due to the doxorubicin in addition to alterations in blood flow, although that is only speculation.
Complications after radiofrequency ablation for hepatic tumors have been reported. Those reports included intraperitoneal bleeding [9, 11, 17], subcapsular bleeding [13, 18], pleural effusion [8,11, 13, 18], hemobilia [11], cholecystitis [11, 14], hemothorax [11], segmental biliary tract dilatation [15], bilioperitoneum [15], abscess formation [15, 16], minor skin burns at the grounding pad sites [15–17], a thermal burn of the gastrointestinal tract [16, 17], tumor seeding [16], and Staphylococcus aureus peritonitis [16]. The rate of complications for the treatment of hepatic tumors is 0–12.7% [7–19]. However, the rate of complications for the treatment of hepatocellular carcinoma is reported to be greater than 5% [12, 14, 17]. The relatively high rate of complications might be due to the prevalence of liver cirrhosis in patients treated. Our results of complications and high fever were similar to those of studies dealing with hepatocellular carcinoma associated with liver cirrhosis [12, 14, 17]. We are encouraged by the results of our combination treatment because it is safe and effective, although the rate of complications was relatively high. Moreover, one biliary stenosis would be exceptional because the targeted nodule was a central lesion, and there are known risks inherent in treating a lesion such as this. If that case is excluded, the rate of complications would be 10% in the combination group, which is not significant compared with the radiofrequency-alone group. Every procedure has merits and drawbacks. To balance risks versus benefits of combined therapies, further studies with more patients and adequate follow-up are needed to confirm our findings, as well as to ascertain whether other combination therapies can enhance the efficacy of radiofrequency ablation or reduce complications.
Multidisciplinary approaches for the treatment of hepatocellular carcinoma, which include combined surgery, tumor ablation, radiation therapy, and chemotherapy, are desirable to eradicate all malignant cells. Although radiofrequency ablation is currently receiving the most clinical study, a substantial percentage of nodules, especially large nodules, are incompletely treated using thermal ablation alone [13, 16]. Combining thermal ablation with adjuvant therapies is important and will certainly receive substantial attention in the near future. This preliminary clinical experience, despite a small number of patients and a relatively short follow-up period, shows the possibility that the combination of radiofrequency ablation and transcatheter arterial chemoembolization using doxorubicin may treat large hepatocellular carcinoma nodules at fewer treatment sessions. Further investigation of how to reduce perfusion-mediated tissue cooling and improve radiofrequency efficacy is required.
Acknowledgments
We thank Kentarou Hiraiwa and members of the operating room for their
anesthetic management
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