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Percutaneous Saline-Enhanced Radiofrequency Ablation of Unresectable Hepatic Tumors: Initial Experience in 26 Patients

¹ Department of Diagnostic Radiology, Division of Angiography and Interventional Radiology, University of Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
² Department of Internal Medicine I, Division of Oncology, University of Vienna Medical School, A-1090 Vienna, Austria.
³ Statistical Analyses Methodical Consulting, Treustr. 15/11, A-1200 Vienna, Austria.
⁴ Department of Anesthesiology and Intensive Care (B), University of Vienna Medical School, A-1090 Vienna, Austria.
⁵ Department of Radiotherapy, University of Vienna Medical School, A-1090 Vienna, Austria.
⁶ Wilhelminenspital, Montlearstr. 37, A-1160 Vienna, Austria.
⁷ University Department Biomedical Engineering, Fachhochschule Furtwangen, Jakob-Kienzle-Str. 17, D-78054 Villingen-Schwenningen, Germany.
⁸ Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, One Deaconess Rd., Boston, MA 02215.

Received May 29, 2002; accepted after revision October 28, 2002.

 
Address correspondence to J. Kettenbach.

Supported in part by the Ludwig-Boltzmann Institute for clinical and experimental radiology. S. N. Goldberg received support from the National Institutes of Health (RO1CA87992-01A1) and Radionics Tyco Healthcare, Boulder, CO.

Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
OBJECTIVE. The purpose of our study was to evaluate the safety and efficacy of percutaneous saline-enhanced radiofrequency ablation for unresectable primary or metastatic hepatic tumors.

SUBJECTS AND METHODS. Twenty-six patients with 15 hepatocellular carcinomas and 33 hepatic metastases (maximum diameter 8.6 cm) were treated; of these, seven tumors in five patients were treated twice. Thus, 44 radiofrequency treatments were performed. Saline-enhanced and impedance-controlled radiofrequency ablation (0.5–1.1 mL/min of saline, 15-mm conductive portion of the electrode tip, 25–60 W, 5–43 min) was performed using MR imaging guidance. Coagulation necrosis, volume indexes, morbidity, and complications were assessed.

RESULTS. The volume of coagulation necrosis 1–7 days after radiofrequency ablation was 1.6–126.6 cm³ (median, 18.9 cm³), corresponding to coagulation diameters of 1.5–6.2 cm (median, 3.2 cm). The coagulation volume was significantly larger if there were more than four radiofrequency applications (p = 0.006). Tumors of 3 cm or less in diameter were eight times as likely to be successfully completely ablated (p = 0.01) and volume indexes of lesions treated with the patient under general anesthesia were significantly larger than those treated with the patient under conscious sedation (p < 0.001). Major complications occurred in four patients (15%). Incomplete ablation in 19 (35%) of 54 radiofrequency lesions was due to cooling by a large vessel nearby (n = 2) or to low power applied in painful (n = 11) or critical (n = 6) locations. Residual tumor was observed in 14 (58%) of 24 tumors evaluated 6–8 months after radiofrequency ablation.

CONCLUSION. Percutaneous saline-enhanced and impedance-controlled radiofrequency ablation can be effective in the treatment of unresectable hepatic tumors and minimizes potential carbonization. A greater number of radiofrequency applications, general anesthesia, and increasing experience provide significantly better results.

Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Encouraging results have been published by a number of authors who describe percutaneous imaging-guided radiofrequency tumor ablation to treat hepatic malignancies [1, 2]. Recently developed techniques have enabled the creation of 5-cm zones of ablation under optimal conditions [3, 4, 5, 6]. However, in vivo it is difficult in many instances to ablate lesions that are larger than 4 cm in diameter [7]. Thus, attempts have been made to increase the amount of energy applied and to deliver energy deeper into the tissue [1, 2, 3, 4, 5, 6, 7, 8]. To accomplish this, one must solve the problem of reduced radiofrequency energy output that occurs when the tissue adjacent to the electrode is charred at tissue temperatures of about 110°C, and the impedance rises dramatically [5, 9]. Although this limitation can be avoided in part by using expandable or internally cooled electrodes [1, 2, 3, 5, 6, 7, 10], these innovations do not completely solve the problem. Another effective approach is to inject a saline solution into the tissue before or during radiofrequency ablation [5, 9, 11, 12]. Normal saline (0.9%) acts as a liquid electrode with a conductivity three to five times greater than that of blood and 12–15 times greater than that of soft tissues [12]. In the spread of the applied radiofrequency energy away from the solid electrode, the saline results in lower current density at the electrode–tissue interface, thereby reducing tissue desiccation and charring [5, 9, 12]. Our objective was to evaluate the feasibility and efficacy of a new impedance-controlled, saline-enhanced radiofrequency ablation technique for unresectable hepatic tumors performed entirely in an open MR system.

Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Approval from our institutional review board and written informed consent from all patients were obtained before treatment. From October 2000 to January 2002, 26 patients were admitted to this study. The patients' baseline characteristics are summarized in Table 1.

Indication for radiofrequency ablation was determined by our institutional multidisciplinary hepatic tumor conference attended by a medical oncologist, a surgeon, an interventional radiologist, and a radiation oncologist. In addition, the patient had to either have refused surgery or be unable to undergo surgical resection as determined by an oncologic surgeon. At least one lesion in each patient had to be a biopsy-proven malignancy. Two patients had known extrahepatic disease at the time of the study. All tumors that met the inclusion criteria were subjected to radiofrequency ablation regardless of size.

Laboratory studies before treatment included a complete blood cell count, hemostatic parameters, hematocrit, serum creatinine, and hepatic enzymes. Serum levels of -fetoprotein (normal value, 8.5 kU/L) were assayed in all patients with hepatocellular carcinoma, and carcinoembryonic antigen (normal value, 0–5 µg/L), in all patients with colorectal cancer metastases. Levels of -fetoprotein (median, 14.0 kU/L; range, 1.4–5260 kU/L) were normal in three patients, ranged between 13.1 and 452.0 kU/L in seven patients, and were 5260 kU/L in one patient. Carcinoembryonic antigen levels (median, 37.3 µg/L; range, 2.2–289.0 µg/L) were normal in two patients and ranged between 6.9 and 289.0 µg/L in six patients. Exclusion criteria included coagulopathy and more than four hepatic tumors at the time of first intervention.

Imaging Before and After Ablation
Before radiofrequency ablation, 24 patients underwent contrast-enhanced CT with a standard protocol for tumor staging. Two patients had contrast-enhanced MR imaging: one patient had pre-treatment MR imaging at an outside institution, and the other patient was allergic to nonionic contrast media. Because the diagnostic equivalence between CT and MR imaging has been previously shown [13], these patients were not required to undergo a second baseline study. Both underwent follow-up MR imaging to match the baseline study. In addition, all patients underwent chest radiography to exclude intrapulmonary metastases. Follow-up included contrast-enhanced CT or MR imaging, clinical examinations, and laboratory tests 1–7 days after treatment and at 1- to 3-month intervals (Figs. 1A, 1B, 1C). When residual or a new distant tumor was identified, the patient was rescheduled, in consensus with the tumor board, for another radiofrequency ablation session.

View larger version (165K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —70-year-old man with primary hepatic tumor. Preprocedural axial T2-weighted MR image (true fast imaging with steady-state free precession; TR/TE, 10/5; flip angle, 70°; echo-train length, 1; thickness, 7mm; matrix, 256 x 256) obtained after IV administration of particles of superparamagnetic iron oxide shows hyperintense primary hepatic tumor (arrow) 4 cm in diameter at level of hepatic dome.

View larger version (121K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —70-year-old man with primary hepatic tumor. Follow-up CT scan obtained 3 days after radiofrequency ablation shows hypodense nonenhancing area (largest diameter, 5.4 x 4.0 cm), which indicates coagulation necrosis and complete ablation of tumor.

View larger version (115K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1C. —70-year-old man with primary hepatic tumor. Follow-up CT scan at 6 months shows decrease in size of coagulation necrosis (largest diameter, 3.9 x 3.2 cm). No tumor recurrence was observed, and tumor markers reached normal values.

Interventional MR Imaging and Radiofrequency Ablation System
Patients were treated percutaneously under MR imaging guidance using an open-configured 0.2-T MR imaging system (Magnetom Open Viva, Siemens, Erlangen, Germany) as reported previously [14].

The saline-enhanced radiofrequency ablation system (Electrotom 106, Berchtold Medizinelektronik, Tuttlingen, Germany) is a device approved by the Food and Drug Administration and Conformite Europeene. The 375-kHz radiofrequency generator operates at 10–60 W (maximum) and delivers a high-frequency alternating current to a maximum of 1.2 A. The radiofrequency generator was positioned 2.5 m from the isocenter of the MR scanner at field strengths of approximately 0.7 mT. A 128-cm² grounding pad (EZ 344-06, Berchtold) was applied to a well-vascularized convex site near the treatment area, usually the right thigh. We used circuitry incorporated in the generator to continuously monitor the tissue impedance between the needle electrode and the grounding pad.

The distal 15-mm conductive portion of the MR-compatible 15-gauge radiofrequency electrode (total length, 20 cm) includes several rectangular apertures and water pockets (Fig. 2). This design permits the even flow of saline into the tissue surrounding the needle tip. To prevent clogging of the probe apertures, we started continuous infusion (0.2 mL/min) of a sterile saline solution (0.9% NaCl) as soon as the radiofrequency needle was inserted in the liver (idle mode). During radiofrequency ablation, the flow of saline (0.5–1.1 mL/min) was automatically controlled by the power-related perfusion system (Vial medical Pilot C, Fresenius, Brezins, France), depending on tissue impedance (automatic mode). An external temperature-sensing thermistor allowed continuous control of temperature inside the radiofrequency needle.

View larger version (71K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2. —Photograph shows MR imaging–compatible radiofrequency ablation electrode for saline-enhanced technique (15-gauge diameter, 20-cm length). Outlets and water pockets (arrowheads) in tip provide saline infusion through needle into surrounding tissue.

Ablation Procedures
Depending on availability of anesthesia support and personal preferences of the anesthetist in 20 radiofrequency sessions, either general anesthesia (n = 15) or conscious sedation and analgesia using remifentanil (Ultiva, Glaxo Wellcome, Vienna, Austria) (n = 5) were provided. During 13 radiofrequency sessions, local anesthesia (2% lidocaine injection) combined with incremental doses of IV piritramide (Dipidolor, Janssen-Cilag Pharma, Vienna, Austria; 1 mg per dose, three to 20 doses) and midazolam (Dormicum, Roche, Vienna, Austria; 1 mg per dose, two to four doses) was provided by the radiologist. The number of analgesic and sedative doses was adjusted as clinically indicated and vital signs were continuously monitored. A single course (2 g IV) of preinterventional antibiotics (Rocefin [ceftriaxon], Roche) was given if a tumor was close to the gallbladder or to the main intrahepatic bile duct.

On the basis of experimental data acquired from laser and radiofrequency ablations, our goal was to deliver a minimum of 1500 W/cm³ to neoplastic tissue, which includes a safety margin of 1 cm [9, 15]. In addition, signal changes seen on MR imaging were used to determine the end point of radiofrequency ablation [14]. Ablation time, power setting, and wattage applied were recorded for each ablation. If the impedance increased to more than 700 ± 50 , the radiofrequency system automatically reduced the radiofrequency power to 5 W until the impedance decreased to 400 . If impedance was raised to 900 , a short bolus (duration, 1.2 sec) of saline solution was injected in an attempt to disperse any gaseous buildup. To prevent hemorrhage and needle tract seeding after radiofrequency ablation, we coagulated the intrahepatic tract using a power setting of 25 W with the perfusion system switched off. In one patient with severely impaired hepatic function, butyl-2-cyanoacrylate (Histoacryl, B. Braun, Melsungen, Germany) was applied through the 13-gauge puncture sheath during removal to avoid bleeding.

Follow-Up Studies
After the ablation session, patients were monitored in the recovery room for 2 hr and subsequently on the ward for at least another 24 hr. During this time, a sonogram of the upper abdomen, a chest radiograph, and blood tests were obtained to exclude abdominal bleeding or pneumothorax. Because percutaneous radiofrequency ablation was being performed for the first time in our hospital and to closely observe early complications, as a common practice the referring clinicians decided to keep the patient on the ward for at least 2–3 days. Patients left the hospital within 1–29 days (median, 3 days) and resumed preoperative life activities within 1 week. Pain management was achieved with IV metamizol (Novalgin, Aventis Pharma, Bad Soden, Germany; 4g/day), tramadol (Tramal, Grünethal, Aachen, Germany; 600 mg/day), and dihydrobenzperidol (droperidol, 2.5 mg/day) given in 500 mL of lactated Ringer's solution immediately after radiofrequency ablation as needed.

Calculation of Tumor and Thermal Lesion Volumes
The maximum diameters of the lesion along and orthogonal to the long axis in the axial plane, and the superoinferior diameter of the lesion, were measured. The lesion volume was then calculated using the formula for an ellipsoid: volume = (4 x / 3) (d₁ / 2) (d₂ / 2) (d₃ / 2), where d₁, d₂, and d₃ represent the lesion diameters as described.

To estimate the percentage of necrosis covering the tumor, we defined a volume index as the ratio of the volume of the coagulation necrosis divided by the tumor volume. An adjusted volume index was further defined to include the known 1-cm safety margin that is required to maximize the chance of complete ablation [16]. The adjusted volume index was calculated as the quotient of necrosis volume divided by the volume generated by the tumor radius plus 1 cm. Values greater than 1 (i.e., necrosis > 100% of the tumor volume) for both the adjusted and nonadjusted volume index were the target goal. This goal was based on the rationale that if the entire tumor were enveloped in the coagulation necrosis, the probability for a successful treatment would be high.

Response Evaluation Criteria
Tumor response was defined as previously described [17]. Irregular enhancement at the periphery of the lesion or a nodular contrast enhancement denoted incomplete ablation. Complications were graded using two scales. The National Cancer Institute Common Toxicity Criteria (CTC) system was used to grade adverse events [18, 19] as follows: 0, no adverse event or within normal limits; 1, mild adverse event; 2, moderate adverse event; 3, severe and undesirable adverse event; and 4, life-threatening or disabling adverse event. The Society of Cardiovascular & Interventional Radiology (SCVIR) classification of complications by outcome was also used [20].

Statistical Evaluation
The size of the coagulation necrosis was compared with the tumor size using two volume indexes. Values for p of less than 0.05 were considered significant. The data were further evaluated with a subset analysis based on tumor type (hepatocellular carcinoma vs hepatic metastases), and the method of analgesia was evaluated using the Mann-Whitney U test. A statistical software system (version 10.0, SPSS, Chicago, IL) was used for all calculations.

Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A total of 48 tumors were treated. By consensus of the tumor board, five patients with seven tumors were treated twice; thus, 55 radiofrequency treatments (ablation sessions) were performed during 33 MR imaging–guided sessions. A maximum of four tumors were ablated during each session. Depending on the size and shape of the tumor, a median of three radiofrequency applications (range, one to nine applications) were performed for each tumor using a mean radiofrequency power of 39 ± 12 W. The mean radiofrequency ablation time was 19.5 ± 9.9 min. The applied energy for each tumor was 3346–138,246 W (median, 33,648 W).

Therapeutic Responses
Imaging after treatment showed induction of coagulation necrosis in all lesions. However, one patient with a single hepatocellular carcinoma underwent liver transplantation before scheduled follow-up imaging. Therefore, 54 radiofrequency lesions of 47 tumors were evaluated to determine the volume of induced coagulation necrosis (median, 18.9 cm³; range, 1.6–126.6 cm³; mean, 26.7 ± 26.9 cm³). The results of radiofrequency treatment according to the number of radiofrequency applications are summarized in Table 2.

The volume index and the adjusted volume index were calculated for each of the 54 radiofrequency ablation sessions in the tumors treated. A volume index greater than 1.0 in 44 (81%) of 54 lesions suggested that the entire tumor was treated. An adjusted volume index greater than 1.0 in 24 (44%) of 54 radiofrequency lesions suggested that the entire tumor, including a safety margin, was treated. A significantly larger coagulation volume (p = 0.006) and volume index (p = 0.020) were achieved if more than four radiofrequency ablations were applied to a given lesion (Table 2). Patients with primary hepatic tumors required a significantly longer duration of radiofrequency energy application (p = 0.030) to achieve a coagulation volume similar to that for hepatic metastases. The corresponding descriptive statistics are presented in Table 3. No significance was observed for energy variables, the size of induced coagulation necrosis, or volume indexes when comparing hepatocellular carcinoma with metastatic disease.

Twenty-five patients with 47 tumors had follow-up imaging 1–7 days after ablation, at which time 13 patients with 14 lesions (30%) had residual tumor based on tumor response criteria [17]. We retreated five patients with seven tumors and repeated imaging at 1–7 days after ablation.

Including these seven retreatment sessions, a total of 19 (35%) of 54 radiofrequency lesions had incomplete ablation at the first procedure imaging (1–7 days after ablation). The reasons for incomplete ablation were attributed to the following: in 11 lesions, the radiofrequency energy deposition was limited because of patient pain when treating large (n = 5) or subcapsular (n = 6) tumors; in six lesions located adjacent to organs such as the bowel or gallbladder, the maximum radiofrequency output was limited to 30 W or to a purposefully short radiofrequency duration of 5–9 min to avoid complications; in two lesions, residual tumor was found adjacent to a large vessel, a known source of cooling and incomplete ablation [5, 9, 21].

At 1–2 months after ablation, 17 (49%) of 35 lesions in 19 patients had been evaluated as incompletely ablated. Three to five months after radiofrequency ablation, 21 (66%) of 32 tumors in 16 patients had been evaluated as incompletely ablated, and incomplete ablation was observed in 14 (58%) of 24 tumors followed up for 6–8 months after radiofrequency ablation.

Multiple logistic regression analysis revealed that the frequency of complete treatment increased by 7% for each ablation (odds ratio, 1.1; 95% confidence interval [CI], 1.0–1.1; p = 0.003). A primary determinant of treatment success was lesion size, because tumors smaller than 3 cm were eight times as likely to be successfully completely ablated (odds ratio, 7.9; 95% CI, 1.6–38.8; p = 0.01).

Although the type of analgesia did not specifically correlate to the size of necroses, the Mann-Whitney U test revealed significantly larger adjusted and nonadjusted volume indexes (p < 0.001) in lesions ablated during general anesthesia (Table 4). Levels of -fetoprotein remained normal in three patients and decreased in five patients (median, 11.9 kU/L; range, 4.1–211.0 kU/L). Two patients were lost to follow-up. Carcinoembryonic antigen levels remained normal in two patients, decreased in four, and increased in two (median, 31.9 µg/L; range, 2.6–247.0 µg/L).

Excluding seven patients who underwent hepatic transplantation, 13 patients with 27 tumors were followed up for at least 6 months (range, 7–22 months; mean, 12 months). Of these patients, three (23%) remained disease-free, six had local recurrence, three had multicentric disease, and one died as a result of advanced cancer. Because of recurrent disease, distant metastases, or advanced disease, six of the 13 patients received further chemotherapy (n = 4) or chemoembolization and radiation therapy (n = 2). Survival 6 months after radiofrequency ablation was 81% (21/26 patients) and at 12 months was 77% (20/26 patients). One patient died of toxicity from treatment (described in the following text), and five patients died from advanced malignant disease 0.1–9 months (mean, 3.5 months) after radiofrequency ablation.

Up to 6 months after radiofrequency ablation, -fetoprotein levels remained normal in three patients and further decreased in five patients (median, 5.5 kU/L; range, 0.9–389.0 kU/L). The levels remained significantly high in two patients (> 200 kU/L) and between 13.9 and 33.3 kU/L in the others. Carcinoembryonic antigen levels remained normal in one patient, decreased in four patients, and increased in three patients because of local recurrence (median, 48.8 µg/L; range, 4.4–247.0 µg/L).

Side Effects and Complications
Despite radiofrequency coagulation of the trajectory and the application of butyl-2-cyanoacrylate through the 13-gauge puncture sheath during removal, one patient (3.8%) with severely impaired hepatic function suffered from moderate bleeding at the puncture site. After the transfusion of blood and fresh frozen plasma, the patient remained hemodynamically stable for 2 days but gradually developed an irreversible lactic acidosis and died from disseminated intravascular coagulation (CTC grade 5; SCVIR grade 6) 3 days after radiofrequency ablation. Another patient (3.8%) required surgical repair of a duodenal perforation (CTC grade 4; SCVIR grade 4) that occurred 18 days after radiofrequency ablation. Furthermore, one thrombosis of the inferior vena cava (CTC grade 3; SCVIR grade 3) and one hepatic abscess (CTC grade 3; SCVIR grade 4) occurred in one patient each. In two patients (7.6%), temporary thrombopenia (CTC grade 2; SCVIR grade 3) was observed.

Minor complications were observed in five patients (19.2%) and included mild fever and pain, and all patients had mild transient increases of serum hepatic enzymes (CTC grades 1–2; SCVIR grade 2). Hyperemia of the skin (CTC grade 2; SCVIR grade 2) (n = 1, 3%) occurred in one patient but disappeared without further therapy.

Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study confirms that saline-enhanced radiofrequency ablation for unresectable hepatic tumors is feasible and effective. The design of the new saline-perfused radiofrequency electrode and the impedance-controlled radiofrequency ablation mode increase the active electric field, producing coagulation necroses 1.5–6.2 cm (median, 3.2 cm) in diameter. When monopolar radiofrequency needle electrodes are used, a coagulation diameter of less than 2 cm has been reported [2, 5]. The use of a conventional monopolar electrode is painstaking, to the extent that, in one study, 212 radiofrequency applications during 108 radiofrequency sessions were necessary to treat 36 hepatocellular carcinomas (diameters 3 cm) [10]. Compared with these studies, lesion sizes were larger in our study.

Although the coagulation size increases with increasing temperature of the electrode tip and duration of energy application, gains are limited by temperatures greater than 110°C, which result in charring and vaporization in the tumor area. In addition to expandable or internally cooled radiofrequency electrodes, saline injection or saline perfusion provides another way to prevent charring around the needle tip. In vitro, lesion sizes of 6.0 ± 1.0 cm were significantly larger using "wet-expanded" electrodes than were those ablated with "expanded-dry" and "unexpanded-wet" electrodes [12]. Similar coagulation diameters ( 5.7 cm) were reported after in vitro coagulation of bovine liver [22] using the same saline-enhanced radiofrequency system (5–60 W) as used in our study. In that study, comparable coagulation diameters were also observed when using the same internally cooled clustered electrodes (5–200 W).

During animal experiments, wet-perfused electrodes have been successfully used to treat tumor tissue, and no significant differences (p = 0.999) in local recurrence or residual tumor were observed when compared with internally cooled radiofrequency electrodes [23]. However, clinically, complete necrosis in 13 (52%) of 25 lesions (diameter, 1.2–3.9 cm) and partial necrosis greater than 50% in 12 lesions (diameter, 1.5–4.5 cm) were reported using modified 21-gauge needles for saline-perfusion and radiofrequency ablation [9].

However, to adequately treat tumors larger than 3.0 cm in diameter, in our study, multiple overlapping radiofrequency ablations from different electrode positions or multiple insertions were unavoidable. Although significantly larger coagulation volumes were possible with more than four radiofrequency applications, the strategy of overlapping ablation zones is time-consuming and can leave residual foci of untreated tumor between regions of adequate ablation (Table 3). The lower efficacy in sessions with one radiofrequency application can be explained by the fact that more energy is required when the tissue surrounding the needle is at 37°C and further cooled by blood flow in the regions of prior coagulation. One factor that influenced the efficacy of tumor ablation might have been our initially limited experience with saline-enhanced radiofrequency ablation of hepatic tumors. Analysis of our data, however, documents that improved ablation skill and experience enabled us to create thermal lesions with greater volume indexes, indicating a more effective radiofrequency ablation over time. This time covered a period of approximately 6 months, further confirming the fact that the procedure requires substantial effort to master.

We initially postulated that the development of a volume index would be beneficial in helping to determine both the technical adequacy of the therapy (i.e., when to stop ablating) and the ultimate outcome. Although the volume index was helpful in achieving the first goal, analysis of our data suggests that this index is less useful in estimating the efficacy of ablation. To our knowledge, this index has not been previously discussed in the literature.

Validation of volume indexes, however, depends on optimal placement of the radiofrequency probe in the tumor; therefore, ablation is not complete if the coagulation necrosis has been eccentric compared with the tumor's geometry. In addition, volume indexes may over-estimate the efficacy of radiofrequency ablation if small residual tumors are retreated, because they are already surrounded by residual necrosis from the first ablation. However, in our study, no distinction was made between first ablation or retreatment of tumors in calculating the volume indexes. Nevertheless, volume indexes may be more useful to evaluate the effectiveness of precise tumor targeting for a given coagulation zone and were useful to estimate the relationship between applied energy and resultant coagulation necrosis in a given hepatic tissue. Regarding efficacy, volume indexes have been significantly larger in patients treated under general anesthesia (Table 4). Although the volume index does not automatically allow one to conclude that complete tumor ablation occurred, it indicates that complete ablation may be more likely even when radiofrequency electrodes are positioned slightly off center in the lesion.

In general, radiofrequency powers up to 200 W, newly designed expandable or cluster electrodes [1, 2, 3, 5, 6, 7, 8], reduced organ perfusion [4, 5], and radiofrequency ablation combined with chemotherapy [5, 24] achieve larger coagulation volumes during a single radiofrequency ablation. When expandable electrodes and one to two radiofrequency applications at the same position were used, the mean coagulation volume was reported to be 14 cm³, corresponding to a coagulation diameter of approximately 2.9 cm [25]. When an internally cooled tip electrode was used, a mean coagulation diameter of 2.9 ± 1.2 cm was reported during a single radiofrequency application [7]. The results in our study (Table 2) are comparable to or better than those achieved in these studies.

Heat Conduction in the Liver
For all thermal ablation techniques, coagulation necrosis in vivo is reduced and is more variable than in ex vivo studies [4, 26, 27]. A likely source for much of this variation is the heterogeneous blood flow and heterogeneity of tumor composition, with alternating heat conduction in the treatment zone [26]. We have observed this effect in primary hepatic tumors, in which a significantly longer duration of radiofrequency heating is required (p = 0.030). Although not significant, a trend toward lower volume indexes in hepatocellular carcinomas was also observed when compared with the hepatic metastasis group (Table 3). Variable response to heat conduction may also explain an out-lier in the hepatic metastasis group showing that the coagulation necrosis was much larger (Table 2).

Another factor attributable to heterogeneous heat conduction in tissue may be the "heat sink effect," which actually preserves the vessels near a treatment area. The protected vessels often harbor adjacent tumor that may eventually regrow [28], which occurred in at least two lesions in our study.

Uneven diffusion of the saline infusion has been previously reported but was not directly documented in our study [23, 29]. However, we consider this to be an important factor, because we observed bowel perforation due to thermal necrosis attributable to saline diffusion. When a monopolar electrode is used, any diffusion from the saline path might be connected to the grounding pad by an infinite number of possible electric field lines [29]. Therefore, radiofrequency energy could dissipate at any distance if the paths were connected with the needle electrode through the saline solution. To reduce the risk of distant damage, a saline-perfused bipolar electrode configuration might focus dissipation of radiofrequency energy between the two electrodes [29].

Pain Management During Radiofrequency Ablation
Radiofrequency ablation performed under general anesthesia can minimize the incidence of incompletely treated lesions. The Mann-Whitney U test revealed significantly greater volume indexes for this group than for the group given conscious sedation (p < 0.001) (Table 4). This knowledge is advantageous because general anesthesia enables pain-free treatment, which allows higher power settings and longer radiofrequency ablation. The probability of insufficient coagulation necrosis is therefore great for patients without general anesthesia. If painful sensations occurred despite conscious sedation, we attempted to compensate for the lower power level by a longer duration of radiofrequency ablation. However, repeated radiofrequency ablations at low energy may not always be useful, because the early equilibrium of heat flux into the tissue and the heat loss by perfusion prevents larger coagulation volumes.

Another advantage of general anesthesia might be the decrease in mean systemic blood pressure during the procedure [30]. Hepatic perfusion and perfusion-mediated cooling may be reduced, which contributes to more effective radiofrequency ablation [5, 26, 29, 30].

Morbidity and Complications of Radiofrequency Ablation
Percutaneous radiofrequency ablation is reported to be relatively safe, but the benefits of such a minimally invasive procedure are accompanied by certain risks. The complication rate reported in various studies ranges from 0% to 12%, and treatment-related death rate ranges from 0% to 1% [25, 31, 32, 33]. These data indicate that extra caution must be taken, and preventive measures need to be ready when using this technique [23, 34]. In our study, an unintentional small puncture of the hepatic capsule during biopsy of a subcapsular lesion might have caused diffusion of saline to the nearby duodenum during radiofrequency ablation, causing subsequent thermal damage. In this case, inducing "ascites" with saline instillation or increasing the distance between a lesion and abutting bowel at laparoscopy might have prevented the complication [8]. Radiofrequency ablation of lesions located near large bile ducts may lead to biliary complications, and careful attention should be paid when a tumor is located close to the main bile ducts. We further speculate that the release of tissue thromboplastin, cytokines such as interleukin-6, or other coagulation-inducing substances may have triggered coagulopathy and thrombopenia [23, 31]. In addition, patients with severely impaired hepatic function should be excluded from radiofrequency ablation.

A temporary inferior vena cava thrombosis in another patient was related to the radiofrequency ablation of a paracaval hepatic metastasis. The area was irradiated twice several months before; therefore, the vascular endothelium might have already been altered and more prone to thrombosis. On the other hand, the low rate of bleeding seen in our study is likely the result of a cauterization effect. This effect could also be used to minimize the incidence of needle-track seeding, which was documented in only 12 patients (0.5%) after radiofrequency ablation of 3554 lesions in 2320 patients [33]. We have not seen tumor seeding during follow-up; however, we are aware of the risk and advocate coagulation of the needle tract, the use of coaxial sheaths, and new radiofrequency needles for each tumor to be ablated [35].

In our study, extrahepatic metastases in the lung were observed in two patients 6–12 months after radiofrequency ablation. However, these patients already had synchronous hepatic metastases at the time of the first ablation, and these findings are consistent with other radiofrequency ablation reports [31]. However, caution is necessary because the static interstitial pressure may force tumor cells to migrate. To lower this risk, we consider infusion of much less saline solution (0.1–0.5 mL/min) at higher concentrations (3–5%), which might also reduce the risk of collateral damage caused by the uneven diffusion of relatively large volumes (30–60 mL/hr of radiofrequency ablation) of saline in the current setting (Gangi A, Müller W, unpublished data).

MR Imaging Guidance
Choosing the right imaging modality to place the radiofrequency electrode accurately in the tumor with respect to its three-dimensional geometry is essential. MR imaging is well suited for this task because of its multiplanar imaging capability and a high tumor-to-liver contrast that can be further improved with liver-specific contrast media. Lewin et al. [14] reported that using interactive MR imaging guidance made placement of custom-made radiofrequency electrodes more time-efficient than using non-MR methods. MR imaging as a radiation-free imaging modality is even more advantageous because of its thermal monitoring capabilities. In our study, we used a commercially available radiofrequency ablation system. Although thermal monitoring was limited to studies after ablation because of radiofrequency interference during MR imaging, MR imaging guidance was particularly useful in lesions with poor conspicuity on other imaging modalities and for lesions located in the hepatic dome or near critical structures.

However, the advantages of MR imaging are not widely appreciated because of system costs, availability (in particular, of open MR designs), and the necessity of an MR-compatible radiofrequency system. Sonography remains the primary imaging modality used to guide radiofrequency ablation.

To date, several series detailing the outcome of radiofrequency ablation for primary or metastatic hepatic tumors have been published [6, 14, 22, 23]. In these studies, complete tumor ablation was achieved in 52–92% of patients. In those studies in which at least 1-year follow-up was available, up to 50% of patients have remained disease-free. Compared with these studies, our rate of 42% complete necrosis at 6–8 months of follow-up was lower. Unresectable, multicentric, or large lesions (maximum diameter, 4.1–8.6 cm), less effective overlapping ablation fields, and pain have contributed significantly to incomplete coagulation. Our reported 6- and 12-month survival results are preliminary for this ongoing study. Radiofrequency ablation was offered as the first line of treatment in this patient population. The survival and good quality of life of those who undergo radiofrequency ablation versus systemic chemotherapy justified this course of action.

Potential benefits and strengths of the impedance-controlled saline-enhanced radiofrequency technique include the use of saline injection (either before or during the radiofrequency procedure), which has been proven to increase electric conductivity in hepatic tissue and enable greater radiofrequency energy deposition [5, 9, 11, 12]. Thus, increased tissue heating during radiofrequency ablation occurs without charring and tissue vaporization at the electrode surface. In addition, the impedance-controlled flow of saline prevents the unexpected increase in impedance and allows the user to focus on the clinical aspects of the ablation procedure rather than on manipulating the perfusion system. The nondeployable needlelike radiofrequency electrode design eliminates stepped deployment and allows easier placement than do multitined expandable electrodes, particularly in areas near critical structures. On the other hand, because of inhomogeneous tissue matrix, diffusion and penetration of injected saline may be less uniform. In a few cases, distant heating was reported when saline followed the insertion path of the electrode needle or when saline was applied near critical structures such as the colon (Gillams A, Lees B, personal communication). To reduce the risk of distant heating, either the amount of saline perfusion may need to be reduced or a saline-perfused bipolar electrode configuration might be needed to direct the path of radiofrequency energy predominantly between the two electrodes [28]. Thus, the optimal parameters for saline perfusion will need to be defined for this type of radiofrequency apparatus, and most likely required individualized optimization for different tumor types and tissues to be treated will also need to be defined.

In conclusion, percutaneous saline-enhanced and impedance-controlled radiofrequency ablation provides effective treatment of hepatic tumors. The impedance-controlled, saline-enhanced ablation technique minimizes potential carbonization, and the single-needle design allows easy placement, particularly near critical or subcapsular locations. Effective pain management, a greater number of radiofrequency applications, and treatment of tumors of 3 cm or less in diameter provide significantly better results. Further development of this radiofrequency ablation technique, with appropriate selection of patients and combined treatment with chemotherapy, may improve efficacy, potentially permit the treatment of larger lesions, and reduce the number of tumor recurrences in ablated areas.

Acknowledgments
 
We acknowledge the cooperation of P. Ferenci, T. Grünberger, G. Kornek, F. Längle, F. Mühlbacher, C. Müller, M. Peck-Radosavljevic, M. Raderer, W. Scheithauer, R. Steiniger, B. Schüll, S. Tomek, C. Wenzel, and C. Zielinski for referring patients for this study; W. Schima, M. Uffmann, M. and C. SchäferProkop for the follow-up imaging; K. Bach for her ambitious support during the MR imaging–guided procedures. We thank Mary McAl-lister, Johns Hopkins University Hospital, Baltimore, MD, for manuscript assistance.

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