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1 Department of Radiology, University of Massachusetts, 55 Lake Ave. N,
Worcester, MA 01655.
2 Department of Radiology, Dana-Farber Cancer Institute and Brigham and Women's
Hospital, Boston, MA 02115.
3 Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115.
Received January 13, 2004;
accepted after revision April 20, 2004.
Address correspondence to S. Shankar
(shankars{at}ummhc.org).
Abstract
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SUBJECTS AND METHODS. We compared two groups of patients: one group treated with radiofrequency ablation alone (radiofrequency-alone group), and a second group treated with radiofrequency ablation and immediate prior injection of alcohol (combined group). The radiofrequency-alone group comprised 20 ablations (mean diameter, 8.4 cm; colorectal cancer metastases [n = 15]; other metastases [n = 5]). The combined group consisted of 30 radiofrequency ablations (mean diameter, 8.8 cm; metastatic colorectal cancer [n = 17]; other metastases [n = 8]; and hepatocellular carcinoma [n = 5]) treated with alcohol injection immediately before radiofrequency ablation. The amount of alcohol injected was determined by the size and location of tumors. Preprocedural laboratory tests (complete blood cell count with differential, liver function tests, and coagulation parameters) were performed in all patients, along with pre- and postprocedural CT, MRI, and PET. Measurements of tissue necrosis were obtained on the postprocedural CT scans and MR images. Volumes of necrosis calculated in each group were corrected for the number of radiofrequency applications and were statistically compared using the Student's t test. In addition, tissue impedances obtained during the radiofrequency ablation procedure were compared between the two groups.
RESULTS. The mean ablation volumes for the radiofrequency-alone
group were 32.3 cm2 (median, 28.6 cm2; range,
14.461.8 cm2) and for the combined group, 84.6
cm2 (median, 78.3 cm2; range, 34.6149
cm2). The difference in the necrosis volumes was significantly
larger (p < 0.0001) in the combined group. Overall, the combined
treatment group underwent fewer radiofrequency applications per session.
Tissue impedance during radiofrequency ablation was higher in the combined
group (mean, 62.7 vs 57.3
in the radiofrequency alone group;
p = 0.0005) at comparable times during the ablations. No major
complications were seen in either group.
CONCLUSION. Percutaneous radiofrequency ablation appears to be potentiated by immediate prior alcohol injection into the tumor. Consistently larger lesions are obtainable in fewer sessions, without any increase of complications, using the combined method.
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The alcohol and radiofrequency ablation combination has also been used in the treatment of HCC in two studies, and the results showed an increased volume of coagulative necrosis [10, 11]. Our study was performed prospectively in human subjects to determine whether injection of alcohol potentiated radiofrequency ablation by obtaining larger volumes of tumor ablation in hepatic tumors of various etiologies. We also assessed the safety and feasibility of the combined technique (compared with radiofrequency ablation alone).
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The study included two groups: patients who underwent percutaneous radiofrequency ablation without injection of alcohol (radiofrequency-alone group) and a second subset of patients who underwent percutaneous injection of alcohol into the tumors initially, followed by radiofrequency ablation (combined group) in the same session. All patients were deemed unresectable and were referred for treatment by their oncologists. All radiofrequency ablations were performed under an institutional review boardapproved innovative therapy protocol. All procedures were performed with the patient under general anesthesia. Written informed consent was obtained from all patients.
Radiofrequency-Alone Group
The radiofrequency-alone group included 12 men, and 8 women (age range,
4988 years; mean, 67.3 years). Twenty ablation sessions were
undertaken, and 22 tumors were treated in this group. Tumor size ranged from
5.5 to 15 cm (mean, 8.8 cm), and volume ranged from 44.8 to 295.8
cm2 (mean, 114 cm2).
Combined Group
This combined group comprised 19 men and 11 women (age range, 3984
years; mean, 67.1 years). Thirty ablation sessions were performed, and 36
lesions were treated in this group. Tumor sizes ranged from 5 to 11. 5 cm in
diameter (mean, 8.4 cm), and volume ranged from 48.6 to 330 cm2
(mean, 126 cm2). Details of the treated tumors are summarized in
Table 1.
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Radiofrequency Ablation Technique
Radiofrequency ablation was performed in all cases using a three-prong,
17.5-g-cluster, Cool-tip probe (Radionics). The probes ranged from 10 to 20 cm
in length, with 2.5-cm-long active tips. Grounding was achieved by attaching
four dispersive pads with a combined surface area greater than 400
cm2 to both thighs in each patient. The electrode was then attached
to a generator capable of producing 200 W of power. Each radiofrequency
application was 12 min long, automatically impedance-controlled by the
internal algorithm of the generator, according to the protocol recommended by
the manufacturer.
Injection of Alcohol
Dehydrated sterile alcohol (98%) was injected through 10- to 20-cm-long
22-g Chiba needles placed into the center of the tumor under CT guidance. The
total volume of alcohol injected varied from 2 to 20 mL (mean, 9.8 mL).
Depending on the size and location of the tumors before radiofrequency
ablation in all cases, we injected alcohol in small aliquots of 12 mL,
using CT imaging to ensure that the needle had not backed out of the intended
injection site and to assess extravasation. The volume of alcohol used was
empiric and based on the maximum volume that we could safely inject into the
tumor without leakage from the sides. The injection of alcohol was
accomplished usually through two or three needles placed in approximately the
center of the tumor. For larger tumors not close to critical structures,
injection was usually begun at the deepest portion of the tumor and continued
while slowly retracting the needle by 1- to 2-cm increments during the
injection, depending on size and location. Radiofrequency ablation followed
the alcohol injection within 25 min in all cases.
Number of Radiofrequency Ablation Applications
Each tumor was treated with a range of 18 radiofrequency ablation
applications of 12 min each in the radiofrequency-alone group (mean, 3.5;
median, 3). In the combined group, a range of 14 radiofrequency
applications (burns) were performed (mean, 2.1; median, 2).
Preprocedural and Follow-Up Imaging
All patients underwent CT, MRI, and PET before the procedure. A
contrast-enhanced CT scan was obtained immediately after the procedure, and a
contrast-enhanced MR image, within 24 hr. Follow-up PET, CT, and MRI were
performed at 3- to 6-month intervals after the procedure.
Volume Calculation
Baseline tumor sizes were measured on the preprocedural MR images (obtained
without and with IV contrast material). Measurements after ablation were
obtained on the postablation MR images (1.5-T scanners, Signa, GE Healthcare).
Transverse T1-weighted spin-echo images (TR/TE, 600/14; section thickness, 4
mm; field of view, 34 cm), transverse T2-weighted fast spin-echo images
(5,100/100; echo-train length, 12; section thickness, 4 mm; field of view, 30
cm), and transverse fast multiplanar spoiled gradient-echo images (285/1.6;
flip angle, 75°; section thickness, 5 mm; field of view, 34 cm with fat
suppression) were obtained, with imaging performed before and after the IV
injection of 20 mL of gadopentetate dimeglumine (Magnevist, Berlex
Laboratories). Measurements were obtained on a PACS system in three dimensions
by two experienced radiologists in consensus using electronic calipers. Volume
calculation was performed using the formula for an ellipsoid (V =
(4
/3)xyz, in which x, y, z are the three radii). The
obtained ablation volume was corrected for number of burns (total
volume/number of radiofrequency applications).
Impedance Measurement
The mean impedance was recorded from the read-out on the radiofrequency
ablation device between the first 36 min (chosen because of consistency
of obtaining readings) of radiofrequency energy application in all cases for
each location in which radiofrequency ablation was applied. The average
impedance in each of the two groups was calculated.
Statistical Analysis
The mean ablation volumes achieved in the two groups were compared using
the two-sample Student's t test. Similarly, the mean impedance values
were also compared using the same statistical test.
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Impedance
In the radiofrequency-alone group (n = 59 radiofrequency
applications), the mean impedance was 57.3
(range, 4874
; median, 57
). In the combined group (n = 55
radiofrequency applications), the value was 62.7
(range, 50108
; median, 61
). The difference was found to be statistically
significant, with a p value of 0.0005, using the two-sample Student's
t test.
Complications
In the radiofrequency-alone group, two patients had brachial plexopathy
(resolved spontaneously in both), one patient had a large biloma requiring
drainage, and three patients experienced prolonged recovery (> 3 days in
hospital). The postablation syndrome, manifested by low-grade fevers (
100°F [37.8°C]), myalgias, and malaise for up to 1 week after the
procedure, was seen in two patients, and one patient was hospitalized for 7
days for various medical problems unrelated directly to the procedure.
In the combined group, one patient had a small biloma that resolved without any specific therapy, and the postablation syndrome occurred in two patients. No other complications were seen in this group, and none of the patients had any symptoms suggesting alcohol toxicity.
Subjective Observations
Larger-than-usual amounts of gas were seen around the probe tip during
radiofrequency ablation in the combined group compared with the
radiofrequency-alone group. Portal venous gas also was seen more frequently in
the combined group.
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Radiofrequency ablation induces coagulation necrosis by ionic agitation and consequent heating of tissue. Substantial evidence suggests that the degree of tissue perfusion determines the extent of coagulation necrosis produced by thermal ablation: the more well perfused the tissue, the less the size of the achieved ablation [7, 22]. This outcome is probably best exemplified by the heat sink effect seen with radiofrequency ablations adjacent to large vessels [23].
Animal experiments have shown that the composite ablation induced by the two successive treatments of ethanol followed by radiofrequency ablation is more than simply additive when alcohol was administered before radiofrequency ablation [9]. Similar results have also been reported in HCC in humans [10]. Our study shows an increased volume of necrosis when radiofrequency ablation is used after intratumoral injection of ethanol in a variety of tumors, compared with radiofrequency ablation alone.
Although the mechanisms of the observed synergy between direct alcohol injection and radiofrequency ablation are not clear, there are several theories. One possible mechanism is the decrease of blood flow to the tumor and consequent tissue cooling before application of radiofrequency energy. The increased temperature of tissue from decreased perfusion-mediated cooling in turn leads to improved heat deposition within the tumor. Injection of alcohol thromboses vessels and probably decreases perfusion and therefore increases the radiofrequency effect. Thus, percutaneous ethanol injection therapy theoretically may also be synergistic when used with other heat ablation techniques such as laser, microwave, or focused ultrasound [9].
Another possible explanation for the observed synergy is that ethanol injected immediately before radiofrequency ablation may be heated or even boiled (boiling point of ethanol, 78.3°C) by radiofrequency heating; this effect results in an increased ablation volume by hot ethanol [24, 25]. Additionally, diffusion of ethanol into the areas not treated by radiofrequency ablation (e.g., adjacent to large vessels) may aid in achieving increased ablation volumes [11].
Significantly greater tissue impedance values were observed in tumors treated with the combined technique compared with radiofrequency alone. This finding may be secondary to both the presence of ethanol within the treatment area and alcohol-induced tissue changes because tissue coagulation can reasonably be expected to increase impedance. Also, decreased perfusion in tissue as a result of alcohol injection may contribute to increased tissue impedance. Increased impedance within tissue that has undergone radiofrequency ablation is best exemplified by the "roll-off" effect that occurs when ablation is complete, using commercially available devices (LeVeen needle probe, Boston Scientific) that use impedance control as an end point [26]. Hence, the increased ablation volume observed in the combined group could be due to greater tissue heating achieved during radiofrequency application secondary to higher tissue impedance.
Subjective observations in our study included a larger-than-usual amount of gas produced around the probe tip during ablations in the combined group and gas seen more frequently in portal venous branches. This increased gas also may account for the increased impedance observed during radiofrequency ablation in the combined group.
Overall, the complications encountered in the combined group were fewer and less severe than in the radiofrequency-alone group. The average number of radiofrequency applications for a given volume of tumor was also less in the combined group than in the radiofrequency-alone group. Taken together, these factors could be extrapolated to mean shorter procedure times and increased safety, obvious goals with ablation therapy, albeit unproven. Brachial plexopathy sustained in two patients in the radiofrequency-alone group was due to what we determined to be improper positioning of the patients' arms on the CT table. The positioning was corrected in our subsequent patients, and we believe that this complication was not related to the type of ablation performed.
A limitation of our study is that outcome analysis was not performed. However, our intention was to determine whether there was a synergistic effect of radiofrequency ablation with direct percutaneous alcohol injection in various hepatic tumors compared with radiofrequency ablation alone. Another possible limitation is that we did not assess ablation volumes stratified by tumor type, even though the tumor types in the two groups we studied were similar. The results of our study should encourage future research using other percutaneously injected substances such as acetic acid and hot saline with thermal ablation. Another outgrowth of our study is the question of whether combined therapy is useful in treating larger tumors in other organs and systems as well.
In summary, our study indicates that direct intratumoral alcohol injection potentiates radiofrequency ablation by achieving significantly larger ablation volumes. The use of the combined technique is straightforward and adds little cost and time to the procedure. Additionally, the data suggest that combined therapy requires fewer radiofrequency applications and may be safer.
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