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1 Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical
School, 330 Brookline Ave, Boston, MA 02215.
2 Present address: Department of Radiology, Johns Hopkins Medical Center,
Baltimore, MD 21287.
3 Department of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA 02215.
Received November 15, 2001;
accepted after revision January 22, 2002.
S. N. Goldberg receives support from Radionics/Tyco Healthcare, Burlington,
MA.
Abstract
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SUBJECTS AND METHODS. Fourteen focal hepatic tumors (diameter: mean ± SD, 4.0±1.8 cm) in 10 patients (colorectal cancer, n = 3 patients; hepatocellular carcinoma, n = 4; neuroendocrine tumor, n = 2; breast cancer, n = 1) were treated with internally cooled radiofrequency ablation. In addition to undergoing radiofrequency, five patients (n = 7 lesions) were randomly assigned to receive 20 mg of IV doxorubicin in a long-circulating stealth liposome carrier (Doxil) 24 hr before ablation. Contrast-enhanced helical CT was performed immediately (within 30 min) after radiofrequency ablation (baseline) and 2-4 weeks after ablation. The volume of induced coagulation was measured by three-dimensional reconstruction techniques, and the measurements were compared.
RESULTS. For tumors treated with radiofrequency alone, the volume of the thermal lesion had decreased 12-24% (mean ± SD, 82.5% ± 4.4% of initial volume) at 2-4 weeks after ablation. By comparison, increased tumor destruction at 2-4 weeks after ablation was observed for all lesions treated with combined Doxil and radiofrequency (p<0.001). Six lesions increased 24-36% in volume, and coagulation surrounding a small colorectal metastasis increased 342%. No coagulation was identified in four unablated control lesions in the two patients receiving Doxil alone.
CONCLUSION. Our pilot clinical study suggests that adjuvant Doxil chemotherapy increases tumor destruction compared with radiofrequency ablation therapy alone in a variety of focal hepatic tumors. Optimization of this synergistic strategy may ultimately allow improved clinical efficacy and outcome.
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In an attempt to overcome this limitation, researchers are currently studying the effects of radiofrequency therapy combined with adjuvants such as percutaneous ethanol instillation [14], saline injection [15, 16], and embolization [17]. These strategies aim to effectively modulate either electric conductivity or blood flow during ablation to promote greater tissue heating and larger zones of contiguous destruction. An alternative adjuvant strategy combines radiofrequency with chemotherapy [18,19,20] on the basis of the known synergistic antineoplastic effects of hyperthermia (i.e., reversible cell damage induced at 42-48°C) and chemotherapeutic agents, such as doxorubicin [21,22,23]. Thus, the goal of this approach is to increase the extent of tumor destruction occurring within a sizable peripheral zone of elevated, but sublethal, temperatures that surround the region of heat-induced coagulation [20].
In small R3230 rat breast tumors, a significant dose-dependent increase in tumor coagulation was observed when radiofrequency was combined with direct intratumoral injection of doxorubicin [18]; in addition, an even greater synergy between radiofrequency and an IV-administered preparation of doxorubicin has been reported [19]. Specifically, increased tumor destruction was noted for tumors treated with radiofrequency and a long-circulating liposomal doxorubicin preparation (Doxil; ALZA Pharmaceuticals, Mountainview, CA) compared with tumors treated with radiofrequency alone. An increase in coagulation diameter from 6.7 to 13.5 mm was achieved 48 hr after the combined intervention [19]. These results suggest a clinical role for this type of adjuvant therapy—that is, for combining systemic chemotherapy with radiofrequency ablation.
On the basis of results in animal studies, we hypothesized that clinically meaningful increases in hepatic tumor destruction could also be achieved in human patients by combining radiofrequency therapy with Doxil. In this article, we report the results of an initial randomized pilot study in which we compared the short-term effects of radiofrequency combined with Doxil therapy with those of radiofrequency ablation alone.
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Patient Demographics
Ten patients with 18 intrahepatic tumors were enrolled in this study.
Patients ranged in age from 46 to 84 years (mean ± SD, 67.3 ±
12.2 years); seven were men, and three were women. Four patients had primary
hepatocellular carcinoma (n = 5 lesions), three patients had
colorectal metastases (n = 5 lesions), two patients had
neuroendocrine tumors (n = 5 lesions), and one patient had breast
cancer (n = 3 lesions). The 14 radiofrequency-treated tumors measured
from 2 to 8.2 cm in diameter (mean ± SD, 4.0 ± 1.8 cm). Four
small tumors (diameter, 
1.7 cm) in the patients receiving Doxil alone were
also identified on the scan obtained before radiofrequency (n = 2) or
at the time of ablation (n = 2). These tumors served as the controls
for the effects of Doxil. Table
1 provides individual tumor types and sizes sorted by
treatment.
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Inclusion criteria for this study were the inability to undergo surgical resection, as determined at our institutional multidisciplinary hepatic tumor conference attended by medical oncologists, surgeons, interventional radiologists, and radiation oncologists; a maximum of four discrete hepatic tumors; and no prior therapy for the hepatic tumors being considered for radiofrequency ablation. No patients had known extrahepatic disease at the time of the study.
Patients selected to receive chemotherapy were given 20 mg of liposomal doxorubicin 24 hr before radiofrequency ablation. A vial of Doxil that contained a dose for one patient was IV administered by a licensed medical oncology nurse. Doxil is a commercially available doxorubicin preparation that is encapsulated in 100-nm polyethylene glycol—coated phosphotidyl choline and cholesterol liposomes. The polyethylene glycol coating affords stearic stabilization and promotes prolonged circulation times of the liposome preparation [23]. This particular agent was selected for several reasons: Doxil has shown therapeutic efficacy in animal tumor models; this agent is known to have a long circulation time, so it would be present in high concentrations at the time of ablation; and it has been approved by the United States Food and Drug Administration for the treatment of several solid tumors. Although a previous animal study showed the greatest synergy to occur when Doxil was administered almost simultaneously with radiofrequency application [19], we selected a 24-hr interval between chemotherapy and radiofrequency ablation because of technical considerations (i.e., 24 hr was the shortest interval that could be implemented into our clinical practice). Nevertheless, an animal study has shown that synergy is almost optimal with the near-simultaneous administration of Doxil and radiofrequency application [19]. Given that the patients who received combined radiofrequency and Doxil therapy were required to have chemotherapy administered, the patients were aware of which therapy they were receiving.
Radiofrequency Ablation
Over the duration of the study, each patient underwent only a single
session of radiofrequency ablation during which one or two tumors were treated
per protocol. For each lesion, depending on the tumor size, one to six courses
of radiofrequency energy were applied for 8-12 min using single (n =
4) or cluster (n = 10) internally cooled electrodes and a pulsed
technique to a maximum of 2000 mA
[24,
25]
(Table 1). The radiofrequency
ablation procedure was guided using a combined sonographic and CT fluoroscopic
approach to permit placement of the electrodes in a manner that would ensure
optimal coverage of the tumor. Procedures were performed using a standardized
regimen of local (1% lidocaine injection) and IV conscious sedation (2-4 mg of
midazolam and 100-300 µg of fentanyl citrate).
Imaging Strategy
For all patients, baseline multiphasic CT was performed within 1 week
before ablation and within 30 min after the ablation session. Similar CT scans
were also obtained 2-4 weeks after therapy. CT parameters for all studies
included a 5- to 8-mm slice thickness through the liver for unenhanced images
and for images obtained 35 sec, 75 sec, and 3 min after IV administration of
contrast material (i.e., during the hepatic arterial, portal venous, and
equilibrium phases of liver contrast enhancement, respectively). Contrast
material (150 mL of Optiray 320 [ioversol]; Mallinckrodt, St. Louis, MO) was
administered at a rate of 3-4 mL/sec
[3,4,5,6,7,8,
11].
Imaging data were subject to further processing for volumetric assessment, as previously described, and were validated [26,27,28,29,30]. Briefly, three-dimensional and volume-rendered models were created from axial scan data using a commercially available workstation (Advantage Windows, version 4.0; General Electric Medical Systems, Milwaukee, WI). The margin of the tumor or radiofrequency-induced thermal lesion was carefully traced using the paintbrush option on all axially acquired images. The tumor area on each axial image was automatically calculated, and the tumor volume was calculated using the system software. The volume can also be displayed as a three-dimensional model.
Data Analysis
Imaging data obtained before therapy, immediately after therapy (i.e., the
baseline), and 2-4 weeks after therapy were analyzed in two ways. Initially,
three-dimensional reconstructed volumes of the tumor and the nonperfused
region of coagulation
[26,27,28,29,30]
were calculated using tracing and advanced imaging processing, as described
earlier. The volume of the radiofrequency-induced thermal lesion was
calculated by investigators who were unaware of whether the patient had
received Doxil chemotherapy and of when the scan had been obtained in relation
to the radiofrequency ablation therapy.
The change in the volume of the thermal lesion—the volume on the delayed scans (obtained at 2-4 weeks after therapy) minus the volume on the baseline scans (obtained immediately after radiofrequency ablation)—was calculated from these blinded data using paired images. The difference in tumor volume shown on scans obtained immediately after radiofrequency ablation and on scans obtained 2-4 weeks later was compared between the two study groups using parametric (paired Student's t test or Fisher's exact test) and nonparametric (Wilcoxon's rank sum) tests. In addition, regression analysis was performed to compare changes in coagulation volume for both the total duration of radiofrequency applications and the timing interval for the delayed scans.
Axial and volumetric images of each patient were also reviewed retrospectively in a nonblinded fashion by two experienced abdominal imagers. These reviewers determined by consensus whether the qualitative appearance of the scans obtained immediately after radiofrequency ablation and those obtained 2-4 weeks after therapy differed for patients who received combined radiofrequency and Doxil therapy versus those who received radiofrequency therapy alone.
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All procedures were technically successful. CT scans obtained immediately after ablation showed induction of thermal lesion volumes that were larger than the initial tumor for 13 (92.9%) of 14 lesions (i.e., all the lesions except the largest, which was 8.2 cm in diameter) (Table 1). However, complete ablation of the entire tumor was apparent at the conclusion of a single radiofrequency ablation session for 11 tumors (78.6%). The three incompletely ablated tumors (two hepatocellular carcinomas treated with radiofrequency alone and one tumor treated with combined radiofrequency and Doxil therapy) were three of the four largest in the series; all measured 4.7 cm or greater in diameter. All three of these tumors and the four unablated tumors received additional courses of radiofrequency therapy after the 2- to 4-week CT study end point. Only one complication—a self-remitting subcapsular hematoma, which did not require transfusion—was identified. This complication occurred during the treatment of the largest tumor.
Quantification of Induced Coagulation
When comparing the baseline scans and the scans obtained immediately after
ablation with the delayed (2-4 weeks) follow-up scans, non-uniform changes in
thermal lesion diameter were encountered in different levels and areas of
tumor. These focal changes were often asymmetric and ranged from a decrease in
coagulation diameter of 3 mm to an increase of up to 15 mm in diameter. Hence,
we could not accurately quantify the true changes in the overall size and
volume of the ablated focus by comparing conventional bidimensional
measurements. Thus, overall changes in volume were used for comparison.
No significant differences between the group receiving combined treatment and that receiving radiofrequency ablation alone were detected in the amount of tumor destruction on the scans obtained immediately after radiofrequency ablation (p = not significant) (Table 2). The volume (mean ± SD) of the thermal lesion for the group receiving Doxil 24 hr before radiofrequency therapy measured 51.8 ± 66.5 mL, whereas that of the thermal lesion in the control tumors receiving radiofrequency ablation alone was 80.2 ± 70.9 mL (p = not significant). However, patients receiving combined radiofrequency and Doxil therapy had increased coagulation. Compared with the scans obtained immediately after ablation, the 2- to 4-week follow-up scans showed a volumetric increase ranging from 24% to 342% for the smallest treatment focus. Excluding this single outlier, the mean increase in treatment volume was 32%. The volumetric increase in tumor destruction ranged from 6.7 to 49.0 mL (mean ± SD, 17.2 ± 15.9 mL). By contrast, the coagulation zone of all lesions treated with radiofrequency alone decreased in size at 2-4 weeks after therapy to 82.5% ± 4.4% of the initial volume (range, 76-88%). The decrease in the volume of tumor destruction ranged from 2.4 to 27.1 mL (mean ± SD, 12.8 ± 9.8 mL).
Given that all tumors treated with combined radiofrequency and Doxil had an increase in volume of the thermal lesion and that all tumors treated with radiofrequency alone had a slight decrease in the size of the thermal lesion at 2-4 weeks, the difference in the groups was highly statistically significant (p < 0.01, Wilcoxon's rank sum and paired Student's t tests). However, regression analysis revealed poor correlation between either the duration of radiofrequency application or the interval delay in scanning and changes in thermal lesion volume (Table 3).
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Qualitative Imaging Findings
Baseline treatment scans obtained immediately after ablation showed
contrast enhancement denoting incomplete ablation at the periphery of four
treated tumors (two from each group) and throughout the four unablated control
lesions in the two patients receiving Doxil alone. Scans obtained immediately
after ablation showed similar findings for tumors subject to radiofrequency
with or without Doxil in regard to the presence of hyperdense central regions
and small pockets of gas scattered throughout the treatment zone. An intense
transient hyperemic rim that surrounded portions or the entire ablation focus
was observed on arterial phase images of four tumors receiving radiofrequency
alone and three tumors receiving both radiofrequency and Doxil (p =
not significant). A major discriminating factor between the two groups was the
presence of regions of decreased peripheral perfusion on arterial and portal
venous phase scans that showed delayed enhancement on equilibrium phase scans
(Fig.
1A,1B,1C,1D).
This finding was observed for five of the seven tumors receiving both
radiofrequency and Doxil, but it was not seen for any of the seven tumors that
received radiofrequency alone (p = 0.02, Fisher's exact test).
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Differences between the tumors treated with combination Doxil and radiofrequency and those treated with radiofrequency alone were more apparent on the 2- to 4-week follow-up studies. For patients receiving radiofrequency alone, relatively uniformly small decreases in the thermal lesion, ranging from 0 to 3 mm, were noted. However, greater variability in dimensional measurements, from 0 to 15 mm, was observed for the increases in the thermal lesion for tumors receiving combined radiofrequency and Doxil therapy. This finding resulted largely from the focal asymmetric nature of the increase in the zone of absent contrast enhancement.
All areas in which ablation increased by more than 4 mm occurred in regions that had delayed contrast enhancement immediately after ablation (Fig. 1A,1B,1C,1D). However, the quantitative or qualitative extent of delayed enhancement was not predictive of the ultimate size of the zone of coagulation at 2-4 weeks after radiofrequency ablation, because many areas with the delayed perfusion pattern either reverted to a more normal enhancement pattern or remained with delayed enhancement. No change in appearance or evidence of delayed treatment effect was observed in the four tumors treated with Doxil alone.
Given that the zone of ablation approximated the initial tumor size for five of the seven lesions receiving both radiofrequency and Doxil treatments, the increase in coagulation was largely in perilesional liver (i.e., extension of the surgical margin) [31] (Fig. 1A,1B,1C,1D). In the remaining two tumors, definitive increases in the extent of tumor destruction were documented (Fig. 2A,2B,2C,2D,2E). Moreover, in both of these cases, an enhancing region of viable tumor surrounding a blood vessel running through the lesion was observed on scans obtained immediately after therapy, but this CT finding was absent at 2-4 weeks (Fig. 2A,2B,2C,2D,2E). In one of these cases, the zone of ablation enlarged to encompass the entire tumor, whereas in the other case (the largest tumor in the series), a second radiofrequency ablation session was required to completely treat the lesion (Fig. 2C).
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Increased tumor destruction was found in both primary hepatocellular carcinoma and intrahepatic metastases from colorectal, neuroendocrine, and breast origins. In addition, the treatment effect extended to encompass the destruction of perilesional normal liver in several cases. This latter finding suggests that administration of Doxil may help promote the destruction of the 0.5- to 1-cm safety margin that is necessary to adequately treat an entire tumor [31]. Equally important, more complete internal tumor destruction—particularly adjacent to intratumoral vessels—was revealed in two patients. Although limited in number, these findings, coupled with those from animal studies [18, 19], suggest that radiofrequency therapy combined with Doxil will be able in at least some cases to destroy residual foci of disease that persist in the ablated tumor focus. Given that the two most likely sites for persistent untreated residual tumor after radiofrequency ablation are adjacent to vessels and at the tumor periphery [3,4,5,6,7,8, 12], our findings suggest that combined radiofrequency and Doxil therapy may be beneficial for improving cytotoxicity in the regions that are currently most difficult to treat with thermal therapy alone.
We postulate that the increased tissue destruction results from the synergy between sublethal thermal damage induced by radiofrequency ablation and the Doxil chemotherapy [23, 32]. Although the threshold for inducing thermal coagulation with radiofrequency ablation alone is approximately 50°C for 4-6 min, the distribution of Doxil deposition—largely to the immediate periphery of a radiofrequency ablation zone [20]—suggests that the resultant increased coagulation obtained from combination therapy most likely occurs in regions of tissue that are heated to 45-50°C. In a study of R3230 rat mammary adenocarcinoma [19], researchers found that Doxil by itself did not induce coagulation at similar doses. However, antitumoral effects of both the doxorubicin and the empty liposome carrier when combined with radiofrequency have been documented. This latter finding of improved tumoral cytotoxicity for radiofrequency in the presence of empty liposomes suggests that the mechanism for improved coagulation may involve free-radical generation [33, 34]. Furthermore, increased delivery of doxorubicin and increased liposomal deposition have been shown in radiofrequency-ablated tumors, particularly through the peripheral zone of inflammation surrounding the thermal coagulation [21]. Kruskal et al. [35] have shown increased blood flow to this zone. In addition, Dudar and Jain [36] have also shown that hyperthermia (i.e., temperatures lower than those that achieve ablation) increases the vascular endothelial pore size and hence allows greater deposition of the liposome-containing doxorubicin.
Given the peripheral distribution of increased treatment effect, other mechanisms that likely play a role in this synergy include reversible damage to the cellular machinery such as the multidrug-resistant membrane efflux pump that is responsible for actively excluding doxorubicin from the cells [37]. Regardless, given that we attribute this synergy to thermal therapy as opposed to factors intrinsic to radiofrequency electromagnetic energy, it is likely that the gains observed, if substantiated in larger studies, can be anticipated with other methods of thermal therapy such as laser, microwave, and high-intensity focused sonography.
The effect we observed at 2-4 weeks after the combination therapy was not uniform: the region of increased treatment extended from 1 mm to greater than 15 mm in various regions in and surrounding the tumor. Nevertheless, all of the increase in tissue destruction was confined to either the tumor or a perilesional area of delayed enhancement on images obtained immediately after ablation. The extent of evolving coagulation in these regions during the 2 weeks after ablation was not uniform. Hence, the predictive value of the scans obtained immediately after the procedure was poor in denoting the true boundaries of ultimate tumor destruction.
This irregular distribution of increased tumor destruction on delayed imaging is likely caused by the heterogeneous thermal distribution throughout the tissues during radiofrequency ablation, a problem further compounded by multiple, often overlapping, radiofrequency applications of varied duration using different-sized electrodes coupled with nonuniform distribution of Doxil. These confounding variables are likely responsible in part for the poor correlations observed between radiofrequency ablation parameters and the size of the thermal lesion observed on initial or delayed scans. Regardless, given the lack of symmetry or uniformity for the increased coagulation, we found that three-dimensional volumetric analysis of the treatment volume was the most useful tool in this study for quantitative comparison of the changes in coagulation over time.
Many of the findings observed in this study can be best understood in the
context of previous investigational observations. Animal studies have shown
that the synergistic effects of Doxil and radiofrequency do not result in
immediate induction of additional coagulation and that at least 48 hr is
required to observe the maximal increase in tumor destruction
[18,
19]. Hence, it is not
surprising that increased treatment effect in this study was observed only
several weeks after ablation. Moreover, although regions of increased
treatment effect were often focal in nature, their extension to 15 mm suggests
that under optimal conditions increases in coagulation of more than the 7 mm
observed in the animal models
[19] can be obtained in
humans. On a clinical level, incomplete ablation of the three largest tumors
(diameter, 
4.7 cm) at the conclusion of a single radiofrequency treatment
session is not surprising, given that procedure success has been linked to
initial tumor size [8].
It is important to underscore the implications of our observations. We are unaware of any prior studies of imaging-guided thermal ablation that have documented increased treatment effect at long-term follow-up from radiofrequency ablation alone. Rather, reduction in the volume of the thermal lesion over the course of months after radiofrequency ablation has been well documented, but never fully characterized. Indeed, the rate and extent of resorption of the thermal lesion have often been described as variable [3,4,5,6,7,8]. Our study shows through careful quantification of three-dimensional volume reconstructions that a small 15-20% reduction in volume can be expected as early as 2-4 weeks after radiofrequency ablation alone. This finding can have clinical implications because many radiologists use studies obtained at this time point for comparison with images obtained before ablation to determine the adequacy of therapy. Because of the reduction in thermal lesion volume, the extent of therapy and the adequacy of surgical margins required for treatment may be underestimated.
Although this study provides positive preliminary results, several important limitations should be mentioned. The small patient population consisting of several heterogeneous tumor types is clearly insufficient to adequately define and accurately quantify the anticipated increase in treatment effect to be expected for a particular tumor type (and further stratification possibly based on size and location). Furthermore, given that a single variable CT follow-up was used as the comparative end point and that only one dose of Doxil and one set of radiofrequency parameters were selected, the maximum benefit achievable with this therapy is unknown. Differences in the extent of treatment effect between tumors from 2 weeks after radiofrequency and those 4 weeks after radiofrequency could emerge with further study.
In addition and most important, given a maximum of 4 weeks' follow-up, it would be premature to determine from the results whether combined radiofrequency and Doxil therapy can improve the extent of local tumor control (complete ablation) for a given population of homogeneous tumors or whether this combined technique can affect patient survival. The answers to these questions clearly require ongoing patient recruitment in a large multicenter trial comparing the effects of radiofrequency alone versus combined radiofrequency and Doxil therapy. These trials would require long-term follow-up to determine the clinical impact of such combination therapy. Moreover, optimization of the methodology—including the dose of Doxil, the time of Doxil administration in relation to radiofrequency, the parameters of the radiofrequency therapy, and the optimal time for imaging—is required. Other chemotherapeutic drugs known to have hyperthermia interactions [21, 22] and potentially greater efficacy for the tumor types treated also need to be studied. Although we are actively pursuing these latter studies in animal models, these parameters ultimately need to be tested in humans. Regardless, the fact that increased tumor destruction with combined radiofrequency and Doxil therapy was shown in a clinical setting is encouraging and strongly suggests that further study is warranted.
In conclusion, our study shows that combined radiofrequency and Doxil therapy can increase tumor destruction in several types of intrahepatic tumors compared with radiofrequency ablation alone, particularly in regions of the tumor that are poorly treated by radiofrequency alone—perivascular zones and the periphery of the tumor. Further ongoing study is likely to define the extent of clinical benefit that can be achieved by this combined method.
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