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Published online before print February 24, 2005, 10.1148/radiol.2351040269
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(Radiology 2005;235:81-88.)
© RSNA, 2005

Experimental Studies

Reduced Tumor Growth with Combined Radiofrequency Ablation and Radiation Therapy in a Rat Breast Tumor Model1

Clare Horkan, MB, BCh, Kshitij Dalal, MD, Jeffrey A. Coderre, PhD, Jingli Liu Kiger, MS, Damian E. Dupuy, MD, Sabina Signoretti, MD, Elkan F. Halpern, MD and S. Nahum Goldberg, MD

1 From the Minimally Invasive Tumor Therapy Laboratory, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Road, WCC 308B, Boston, MA 02215 (C.H., K.D., S.N.G.); Department of Nuclear Engineering, Massachusetts Institute of Technology, Cambridge, Mass (J.A.C., J.L.K.); Department of Radiology, Rhode Island Hospital, Providence, RI (D.E.D.); Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (S.S.); and Institute for Technology Assessment, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass (E.F.H.). From the 2003 RSNA Annual Meeting. Received February 11, 2004; revision requested April 14; revision received May 19; accepted June 28. Address correspondence to S.N.G. (e-mail: sgoldber@bidmc.harvard.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To determine whether use of combined radiofrequency (RF) ablation and external-beam radiation therapy increases end-point survival beyond that with either RF ablation or radiation therapy alone in an animal tumor model.

MATERIALS AND METHODS: With a protocol approved by the institutional animal care and use committee, R3230 mammary adenocarcinoma (12.5 mm ± 0.6 [standard deviation]) was implanted subcutaneously into 107 female Fischer 344 rats. Initially, 42 tumors were randomized into four treatment groups: (a) RF ablation (70°C for 5 minutes) alone, (b) RF ablation followed by radiation therapy with a total dose of 20 Gy, (c) 20-Gy radiation alone, and (d) no treatment. Another 19 tumors were randomized to receive (e) RF ablation (70°C for 5 minutes) followed by 5-Gy radiation, (f) 5-Gy radiation alone, or (g) no treatment. Animals were followed up until survival end point (either until tumor growth to 30 mm in diameter, or for 120 days if no tumor was seen in mammary fat pad or chest wall). Results were analyzed with the Kaplan-Meier method. Histopathologic analysis was performed in 15 additional tumors at survival end point and 18 other representative tumors at other specified end points.

RESULTS: Combined RF ablation and 20-Gy radiation resulted in complete local control in nine (82%) of 11 tumors, compared with one (9%) of 11 tumors treated with RF ablation alone and one (17%) of six treated with RF ablation and 5-Gy radiation (P < .001). No local control was achieved in rats with radiation therapy alone or in controls. Median end-point survival was 12 days for controls, 20 days with RF ablation or 5-Gy radiation alone, 30 days with RF ablation plus 5-Gy radiation, 40 days with 20-Gy radiation alone, and 120 days with RF ablation plus 20-Gy radiation. Mean end-point survival was 13 days ± 5 (standard deviation) for the control group, 34 days ± 31 with RF ablation alone, and 43 days ± 16 with 20-Gy radiation alone. Mean survival was significantly greater with 20-Gy radiation and RF ablation combined: 94 days ± 34 (P < .001 compared with all other groups). Mean survival for rats that received 5-Gy radiation with RF ablation versus without was 46 days ± 37 versus 24 days ± 11, respectively.

CONCLUSION: Combined RF ablation and external-beam radiation therapy increased animal survival compared with that with either of the treatments alone or with no treatment.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Radiofrequency (RF) ablation is rapidly developing as an image-guided tumor therapy, as experience increases with its use in treating liver, renal, bone, and lung neoplasms (1–4). Two recent large studies have shown it to have an acceptable profile with regard to adverse effects, despite its frequent use in patients who are not good candidates for surgery (5,6). The success of this method, however, is limited by tumor size, as treatment effectiveness is decreased in tumors with a diameter of 2.5 cm or larger (7). It is also limited by the high incidence of local tumor progression (8).

This latter limitation has led to the use of combined therapies, including modulators of conductivity (9) and blood flow (10), as well as adjuvant chemotherapy (11–15), to achieve synergy. For example, the results of several studies in which RF ablation was combined with liposomal doxorubicin in animal models and in patients showed improved results over those with either therapy alone (11–13). Furthermore, several studies have shown promising results for RF and other thermal ablation therapies combined with hepatic artery infusion chemotherapy with floxuridine and 5-fluorouracil or combined with chemoembolization with doxorubicin to treat hepatocellular carcinoma (14–16), with tolerable toxic effects and improved local control. Other possible therapies include microwave- and laser-induced ablation. Shibata et al (17) showed equal effectiveness with RF ablation versus microwave ablation in the treatment of hepatocellular carcinoma in 36 patients. In a recent study, Vogl et al (18) found mean survival of 4.4 years for laser-induced therapy in colorectal metastases to the liver.

Data from the literature suggest that external-beam radiation therapy and low-temperature hyperthermia can be useful for treating tumors in the lung (19), prostate (20), bladder (21), and other sites (21,22). In RF ablation, radiofrequency waves create frictional resistance and, thus, heat the tissue to more than 50°C to achieve coagulation (23). In this process, much of the tissue is heated to higher temperatures for a shorter time than with conventional methods of heating for 1–2 hours at 42°–45°C (24), yet a substantial portion of the tissue is subject to hyperthermic temperatures (25). Nonetheless, the potential effect of the combination of RF ablation with radiation therapy has not been well studied. Thus, the purpose of this study was to determine whether use of combined RF ablation and external-beam radiation therapy increases end-point survival over that with either RF ablation or radiation therapy alone in an animal tumor model.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Animal Model
The protocol was approved by the institutional animal care and use committee at Beth Israel Deaconess Medical Center. For all experiments and procedures, anesthesia was induced by administering an intraperitoneal injection consisting of a mixture of ketamine (Ketaject; Phoenix Pharmaceutical, St Joseph, Mo), at a dose of 50 mg per kilogram body weight, and xylazine (Bayer, Shawnee Mission, Kan), at a dose of 5 mg/kg. When necessary, booster anesthetic injections at one-tenth of those doses were administered every 30–60 minutes intraperitoneally. The experiments were performed by using a well-established tumor model (26,27), R3230 mammary adenocarcinoma (Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, Mass), in 107 Fischer 344 female rats (Taconic Farms, Germantown, NY) of the same strain as the rat from which the tumor was originally derived (mean weight, 150 g ± 20 [standard deviation]; age range, 7–9 weeks).

The tumor (approximately 1 cm in diameter) was initially harvested from a live carrier. Within 30 minutes of its dissection and removal, the tumor was homogenized with a tissue grinder (model 23; Kontes Glass, Vineland, NJ) by using aseptic technique, and the tumor cells were suspended in 7 mL of a culture medium (RPMI 1640; INC Biomedicals, Aurora, Ill). In prior control experiments in our laboratory, this process resulted in a concentration of 1 x 108 cells per milliliter, with more than 95% cellular viability. During direct visualization, 0.2–0.3 mL of the tumor cell suspension was injected slowly via an 18-gauge needle into the mammary fat pad. Animals were monitored every 3–4 days to measure tumor growth. Solid nonnecrotic tumors (as determined with ultrasonography [US]) with a mean diameter of 12.5 mm ± 0.6 and diameter range of 10–15 mm were used for ablation studies. Tumors were allowed to grow for 14–24 days, until the desired treatment size was achieved. Tumor induction, monitoring, and randomization were performed by two authors (C.H., K.D.).

Experimental and Control Groups
Forty-two tumors were randomly stratified into four treatment groups. To avoid bias due to an overestimated or underestimated difference between treatments, we used simple block randomization as described previously (28). The four groups underwent (a) RF ablation (heating to 70°C for 5 minutes) alone (n = 11), (b) RF ablation followed within 2 hours by external-beam radiation therapy with a total dose of 20 Gy (n = 11), (c) 20-Gy radiation alone (n = 9), or (d) no treatment (n = 11). Subsequently, 19 additional tumors were randomized into three groups to undergo (e) RF ablation followed within 2 hours by external-beam radiation therapy with a total dose of 5 Gy (n = 6), (f) 5-Gy radiation alone (n = 7), or (g) no treatment (n = 6).

As a next step, 18 additional tumors underwent treatments identical to those administered to tumors in the four groups in the initial experiment. The 18 rats with these tumors were sacrificed at day 0 or day 7 after treatment to document differences in gross and histopathologic findings among the treatment groups at defined time points. In each of the two groups that received either RF ablation plus 20-Gy radiation or 20-Gy radiation alone, two animals were sacrificed at day 0 and three animals were sacrificed at day 7. In each of the groups that received either RF ablation alone or no treatment, two animals were sacrificed at day 0 and two animals were sacrificed at day 7. Tumor growth measurements in these animals were not included in the statistical analysis according to treatment group, because these tumors were not followed up until the defined survival end points.

RF Ablation
A 500-kHz RF generator (CC-1; Radionics, Burlington, Mass) was used for conventional monopolar application of RF energy (C.H., K.D.). The animal was placed on a standardized grounding pad (Radionics) to complete the RF circuit, with proper contact ensured by shaving of, and application of US gel to, the contact area. With US guidance, the 1-cm tip of a 21-gauge 0.81-mm-diameter electrode was placed in the center of the tumor. With the exception of this distal tip, the electrode was insulated to allow focused energy deposition. RF energy was applied for 5 minutes, with the generator output (mean, 90.4 mA ± 25.8; range, 48–160 mA) titrated to maintain a designated mean tip temperature (70°C ± 2). In previous use, these parameters were demonstrated to produce a tumor ablation zone measuring 6–7 mm in short-axis diameter, thereby allowing us to gauge the increased effect of combined therapy and to compare effects with those in other studies in which RF ablation alone was compared with combined RF ablation and liposomal doxorubicin (13,29). Thus, it was not our intent to use a curative dose of RF ablation in this study but rather to use a dose sufficient to enable detection of enhanced tumor destruction with adjuvant external-beam radiation therapy (11). Local temperature was measured during ablation by using a thermocouple located at the tip of the RF electrode, a procedure that enabled proper adjustment of generator output. Tip temperature, tissue impedance, and applied current were recorded at baseline and at 60-second intervals thereafter for the duration of the RF energy application.

Radiation Therapy
In the combined-therapy group, external-beam radiation therapy was performed within 2 hours (60–114 minutes) after RF ablation, as the results of prior studies suggested that this was the most effective window for application of low-temperature hyperthermia (19,30). This timing of radiation therapy also allowed comparison of the results of our study with those of prior studies in which chemotherapy was given after RF ablation (11). The animal was positioned on its side, atop a lead shield with a small slit through which the radiation would be delivered. The shield was then inverted, and a second piece of lead was used to protect the lungs. An irradiator (RT 250; Philips Medical Systems, Eindhoven, the Netherlands) was operated at 250 kV and 12 A with filtration of 0.4 mm of tin and 0.25 mm of copper. The distance from the source to the skin was 32 mm. The radiation dose was delivered at a rate of 1 Gy ± 0.1 per minute for 5 or 20 minutes, depending on the treatment group. The 5-Gy and 20-Gy total doses were chosen on the basis of the results of prior studies by Brizel et al (31) and Dewhirst et al (32) in the same tumor model and were not expected to be curative but merely to delay tumor growth and, thus, to allow comparison between the study groups.

Survival End Point, Tumor Measurement, and Histopathologic Analysis
Tumor diameters were measured every 2–4 days in the longitudinal and transverse directions with mechanical calipers by two authors (C.H., K.D.), who, because of the requirement that all cages be labeled with any treatment given to the animals, were not blinded to treatment group. The animals were anesthetized to ensure the accuracy of measurement. At each time point, the largest diameter was recorded. The animals were euthanized when the largest diameter of the tumor reached 30 mm (C.H., K.D.). Accuracy of the final measurement was verified by the senior author (S.N.G.), who was blinded to treatment group. This surrogate end point was necessary because of the tumor burden to the animal: According to the U.S. Department of Agriculture Animal Welfare Act (33), any animal with a tumor that constitutes more than 10% of its body weight (equivalent to a tumor diameter of 30 mm in this model) is moribund and should be sacrificed. The other end point was local control (ie, no tumor visible on the chest wall or in the mammary fat pad). The survival end point was thus a tumor diameter of 30 mm or survival of 120 days, whichever was reached first. Animals were euthanized with an overdose (200 mg/kg) of pentobarbital (Nembutal; Abbott Laboratories, North Chicago, Ill) injected intraperitoneally. The tumor or tumor bed was then excised, and histologic sections were prepared for analysis (C.H., K.D.). Histopathologic analysis of the tumor or tumor bed was performed with hematoxylin-eosin staining in two representative animals from each treatment group. Another three specimens with local tumor control, from the group of tumors that underwent RF ablation plus 20-Gy radiation, were examined to ensure that there was no viable tumor remaining at 120 days.

Histopathologic analysis was performed to identify heat-fixed tissue, coagulation necrosis, evidence of viable tumor including mitotic figures, local edema, and neovascularization. All histopathologic examinations were performed by one author (S.S.) who was blinded to the treatment groups.

Autopsy and gross pathologic analysis were performed for all animals that died before 120 days. Histopathologic analysis with hematoxylin-eosin staining was performed in tissues in which the presence of malignant foci was suspected.

Statistical Analysis
The Kaplan-Meier method was used for end-point survival analysis, which was performed with the aid of statistical software (SAS, version 8.1; SAS Institute, Cary, NC). Spreadsheet software (Excel; Microsoft, Redmond, Wash) was used to perform two-sample Student t tests, and a P value of .01 was considered to indicate a statistically significant difference. The combined therapy group that received 20-Gy radiation therapy plus RF ablation was compared with the groups that received 20-Gy radiation therapy alone, 5-Gy radiation therapy alone, 5-Gy radiation therapy plus RF ablation, RF ablation alone, and no treatment. Median end-point survival, as well as the mean and standard deviation, were calculated for each group. One-way analysis of variance was performed to compare survival end points among all the animals.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Local Control
Local tumor control was achieved in nine (81%) of the 11 animals that received RF ablation and 20-Gy radiation therapy (Fig 1). One case of local control (9%) was also seen among the 11 animals treated with RF ablation alone and in one (17%) of the six animals in the group that underwent RF ablation plus 5-Gy radiation therapy. No local control was seen in any other group. Thus, a significant difference was seen in local control achieved in the group of rats that received the high-dose radiation therapy combined with RF ablation, compared with that achieved in all other treatment groups (P < .01 for all comparisons).



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  		Figure 1a. Graphs show tumor growth patterns and end-point survival in individual animals in four tumor treatment groups: (a) no treatment (controls), (b) treatment with RF ablation alone, (c) treatment with 20-Gy radiation alone, and (d) treatment with RF ablation plus 20-Gy radiation. Sacrifice was mandated at a tumor diameter of 30 mm because of animal welfare concerns. Control tumors showed the most rapid growth. Tumors treated with either RF ablation or radiation therapy alone showed a growth trend similar to that in controls but a decreased growth rate. Tumors treated with combined RF ablation and radiation therapy initially increased in size, probably because of hyperemia and edema, which were followed by tumor involution and healing in nine (82%) of 11 animals.

 


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  		Figure 1b. Graphs show tumor growth patterns and end-point survival in individual animals in four tumor treatment groups: (a) no treatment (controls), (b) treatment with RF ablation alone, (c) treatment with 20-Gy radiation alone, and (d) treatment with RF ablation plus 20-Gy radiation. Sacrifice was mandated at a tumor diameter of 30 mm because of animal welfare concerns. Control tumors showed the most rapid growth. Tumors treated with either RF ablation or radiation therapy alone showed a growth trend similar to that in controls but a decreased growth rate. Tumors treated with combined RF ablation and radiation therapy initially increased in size, probably because of hyperemia and edema, which were followed by tumor involution and healing in nine (82%) of 11 animals.

 


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  		Figure 1c. Graphs show tumor growth patterns and end-point survival in individual animals in four tumor treatment groups: (a) no treatment (controls), (b) treatment with RF ablation alone, (c) treatment with 20-Gy radiation alone, and (d) treatment with RF ablation plus 20-Gy radiation. Sacrifice was mandated at a tumor diameter of 30 mm because of animal welfare concerns. Control tumors showed the most rapid growth. Tumors treated with either RF ablation or radiation therapy alone showed a growth trend similar to that in controls but a decreased growth rate. Tumors treated with combined RF ablation and radiation therapy initially increased in size, probably because of hyperemia and edema, which were followed by tumor involution and healing in nine (82%) of 11 animals.

 


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  		Figure 1d. Graphs show tumor growth patterns and end-point survival in individual animals in four tumor treatment groups: (a) no treatment (controls), (b) treatment with RF ablation alone, (c) treatment with 20-Gy radiation alone, and (d) treatment with RF ablation plus 20-Gy radiation. Sacrifice was mandated at a tumor diameter of 30 mm because of animal welfare concerns. Control tumors showed the most rapid growth. Tumors treated with either RF ablation or radiation therapy alone showed a growth trend similar to that in controls but a decreased growth rate. Tumors treated with combined RF ablation and radiation therapy initially increased in size, probably because of hyperemia and edema, which were followed by tumor involution and healing in nine (82%) of 11 animals.

 
End-Point Survival
The results of one-way analysis of variance showed a significant effect for both radiation therapy and RF ablation, whether used in combination or separately, on end-point survival (P < .001). No significant difference was seen in end-point survival or in other statistical parameters between the first and second control groups (P > .7) or between the other treatment groups and controls analyzed as a single control group or as two separate control groups. The mean end-point survival (ie, the interval between the time of treatment and the time when the tumor reached 30 mm in diameter, or 120 days) for all controls was 13 days ± 5 (Table, Fig 2). The mean end-point survival in the group treated with 20-Gy radiation alone and the group treated with RF ablation alone was similar (43 days ± 16 and 34 days ± 31, respectively), but the end-point survival was significantly improved in the group treated with combined RF ablation and 20-Gy radiation, 94 days ± 34 (P < .001 for comparisons with 20-Gy radiation therapy alone, RF ablation alone, and no treatment). The median end-point survival was much better in the group in which the tumor was treated with RF ablation plus 20-Gy radiation, compared with all the other groups (Table). Equally important, in the group treated with combined RF ablation and 20-Gy radiation, three of the nine animals showed local tumor control at the time of death but succumbed to lung metastases at 44, 57, and 59 days. The other six of nine animals with local control from the combined-treatment group, as well as one animal from the group treated with RF ablation alone and one from the group treated with RF ablation plus 5-Gy radiation, survived until the end point of 120 days.


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  		Effect of RF Ablation and/or Radiation Therapy on End-Point Survival

 


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  		Figure 2. Graph shows results of Kaplan-Meier analysis of animal end-point survival after no treatment (both control groups combined), RF ablation alone, radiation therapy (XRT) alone (at total dose of 5 Gy or 20 Gy), and combined RF ablation and radiation therapy (at total dose of 5 Gy or 20 Gy). Longest end-point survival was observed with combined RF ablation and 20-Gy radiation therapy. Dose dependency of the effect of external-beam radiation therapy is also demonstrated.

 
In the subsequent 13 rats treated with 5-Gy radiation, the mean end-point survival was 46 days ± 37 in the group that received RF ablation and 24 days ± 11 in the group that received radiation therapy alone. Thus, greater local tumor control and end-point survival were achieved with radiation therapy at the 20-Gy dose than at the 5-Gy dose (P < .05), both with and without RF ablation.

The tumors in which local control was achieved all showed a similar pattern of growth and involution (Fig 3). In gross appearance, by day 4, the superficial portion of the completely treated tumors began to involute. The tumor diameter, however, continued to increase slightly during this period, probably because of local edema and the formulation of granulation tissue (see the section about Histopathologic Examination). By days 7–10, the tumor was almost completely resorbed, and some hair growth was seen. A scar on the chest wall was all that remained by day 120. The one rat from the group that received RF ablation and the one from the group that received RF ablation plus 5-Gy radiation and that survived until the end point of 120 days had similar scars.



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  		Figure 3. Gross tumor progression in rats treated with combined RF ablation and radiation therapy. A, Tumor (arrow) with 11-mm diameter at day 0, prior to therapy. B, At day 4, after RF ablation and 20-Gy radiation therapy, beginning of involution is evident in tumor (arrow). C, At day 7, granulation tissue (arrow) can be seen, and there are signs of hair regrowth. (All that will remain by day 25 is scar tissue.) D, Scar (arrow) on chest wall at day 120.

 
Histopathologic Examination
Two animals from each of the groups that underwent RF ablation alone, RF ablation plus 20-Gy radiation therapy, 20-Gy radiation therapy alone, or no treatment were euthanized at day 0. At that time, viable tumor was seen in rats in all groups, including the group treated with RF ablation plus radiation. However, in the 10 animals that were euthanized on day 7 after therapy, the results were strikingly different (Fig 4). Viable cells at the tumor periphery were noted at histopathologic analysis in all samples except those from the tumor that underwent both RF ablation and 20-Gy radiation therapy. This specimen showed central coagulation necrosis with a new peripheral zone of marked edema and hyperemia, which was not present in the specimens that received RF ablation alone. In the radiation therapy and control groups, all the cells appeared viable, and no coagulation necrosis was seen at 7 days.



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  		Figure 4. Photomicrographs show histopathologic sections from tumors excised at day 7 after therapy. A, Slice from tumor treated with RF ablation alone (70°C for 5 minutes) shows typical appearance of heat-fixed tissue with rim of coagulative necrosis and peripheral areas of viable tumor. B, Slice from tumor treated with combined RF ablation and 20-Gy radiation therapy also shows an area of heat-fixed tissue. In this slice, however, marked hyperemia also is seen, with neovascular proliferation (black arrows) and edema (white arrows), and there is no evidence of viable tumor in the peripheral zone, which is composed of cellular debris. C, Slice from tumor treated with 20-Gy radiation therapy alone shows nothing but viable tumor cells. (Hematoxylin-eosin stain; original magnification, x10 [A and B] and x40 [C].)

 
Three animals from the group that received combined RF ablation and 20-Gy radiation therapy showed evidence of local tumor control before succumbing to lung metastases at 44, 57, and 59 days. At histologic analysis with hematoxylin-eosin staining, the tumor specimens were noted to be R3230 adenocarcinoma.

Histopathologic specimens from the tumors that reached 30 mm in diameter all showed viable tumor cells. A central zone of necrosis of less than 5 mm in diameter, which presumably corresponded to the postablation involuted zone, was seen in the two tumors subjected to RF ablation alone.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Image-guided thermal therapies are increasingly available for treatment of tumors (34). The need to create larger zones of coagulation necrosis in tumors has prompted developments in electrode and generator technology, as well as the search for adjuvant therapies (35,36). New methods like combined therapy with RF ablation and chemotherapy or radiation therapy, however, are still needed to maximize tumor cell death and optimize patient safety and tolerance.

The induction of hyperthermia at 40°–43°C for 60 minutes (for multiple doses), in combination with radiation therapy, has had limited success (20). Sakurai et al (19) reported the results of treatment in a small group of patients with non–small cell lung carcinoma metastases in bone, with a 2-year survival rate of 44.4% for combined therapy versus 15.4% in historical controls treated with radiation alone. Kalapurakal et al (20) presented results from a small nonrandomized study of hyperthermia used with radiation therapy for locally advanced hormone-refractory prostate cancer. In most patients, the combined therapy was well tolerated. Although the tumors in three (23%) of 13 patients progressed after therapy, all 13 patients experienced a substantial alleviation of symptoms within 3 months of therapy.

In this study, we observed local tumor control in nine of the 11 animals that received RF ablation and 20-Gy radiation therapy. These results are very promising, as local control was seen in only two other cases, one treated with RF ablation alone and one treated with a combination of RF ablation and 5-Gy radiation. Histopathologic analysis at day 7 in the rats that underwent a combination of RF ablation and 20-Gy radiation showed a new peripheral area of hyperemia and edema, but no viable tumor.

In a previous study, D’Ippolito et al (11) showed increased end-point survival with use of combined RF ablation and intravenous liposomal doxorubicin in the same animal model. In that study, however, local control was observed in only one (20%) of five rats, and that animal received a higher RF ablation dose than was used in this study (90°C vs 70°C), as well as liposomal doxorubicin. Thus, a local cure rate of 82% and 120-day survival rate of 55% may represent a major improvement over other combined RF ablation–hyperthermia strategies.

In this study, three animals showed evidence of local tumor control before succumbing to lung metastases at 44, 57, and 59 days. This result suggests that combined RF ablation and 20-Gy radiation therapy actually changed the time and site of disease manifestation, as death from metastases was not seen in the study reported by D’Ippolito et al (11). The fact that the tumors were healing by 7–10 days also suggests synergy between RF ablation and radiation therapy, as radiation therapy alone at this dose would not be expected to show histologic effects until 2–3 weeks after therapy (30).

The results in the group that received RF ablation plus 5-Gy radiation therapy were not significantly different from those in the groups that received RF ablation alone or 20-Gy radiation therapy alone, in contrast with the greatly increased end-point survival and/or local cure in the group that received RF ablation plus 20-Gy radiation therapy. These findings suggest a dose-related effect of radiation therapy, a hypothesis that necessitates further study.

Clinical data in the literature about combined therapies is currently quite limited. Jain et al (37) reported the results of combined therapy in three patients who were unsuitable for surgery and who successfully underwent percutaneous RF ablation and subsequent brachytherapy for treatment of lung neoplasms. Friedman et al (38) reported a single case study of a patient with a previously irradiated liver, who underwent successful RF ablation of the liver 1 month after irradiation. Of course, it must be noted that the mechanism of action is probably different from that in our study, as the time interval between radiation therapy and RF ablation was much greater and as radiation therapy was administered first in that study. Indeed, Friedman et al believed that the increased effectiveness of RF ablation was due to a radiation therapy–induced decrease in blood flow. Our observations suggest the contrary: A demonstrated increase in hyperemia and neovascularity accompanied the increase in the effectiveness of radiation therapy in this group. Indeed, both increased and decreased blood flow have been reported at different levels of RF-induced heating and at various times in relation to heating (39). Hence, further study is needed to elucidate both early and late mechanisms of this combined therapy.

One potential cause of the synergy we observed may be increased oxygenation in blood flow to the tumor, caused by local hyperthermia induced in tissues peripheral to the ablated region. Increased oxygenation has been implicated in the sensitization of the tumor to subsequent radiation therapy (30). Another possible mechanism, which has been seen in cell cultures, is an inhibition of radiation-induced repair and recovery, induced by hyperthermia (40).

Alteration in the timing of RF ablation in relation to radiation therapy may help to further elucidate these mechanisms, and this is one area of future research that has gained our attention. Future work also is needed to identify the optimal temperature for RF ablation and optimal radiation dose, as well as the most effective method of administering radiation therapy (external-beam radiation therapy vs brachytherapy [41] or yttrium microspheres [42]), on an organ-by-organ basis.

Although these results are promising, this study, as a first step in exploring these combined therapies, was limited to a radiation-sensitive mammary adenocarcinoma model. In addition, a single high radiation dose with lead shielding was used in the most successful groups and, thus, is not directly translatable to other tumor models or to tumors in areas near structures such as the lung, which may not tolerate such high radiation doses and may be vulnerable to adverse sequelae such as radiation pneumonitis (43).

In addition, one animal in the group that underwent RF ablation alone showed complete local control. This result may be due to an aberrant RF generator output resulting in an actual dose higher than that recorded or, alternatively, to some unexplained differences in animal physiology that might alter conductivity, blood flow, or other biophysical parameters (44).

We also considered only end-point survival data and histopathologic findings obtained with hematoxylin-eosin staining. Quantification of increased tumor destruction, and correlation of increases in tumor destruction with total absorbed radiation doses from external-beam radiation therapy and with further histologic and immunohistochemical parameters indicative of processes such as apoptosis and heat-shock protein production, are needed to better elucidate the mechanisms of action of RF ablation and external-beam radiation therapy and will be the subject of a future study.

Practical applications: Combined RF ablation and external-beam radiation therapy induced local tumor control in nine of 11 animals and greatly improved end-point survival in this rat model compared with survival in controls, with effectiveness greater than that with combined RF ablation and intravenous liposomal doxorubicin (11). This therapy combination may be useful in tumors that are currently treated with irradiation, such as lung and bone tumors (45,46). For clinical use, the ideal RF ablation therapy would be safe and effective, destroying the maximum number of tumor cells in the minimum time (47). The ideal radiation dose would have the maximum effect on the tumor while minimizing risk to surrounding tissues (30). The aim in combining treatments is to maximize the benefits of each while minimizing the risks. More detailed study is essential to understand this synergy and to advance it into the realm of patient care.


   FOOTNOTES
 
Abbreviation: RF = radiofrequency

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, S.N.G.; study concepts, C.H., D.E.D., S.N.G.; study design, C.H., J.A.C., D.E.D., S.N.G.; literature research, C.H., J.A.C., D.E.D., S.N.G.; experimental studies, C.H., K.D., J.L.K., S.N.G.; data acquisition, C.H., K.D., J.L.K.; data analysis/interpretation, C.H., S.S., S.N.G.; statistical analysis, C.H., E.F.H., S.N.G.; manuscript preparation, C.H., S.N.G.; manuscript definition of intellectual content, editing, revision/review, and final version approval, all authors


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

  1. Solbiati L, Livraghi T, Goldberg SN, et al. Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 2001; 221:159-166.[Abstract/Free Full Text]
  2. Gervais DA, McGovern FJ, Arellano RS, McDougal WS, Mueller PR. Renal cell carcinoma: clinical experience and technical success with radio-frequency ablation of 42 tumors. Radiology 2003; 226:417-424.[Abstract/Free Full Text]
  3. Goetz MP, Callstrom MR, Charboneau JW, et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol 2004; 22:300-306.[Abstract/Free Full Text]
  4. Suh RD, Wallace AB, Sheehan RE, Heinze SB, Goldin JG. Unresectable pulmonary malignancies: CT-guided percutaneous radiofrequency ablation—preliminary results. Radiology 2003; 229:821-829.[Abstract/Free Full Text]
  5. Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003; 226:441-451.[Abstract/Free Full Text]
  6. de Baere T, Risse O, Kuoch V, et al. Adverse events during radiofrequency treatment of 582 hepatic tumors. AJR Am J Roentgenol 2003; 181:695-700.[Abstract/Free Full Text]
  7. Livraghi T, Goldberg SN, Lazzaroni S, et al. Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions. Radiology 2000; 214:761-768.[Abstract/Free Full Text]
  8. Harrison LE, Koneru B, Baramipour P, et al. Locoregional recurrences are frequent after radiofrequency ablation for hepatocellular carcinoma. J Am Coll Surg 2003; 197:759-764.[CrossRef][Medline]
  9. Ahmed M, Lobo SM, Weinstein J, et al. Improved coagulation with saline solution pretreatment during radiofrequency tumor ablation in a canine model. J Vasc Interv Radiol 2002; 13:717-724.[Medline]
  10. Horkan C, Ahmed M, Liu Z, et al. Radiofrequency ablation: effect of pharmacologic modulation of hepatic and renal blood flow on coagulation diameter in a VX2 tumor model. J Vasc Interv Radiol 2004; 15:269-274.[Medline]
  11. D’Ippolito G, Ahmed M, Girnun GD, et al. Percutaneous tumor ablation: reduced tumor growth with combined radio-frequency ablation and liposomal doxorubicin in a rat breast tumor model. Radiology 2003; 228:112-118.[Abstract/Free Full Text]
  12. Goldberg SN, Kamel IR, Kruskal JB, et al. Radiofrequency ablation of hepatic tumors: increased tumor destruction with adjuvant liposomal doxorubicin therapy. AJR Am J Roentgenol 2002; 179:93-101.[Abstract/Free Full Text]
  13. Ahmed M, Monsky WE, Girnun G, et al. Radiofrequency thermal ablation sharply increases intratumoral liposomal doxorubicin accumulation and tumor coagulation. Cancer Res 2003; 63:6327-6333.[Abstract/Free Full Text]
  14. Kainuma O, Asano T, Aoyama H, et al. Combined therapy with radiofrequency thermal ablation and intra-arterial infusion chemotherapy for hepatic metastases from colorectal cancer. Hepatogastroenterology 1999; 46:1071-1077.[Medline]
  15. Scaife CL, Curley SA, Izzo F, et al. Feasibility of adjuvant hepatic arterial infusion of chemotherapy after radiofrequency ablation with or without resection in patients with hepatic metastases from colorectal cancer. Ann Surg Oncol 2003; 10:348-354.[Abstract/Free Full Text]
  16. Kitamoto M, Imagawa M, Yamada H, et al. Radiofrequency ablation in the treatment of small hepatocellular carcinomas: comparison of the radiofrequency effect with and without chemoembolization. AJR Am J Roentgenol 2003; 181:997-1003.[Abstract/Free Full Text]
  17. Shibata T, Iimuro Y, Yamamoto Y, et al. Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology 2002; 223:331-337.[Abstract/Free Full Text]
  18. Vogl TJ, Straub R, Eichler K, Sollner O, Mack MG. Colorectal carcinoma metastases in liver: laser-induced interstitial thermotherapy—local tumor control rate and survival data. Radiology 2004; 230:450-458.[Abstract/Free Full Text]
  19. Sakurai H, Hayakawa K, Mitsuhashi N, et al. Effect of hyperthermia combined with external radiation therapy in primary non-small cell lung cancer with direct bony invasion. Int J Hyperthermia 2002; 18:472-483.[CrossRef][Medline]
  20. Kalapurakal JA, Pierce M, Chen A, Sathiaseelan V. Efficacy of irradiation and external hyperthermia in locally advanced, hormone-refractory or radiation recurrent prostate cancer: a preliminary report. Int J Radiat Oncol Biol Phys 2003; 57:654-664.[CrossRef][Medline]
  21. van der Zee J, Gonzalez Gonzalez D, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet 2000; 355:1119-1125.
  22. Xia T, Sun Q, Shi X, Fan N, Hiraoka M. Relationship between thermal parameters and tumor response in hyperthermia combined with radiation therapy. Int J Clin Oncol 2001; 6:138-142.[CrossRef][Medline]
  23. Cosman ER, Nashold BS, Ovelman-Levitt J. Theoretical aspects of radiofrequency lesions in the dorsal root entry zone. Neurosurgery 1984; 15:945-950.[Medline]
  24. Seegenschmiedt MH, Brady LW, Sauer R. Interstitial thermoradiotherapy: review on technical and clinical aspects. Am J Clin Oncol 1990; 13:352-363.[Medline]
  25. Goldberg SN, Gazelle GS, Halpern EF, Rittman WJ, Mueller PR, Rosenthal DI. Radiofrequency tissue ablation: importance of local temperature along the electrode tip exposure in determining lesion shape and size. Acad Radiol 1996; 3:212-218.[CrossRef][Medline]
  26. Less JR, Skalak TC, Sevick EM, Jain RK. Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. Cancer Res 1991; 51:265-273.[Abstract/Free Full Text]
  27. Goldberg SN, Girnan GD, Lukyanov AN, et al. Percutaneous tumor ablation: increased necrosis with combined radio-frequency ablation and intravenous liposomal doxorubicin in a rat breast tumor model. Radiology 2002; 222:797-804.[Abstract/Free Full Text]
  28. Altman DG, Bland JM. How to randomise. BMJ 1999; 319:703-704.[Free Full Text]
  29. Goldberg SN, Saldinger PF, Gazelle GS, et al. Percutaneous tumor ablation: increased necrosis with combined radio-frequency ablation and intratumoral doxorubicin injection in a rat breast tumor model. Radiology 2001; 220:420-427.[Abstract/Free Full Text]
  30. Hall E. Radiobiology for the radiologist 4th ed. Philadelphia, Pa: J. B. Lippincott, 1993; 293-325.
  31. Brizel DM, Hage WD, Dodge RK, Munley MT, Piantadosi CA, Dewhirst MW. Hyperbaric oxygen improves tumor radiation response significantly more than carbogen/nicotinamide. Radiat Res 1997; 147:715-720.[Medline]
  32. Dewhirst MW, Oliver R, Tso CY, Gustafson C, Secomb T, Gross JF. Heterogeneity in tumor microvascular response to radiation. Int J Radiat Oncol Biol Phys 1990; 18:559-568.[Medline]
  33. Wallace J. Humane endpoints and cancer research. Ilar J 2000; 41:87-93.[Medline]
  34. Dodd GD, 3rd, Soulen MC, Kane RA, et al. Minimally invasive treatment of malignant hepatic tumors: at the threshold of a major breakthrough. RadioGraphics 2000; 20:9-27.[Abstract/Free Full Text]
  35. de Baere T, Denys A, Wood BJ, et al. Radiofrequency liver ablation: experimental comparative study of water-cooled versus expandable systems. AJR Am J Roentgenol 2001; 176:187-192.[Abstract/Free Full Text]
  36. Goldberg SN. Comparison of techniques for image-guided ablation of focal liver tumors. Radiology 2002; 223:304-307.[Free Full Text]
  37. Jain SK, Dupuy DE, Cardarelli GA, Zheng Z, DiPetrillo TA. Percutaneous radiofrequency ablation of pulmonary malignancies: combined treatment with brachytherapy. AJR Am J Roentgenol 2003; 181:711-715.[Abstract/Free Full Text]
  38. Friedman MA, Altemus R, Wood BJ. Radiofrequency ablation in a previously irradiated liver. J Vasc Interv Radiol 2003; 14:1345-1348.[Medline]
  39. Kruskal JB, Oliver B, Huertas JC, Goldberg SN. Dynamic intrahepatic flow and cellular alterations during radiofrequency ablation of liver tissue in mice. J Vasc Interv Radiol 2001; 12:1193-1201.[Medline]
  40. Armour EP, Wang ZH, Corry PM, Martinez A. Sensitization of rat 9L gliosarcoma cells to low dose rate irradiation by long duration 41 degrees C hyperthermia. Cancer Res 1991; 51:3088-3095.[Abstract/Free Full Text]
  41. Coughlin CT, Wong TZ, Strohbehn JW, et al. Intraoperative interstitial microwave-induced hyperthermia and brachytherapy. Int J Radiat Oncol Biol Phys 1985; 11:1673-1678.[Medline]
  42. Wollner IS, Knutsen CA, Ullrich KA, et al. Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs. Cancer Res 1987; 47:3285-3290.[Abstract/Free Full Text]
  43. Ozturk B, Egehan I, Atavci S, Kitapci M. Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer: a double-blind randomized trial. Int J Radiat Oncol Biol Phys 2004; 58:213-219.[CrossRef][Medline]
  44. Ahmed M, Liu Z, Afzal KS, et al. Radiofrequency ablation: effect of surrounding tissue composition on coagulation necrosis in a canine tumor model. Radiology 2004; 230:761-767.[Abstract/Free Full Text]
  45. Wu KL, Jiang GL, Liao Y, et al. Three-dimensional conformal radiation therapy for non-small-cell lung cancer: a phase I/II dose escalation clinical trial. Int J Radiat Oncol Biol Phys 2003; 57:1336-1344.[CrossRef][Medline]
  46. Goblirsch M, Mathews W, Lynch C, et al. Radiation treatment decreases bone cancer pain, osteolysis and tumor size. Radiat Res 2004; 161:228-234.[CrossRef][Medline]
  47. Dupuy DE, Goldberg SN. Image-guided radiofrequency tumor ablation: challenges and opportunities—part II. J Vasc Interv Radiol 2001; 12:1135-1148.[Medline]



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