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DOI: 10.1148/radiol.2442061005
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(Radiology 2007;244:464-470.)
© RSNA, 2007

Experimental Studies

Combination of Radiofrequency Ablation with Antiangiogenic Therapy for Tumor Ablation Efficacy: Study in Mice1

Antoine Hakimé, MD2, Andrew Hines-Peralta, MD, Himaja Peddi, MD, Michael B. Atkins, MD, Vikas P. Sukhatme, MD, PhD, Sabina Signoretti, MD, PhD, Meredith Regan, PhD, and S. Nahum Goldberg, MD

1 From the Laboratory for Minimally Invasive Tumor Therapy (A. Hakimé, A. Hines-Peralta, H.P., S.N.G.), Department of Radiology (A. Hines-Peralta, S.N.G.), and Department of Medicine (M.B.A., V.P.S., M.R.), Beth Israel Deaconess Medical Center, 1 Deaconess Rd, WCC 308B, Boston, MA 02215; and Department of Pathology, Brigham and Women's Hospital, Boston, Mass (S.S.). Received June 10, 2006; revision requested August 15; revision received September 27; accepted October 31; final version accepted November 21. Supported by National Cancer Institute Dana Farber/Harvard Cancer Center Renal Cancer SPORE grant 1 P50 CA10194-01. Address correspondence to S.N.G. (e-mail: sgoldber{at}caregroup.harvard.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Purpose: To prospectively determine whether modulation of renal cell carcinoma (RCC) tumor microvasculature by using the antiangiogenic drug sorafenib could increase the extent of radiofrequency (RF)-induced coagulation in an RCC animal tumor model.

Materials and Methods: All investigations received animal care and utilization committee approval. RCC (human 786-0) was implanted subcutaneously into 27 nude mice. Sixteen mice were randomly assigned into one of three groups when tumors reached 12 mm in diameter: Six mice received 80 mg of sorafenib, a Raf kinase and vascular endothelial growth factor receptor inhibitor, per kilogram of body weight; five mice received 20 mg/kg sorafenib; and five mice received a control carrier vehicle alone. Antiangiogenic therapy was administered until a mean 1-mm reduction in tumor diameter was noted in one group. These 16 mice received a standard dose of RF ablation. Ablation size was visualized by using 2% triphenyltetrazolium chloride. An additional 11 tumors in mice treated with sorafenib alone were stained with CD31 to determine microvascular density (MVD). Resultant size of ablation was compared among groups; statistical significance was determined with analysis of variance. Differences in MVD were assessed with the Kruskal-Wallis test.

Results: Over the 9-day administration of sorafenib, mean tumor size in the control group reached 15.2 mm ± 0.8 (standard deviation). Tumors in mice receiving 20 mg/kg and 80 mg/kg sorafenib measured 12.2 mm ± 0.6 and 11.1 mm ± 0.5, respectively (P < .05). RF-induced coagulation diameter was 8.5 mm ± 0.4 and 11.1 mm ± 0.3 in the 20 mg/kg and 80 mg/kg sorafenib groups, respectively, but was only 6.7 mm ± 0.7 for animals that underwent RF ablation alone (P < .01). Likewise, significant decreases in MVD were noted in the sorafenib-treated animals (P < .01).

Conclusion: Treatment of RCC in nude mice with the antiangiogenic agent sorafenib resulted in markedly decreased MVD and significantly larger zones of RF-induced coagulation necrosis.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Image-guided radiofrequency (RF) tumor ablation, a minimally invasive procedure, is a potentially viable treatment option for achieving focal destruction of solid tumors because it provides some potential advantages compared with surgical resection, including reduced morbidity, the ability to treat patients on an outpatient basis, and the ability to treat poor surgical candidates (1–3). Initially, RF ablation was used to treat hepatic malignancy in cases in which hepatic resection might cause substantial morbidity (3–7), but favorable outcomes with RF ablation have now fueled the expansion of this technique to include the treatment of neoplasms in other sites, including the kidney (8), breast (9), bone (10), and lung (11).

A major obstacle to wide-scale adoption of this treatment option is the inability to reliably create adequate volumes of complete tumor destruction (2). Indeed, RF ablation can be effective for the destruction of small (<3 cm) tumors (12), but success for index tumors larger than 3.5 cm in diameter has been less robust (4–7). The difficulty in treating moderate to large tumors is often attributed to the powerful heat-sink effect of tumor blood flow, which draws heat away from the tumor site, substantially limiting the size and uniformity of tumor destruction (13,14). For this reason, even small vascular tumors, such as centrally located renal cell carcinoma (RCC), may pose challenges for RF ablation (8). Current techniques for decreasing tumor blood flow to aid in RF ablation have included the Pringle maneuver (ie, vascular clamping of portal inflow at hepatic surgery) and chemoembolization (15,16), but these techniques are disadvantageous in that they require invasive procedures, negating some of the purported benefit of minimally invasive therapy. Thus, concomitant administration of antivascular or antiangiogenic pharmaceutical agents capable of reducing tumor blood flow might be of considerable clinical value. Along these lines, Hines-Peralta et al (17) demonstrated that administration of arsenic trioxide, a potent antivascular agent, significantly (P < .05) increased the size of RF-induced coagulation necrosis when it was administered immediately before ablation. However, optimal results were achieved with a relatively high dose of this toxic drug, and the effect may have a transient synergistic window (60 minutes peak efficacy). Nonetheless, their work established that pharmacologic reduction in blood flow could indeed significantly improve RF ablation, but a safer and perhaps longer therapeutic window is likely required to make this strategy clinically viable.

One potential candidate is the new group of antiangiogenic agents that have been developed to block vascular endothelial growth factor (VEGF) receptor signaling and subsequent tumor angiogenesis (18,19). Accordingly, we hypothesized that combining thermal RF ablation with antiangiogenic therapy may prove to increase ablation efficacy. Several VEGF receptor inhibitors have shown potent antitumor activity in RCC xenograft models and sufficient antitumor effects in patients with advanced RCC to merit their recent regulatory approval for this patient population (20,21). Thus, the purpose of our study was to prospectively determine whether modulation of RCC tumor microvasculature by using the antiangiogenic drug sorafenib could increase the extent of RF-induced coagulation in an RCC animal tumor model.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Industry Support
Bayer (West Haven, Conn) donated sorafenib (Nexavar) and provided CD31 immunohistochemical staining components through a materials-transfer agreement with the Dana Farber/Harvard Cancer Center Kidney Cancer Program. The authors had full control of the data and information submitted for publication.

Overall Experimental Design
Human RCC was implanted subcutaneously into the anterior abdominal walls of 27 nude mice (Fisher Scientific, Fairlawn, NJ) (by A. Hakimé and H.P., with 2 years and 1 year of experience, respectively) in two experimental phases. For the first 16 animals, when tumors reached 12 mm in diameter, each animal was randomly assigned to one of three groups. In one experimental group (n = 6), 80 mg sorafenib per kilogram of body weight was administered daily with oral gavage (by A. Hakimé and H.P.). In the second experimental group (n = 5), animals received 20 mg/kg sorafenib daily with oral gavage so that we could assess the dose dependency of sorafenib on RF ablation. The control group (n = 5) received the carrier vehicle alone for a similar time course. Tumor sizes were measured daily with calipers (by A. Hakimé and H.P.), and drug administration was terminated when an average 1-mm reduction in tumor diameter was observed in one of the three groups. Mice in each group then underwent a standard dose of RF ablation with a 1-cm active-tip electrode at 70°C ± 2 for 5 minutes (A. Hakimé, A. Hines-Peralta [with 4 years of experience], and H.P.). Ablation size was visualized by staining for mitochondrial activity with triphenyltetrazolium chloride (TTC), which stains viable tissue red while ablated nonviable tissue remains white. These results were measured in a blinded fashion with calipers sensitive to 0.2 mm (by A. Hakimé, H.P., and S.N.G. [with 13 years of experience]) and then compared and correlated with sorafenib administration. Thus, our study was powered to have an 80% chance of detecting a 1-mm change in coagulation diameter (P = .05).

In the second experimental phase, 11 additional tumors were obtained from mice that did not undergo RF ablation and were randomized into three groups as above. These representative tissue samples (four from mice treated with 80 mg/kg sorafenib, three from mice treated with 20 mg/kg sorafenib, and four from mice not treated with sorafenib) were stained with CD31 to determine microvascular density (MVD). MVD was then correlated with tumor growth and ablation outcome (by S.S., with 9 years of experience).

Animal Models and Tumor Preparation
We received prior permission for all investigations from the animal care committee of Beth Israel Deaconess Medical Center. Given prior experience with RF ablation in this tumor model (8), subcutaneous human RCC 786-0 in nude mice was chosen as the study model. Tumor harvesting and innoculation were performed as described in detail by Horkan et al (22), with a slight modification in that tumor resuspension in this study was performed in 4 mL RPMI 1640 medium (INC Biomedicals, Aurora, Ill) so we could obtain adequate tumor concentration. For tumor implantation, 2 x 106 cells (approximately 0.1 mL by volume) were injected subcutaneously into the subcutaneous tissue of the back of female nude mice (mean weight, 25 g ± 5), yielding a single tumor per mouse. Solid, nonnecrotic tumors (as determined with ultrasonography [US]) that measured 12 mm ± 0.5 in diameter (after approximately 1 month of growth) were included for the study. RF ablations were performed after 9 days of sorafenib or placebo administration when one group of tumors was observed to have shrunk by an average of 1 mm (as directly measured with calipers by A. Hakimé and H.P.). Animals were anesthetized with ketamine and xylazine (both: Fort Dodge Animal Health, Fort Dodge, Ia) and were monitored by institutional animal care and use committee–approved personnel for all procedures.

Sorafenib Administration
Sorafenib mediates antiangiogenesis by inhibiting both VEGF and platelet-derived growth factor, or PDGF, receptors, as well as by acting as an anti–RAF kinase agent (20,21). Sorafenib was chosen for this study given evidence indicating its antiangiogenic effect on RCC (20,21). Sorafenib was administered daily through oral gavage in blinded fashion as 20 or 80 mg/kg, depending on the experimental group. Sorafenib was dissolved in a 50% cremophor EL (Sigma, St Louis, Mo)–50% ethanol (Pharmaco Products, Brookfield, Conn) mixture at four times the desired highest concentration (for the 80 mg/kg dose, the concentration of the dosing solution was 8 mg/mL, with the four-times solution measuring 32 mg/mL). The compounds were heated to 60°C for 1 minute and sonicated for 20–30 minutes to suspend the sorafenib. Once in solution, the aqueous component was gradually added and diluted to generate the one-times dosing solution. The lower dose levels were then created by dilution of this preparation with 12.5% cremophor EL, 12.5% ethanol, and 75% water. Each blinded dose of sorafenib was weighed and stored in dry form away from light and dissolved to liquid form immediately prior to administration.

RF Ablation
A 500-kHz RF generator (CC-1; ValleyLab, Boulder, Colo) was used to apply conventional monopolar RF. RF parameters were selected to allow for comparison with results of previous studies (17,22). RF was applied for 5 minutes with the generator output titrated to maintain a designated tip temperature (70°C ± 2, 90 mA ± 20). RF ablation was performed as described previously by Horkan et al (22) in random order by an investigator who was unaware of the sorafenib treatment group.

Assessment of Coagulation Necrosis
Animals were euthanized 30–60 minutes after RF ablation with pentobarbital (Fatal Plus [0.25 mL/kg]; Vortech Pharmaceuticals, Dearborn, Mich). Staining was performed for mitochondrial enzyme activity by incubating thin representative tissue slices for 30 minutes in 2% TTC (Fisher Scientific). The absence of mitochondrial enzyme activity has been shown to accurately reveal irreversible cellular injury induced by percutaneous tumor ablation (23). With this method, viable tissue with intact mitochondrial enzyme activity stains red, while ablated tissue does not turn red. Tumors were sliced in multiple 2–3-mm slices perpendicular to the electrode axis. Gross measurements of tumor destruction were performed on both TTC-stained and unstained slices, and the extent of visible coagulation was measured with calipers. Coagulation diameter, as determined by the extent of nonstained tissue extending to viable red tissue (longest measurement perpendicular to the inserted electrode), was determined for all samples in blinded fashion (by A. Hakimé, H.P., and S.N.G.). Histopathologic examination was also performed in all ablated tumors with hematoxylin-eosin staining (by S.S.).

Assessment of MVD
Tissue samples were obtained at the midpoint of the tumor from 11 additional tumors in mice treated with no sorafenib or 20 or 80 mg/kg sorafenib for 9 days. After 9 days, the animals were euthanized, and the tumors were excised and sliced as described above. The tumors were stained with CD31 by using standardized immunohistochemical techniques to determine MVD. Tumors were also treated with TTC to assess for necrosis as described above (by A. Hakimé, S.N.G., and S.S.).

Statistical Analysis
For tumor growth and RF ablation, the outcome measures included assessment of the short-axis coagulation diameter (obtained perpendicular to the RF electrode). One-way analysis of variance (Origin, version 6.1; Origin, Northampton, Mass) was used to assess for significant differences between the three groups.

For tumors at the histologic level, overall MVD was determined for the tumor by using a four-point scale, where grade I indicated no or minimal peripheral vascularity; grade II, scant vascularity throughout; grade III, moderate vascularity throughout; and grade IV, exuberant vascularity throughout. Each of the 11 tumors in this section were analyzed and assigned a vascularity grade in blinded fashion. The Kruskal-Wallis test was then used to determine significance among the treatment arms at a P level of .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Tumor Growth
Tumor growth was significantly different among the three groups determined by the dose of sorafenib (P < .05). Mice were treated for 9 days, at which point average tumor size in the group with the highest (80 mg/kg) dose of sorafenib decreased by 1 mm to 11.1 mm ± 0.5, the predetermined end point of treatment. After 9 days, tumors in the control group measured 15.2 mm ± 0.8, corresponding to a mean of 3.2 mm growth (Table). Tumors from mice treated with 20 mg/kg sorafenib measured 12.2 mm ± 0.6, corresponding to no appreciable growth compared with initial tumor size (12.3 mm ± 0.5).


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  		Combining RF Ablation with Sorafenib Therapy for Subcutaneous RCC in Nude Mice

 
Effect of Sorafenib on RF-induced Tumor Coagulation
The extent of RF-induced tumor coagulation was significantly greater in the two experimental groups treated with sorafenib. RF coagulation in control tumors measured 6.7 mm ± 0.7 in diameter. For tumors in mice pretreated with 20 or 80 mg/kg sorafenib, RF coagulation diameter significantly increased in a dose-dependent manner, measuring 8.5 mm ± 0.4 and 11.1 mm ± 0.3, respectively, according to results of TTC staining (P < .01, analysis of variance) (Table, Fig 1).


Figure 1
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  		Figure 1: RCC tumors treated with combined of RF ablation and sorafenib. Cross sections of three gross pathologic specimens stained with TTC (no magnification), show mitochondrial activity as red. Nonviable ablated tumor remains white. Greater zones of coagulation (black arrows) are seen in (middle) a tumor in a mouse pretreated with a 9-day course of 20 mg/kg sorafenib before RF ablation than in (left) a tumor in a mouse treated with RF ablation alone. Near-total ablation of (right) a tumor in a mouse treated with 80 mg/kg sorafenib is seen, with a small rim of viable tumor (white arrow) at the edge.

 
Histologic Results
Specimens treated with RF ablation combined with 80 mg/kg sorafenib showed large areas of geographic necrosis in the center. Features of RF-induced coagulation were identified around the areas of necrosis (Fig 2) (24). Surrounding the areas of RF-induced coagulation were small peripheral areas of tumor that appeared to be viable. Tumors in mice treated with 20 mg/kg sorafenib showed some areas of geographic necrosis in the center; however, these areas were diminished compared with those in tumors in the higher-dose group. Again, features of RF coagulation were identified around the areas of necrosis. Furthermore, larger areas of tumor that appeared to be viable were seen, mainly at the periphery. For tumors in mice treated with RF ablation alone, even less central necrosis, surrounded by RF coagulation and larger zones of viable tumor, was noted. As anticipated, regions of absent TTC staining corresponded approximately to the combined zones of RF coagulation plus central necrosis for all RF-treated tumors.


Figure 2A
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  		Figure 2a: Photomicrographs show histologic findings of RF ablation in RCC tumor in mouse treated with 20 mg/kg sorafenib. (a) There is a central necrotic area surrounded by tumor cells that are characterized by nuclei with condensed chromatin and no visible nucleoli (indicating coagulation). Such cytologic changes are consistent with RF-induced cell damage (24). (b) Viable tumor cells are characterized by open chromatin and visible nucleoli peripheral to the RF coagulation zone. (Hematoxylin-eosin stain; original magnification, x20.)

 

Figure 2B
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  		Figure 2b: Photomicrographs show histologic findings of RF ablation in RCC tumor in mouse treated with 20 mg/kg sorafenib. (a) There is a central necrotic area surrounded by tumor cells that are characterized by nuclei with condensed chromatin and no visible nucleoli (indicating coagulation). Such cytologic changes are consistent with RF-induced cell damage (24). (b) Viable tumor cells are characterized by open chromatin and visible nucleoli peripheral to the RF coagulation zone. (Hematoxylin-eosin stain; original magnification, x20.)

 
MVD Findings
Tumors in mice treated with sorafenib demonstrated marked differences in tumor vascularity compared with that of control tumors at evaluation of tumors with CD31 staining. All control tumors had grade III or IV vascularity (Fig 3). Statistically significant reductions in MVD were seen in the sorafenib-treated animals (P < .01, Kruskal-Wallis test). All four tumors in mice treated with 80 mg/kg sorafenib had nearly absent vascularity (grade I), with minimal residual vessels at the periphery (Fig 2). Three tumors in mice treated with 20 mg/kg sorafenib had grade II (n = 2) or grade III (n = 1) vascularity, with the greatest reduction in vascularity in the center of the tumor.


Figure 3A
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  		Figure 3a: Photomicrographs show MVD of treated RCC tumors. (a, b) Images in control animals. (c, d) Images in animals pretreated with 80 mg/kg sorafenib for 9 days. A dramatic reduction in MVD is observed in the treated animals, as only minimal peripheral MVD is seen (arrow). These representative tumor images (chosen to reflect characteristic findings) were obtained in mice that did not undergo RF ablation. (CD31 stain; original magnification, x4 for a and c and x10 for b and d.)

 

Figure 3B
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  		Figure 3b: Photomicrographs show MVD of treated RCC tumors. (a, b) Images in control animals. (c, d) Images in animals pretreated with 80 mg/kg sorafenib for 9 days. A dramatic reduction in MVD is observed in the treated animals, as only minimal peripheral MVD is seen (arrow). These representative tumor images (chosen to reflect characteristic findings) were obtained in mice that did not undergo RF ablation. (CD31 stain; original magnification, x4 for a and c and x10 for b and d.)

 

Figure 3C
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  		Figure 3c: Photomicrographs show MVD of treated RCC tumors. (a, b) Images in control animals. (c, d) Images in animals pretreated with 80 mg/kg sorafenib for 9 days. A dramatic reduction in MVD is observed in the treated animals, as only minimal peripheral MVD is seen (arrow). These representative tumor images (chosen to reflect characteristic findings) were obtained in mice that did not undergo RF ablation. (CD31 stain; original magnification, x4 for a and c and x10 for b and d.)

 

Figure 3D
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  		Figure 3d: Photomicrographs show MVD of treated RCC tumors. (a, b) Images in control animals. (c, d) Images in animals pretreated with 80 mg/kg sorafenib for 9 days. A dramatic reduction in MVD is observed in the treated animals, as only minimal peripheral MVD is seen (arrow). These representative tumor images (chosen to reflect characteristic findings) were obtained in mice that did not undergo RF ablation. (CD31 stain; original magnification, x4 for a and c and x10 for b and d.)

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCE IN KNOWLEDGE
 References
 
Our results suggest that pretreatment of RCC tumors in nude mice with the antiangiogenic agent sorafenib can decrease tumor MVD and substantially enhance RF ablation in a dose-dependent manner. This interaction is likely mediated by the well-documented antiangiogenic properties of sorafenib. Sorafenib is a potent inhibitor of Raf kinase (wild-type c-Raf-1, as well as wild-type and V600E mutant B-Raf) (20,21). In addition, sorafenib inhibits tyrosine kinases such as human VEGF receptor 2, Flt-3, c-KIT, and fibroblast growth factor receptor 1, or FGFR1, that have been shown to mediate tumor angiogenesis (20,21). In RCC, constitutive activation of Raf, mitogen-activated protein kinase, or MEK, and extracellular-signal-regulated kinase, or ERK, has been observed in approximately 50% of tumors; however, the contribution of Raf inhibition, rather than VEGF receptor inhibition, to the antitumor effects of sorafenib remains conjectural (20,21). The antiangiogenic effects of sorafenib are more clearly established and are believed to be related to possible dual inhibition of both VEGF receptor and Raf pathways within tumor endothelial cells. Recent clinical results in patients with RCC have been sufficiently promising to justify regulatory approval of sorafenib for patients with this disease (20,21).

Combined use of sorafenib (or other antiangiogenic therapies) with RF ablation (or other methods of thermal ablation) may help overcome the three major limitations facing ablation of RCC: (a) the size of tumors that can be treated, (b) the efficiency of the technique, and (c) the completeness of treatment. Specifically, larger volumes of tumor destruction could potentially enable the complete eradication of tumors measuring 5–7 cm in size—tumors that currently are considered too large to treat effectively (8). Additionally, larger-volume ablation may enable minimally invasive tumor debulking, making RF ablation feasible for patients with stage IV disease prior to immunotherapy (25,26). Several reports have suggested a survival benefit with cytoreductive nephrectomy (despite its well-defined morbidity and mortality) in patients with stage IV RCC when it is performed prior to biologic therapy. Tumor debulking with minimally invasive procedures such as RF ablation would likely represent a superior alternative, given the morbidity associated with an open surgical procedure. For smaller (3–5-cm) tumors, RF combined with antiangiogenic therapy could reduce the number of RF applications required, potentially increasing the efficiency of the technique. Second, combined treatment may have the potential to achieve equivalent tumor destruction with a reduction in the duration and extent of therapy (27), assuming that tumor perfusion does not lead to an increase in resistance or change in tissue conductivity or necessitate an increased energy application. Third, a reduction in blood flow could eliminate heterogeneous "heat sinks" that can occur in tumors of all sizes—particularly central tumors (28)—thereby improving uniformity of heat deposition during RF ablation and potentially reducing the rate of incomplete treatment.

We acknowledge several limitations of our study. First, our analysis was limited by investigating only one animal tumor model. Further investigation is necessary to determine if the interaction observed here in RCC in nude mice is also observed in other tumor types. Sorafenib has a broad spectrum of activity, as described above, but in combination with RF ablation, its activity may likely be dependent on the sensitivity of the tumor to antiangiogenic therapy, as well as on tumor size. Second, although we did investigate MVD after sorafenib administration, we did not directly assess tumor perfusion. Thus, it is possible that alternate mechanisms influenced the significant gains in RF coagulation diameter. The exact influence of tumor perfusion secondary to decreases in MVD, as determined at perfusion imaging with computed tomography (CT) or magnetic resonance (MR) or direct Doppler US analysis, may enable more accurate predictions of RF ablation size and more precise determination of the sufficiency of antiangiogenic therapy before RF ablation. Thus, direct assessment with CT or MR perfusion protocols is the focus of ongoing research in our laboratory and will likely yield insight in future clinical trials (29,30). Last, in our studies, treatment was provided for 9 days on the basis of observed changes in tumor size, but optimal dosing concentration and duration is still unclear and warrants further tumor-specific study.

In conclusion, our results suggest a potential role for combining RF ablation with antiangiogenic therapy, but further study is necessary, including evaluation of the response to sorafenib with RF ablation in other tumor types besides human RCC in nude mice. It is also necessary to study other antiangiogenic therapies, as well as to evaluate these therapies in combination with other forms of thermal ablation, such as microwave ablation. Such future studies will be of importance as clinical trials are formulated to investigate these potentially additive therapies for the treatment of RCC, and possibly other tumor types as well.

Practical application: As sorafenib has recently become approved by the U.S. Food and Drug Administration for use in renal cancer, results of this trial could potentially be translated into clinical care for patients undergoing RF ablation. Achieving greater ablation with combined treatment than with RF alone could potentially justify combination therapy in many patients and further support delaying RF ablation until after initiation of sorafenib in patients who are scheduled to receive both therapies. Sufficiently large increases in coagulation diameter would potentially permit consideration of trials that could assess the relative merits of image-guided palliative debulking versus nephrectomy in terms of both safety and efficacy. Combined treatment also offers the opportunity for improved therapy in patients with medically unresectable primary tumors or distant metastases. Last, RF ablation may be beneficial for treatment of isolated tumors that have become refractory to antiangiogenic therapy, thus expanding the duration and utility of such treatment. Thus, given the encouraging results of our animal study demonstrating improved therapy by combining RF ablation and antiangiogenic therapy, further study in animals and, ultimately, clinical trials is likely warranted.


   ADVANCE IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: MVD = microvascular density • RCC = renal cell carcinoma • RF = radiofrequency • TTC = triphenyltetrazolium chloride • VEGF = vascular endothelial growth factor

2 Current address: Department of Radiology, Beaujon Hospital, Paris, France. Back

See Materials and Methods for pertinent disclosures.

Author contributions:Guarantors of integrity of entire study, A. Hakimé, S.N.G.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, A. Hines-Peralta, H.P., M.B.A., V.P.S., S.N.G.; experimental studies, A. Hakimé, H.P., S.S., S.N.G.; statistical analysis, A. Hines-Peralta, M.R., S.N.G.; and manuscript editing, A. Hakimé, A. Hines-Peralta, H.P., M.B.A., V.P.S., S.S., S.N.G.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 

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A. X. Zhu and G. K. Abou-Alfa
Expanding the Treatment Options for Hepatocellular Carcinoma: Combining Transarterial Chemoembolization With Radiofrequency Ablation
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