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DOI: 10.1148/radiol.2372041494
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(Radiology 2005;237:479-484.)
© RSNA, 2005

Experimental Studies

Liver Metastases in Rats: Chemoembolization Combined with Interstitial Laser Ablation for Treatment1

Adel Maataoui, MD, Jun Qian, MD2, Martin G. Mack, MD, Mohammad F. Khan, MD, Elsie Oppermann, Mehry Roozru, Sabine Schmidt, Wolf O. Bechstein, MD and Thomas J. Vogl, MD

1 From the Institute for Diagnostic and Interventional Radiology (A.M., J.Q., M.G.M., M.F.K., M.R., S.S., T.J.V.) and Department of Visceral Surgery (E.O., W.O.B.), Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Received August 30, 2004; revision requested October 29; revision received December 23; accepted January 24, 2005. Address correspondence to A.M. (e-mail: adel.maataoui{at}gmx.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To assess the effect of transcatheter arterial chemoembolization (TACE) combined with laser-induced thermotherapy (LITT) for treatment of liver metastases in an animal model.

MATERIALS AND METHODS: All experiments were approved by the German government and the institutional animal research review board. After subcapsular liver implantation of colorectal cancer cells in 30 WAG rats (on day 0), the animals were randomly assigned to three interventional treatment groups. In the 10 rats in group A, TACE was performed: Fourteen days after cancer cell implantation and within 20 minutes after laparotomy and retrograde placement of a microcatheter into the gastroduodenal artery, these rats were injected with mitomycin (0.1 mg), iodized oil (0.1 mL), and degradable starch microspheres (5.0 mg). In the 10 rats in group B, LITT was performed: Also on day 14, the tumors in these animals were exposed to Nd:YAG laser light of 1064 nm at 2 W for 5 minutes. In the 10 rats in group C, combined treatment was administered: TACE was performed on day 14, and LITT was performed on day 21. Tumor volumes were measured before (on day 13) and after (on day 28) treatment with magnetic resonance (MR) imaging, and the mean tumor growth ratio (day 13 tumor volume divided by day 28 tumor volume) was calculated.

RESULTS: The mean tumor volumes measured before and after the treatments were, respectively, 0.11 and 0.60 cm3 in group A, 0.11 and 0.68 cm3 in group B, and 0.11 and 0.35 cm3 in group C. The mean tumor growth ratio was 5.42 in group A, 6.14 in group B, and 3.15 in group C. According to Bonferroni test results, compared with the rats in groups A and B (controls), the group C rats had significantly inhibited tumor growth (P < .01 for both comparisons).

CONCLUSION: Use of combined TACE-LITT treatment, compared with the use of TACE or LITT alone, significantly inhibits tumor growth.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The liver is the most common site of distant metastases originating from colorectal cancer. One-half of patients with colorectal cancer ultimately develop liver involvement during the course of the disease (1,2). Surgical resection of liver metastases is still regarded as one of the best options for radical treatment of malignant tumors; however, only 20%–25% of patients are suitable for surgical therapy (1,3–5). These facts have led to the development of alternative therapies for liver metastases, such as chemotherapy, ethanol ablation, radiofrequency ablation, microwave ablation, ultrasound ablation, cryoablation, transcatheter arterial chemoembolization (TACE), and laser-induced thermotherapy (LITT) (1,6–9).

TACE enables high concentrations of therapeutic agents to be delivered directly to the liver metastasis for prolonged therapeutic periods and currently is performed mainly for the palliative treatment of liver metastases (10). Since TACE is not a curative treatment, viable tumor cells may remain after this intervention (11,12).

Percutaneous LITT performed with local anesthesia is an in situ ablative technique used for the treatment of liver metastases originating from colorectal cancer. LITT reportedly results in improved clinical outcomes and survival rates (13,14). In patients treated with magnetic resonance (MR) imaging–guided LITT for unresectable colorectal liver metastases, mean survival times of 41.8–46.8 months have been reported (15,16). Despite advancements in the treatment of liver metastases originating from colon adenocarcinoma, the clinical use of LITT is still limited, mainly because of the small size of the inducible coagulation necrosis (17,18).

It has been suggested that the therapeutic effects of treatments on malignant liver tumors can be improved by using a combination of therapies (19). Pacella et al (20) reported 1-, 2-, and 3-year cumulative survival rates of 92%, 68%, and 40%, respectively, for patients with hepatocellular carcinoma who were treated with LITT combined with TACE. Germer et al (18) found that the use of LITT combined with transarterial embolization with degradable starch microspheres considerably increased the effectiveness of LITT in the treatment of liver metastases in an animal model. However, to our knowledge, no experimental or clinical reports on the therapeutic effectiveness of TACE plus LITT for treatment of liver metastases had been published. Thus, the purpose of our study was to assess the effect of combined TACE-LITT treatment of liver metastases in an animal model.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Animal Model
The implanted tumor was a rapidly growing, moderately differentiated adenocarcinoma of the rat colon (tumor cell line CC531) that we obtained from the German Cancer Research Center (Deutsches Krebs ForschungsZentrum, Heidelberg, Germany). All experiments were approved by the German government and our institutional animal research review board.

Thirty inbred male WAG rats (Charles River Laboratories, Sulzfeld, Germany) that weighed 200–240 g were used in this experimental study. The animals were kept in standard conditions at a mean temperature of 22°C ± 2 (standard deviation), with a relative humidity of 55% ± 10, and with a pattern of 12 hours of dark and 12 hours of light. The rats were fed standard laboratory chow and tap water ad libitum.

Intrahepatic tumor inoculation of a tumor suspension produced in vitro was performed. The tumor cell line was cultivated in an incubator at 37°C and with 8% CO2 in 20 mL of complete medium, which consisted of RPMI 1640 (Gibco-Life Technologies, Eggenstein, Germany), 10% fetal calf serum (Seromed; Biochrom, Berlin, Germany), and 1% penicillin-streptomycin (Seromed). After 3 days, the cells were washed twice with phosphate-buffered saline and detached with 3 mL of trypsin. The trypsin was deactivated by adding the complete medium. After centrifugation, washing, and resuspension of the cells with phosphate-buffered saline, the vitality of the cells was evaluated in a Bürker hemocytometer after the addition of trypan blue. After vital cell counting, the suspension was adjusted to 97% vitality with a density of 1 x 106 vital cells per 100 µL of suspension by means of recentrifugation and resuspension (18).

For tumor implantation (on day 0), which was performed by one of the authors (J.Q.), a midline abdominal incision was made to expose the liver. Tumor cells were injected into the left liver lobe with a 30-gauge needle. The abdominal wall was then closed by using two layers of silk suture.

Anesthesia
For all interventional and imaging procedures, the animals were anesthetized by means of intraperitoneal injection of 100 mg · kg–1 ketamine hydrochloride (Ketanest; Parke-Davis, Freiburg, Germany) and 15 mg · kg–1 xylazinhydrochloride (Rompun; Bayer, Leverkusen, Germany).

Interventional Procedures
The 30 animals were randomly assigned to one of two control groups (groups A and B) of 10 rats each or to the therapeutic group (group C) of 10 rats. The rats in groups A and B were treated with TACE (group A) or LITT (group B) 13 days after tumor implantation. The group C rats received combined interventional treatment on days 14 (TACE) and 21 (LITT).

TACE.—The chemoembolizations were performed by two authors (J.Q. and A.M.). A polyethylene catheter (PE-10; Wenzel, Heidelberg, Germany) with an inner diameter of 0.28 mm and an outer diameter 0.61 mm was used for catheterization in a second laparotomy (performed in the group C rats only). With use of a binocular operative microscope (model M651; Leica, Wetzlar, Germany), the catheter was inserted retrogradely into the gastroduodenal artery and pushed forward to the common hepatic artery (Fig 1). Within 20 minutes after a prepared silk suture was slightly drawn around the common hepatic artery, 0.1 mg of mitomycin (Medac; Hamburg, Germany) in 0.1 mL of 0.9% NaCl (21), 0.1 mL of iodized oil (Lipiodol; Byk Gulden, Konstanz, Germany) (22,23), and 5.0 mg of degradable starch microspheres (Spherex; Pharmacia & Upjohn, Erlangen, Germany) in 0.1 mL of 0.9% NaCl (18,24) were injected through the catheter into the hepatic artery by using the sandwich technique (injection of mitomycin was followed by injection of iodized oil and then by injection of degradable starch microspheres).



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  		Figure 1. Catheterization and TACE performed in vivo in a rat. A polyethylene catheter was retrogradely inserted into the gastroduodenal artery (curved arrow) and pushed forward to the common hepatic artery. After the prepared silk suture was slightly drawn around the common hepatic artery (arrowhead), mitomycin, iodized oil, and degradable starch microspheres were slowly injected. Straight arrow points to proper hepatic artery.

 
Compressing the right hepatic artery made it possible to direct the main flow of the contrast agent into the left hepatic artery. After this technique, a kind of selective embolization was performed. The gastroduodenal artery was then fixed with a silk suture. Finally, the abdominal wall was closed by using two layers of silk suture. The animals were kept under standard conditions after treatment. None of the animals died during tumor cell implantation or surgery. We observed no fistulas or injuries to the bile ducts, vessels, or other surrounding structures during treatment.

LITT.—The LITT procedures were performed by three authors (J.Q., A.M., and M.G.M.). For LITT of liver tumors, an Nd:YAG laser (Laser-und Medizin-Technologie, Berlin, Germany) with a wavelength of 1064 nm was used. Laser light energy (2-W power) was delivered in the continuous wave mode through a 400-µm fiber, which at its distal end had a diffuser tip applicator (Laser-und Medizin-Technologie) that was 0.8 mm in outer diameter and 5.0 mm in active length. For laser application, the applicator was inserted along the longest diameter of the tumor in its center at a depth of 0.5 cm after laparotomy (Fig 2). A power meter (Huettinger, Umkirch, Germany) was used to measure the laser power before the laser application at the distal end of the applicator. The laser application time was 5 minutes (18).



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  		Figure 2. LITT performed in vivo in a rat. An Nd:YAG laser with a wavelength of 1064 nm was applied to the tissue by using a diffusing applicator (outer diameter of 0.8 mm, active length of 5.0 mm). The applicator was inserted along the longest diameter of the tumor in its center at a depth of about 0.5 cm. Laser application time was 5 minutes. At this wavelength, the laser light energy (power of 2 W) penetrated deeply into the tissue, where photon absorption and heat conduction produced coagulative and hyperthermic effects.

 
MR Imaging and Analysis
All MR imaging examinations were performed before (day 13) and after (day 28) the interventional treatments by using a 1.5-T superconducting system (Sonata; Siemens, Erlangen, Germany) supplemented by a wrist coil. T1-weighted spin-echo (repetition time msec/echo time msec, 460/15) and T2-weighted turbo spin-echo (3170/99) transverse images with a section thickness of 2 mm and a 184 x 256 matrix were acquired. There was no gap between the sections, and no contrast medium was administered. The tumor volume was determined and evaluated on T2-weighted images according to the following formula (25): T = (DL · DS2)/2, where T is the tumor volume in cubic millimeters, DL is the largest diameter in millimeters, and DS is the smallest diameter in millimeters. With use of this formula, the volume of intratumoral coagulation appearing as a hypointense area in a hyperintense tumor on T2-weighted MR images was determined.

Image analyses and tumor volume determinations were performed by two experienced staff radiologists (A.M. and J.Q.). Decisions regarding the extensions of tumors were made in consensus by both radiologists. Before analysis, the two radiologists were blinded to the treatment groups in which the images were obtained.

Statistical Analyses
The normality of distributions was analyzed by using the Shapiro-Wilk W test, and one-way analysis of variance was performed by using the Bartlett test for equal variances. The mean growth ratio—that is, the day 13 (before treatment) tumor volume divided by the day 28 (after treatment) tumor volume—was analyzed by using the Bonferroni test to compare the effects between each pair of treatment groups. The mean intratumoral coagulation rate was analyzed by using the one-sided t test to compare the coagulation volumes in groups B and C. Results were considered to be significant at P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The tumor model that we used yielded a high tumor growth success rate (100%), and tumor growth was confirmed at MR imaging in this experimental study. A total of 30 individual tumors were seen at unenhanced MR imaging of the liver in all 30 WAG rats (100%) before treatment.

The mean tumor volumes measured before and after treatment were, respectively, 0.11 cm3 ± 0.0036 (standard deviation) and 0.60 cm3 ± 0.0267 in group A, 0.11 cm3 ± 0.0058 and 0.68 cm3 ± 0.0366 in group B, and 0.11 cm3 ± 0.0055 and 0.35 cm3 ± 0.0254 in group C. The mean tumor growth ratio was 5.42 ± 0.18 in group A, 6.14 ± 0.14 in group B, and 3.15 ± 0.11 in group C. Compared with the rats in either control rat group—that is, group A (treated with TACE only) or group B (treated with LITT only)—the group C rats (treated with TACE plus LITT) had significantly inhibited tumor growth ratios at Bonferroni test analysis (P < .01).

After different interventional treatments, intrahepatic metastases developed in one of the 10 rats in groups A and in one of the 10 rats in group B. Incomplete intratumoral coagulation was observed in one of the 10 rats in group A and in all 20 rats in groups B and C combined (Table, Figs 3–5).


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  		Tumor Volume Ratios in Different Treatment Groups

 


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  		Figure 3a. Transverse MR images of solid liver metastasis in a group A (TACE alone) WAG rat. (a) Pretreatment unenhanced T1-weighted spin-echo MR image (460/15) shows a small hypointense tumor (arrow) in the left lateral liver lobe. (b) On the pretreatment unenhanced T2-weighted turbo spin-echo MR image (3170/99), the lesion in a is seen as a hyperintense 0.66 x 0.58-cm tumor (arrow) that is well discernible from the surrounding liver tissue. (c) On the posttreatment unenhanced T1-weighted spin-echo MR image (460/15), the same lesion is a relatively large hypointense tumor (arrow) in the left lateral liver lobe and is accompanied by a small subcapsular hypointense tumor. (d) On the posttreatment unenhanced T2-weighted spin-echo MR image (3170/17), the same lesion appears as a 1.14 x 1.05-cm tumor (arrow) with relatively rapid growth compared with its growth before therapy. A small subcapsular hyperintense area corresponding to the intrahepatic metastasis also is seen.

 


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  		Figure 3b. Transverse MR images of solid liver metastasis in a group A (TACE alone) WAG rat. (a) Pretreatment unenhanced T1-weighted spin-echo MR image (460/15) shows a small hypointense tumor (arrow) in the left lateral liver lobe. (b) On the pretreatment unenhanced T2-weighted turbo spin-echo MR image (3170/99), the lesion in a is seen as a hyperintense 0.66 x 0.58-cm tumor (arrow) that is well discernible from the surrounding liver tissue. (c) On the posttreatment unenhanced T1-weighted spin-echo MR image (460/15), the same lesion is a relatively large hypointense tumor (arrow) in the left lateral liver lobe and is accompanied by a small subcapsular hypointense tumor. (d) On the posttreatment unenhanced T2-weighted spin-echo MR image (3170/17), the same lesion appears as a 1.14 x 1.05-cm tumor (arrow) with relatively rapid growth compared with its growth before therapy. A small subcapsular hyperintense area corresponding to the intrahepatic metastasis also is seen.

 


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  		Figure 3c. Transverse MR images of solid liver metastasis in a group A (TACE alone) WAG rat. (a) Pretreatment unenhanced T1-weighted spin-echo MR image (460/15) shows a small hypointense tumor (arrow) in the left lateral liver lobe. (b) On the pretreatment unenhanced T2-weighted turbo spin-echo MR image (3170/99), the lesion in a is seen as a hyperintense 0.66 x 0.58-cm tumor (arrow) that is well discernible from the surrounding liver tissue. (c) On the posttreatment unenhanced T1-weighted spin-echo MR image (460/15), the same lesion is a relatively large hypointense tumor (arrow) in the left lateral liver lobe and is accompanied by a small subcapsular hypointense tumor. (d) On the posttreatment unenhanced T2-weighted spin-echo MR image (3170/17), the same lesion appears as a 1.14 x 1.05-cm tumor (arrow) with relatively rapid growth compared with its growth before therapy. A small subcapsular hyperintense area corresponding to the intrahepatic metastasis also is seen.

 


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  		Figure 3d. Transverse MR images of solid liver metastasis in a group A (TACE alone) WAG rat. (a) Pretreatment unenhanced T1-weighted spin-echo MR image (460/15) shows a small hypointense tumor (arrow) in the left lateral liver lobe. (b) On the pretreatment unenhanced T2-weighted turbo spin-echo MR image (3170/99), the lesion in a is seen as a hyperintense 0.66 x 0.58-cm tumor (arrow) that is well discernible from the surrounding liver tissue. (c) On the posttreatment unenhanced T1-weighted spin-echo MR image (460/15), the same lesion is a relatively large hypointense tumor (arrow) in the left lateral liver lobe and is accompanied by a small subcapsular hypointense tumor. (d) On the posttreatment unenhanced T2-weighted spin-echo MR image (3170/17), the same lesion appears as a 1.14 x 1.05-cm tumor (arrow) with relatively rapid growth compared with its growth before therapy. A small subcapsular hyperintense area corresponding to the intrahepatic metastasis also is seen.

 


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  		Figure 4a. Transverse MR images of solid liver metastasis (arrow) in a group B (LITT alone) WAG rat. (a) Posttreatment unenhanced T1-weighted spin-echo MR image (460/15) shows a hypointense tumor with a hyperintense intratumoral focus in the left lateral liver lobe. (b) On the posttreatment unenhanced T2-weighted turbo spin-echo MR image (3170/99), the same tumor (1.25 x 1.08 cm) is hyperintense and has a central hypointense area corresponding to intratumoral coagulation. No intrahepatic metastasis was observed.

 


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  		Figure 4b. Transverse MR images of solid liver metastasis (arrow) in a group B (LITT alone) WAG rat. (a) Posttreatment unenhanced T1-weighted spin-echo MR image (460/15) shows a hypointense tumor with a hyperintense intratumoral focus in the left lateral liver lobe. (b) On the posttreatment unenhanced T2-weighted turbo spin-echo MR image (3170/99), the same tumor (1.25 x 1.08 cm) is hyperintense and has a central hypointense area corresponding to intratumoral coagulation. No intrahepatic metastasis was observed.

 


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  		Figure 5. Transverse posttreatment unenhanced T2-weighted turbo spin-echo MR image (3170/99) of a solid liver metastasis (arrow) in a group C (TACE plus LITT) WAG rat. Image shows a 0.92 x 0.89-cm hyperintense tumor with a central hypointense area corresponding to intratumoral coagulation. No intrahepatic metastasis was observed. The smaller size of this tumor, compared with the sizes of the tumors in rat groups A and B, indicates the absence of marked tumor growth after therapy compared with the tumor growth before therapy.

 
Pretreatment unenhanced T1-weighted spin-echo MR imaging (460/15) (Fig 3a) depicted a small homogeneous hypointense tumor in the left lateral lobe of the rat livers. The T2-weighted turbo spin-echo MR images (3170/99) (Fig 3b) showed a hyperintense tumor that was well discernible from the surrounding liver tissue. In one group A control rat, posttreatment unenhanced T1-weighted MR imaging (Fig 3c) depicted a relatively large hypointense tumor and a small subcapsular hypointense tumor. The T2-weighted MR image (Fig 3d) showed a small homogeneous hyperintense tumor corresponding to the intrahepatic metastasis in this rat liver.

In the control group B rats (treated with LITT alone), we observed incomplete intratumoral coagulation with a nonhomogeneous hyperintense pattern on the T1-weighted images (Fig 4a) and a hypointense pattern on the T2-weighted images (Fig 4b) after treatment. The mean intratumoral coagulation volume was 61.10% ± 3.38. However, relatively rapid tumor progression was seen in this group. The mean volume growth ratio was 6.14.

In the group C rats (treated with TACE plus LITT), posttreatment T1-weighted MR imaging depicted a solid nonhomogeneous hypointense tumor that had an intratumoral hyperintense focus in the left lateral liver lobe. The intratumoral focus corresponded to intratumoral coagulation and was seen at T2-weighted MR imaging (Fig 5). The mean intratumoral coagulation volume was 79.39% ± 4.00. The difference in intratumoral coagulation volume between groups B and C was significant (P < .01). The smaller tumors observed in group C, compared with the sizes of the tumors seen in groups A and B, indicated that there was no marked tumor growth after therapy compared with the pretreatment tumor size in the group C rats. No intrahepatic metastases were observed in this group.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Since the introduction of TACE as a palliative treatment for patients with unresectable liver metastases, it has become one of the most common forms of therapy for colorectal hepatic metastases. (10). With chemoembolization, embolization of the hepatic artery reduces the blood flow, creates ischemia, and increases the time of contact between the chemotherapeutic agent and the tumor cells (10,26,27). Subsegmental chemoembolization enhances the local effect on the neoplasm while minimizing further damage to the surrounding liver tissue (26,27). However, TACE is not a curative treatment. Although varying degrees of tumor coagulation can be observed after effective TACE, this form of chemoembolization of liver metastases does not eliminate all malignant cells or facilitate an improvement in overall patient survival (11,12). In patients with large tumors, multiple TACE sessions are necessary to control tumor growth and increase the risk of worsening hepatic function owing to damage to noncancerous liver parenchyma (28).

To overcome the limits of TACE, recent technical advancements have enabled the development of other nonsurgical interventions for liver metastases. Recently, more interest has been directed toward the use of the Nd:YAG laser to deliver ablative energy. In the (to our knowledge) first clinical report on the use of MR imaging–guided LITT, the investigators stated that tumorous tissue was very sensitive to heat and that this sensitivity caused a wider temperature distribution of the delivered energy (29).

Low-power laser beam applications, in which light energy is delivered through thin optical fibers, yield well-defined areas of coagulation. Tumor destruction with direct heating is therefore possible, with greatly limited damage to the surrounding structures (2,30). Thus, use of LITT results in high local tumor control. A mean survival time of 41.8–46.8 months has been reported in patients who were treated with MR imaging–guided LITT for unresectable colorectal liver metastases (15,16). In addition, MR imaging–guided LITT performed with local anesthesia is safe and associated with an acceptably low rate of major complications (13,17,31,32). However, the clinical use of LITT is usually limited by the large size of metastases (diameters < 5 cm), the risk of bleeding, and the small size of the inducible coagulation necroses (15–18).

It has been suggested that the overall therapeutic effects of liver cancer treatments could be improved by combining TACE and LITT (19). An approach of combining TACE and LITT has been applied to increase the effectiveness of TACE or LITT alone. Pacella et al (20) reported 1-, 2-, and 3-year cumulative survival rates of 92%, 68%, and 40%, respectively, for patients with hepatocellular carcinoma treated with LITT combined with TACE. One can also substantially increase the thermal effect by interrupting the blood flow before or during the thermal ablation. Germer et al (18) found that the combination of LITT and transarterial embolization of degradable starch microspheres considerably increased the effectiveness of LITT in the treatment of liver metastases in rats. Heisterkamp et al (33) also injected degradable starch microspheres into the proper hepatic artery through an MR imaging–visible catheter directly before the laser treatment. They found that LITT of liver metastases performed by using an open MR imaging system and in combination with arterial inflow reduction was both technically feasible and safe.

Thermometric evaluation has revealed that the increase in tumor size associated with hepatic artery occlusion is due to reduced heat dissipation achieved by eliminating perfusion-mediated tissue cooling (34,35). However, to our knowledge no experimental or clinical reports on the therapeutic effectiveness of TACE combined with LITT for the treatment of liver metastases had been published yet.

To our knowledge, our study was the first investigation in which the antitumoral effect of TACE combined with LITT on liver metastases originating from colon carcinoma was evaluated. This animal model was similar to clinical situations in terms of the treatment of most human liver metastases, and the conclusions reached are promising. In our investigation, the mean tumor growth ratio was 5.42 in the group A rats (treated with TACE alone), 6.14 in the group B rats (treated with LITT alone), and 3.15 in the group C rats (treated with TACE plus LITT). The intratumoral destruction and coagulation achieved with LITT and the blockage of tumor vessels around the focus achieved with TACE simultaneously led to the marked shrinkage of the tumors in the group C rats compared with the shrinkage achieved with TACE or LITT alone. Wilcoxon two-sample test results showed that compared with the group A and group B rats (controls), the group C rats had significantly inhibited and reduced tumor growth ratios (P = .001).

We believe that the advantages of and rationales for using TACE combined with LITT to treat liver metastases are as follows: (a) TACE decreases the hypervascularity of liver metastases, thereby reducing the risk of bleeding during the following ablative procedure; (b) TACE increases the effectiveness of the laser treatment by reducing the cooling effect of blood flow through the intratumoral vessels; (c) LITT is still a necessary component in the treatment of tumors larger than 5 cm in diameter and cannot be substituted with TACE alone, and, therefore, sequential laser ablation of a large liver tumor is advocated as a possible locally curative therapy after effective TACE (36); (d) LITT reduces the volume of viable tissue such that the tumor volume returns to a range at which TACE can be effective (20); (e) an important advantage of LITT combined with TACE is the small number of sessions required to achieve complete necrosis of larger or multiple tumors (20); and (f) the possibility that the use of this combined treatment reduces the number and severity of detrimental consequences and deleterious side effects of embolization deserves further study (20). Our experiment results also prove the benefits of this alternative therapeutic modality for liver metastases.

Although promising results were obtained, our study had limitations. The tumor model that we used was a simulated liver metastasis that was injected directly into the organ. The hematogenously or locally spread metastases observed in humans may behave entirely differently owing to their multifocal location. Furthermore, we must emphasize that a second laparotomy was not performed in the animals in groups A and B. Although it is unlikely that the second laparotomy performed in group C affected the results—either positively or negatively—ideally, a sham laparotomy should have been performed in the group A and group B rats on day 21.

In conclusion, the use of TACE combined with LITT, compared with the use of TACE or LITT alone, results in a significant reduction in the volume of liver metastases in WAG rats. These results suggest that this combined interventional therapy merits further clinical investigations with patients who have unresectable liver metastases. Details regarding the underlying therapeutic mechanisms, therapeutic indications, required monitoring, and validation of these combined therapies remain unclear and warrant more clinical studies, as well as randomized animal studies to support our theory.

Practical application: The presented results underline the importance of using a combined, minimally invasive approach to treat liver metastases. With use of TACE to downsize the tumor volume before performing thermoablation, an increased number of patients may become eligible for thermoablation. Prospective clinical studies to further investigate the effectiveness of this combined therapy should follow.


   FOOTNOTES
 

Abbreviations: LITT = laser-induced thermotherapy • TACE = transcatheter arterial chemoembolization

2 Current address: Department of Radiology, Xiehe Hospital, Huazhong University of Science and Technology, Wuhan, China Back

See also the Science to Practice in this issue.

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, T.J.V.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, A.M., J.Q.; experimental studies, A.M., J.Q., M.G.M., E.O., M.R., S.S., W.O.B., T.J.V.; statistical analysis, A.M., J.Q., M.R., S.S., T.J.V.; and manuscript editing, A.M., J.Q., M.G.M., M.F.K., W.O.B., T.J.V.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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S. O. Trerotola
Can Combination Therapy for Colorectal Liver Metastases Improve Results over Chemoembolization or Ablation Alone?
Radiology, November 1, 2005; 237(2): 381 - 382.
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