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DOI: 10.1148/radiol.2371040526
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(Radiology 2005;237:144-150.)
© RSNA, 2005

Experimental Studies

Functional CT Quantification of Tumor Perfusion after Transhepatic Arterial Embolization in a Rat Model1

Zuxing Kan, MD, PhD, Satoshi Kobayashi, MD, Sith Phongkitkarun, MD and Chusilp Charnsangavej, MD

1 From the Division of Diagnostic Imaging, Department of Diagnostic Radiology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 57, Houston, TX 77030. From the 2002 RSNA Annual Meeting. Received March 24, 2004; revision requested June 2; final revision received October 21; accepted December 14. Supported by grant CA 90270 from the National Institute of Health, grant CA90810 from the National Cancer Institute, and an Institutional Research Grant (IRG-3721225) from the University of Texas M. D. Anderson Cancer Center. Address correspondence to Z.K. (e-mail: zkan{at}di.mdacc.tmc.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE:To quantify tumor perfusion after transcatheter arterial embolization (TAE) with functional computed tomography (CT) and to validate the reproducibility of quantification measurements.

MATERIALS AND METHODS:This study was conducted in accordance with an institutional animal care and use committee–approved protocol. Sixteen rats with liver tumors underwent TAE with 1 mg (group 1) or 3 mg (group 2) of polyvinyl alcohol particles. In each group, four rats underwent functional CT immediately after TAE (day 0) and four others underwent functional CT 2 days after TAE (day 2). Another four rats served as control rats. Blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability–surface area product were measured by using a functional CT software program. For evaluation of reproducibility, six additional rats with mammary tumors underwent functional CT twice, with examinations 2 hours apart. The mixed-effect model was used to assess the TAE treatment effect, and the Pearson correlation test was used to determine measurement reproducibility.

RESULTS:With the exception of BF in group 1 on day 2 (P = .41), BF and BV values in both groups on both days were significantly lower than BF and BV values in the control rats (with P values ranging from .018 to <.001). BF was significantly lower in group 2 than in group 1 on days 0 and 2 (P = .043 and P = .02, respectively). BV was significantly lower on day 2 than on day 0 in group 2 (P = .016). MTT was generally inversely related to BF. MTTs in group 2 on days 0 and 2 were significantly longer than those in the control rats (P < .001 and P = .03, respectively), and MTT was shorter on day 2 than on day 0 in group 2 (P = .02). Permeability–surface area product changes were similar to BF changes. There were no significant differences (P values ranged from .2 to .5) between perfusion parameters in the reproducibility study.

CONCLUSION:The results of this study validate the use of functional CT in the quantification of tumor perfusion after TAE and the reproducibility of such quantification measurements.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Hepatocellular carcinoma is the most common malignant tumor of the liver and is one of the most common tumors in the world, causing an estimated 1 million deaths per year (1,2). Transhepatic arterial embolization (TAE) is a treatment option for inoperable hepatocellular carcinoma and for other hypervascular metastatic hepatic tumors such as neuroendocrine tumors, carcinoid tumors, ocular melanomas, and even the hypovascular hepatic metastases of colorectal cancer (3–5). The use of TAE induces tumor necrosis, improves tumor resectability, reduces the likelihood of recurrence, and improves quality of life and survival time (3–8). Although the therapeutic outcome of TAE depends on the adequacy of the obstruction of tumor blood supply, an accurate measurement of tumor blood perfusion has never been available for the clinical practice of TAE, mainly because of the lack of an applicable technique. Almost 30 years after the introduction of TAE into clinical practice and worldwide use, basic TAE techniques—such as selection of the type and dosage of the embolic agent used, the timing and frequency of repeat TAE, and the criteria used to evaluate the procedure's sufficiency and its relationship with therapeutic results—continue to be subject to personal experience and based on inaccurate estimations of blood supply to the tumor calculated on the basis of results of arteriography, conventional computed tomography (CT), and magnetic resonance imaging. This lack of standardization has hindered efforts to improve techniques and maximize the therapeutic benefits of TAE. It has also been difficult to evaluate the efficacy of TAE as reported by different institutions, at which various techniques and estimation criteria have been used (9–11).

In recent years, functional CT has been developed to enable quantitative measurement of tissue perfusion, and its development has expanded CT from a purely anatomic imaging technique to a combined morphologic-physiologic technique (12). Because of its easy accessibility and simplicity, functional CT has been used in the early detection and staging of stroke and ischemic heart disease and in the monitoring of tumor antiangiogenic therapy (12,13). Functional CT has also shown potential in the early detection of hepatic tumors, cirrhosis, and other pathophysiologic conditions in various organs (12–17). Thus, the purpose of our study was to quantify tumor perfusion after TAE with functional CT and to validate the reproducibility of these quantification measurements.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Animal Model and TAE Procedure
Fischer 344 rats that ranged in weight from 150 to 200 g were obtained from Charles River Laboratories (Wilmington, Mass) and maintained in the animal care facility of the Department of Veterinary Medicine and Surgery at our institution. The rats were caged in groups of three and fed with standard rodent food and water ad libitum. Animal experiments were conducted in accordance with a protocol approved by the animal care and use committee of our institution.

FN13762 murine mammary cancer cells (18)—that is, 1 x 106 cells in 0.1 mL of phosphate-buffered saline solution—were injected into the mammary fat pad of one female Fischer 344 rat. When the tumor grew to approximately 10 mm in diameter, the animal was killed humanely by intravenous injection of a 100-mg-per-kilogram-of-body-weight overdose of pentobarbital (Nembutal; Abbott Laboratories, North Chicago, Ill), and the tumor was harvested for implantation into the livers of 20 rats. After intraperitoneal administration of 50 mg/kg of pentobarbital for anesthesia, an incision was made in the upper middle part of the abdomen of each rat; the middle hepatic lobe was exposed, and a small cut on the liver surface was made with a sharp scalpel. Fresh tumor tissue measuring 2 x 2 x 2 mm was embedded 5 mm deep in the liver parenchyma of each rat. The cut was then closed with pressure from a cotton-tipped applicator, and the abdomen was closed with sutures. Tumor inoculations were performed by one of the authors (S.K.).

TAE was performed 13 days after tumor inoculation, when the liver tumors were estimated to have grown to approximately 10 mm in diameter (according to the growth rate of the tumors inoculated into the mammary fat pad of the original female rat in this study). Each rat was anesthetized, a midline abdominal incision was made, and the gastroduodenal artery was exposed. Silastic tubing (SFM-10350; SF Medical, Hudson, Mass) was inserted in a retrograde position, with the tip placed distal to the opening of the proper hepatic artery. Each of the 20 rats with liver tumors was assigned randomly to one of three groups on the basis of the dose of the embolic agent injected into the hepatic artery: Group 1 (n = 8) received 1 mg of 50-µm polyvinyl alcohol (PVA) particles (PVA-50; Cook, Bloomington, Ind) suspended in 0.3 mL of saline; group 2 (n = 8), 3 mg of PVA suspended in 0.3 mL of saline; and group 3 (n = 4), which served as the control group, 0.3 mL of saline only. All TAE procedures were performed under a Stemi SV6 dissection microscope (Carl Zeiss; Thornwood, NY). To ensure that the embolic agent was delivered into the liver, the entire injection process was observed by using the microscope; the embolic particles in saline suspension were washed into the proper hepatic artery by the blood flow from the common hepatic artery. All TAE procedures were performed by one of the authors (Z.K.).

Functional CT Quantification of Tumor Perfusion
Four rats each in groups 1 and 2 were randomly chosen to undergo functional CT approximately 30 minutes after the completion of the TAE procedures (day 0); the remaining four rats in these groups underwent functional CT 2 days after TAE (day 2). Before functional CT scanning was performed, a cannula with a 0.3-mm inside diameter and a 0.5-mm outside diameter (Dow Corning, Midland, Mich) was inserted and secured in the jugular vein of each animal for contrast agent injection. Each animal was placed at the center of the CT scanner (Lightspeed; GE Medical Systems, Milwaukee, Wis) and underwent unenhanced scout scanning through the tumor for selection of the appropriate transverse level for the perfusion CT study. At the selected location of the tumor, four-section (section width, 1.25 mm) cine CT scanning was performed beginning 3 seconds before the intravenous bolus injection of 0.15 mL/kg of an iodinated contrast agent (Optiray 320; Mallinckrodt, St Louis, Mo) and continued for 50 seconds at a speed of 0.8 second per rotation; 62 images of each section were acquired. All images were acquired by using a 120-kVp tube voltage, an 80-mA tube current, and a 96-mm field of view. The CT scans were then reconstructed onto a 512 x 512 image matrix, with an improved temporal resolution of 0.4 second between images. All contrast agent injections were performed by one of the authors (S.P.).

Immediately after CT, the skin over the locations where the four transverse planes of the CT sections had been acquired was marked with ink before the animals were removed from the CT table. The animals were then killed humanely with an overdose of pentobarbital and the tumors were cut according to the marked planes of the CT scan. The location, shape, length (L), and width (W) of the tumor in the liver were measured. The areas of the tumors were calculated with the following formula: {pi}(L · W).

The reconstructed image data were then transferred to an imaging workstation (Advantage Windows; GE Medical Systems) for functional analysis with CT perfusion software (Perfusion 2; GE Medical Systems). Before measurement, the cine image of every functional CT study was reviewed to ensure the quality of the scan. Cine images with movement-caused imaging misregistration of greater than 30% were excluded from the data analysis. The cardiac function of the animals, which affects perfusion measurements, was evaluated (Z.K.) by calculating the time it took (from the start of the injection) for the contrast agent to reach the aorta and the time it took (from the start of the injection) for the contrast agent to reach peak enhancement in the aorta.

To quantify functional CT parameters, we first used cursors to indicate a 6-pixel region of interest within the aorta to determine the enhancement value of arterial input (12). We then drew regions of interest on raw CT images on which tumor nodules were delineated by contrast enhancement. To ensure the accuracy of the measurement, the region of interest was adjusted by comparing its location, shape, and dimensions with the location, shape, and dimensions of tumor specimens. To rule out the influence of large vessels on tumor measurement, we set the maximum level of blood flow (BF) in the calculated pixels to 100 mL per minute per 100 g of rat body weight. The functional CT perfusion parameters BF (in milliliters per minute per 100 g), blood volume (BV) (in milliliters per 100 g), mean transit time (MTT) (in seconds), and permeability–surface area product (in milliliters per minute per 100 g) were measured, and their parametric maps were generated by using the highest spatial resolution pixel-by-pixel calculation technique. Four-section images were obtained in each tumor so that we could calculate the mean values of the functional CT parameters. Two radiologists (S.K. and S.P.) performed the measurements independently, and interobserver variance was analyzed.

Functional CT Reproducibility Study
To evaluate the reproducibility of the functional CT measurements of tumor perfusion values, a separate experiment was designed. An additional six Fischer 344 rats had a tumor implanted in the mammary fat pad at the level of the xiphoid process. On day 13 after tumor inoculation, when the tumors were approximately 10 mm in diameter, all six rats underwent functional CT twice, with examinations performed 2 hours apart. The CT scanning protocol and the data acquisition and postprocessing analysis methods were the same as those previously described.

Statistical Analyses
The tumor perfusion values BF, BV, MTT, and permeability–surface area product were recorded as means ± standard deviations. Because of the unequal sample sizes in the experimental groups, the mixed-effect model (SAS 8.0; SAS, Cary, NC) was used to determine the effect of treatment on BF, BV, MTT, and permeability–surface area product values. A one-way analysis of variance was used for power analysis for each measurement outcome given two scenarios of sample size: 12 and 16 samples per subgroup (PASS 2000; NCSS, Kaysville, Utah). The average values of each perfusion parameter in each group were compared by using a mixed-effect model. The standard deviation was assumed to be equal across the groups. The two-tailed Student t test was used to compare the functional CT perfusion values measured in the repeat-examination reproducibility study. The McNemar test was used to compare the variances in the tumor perfusion values measured by two radiologists (S.K. and S.P.). A P value of less than .05 was considered to indicate a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Three rats were excluded from the data analysis: One rat in the control group was excluded because of failure of tumor growth, and two rats (one from group 1 on day 0 and one from group 2 on day 0) were excluded because of movement during CT scanning that caused imaging misregistration of more than 30%. In the remaining 17 rats, the mean tumor areas measured in tissue specimens were 69.3 mm2 ± 12.2 (standard deviation) on day 0 and 81.5 mm2 ± 17.3 on day 2 (P = .004). The mean tumor areas measured on functional CT images were 69.1 mm2 ± 11.6 on day 0 and 87.7 mm2 ± 19.7 on day 2 (P < .001). Significant correlations were observed between the tumor areas measured in tissue specimens and those measured on functional CT images on both day 0 (r = 0.60, P < .001) and day 2 (r = 0.71, P < .001) (Table 1). The mean time from the start of the bolus injection of the contrast agent to its arrival in the aorta was 1.8 seconds ± 0.3, and the mean time to peak enhancement was 3.1 seconds ± 0.4.


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  		TABLE 1. Tumor Areas Measured in Tissue Specimens versus Those Measured on Functional CT Images

 
Power analysis revealed that a sample size of 12 in each group could have achieved at least 77% power for detecting differences in BF, BV, and permeability–surface area product across five treatment subgroups at a significance level of .05. With 12 samples in each subgroup, there would be only 31% power for detecting differences in MTT.

The values of BF, BV, MTT, and permeability–surface area product in all groups are summarized in Table 2 and Figure 1. The mean BF in group 1 on day 0 and that in group 2 on both days 0 and 2 was significantly lower than the mean BF in the control group (P < .05 for all) (Table 2, Fig 2); however, the difference in mean BF value between group 1 and the control group on day 2 was not statistically significant (P = .41). The mean BF was significantly lower in group 2 than in group 1 on both days 0 and 2 (P = .043 and P = .02, respectively) (Table 2, Fig 3). The mean BF on day 2 in both groups 1 and 2 was not significantly different from the mean BF on day 0 (P = .076 and P = .11, respectively).


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  		TABLE 2. Functional CT Measurements of Perfusion Parameters in Both Groups of TAE-treated Rats and the Control Rats

 


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  		Figure 1a. Graphs depict differences in the following functional CT–measured perfusion parameters (y-axes) between the control group and the TAE-treated groups: (a) BF (in milliliters per minute per 100 g), (b) BV (in milliliters per 100 g), (c) MTT (in seconds), and (d) permeability–surface area product (in milliliters per minute per 100 g).

 


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  		Figure 1b. Graphs depict differences in the following functional CT–measured perfusion parameters (y-axes) between the control group and the TAE-treated groups: (a) BF (in milliliters per minute per 100 g), (b) BV (in milliliters per 100 g), (c) MTT (in seconds), and (d) permeability–surface area product (in milliliters per minute per 100 g).

 


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  		Figure 1c. Graphs depict differences in the following functional CT–measured perfusion parameters (y-axes) between the control group and the TAE-treated groups: (a) BF (in milliliters per minute per 100 g), (b) BV (in milliliters per 100 g), (c) MTT (in seconds), and (d) permeability–surface area product (in milliliters per minute per 100 g).

 


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  		Figure 1d. Graphs depict differences in the following functional CT–measured perfusion parameters (y-axes) between the control group and the TAE-treated groups: (a) BF (in milliliters per minute per 100 g), (b) BV (in milliliters per 100 g), (c) MTT (in seconds), and (d) permeability–surface area product (in milliliters per minute per 100 g).

 


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  		Figure 2a. Transverse functional CT map images obtained through the maximum diameter of a liver tumor in (a, b) a group 2 rat (which underwent TAE with 3 mg of PVA) and (c, d) a control rat (which underwent a sham TAE procedure performed without PVA) on day 0 show that (a, c) BF and (b, d) BV in the tumors (arrows) were markedly reduced immediately after TAE in the group 2 rat but not in the control rat. The color spectrum indicates the parameter value, ranging from high (red) to low (blue).

 


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  		Figure 2b. Transverse functional CT map images obtained through the maximum diameter of a liver tumor in (a, b) a group 2 rat (which underwent TAE with 3 mg of PVA) and (c, d) a control rat (which underwent a sham TAE procedure performed without PVA) on day 0 show that (a, c) BF and (b, d) BV in the tumors (arrows) were markedly reduced immediately after TAE in the group 2 rat but not in the control rat. The color spectrum indicates the parameter value, ranging from high (red) to low (blue).

 


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  		Figure 2c. Transverse functional CT map images obtained through the maximum diameter of a liver tumor in (a, b) a group 2 rat (which underwent TAE with 3 mg of PVA) and (c, d) a control rat (which underwent a sham TAE procedure performed without PVA) on day 0 show that (a, c) BF and (b, d) BV in the tumors (arrows) were markedly reduced immediately after TAE in the group 2 rat but not in the control rat. The color spectrum indicates the parameter value, ranging from high (red) to low (blue).

 


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  		Figure 2d. Transverse functional CT map images obtained through the maximum diameter of a liver tumor in (a, b) a group 2 rat (which underwent TAE with 3 mg of PVA) and (c, d) a control rat (which underwent a sham TAE procedure performed without PVA) on day 0 show that (a, c) BF and (b, d) BV in the tumors (arrows) were markedly reduced immediately after TAE in the group 2 rat but not in the control rat. The color spectrum indicates the parameter value, ranging from high (red) to low (blue).

 


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  		Figure 3a. Transverse functional CT map images of rat liver tumors (arrows) obtained 2 days after TAE in (a, b) a group 1 rat (which underwent TAE with 1 mg of PVA) and (c, d) a group 2 rat (which underwent TAE with 3 mg of PVA) show that (a, c) BF (arrowhead) and (b, d) BV (arrowhead) were substantially higher in the group 1 rat than in the group 2 rat. The color spectrum indicates the parameter value, ranging from high (red) to low (blue).

 


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  		Figure 3b. Transverse functional CT map images of rat liver tumors (arrows) obtained 2 days after TAE in (a, b) a group 1 rat (which underwent TAE with 1 mg of PVA) and (c, d) a group 2 rat (which underwent TAE with 3 mg of PVA) show that (a, c) BF (arrowhead) and (b, d) BV (arrowhead) were substantially higher in the group 1 rat than in the group 2 rat. The color spectrum indicates the parameter value, ranging from high (red) to low (blue).

 


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  		Figure 3c. Transverse functional CT map images of rat liver tumors (arrows) obtained 2 days after TAE in (a, b) a group 1 rat (which underwent TAE with 1 mg of PVA) and (c, d) a group 2 rat (which underwent TAE with 3 mg of PVA) show that (a, c) BF (arrowhead) and (b, d) BV (arrowhead) were substantially higher in the group 1 rat than in the group 2 rat. The color spectrum indicates the parameter value, ranging from high (red) to low (blue).

 


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  		Figure 3d. Transverse functional CT map images of rat liver tumors (arrows) obtained 2 days after TAE in (a, b) a group 1 rat (which underwent TAE with 1 mg of PVA) and (c, d) a group 2 rat (which underwent TAE with 3 mg of PVA) show that (a, c) BF (arrowhead) and (b, d) BV (arrowhead) were substantially higher in the group 1 rat than in the group 2 rat. The color spectrum indicates the parameter value, ranging from high (red) to low (blue).

 
The mean BV on days 0 and 2 in both groups 1 and 2 was significantly lower than the mean BV in the control group (P ≤ .001 for all four comparisons) (Table 2, Fig 2). The mean BV did not differ significantly between groups 1 and 2 on either day 0 or day 2 (P = .79 and P = .66, respectively). The mean BV on day 2 was not significantly different from that on day 0 in group 1 (P = .097) but was significantly lower on day 2 than on day 0 in group 2 (P = .016).

The MTT in group 1 on both days 0 and 2 did not differ significantly from the MTT in the control group (P = .68 and P = .17, respectively), but the MTT in group 2 on both days 0 and 2 was significantly longer than the MTT in the control group (P < .001 and P = .03, respectively). The MTT was significantly longer in group 2 than in group 1 on day 0 (P = .02) but was not significantly different on day 2 (P = .89). The MTT on day 2 was not significantly different from that on day 0 in group 1 (P = .89) but was significantly shorter on day 2 than on day 0 in group 2 (P = .02).

The mean permeability–surface area products in group 1 on days 0 and 2 and in group 2 on days 0 and 2 were significantly lower than those in the control group (P = .001, P < .001, P = .049, and P < .001, respectively). The permeability–surface area product on day 0 in group 2 was not significantly different from that in group 1 on day 0 (P = .81), but the permeability–surface area product on day 2 was significantly lower in group 2 than in group 1 (P = .038). The permeability–surface area product value on day 2 was significantly higher than that on day 0 in group 1 (P = .003) but not in group 2 (P = .064).

The values from the reproducibility study of tumor perfusion parameters measured at two functional CT examinations performed in the same tumors are shown in Table 3. The results indicated that there was no significant difference in any perfusion parameter measurement between the two examinations.


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  		TABLE 3. Results of Repeat-Examination Study of Reproducibility of Functional CT Perfusion Values

 
For the analysis of interobserver variance, McNemar testing revealed that the measurements of the two radiologists strongly agreed with each other (P > .99 for the measurement of BF, BV, and permeability–surface area product; and P = .81 for the measurement of MTT).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Normal liver obtains 70%–80% of its blood supply from the portal vein and the remaining 20%–30% from the hepatic artery. However, hepatic tumors receive blood supply predominantly (>90%) from the hepatic artery (19,20). The use of TAE obstructs arterial blood supply to hepatic tumors while preserving adequate blood perfusion from the portal vein to the normal liver. When chemotherapeutic drugs are added to TAE—a process known as transhepatic arterial chemoembolization—the drugs are delivered into the tumor at a high concentration, which results in prolonged drug retention by the tumor and reduced systemic toxicity (6). The therapeutic results of TAE and transhepatic arterial chemoembolization depend largely on the sufficiency of the blockade of the tumor's blood supply. An inadequate blockade has been described as the major reason that the treatment fails to yield survival benefits (21–23). Hence, assessment of the functional status of the tumor and the host liver—especially the condition of tumor blood perfusion—is of essential importance in the planning of TAE techniques and in the evaluation of their efficacy (24–26).

With the advent of high-speed CT technology, a rapid cine CT examination performed at a fixed location after bolus injection of an iodinated contrast agent can enable the generation of a time-attenuation curve. Analyzing the time-attenuation curve with appropriate kinetic modeling techniques enables the quantification of various parameters of tissue perfusion, such as BF, BV, MTT, and permeability–surface area product. On the basis of the linear relationship between the blood concentration of the contrast agent and the CT-measured attenuation value, functional CT enables one to calculate the absolute values of the perfusion parameters, allowing comparison of tumor perfusion between examinations, between patients, or even between different organs. Automated image analysis on a pixel-by-pixel basis yields parametric images (ie, functional maps) on which quantitative information about each of the perfusion parameters is displayed.

Several modeling methods have been developed for analyzing tissue perfusion according to the hemodynamic properties (especially the degree of leakage from the tissue vasculature) of the tissues examined. The software program used in the present study involved a deconvolution-based method that took into consideration the permeable nature of blood vessels such as those in tumors. The main advantage of this method is that it allowed measurements of four physiologic parameters (BF, BV, MTT, and permeability–surface area product) from a single CT study. This method of quantification is affected less by the contrast material volume, the rate of bolus injection, and the patient's cardiac output than other analytic methods are; this distinction is important, especially in small-animal studies in which only a small amount of contrast agent is injected (12,13,27–29). The deconvolution method requires a longer scanning time (>30 seconds) with shorter intervals (scanning time, 1 second; retrospectively reconstructed temporal interval, 0.5 second). This requirement is easily satisfied with the current "slip-ring" CT technique used in this study (scanning time, 50 seconds; scan interval, 0.8 second; reconstructed temporal resolution, 0.4 second). The accuracy and reproducibility of functional CT measurements have been validated with classic microsphere-output techniques in animal models and with xenon washout and positron emission tomography in human studies (30,31). Good reproducibility of functional CT measurements of tissue perfusion has also been demonstrated in interscan and interobserver repeatability studies (30,31).

In our study, we validated the reproducibility of measurements produced in a repeat-examination experiment and the interobserver variability of measurements of tumor perfusion parameters. There was no significant difference (P > .05) in the values of BF, BV, MTT, and permeability–surface area product measured at two CT examinations of the same tumor on the same day. Strong correlations were observed between the values measured by the two independent readers for all four perfusion parameters. Because cardiac function can affect measurement accuracy, the times it took for the contrast agent to reach the aorta from the injection site and to reach peak enhancement in the aorta were calculated, and a consistent circulation time between animals was shown. In addition, the original cine CT images were reviewed for every rat in this study, and this process helped ensure the quality and reliability of the measurements (29).

Our findings indicate that functional CT enables the detection and measurement of changes in tumor perfusion after TAE. Functional CT measurements revealed that BF and BV in tumors decreased significantly after TAE; the reductions in BF and BV were significantly greater in tumors treated with a high dose (3 mg, group 2) than in tumors treated with a low dose (1 mg, group 1) of PVA. Two days after TAE, functional CT measurements revealed reperfusion of the tumors, reflected by substantial increases in BF and BV, with the BF in rats that were treated with low doses of PVA recovering to levels similar to those observed in the control rats. Although the reduction in BF was significantly lower in the high-dose than in the low-dose group, there was no significant difference in the reduction in BV between the two groups. This finding may be explained by the fact that because the same-sized embolic particles occlude the same-sized vessels, more embolic particles accumulate in the proximal portions of the vessels. As a result, high doses of the embolic agent did not further reduce vascular space and BV but did reduce BF more than low doses of the embolic agent did.

Changes in MTT, a measurement of the mean time it takes for the blood to pass through the tumor vasculature, were generally inversely related to changes in BF and BV. The MTT increased because TAE resulted in obstruction of the tumor vessels and reduction of the BF. As compared with MTT values in the control group, the increases in MTT were significant in the high-dose PVA group but not in the low-dose group. The recovery of MTT 2 days after TAE was also significant in the high-dose group but not in the low-dose group.

Tumor growth and metastasis depend on angiogenesis (32). The high degree of permeability of the tumoral vasculature allows leakage of plasma proteins from the circulation to the extravascular stroma, an occurrence that facilitates the reconstruction of the tumor-tissue matrix and, consequently, the formation of new tumor vessels (33). Tumor angiogenesis is induced by hypoxia (34,35), and TAE-associated hypoxia will stimulate tumor angiogenesis and increase vascular permeability. The measurement of tumor permeability in TAE may thus be an important means of assessing the therapeutic effect and tumor angiogenic response—assessments that may help in the design of a novel antivascular therapy that combines TAE and antiangiogenic therapy (36). In our study, permeability–surface area products in the TAE-treated groups were lower than those in the control group. The changes in permeability–surface area products were similar to the changes in BF, suggesting that measurement of permeability with functional CT was substantially affected by the functional condition of tumor vessels. The permeability–surface area product in a vessel that was highly permeable but whose BF had been compromised by TAE was most likely underestimated. Other factors might also affect the measurement of permeability–surface area product; for example, the use of a low-molecular-weight CT contrast agent in this study might have resulted in an overestimation of the permeability–surface area products in the control tumors. In addition, 2 days might be too short a period for functional CT to reveal any difference. Our results suggest that functional CT measurement of vascular permeability remains a challenge not only in TAE studies but also in other tumor angiogenesis studies (31,37,38).

This study had potential limitations. First, our quantification of perfusion parameters relied only on the software and lacked validation with other techniques. Second, the accuracy of the perfusion measurements in a tumor might be affected by the way that the region of interest is drawn. In this experimental study, the tumor region of interest was drawn on the basis of CT enhancement and adjusted by consulting the location, shape, and size of the tumor specimen to ensure the accuracy of measurements. This method is not practical in a clinical setting. Further study is needed to define a method that best demarcates a tumor from normal tissue on either conventional CT or functional CT parameter images.

Practical application: The results of this study have shown that functional CT enables quantification of changes in tumor perfusion parameters after TAE. Our reproducibility studies have validated the consistency of functional CT measurements of tumor perfusion values. Precise quantification helps optimize TAE techniques, provides a more precise basis for evaluating therapeutic outcomes, and improves the beneficial effects of and patient survival after the procedure. Functional CT holds promise for use in not only TAE therapy but also other therapies in which tumor perfusion or microcirculation is involved.


   ACKNOWLEDGMENTS
 
The authors thank Ting Y. Lee, PhD, for his discussion of the study; Xian Zhou, MS, for statistical consultation of the data; Ella Anderson, RT, and Delise Herron, RT, for technical assistance; and Mariann Crapanzano, PhD, and Ellen McDonald, PhD, for editorial review.


   FOOTNOTES
 

Abbreviations: BF = blood flow • BV = blood volume • MTT = mean transit time • PVA = polyvinyl alcohol • TAE = transhepatic arterial embolization

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, Z.K.; study concepts and design, Z.K.; literature research, Z.K.; experimental studies, Z.K., S.K., S.P.; data acquisition, Z.K., S.K., S.P.; data analysis/interpretation, all authors; statistical analysis, Z.K., S.K., S.P.; manuscript preparation, definition of intellectual content, editing, and revision/review, Z.K.; manuscript final version approval, Z.K., C.C.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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