Comparison of Liver Tumor Motion With and Without Abdominal Compression Using Cine-Magnetic Resonance Imaging

Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 2, pp. 602–608, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter

doi:10.1016/j.ijrobp.2010.04.028

PHYSICS CONTRIBUTION

COMPARISON OF LIVER TUMOR MOTION WITH AND WITHOUT ABDOMINAL COMPRESSION USING CINE-MAGNETIC RESONANCE IMAGING CYNTHIA L. ECCLES, B.SC.,* RITESH PATEL, B.SC.,y ANNA K. SIMEONOV, M.SC.,* GINA LOCKWOOD, M.MATH.,z MASOOM HAIDER, M.D.,x AND LAURA A. DAWSON, M.D.* *Radiation Medicine Program, Princess Margaret Hospital, University of Toronto Faculty of Medicine, yInstitute of Biomaterials and Biomedical Engineering, University of Toronto, zDepartment of Biostatistics, University Health Network, and xJoint Department of Medical Imaging, Mount Sinai Hospital and University Health Network, University of Toronto Faculty of Medicine, Toronto, ON, Canada Purpose: Abdominal compression (AC) can be used to reduce respiratory liver motion in patients undergoing liver stereotactic body radiotherapy. The purpose of the present study was to measure the changes in three-dimensional liver tumor motion with and without compression using cine-magnetic resonance imaging. Patients and Methods: A total of 60 patients treated as a part of an institutional research ethics board-approved liver stereotactic body radiotherapy protocol underwent cine T2-weighted magnetic resonance imaging through the tumor centroid in the coronal and sagittal planes. A total of 240 cine-magnetic resonance imaging sequences acquired at one to three images each second for 30–60 s were evaluated using an in-house–developed template matching tool (based on the coefficient correlation) to measure the magnitude of the tumor motion. The average tumor edge displacements were used to determine the magnitude of changes in the caudal–cranial (CC) and anteroposterior (AP) directions, with and without AC. Results: The mean tumor motion without AC of 11.7 mm (range, 4.8–23.3) in the CC direction was reduced to 9.4 mm (range, 1.6–23.4) with AC. The tumor motion was reduced in both directions (CC and AP) in 52% of the patients and in a single direction (CC or AP) in 90% of the patients. The mean decrease in tumor motion with AC was 2.3 and 0.6 mm in the CC and AP direction, respectively. Increased motion occurred in one or more directions in 28% of patients. Clinically significant (>3 mm) decreases were observed in 40% and increases in <2% of patients in the CC direction. Conclusion: AC can significantly reduce three-dimensional liver tumor motion in most patients, although the magnitude of the reduction was smaller than previously reported. Ó 2011 Elsevier Inc. Liver radiotherapy, Abdominal compression, Liver motion, Cine-magnetic resonance imaging, Liver tumor motion.

INTRODUCTION

Liver and liver tumor motion are primarily related to breathing, which results in the greatest movement in the caudal-cranial (CC) direction, with a range of 5–50 mm (11–13). Its adverse effects on radiotherapy (RT) planning and performance include the introduction of artifacts on the planning computed tomography (CT) scans, leading to inaccurate tumor and normal tissue volume delineation (14–16), altered dosimetry using a static plan (17), an increased volume of normal tissue exposed (17), an increased required planning target volume (PTV) (18), and a greater risk of toxicity. Various methods have been used to account for respiratory tumor motion during SBRT, including active breathing

Stereotactic body radiotherapy (SBRT) for patients with unresectable primary and metastatic liver cancer has shown high rates of local control (1–10). The accuracy required for safe, daily SBRT to the liver is achieved by ensuring reliable and reproducible patient positioning and using accurate planning and treatment correlation, image guidance, and a method of accounting for tumor and organ motion during treatment. Because of the high dose per fraction used with SBRT, one of the most significant challenges to achieving safe, accurate treatment is defining and limiting the tumor motion during treatment.

Reprint requests to: Laura A. Dawson, M.D., Princess Margaret Hospital, 610 University Ave., Toronto, ON M5G 2M9 Canada. Tel: (416) 946-2124; Fax: (416) 946-6566; E-mail: laura.dawson@ rmp.uhn.on.ca Presented in part at the American Society for Therapeutic Radiology and Oncology 50th Annual Scientific Meeting, Boston, MA, October 2008.

Patients included in the present study were treated using research protocols funded in part by Elekta Oncology Systems and the National Cancer Institute of Canada (Grant 018207; primary investigator, L. A. Dawson). Conflict of interest: none. Received Jan 19, 2010, and in revised form April 18, 2010. Accepted for publication April 20, 2010. 602

MRI liver compression d C. L. ECCLES et al.

control, gating, antianxiety medications, and abdominal compression (AC) (17, 19–31). For patients receiving a hypofractionated SBRT liver protocol, active breathing control breath holding is the preferred method of respiratory liver motion management. However, as previously described, not all patients eligible for liver SBRT are suitable for assisted breath holding (27, 32). Thus, an alternate method of motion reduction must be considered to keep the PTV to a minimum and ensure maximal avoidance of the normal tissues. AC has been widely used to minimize respiratory-associated tumor movement during SBRT to the lung and liver (33, 34). Most published data have reported on the use of anterior (AP) kilovoltage fluoroscopy, fourdimensional CT, or cine-magnetic resonance imaging (MRI) to evaluate the liver or diaphragm motion during AC (5, 34, 35) as a surrogate for liver tumor motion. Changes in liver tumor motion with and without AC have not been previously described. The purpose of the present study was to measure the changes in liver tumor breathing motion with and without AC, using cine-MRI. PATIENTS AND METHODS Patients The patients evaluated in the present study had undergone treatment planning on an institutionally approved, Phase I-II liver SBRT protocol. The inclusion criteria included unresectable liver cancer, Child-Pugh A liver score, >800 cm3 uninvolved liver, and no contraindications to MRI. The exclusion criteria for the use of AC included ascites and the presence of a colostomy tube. All patients underwent cine-MRI with and without AC. Some of the patients also underwent fluoroscopy with and without AC, and those who subsequently were treated with AC also underwent respiratorycorrelated cone-beam CT scans with AC so that the liver motion could be compared between the planning and treatment scans and the CT and MRI scans.

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of one to three images each second for 30–60 s. As described by Kirilova et al. (36), if the frequency of imaging appeared to be in phase with the respiratory frequency, a short pause (0.5 s) was introduced to ensure a noticeable phase difference and to ensure the maximal excursion was measured. The slices were selected such that the largest dimension of the tumor was seen, in addition to the dome of the diaphragm. Slice selection was confirmed by visual comparison with a recent contrast-enhanced diagnostic CT data set and/or contrast-enhanced MRI scan. The reproducibility of patient position with and without AC was maximized by imaging patients in a single session. Patients were imaged in free breathing with no AC (FB), followed immediately by AC applied during a single imaging session, using the same imaging parameters for FB and AC imaging.

Abdominal compression Abdominal compression was performed using an in-house–developed MRI-compatible compression device (Fig. 1) that consisted of an evacuated cushion that sat inside a wooden, indexed frame with a compression plate secured by an adjustable screw to an arced support. Patients underwent imaging in the axial, coronal, and sagittal planes, first in FB without AC, followed by imaging with AC (Fig. 2).

Region of interest selection Regions of interest (ROIs) at the superior, inferior, right, left, anterior, and posterior tumor edges on the coronal and sagittal images were selected for motion evaluation whenever possible (Fig. 3). Some ROIs were not usable owing to the presence of artifact or an inability to clearly identify the tumor edges because of a lack of contrast between the tumor and normal liver. If feasible, tumor surrogates, such as a blood vessel at or near the tumor edge, were used in patients for whom the tumor edges were not visible on all

RT planning All patients were treated using an institutionally approved individualized isotoxicity liver SBRT study, as previously described (35). Individualized PTV margins were generated, and the prescription doses were determined according to the amount of normal liver irradiated. Thus, respiratory motion management strategies were evaluated for all patients at treatment planning; all patients with respiratory motion >5 mm were considered for active breath control breath holding or AC.

Magnetic resonance imaging All patients underwent cine-MRI to evaluate the liver tumor motion with and without AC. As previously described (36), the patients underwent MRI on a flat table top or evacuated cushion and inhouse–developed compression device with their arms extended above their head .The imaging sequences varied slightly over time because of machine upgrades but, in general, were as follows: a single 5–10-mm slab was acquired in the axial, sagittal, and coronal planes on a 1.5T GE Signa Twin Speed Magnet (Milwaukee, WI), using a four- or eight-channel phased-array TORSO coil and a two-dimensional Fiesta T2-weighted single shot fast spin echo with an echo time of 90 ms, repetition time of 1,300 ms, field of view of 32–48 cm, matrix of 256  192, and temporal resolution

Fig. 1. Patient under abdominal compression, with in-house indexed frame demonstrating plastic compression plate and adjustable screw.

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Fig. 2. Sagittal views of patient with (Right) and without (Left) compression.

slices. When the tumors were small, a single ROI was selected that encompassed the tumor.

Statistical analysis The liver tumor motion on MRI was measured using Motion Track, an in-house–developed template matching tool based on the coefficient correlations (37, 38). The images were exported to a Digital Imaging and Communications in Medicine (DICOM) server and imported into Motion Track, where ROIs were selected on the first temporal image, as described in the previous section. The displacements across each image relative to the exhale position were quantified using the previously validated supervised automated tracking software (38). Software accuracy was confirmed by calculating the intraobserver variability using repeated measurements from a sampling of 10 patients included in the present analysis. The motion measurement ranges were recorded using frame-byframe displacements for up to four ROIs per image (maximum of six ROIs/tumor) in the coronal and sagittal planes, for both the compressed and noncompressed scenarios. The four ROIs were selected at each of the tumor edges whenever possible. The selection of these points was hindered by artifacts, lack of tumor visibility (due to reduced T2-weighted), nonrespiratory motion (e.g., cardiac), or the inability of the software to track the marker accurately. The medial–lateral motion was not included in the present analysis, because it is the smallest source of breathing motion, and the potential for in and out of axial plane effects created by motion in the CC and AP directions for motion were estimated to be possibly greater than the actual medial–lateral motion. The range of tumor motion was determined as the 95th percentile minus the 5th percentile. To determine the change in tumor motion from FB to AC, the AC range of motion was subtracted from the FB range of motion, with a negative result indicating an increase in motion with AC and a positive result indicating a decrease in motion with AC. Statistical analysis was performed using the Statistical Package for Social Sciences software, version 16 (SPSS, an IBM Company, Chicago, IL) using descriptive statistics and Pearson correlations. Clinically significant changes in motion were defined as $3 mm, because this was the threshold for repositioning using imageguided RT.

RESULTS A total of 60 evaluable patients, accrued between March 2004 and April 2007, underwent cine-MRI with and without AC for tumor motion analysis. Of the 60 patients, 32 were men and 28 were women, with a median age of 64.2 years (range, 30–85). The patients had unrescectable hepatocellular carcinoma (n = 24), cholangiocarcinoma (n = 6), or metastatic liver cancer (n = 30). A total of 219 ROIs were evaluated. Of the 60 patients, 51 had evaluable ROIs on both the coronal and the sagittal image sets. Because of the reduction in T2-weighting to achieve satisfactory temporal resolution, the tumor edges were not well visualized in at least one plane

Fig. 3. Region of interest (ROI) selection on sagittal and coronal images.

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Table 1. Average, minimum, maximum, and standard deviations of liver tumor motion by region of interest with and without abdominal compression on coronal and sagittal images CC motion (mm) Coronal images ROI No AC Average Minimum Maximum SD AC Average Minimum Maximum SD

AP motion (mm) All planes

Sagittal images

Sagittal images

Superior

Inferior

Average

Superior

Inferior

Average

CC average

Anterior

Posterior

Average

11.5 0 26.3 5.1

10.9 3.1 19.6 4.3

11.3 0 26.3 5.0

12.3 4.8 23.7 5.0

11.1 5.2 23.4 4.4

12.2 5.8 23.7 4.9

11.6 0 23.3 4.5

5.1 1.3 10.4 2.6

5.8 1.5 15.5 3.3

5.6 1.5 15.5 3.1

9.2 1.2 28.1 48

8.5 3.0 16.2 3.8

9.0 1.2 28.1 4.7

10.2 2.4 28.9 5.2

8.6 3.6 21.9 3.6

9.7 3.6 28.9 4.7

9.4 1.6 23.4 4.3

4.1 0 9.7 2.1

5.3 1.3 19.3 3.8

4.9 0 19.3 3.6

Abbreviations: ROI = range of motion; CC = cranial-caudal; AP = anteroposterior; AC = abdominal compression; SD = standard deviation.

reduced. Of the 60 patients, 47% had a decrease in motion by $3 mm and 8% had an increase by $3 mm in at least one plane. In the CC direction, 40% of patients had a >3 mm decrease with AC and <2% had a >3 mm increase. In the AP direction, 21% of patients demonstrated a >3 mm decrease in respiratory motion with AC and 10% had a >3 mm increase. Figure 5 shows a plot of the changes in tumor motion in the CC and AP directions with and without AC for all patients. For patients in whom increased motion was seen with AC, the increases occurred more frequently in the AP direction (n = 16) than in the CC direction (n = 11). Tumors with greater AP motion with AC tended to be located mid-line in the AP direction and in the mid to right lobe of the liver. A location in the superoinferior direction varied. The data in Fig. 6 demonstrate the per patient change in tumor motion in the CC and AP direction, respectively.

Motion (mm)

25

Change in motion (mm)

for 9 patients, for whom the analysis was performed on either the sagittal or coronal images alone. The axial views were not included in the present analysis, because it was determined that the in- and out-of-plane effects of the large caudal cranial respiratory motion were as great as, if not greater than, the tumor motion in the right–left and AP directions in this plane. The intraobserver variability for the present study was in keeping with previously published results (38). The population tumor motion was evaluated in the sagittal and coronal planes by tracking the change in motion with breathing of each tumor edge for each ROI and averaging the range of motion amplitude in the CC and AP directions. The average range was determined for all ROI ranges for each patient, with the range determined as the 95th percentile minus the 5th percentile of tumor motion for each ROI for each patient (Table 1). Overall, the mean motion without compression was 11.7 mm (range, 4.8–23.3) and 5.6 mm (range, 1.5–15.5) in the CC and AP directions, respectively, for all patients evaluated. With compression, the mean motion was reduced to 9.4 mm (range, 1.6–23.4) and 5.0 mm (range, 0–19.3) in the CC and AP directions, respectively. The change in population tumor motion was calculated using the change for each ROI, by determining the per patient mean for the AP and CC directions and averaging for all the patients. Overall, the mean change in tumor motion with AC was a reduction of 2.4 mm in the CC direction and 0.6 mm in the AP direction. Of the 60 patients, 90% showed a decrease in tumor motion in at least one direction and 52% did so in both directions. For the patients with a decrease in motion with AC, the mean decrease in tumor respiratory motion was 3.3 mm in the CC direction and 1.9 mm in the AP direction. Also, 28% of patients had an increase in motion in at least one direction and 9% in both. For patients with an increase in motion with AC, the mean increases were small (1.3 and 2.1 mm in the CC and AP directions, respectively; Fig. 4). Using our image-guided RT on-line guidance threshold of 3 mm as an indicator of ‘‘clinically significant change’’ in motion with AC, the benefits of AC were substantially

FB AC ALL INC DEC

20 15 10 5 0 8

FB

AC

FB

Free Breathing Abdominal Compression All Patients Patients with Increase Patients with Decrease Anterior- Posterior Caudal -Cranial

AC

6 4 2 0 -2 -4 -6 -8

ALL n=60

DEC INC n=47 n=11

ALL n=50

DEC n=29

INC n=16

Fig. 4. Box plots showing first to third quartiles of liver tumor motion in caudal-cranial (CC) and anteroposterior (AP) directions (Top) and changes in motion in CC and AP directions (Bottom), with and without abdominal compression (AC) for all patients and for patients demonstrating increased or decreased motion. Whiskers represent 90th percentiles of motion and change in mean motion, respectively.

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Motion with and without Compression 25

C Compression n

20

15

10

5 CC Motion (mm) AP Motion (mm)

0

0

5

10

15

20

25

No Compression

Fig. 5. Scatter plot of caudal-cranial (CC) and anteroposterior (AP) tumor breathing motion with and without abdominal compression.

DISCUSSION T2-weighted cine-MRI was successfully used to evaluate the liver tumor motion with satisfactory temporal resolution in single or multiple imaging planes in 60 and 51 patients, respectively. A minimum of one and a maximum of four tumor edges were clearly visible in each plane. The results of the present study have confirmed that AC reduces respiratory liver tumor motion in the CC and AP directions in most patients evaluated using cine-MRI. However, in some patients, no significant change in respiratory motion or increased motion was observed with AC in one or more directions. The reductions in motion were clinically significant ($3 mm) in only 47% of the patients studied. Cine-MRI analysis of the liver tumor motion with AC confirmed the findings previously describing liver respiratory motion with AC evaluated using fluoroscopy, both in published studies and in a subset of 27 patients from the present study (data not included in the present report). However, the magnitude of liver tumor respiratory motion reduction using AC reported in the present study was less than that others have reported (33, 39, 40).

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To our knowledge, this is the first report comparing liver tumor motion with and without AC, using MRI. The strengths of the present study include the large patient numbers; the attempt to evaluate the tumor edge motion instead of simply averaging the whole tumor or liver motion; the use of multiple planes to evaluate the motion in more than one direction; the use of a previously validated automated motion analysis tool (37, 38); and the ability to perform imaging with and without AC in a single imaging session. The novelty of the present study was that it has demonstrated that AC might not be appropriate for all patients, because it failed to reduce the respiratory motion in some patients and increased the motion in a few patients in one or more directions. Clinically significant increases in motion were rare (<8% of patients). The basis for the increases in motion are unclear. One hypothesis is that with the application of AC, patients become more conscious of their respiration and this could have inadvertently caused breathing to become more forced. Previously, investigators have reported on liver motion with and without AC (33, 39) but were unable to describe the tumor motion. Another limitation of these studies was the limited patient numbers. Heinzerling et al. (34) investigated liver motion with varying levels of AC in 10 patients and Wunderink et al. (39, 40) used four-dimensional CT to evaluate liver motion with AC in 12 patients. The ability to reduce respiratory liver motion to #0.5 cm for liver SBRT using AC has been reported by Schefter et al. (5) and others (34, 41, 42), but no report has yet been published on the tumor motion or the comparison of FB liver respiratory motion to respiratory motion with AC. Kirilova et al. (36) reported on the CC motion of liver tumors using cine-MRI and compared this liver tumor motion to respiratory liver motion using fluoroscopy. They concluded that the diaphragm is not always a suitable surrogate for liver tumor motion (36). Recent studies and the present study included the evaluation of interfraction liver motion reproducibility under AC using respiratory-correlated conebeam CT (43, 44) and cine-MRI (45) and the evaluation of interfraction liver shape variability under AC using

Fig. 6. Scatter plots of per patient liver tumor motion with abdominal compression (AC) and without abdominal compression (free breathing [FB]) in (a) caudal-cranial (CC) and (b) anteroposterior direction.

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respiratory-correlated cone-beam CT (46). Future work will include the reproducibility of liver tumor motion during AC. The limitations of the present study included the reduction in T2-weighting to achieve satisfactory temporal resolution, which resulted in poor tumor to liver contrast; the inability to analyze the medial–lateral tumor motion because of in- and out-of-plane effects; and the lack of volumetric information for full three-dimensional tumor motion analysis with and without AC. The magnitude of tumor motion is only a part of the liver tumor motion, and true volumetric information, in particular with contrast enhancement, might provide information regarding tumor hysteresis and allow for more accurate margin generation. What is determined as clinically significant motion reductions will take into consideration PTV margins and image guidance strategies among other factors relating to the protocol to be followed by each RT center for each patient population. By reducing the T2-weighted relaxation time to achieve suitable temporal resolution, the T2-weighting of the image would be reduced and hence the ability to distinguish tumor from normal liver would be diminished, limiting the tumor edge definition. Thus, we were unable to evaluate all points for all patients. The tumor edges were assessed as not well vi-

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sualized if the observer (and LAD an experienced physician) had difficulty choosing the ROI over an edge. This ‘‘difficult edge assessment’’ was confirmed, because the automated tracking failed to work if inadequate contrast was present within the ROI. Additionally, because motion occurs in multiple planes at any point, with CC motion the greatest contributor, the in- and out-of-plane effects limited the ability to accurately measure small motions such as those in the right and left (or medial–lateral directions). Although tumor motion was evaluated on multiple imaging planes, a single slice of two-dimensional information was used and might only be suggestive of the true three-dimensional motion of liver tumors with and without AC. We have previously reported on liver tumor motion using cine-MRI with similar limitations. Volumetric intra- and interfraction liver tumor measurement is required to validate the present results. Abdominal compression reduces three-dimensional liver tumor motion in most patients; however, the magnitude of motion reduction is patient specific and, overall, smaller than suggested by results from previous kilovoltage fluoroscopy (<50% of patients had reductions in motion of $3 mm). Owing to the large patient to patient variability in the magnitude of motion reduction, individualized patient screening for AC is recommended.

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