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Clinical Observations |
1 All authors: Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, 601 N Caroline St., Rm. 3235A, Baltimore, MD 21287.
Received April 25, 2007;
accepted after revision January 6, 2008.
M. Buijs and J. A. Vossen contributed equally to the manuscript.
Abstract
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CONCLUSION. In patients with ocular melanoma and liver metastasis treated with transarterial chemoembolization, functional MRI showed significant changes in the lesions. These changes included a decrease in tumor enhancement and an increase in the apparent diffusion coefficient of the tumor, suggesting increasing tumor necrosis and cell death.
Keywords: diffusion-weighted MRI • hepatic metastases • liver • metastatic ocular melanoma • perfusion MRI • transarterial chemoembolization • treatment response
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Various treatment techniques exist for patients with metastatic ocular melanoma, including surgical resection, systemic chemotherapy, and locoregional therapy [7, 8]. Monitoring the effectiveness of transarterial chemoembolization (TACE), a locoregional therapy, with imaging is important in determining treatment success and in guiding future therapy. However, imaging techniques and imaging response criteria have been limited in giving clinically satisfactory information about the extent of tumor necrosis.
The apparent diffusion coefficient (ADC) calculated in diffusion-weighted MRI has become a promising biomarker of tumor response to therapy [9]. The ADC is a measure of the mobility of water in tissues. Viable tumors are high in cellularity, and the cells have an intact cell membrane that restricts the mobility of water molecules and results in a relatively low ADC. Conversely, cellular necrosis increases membrane permeability, allowing water molecules to move freely and causing a relative increase in ADC. Diffusion-weighted MRI has been used to assess tumor response after chemotherapy and radiation therapy.
The primary application of diffusion-weighted MRI has been in brain imaging [10–12]. In the liver, diffusion-weighted imaging has been used to characterize focal hepatic lesions and to assess tumor response to locoregional therapy [13, 14]. We hypothesize that diffusion-weighted MRI can be added to contrast-enhanced MRI to determine the presence of cellular necrosis and therefore be useful in obtaining information about tumor response to TACE. To our knowledge, the use of diffusion-weighted imaging in the follow-up of metastatic ocular melanoma has not been described. The purpose of our study was to assess the value of diffusion-weighted MRI in the evaluation of tumor response to TACE for metastatic ocular melanoma.
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Chemoembolization Technique
All chemoembolization procedures were performed by one experienced
interventional radiologist using the same technique in all pro cedures. A
5.0-French micropuncture intro ducer set was used to access the right common
femoral artery with the Seldinger technique. After a 0.035-inch Bentson
guidewire was advanced into the abdo minal aorta, the needle was exchanged for
a 5-French vascular sheath, which was placed into the right common femoral
artery under fluoro scopic guidance. Through the sheath, a 5-French catheter
(Glidecath Simmons-1, Terumo) was advanced into the aorta and reformed in the
aortic arch. Selective angiography of the celiac axis was performed. The
catheter was advanced into the hepatic artery branch indicated by the tumor
location. If selective catheterization was necessary, a 3-French catheter
(Renegade Hi-Flow, Boston Scientific) was used.
Once the appropriate catheter (5-French Sim mons 1, 3-French microcatheter, or other selected catheter) was in position, TACE was performed through the catheter to achieve lobar or segmental embolization according to the target lesions. A solution containing 100 mg of cisplatin (Platinol, Bristol-Myers Squibb), 50 mg of doxorubicin (Adriamycin, Pharmacia-Upjohn), and 10 mg of mitomycin C (Mutamycin C, Bedford Laboratories) in a 1:1 mixture with iodized oil followed by infusion of 300- to 500-µm embolic microspheres (Embo sphere, Biosphere Medical) was admin istered until stasis was achieved.
CT Technique
Within 1 day after chemoembolization, all patients underwent unenhanced
helical CT (Sens ation 16 scanner, Siemens Medical Solu tions). The scanning
parameters were 120 kVp, 210 mA, 5-mm section collimation, and 5-mm image
reconstruction. Technical success of the procedure was confirmed with focal
deposition of iodized oil in the targeted segment or lobe of the liver.
MRI Technique
A 1.5-T MRI unit (CV/i, GE Healthcare) and phased-array torso coil were
used. The imaging protocol consisted of T2-weighted fast spin-echo images
(TR/TE, 5,000/100; matrix size, 256 x 256; slice thickness, 8 mm;
interslice gap, 2 mm; receiver bandwidth, 32 kHz), breath-hold
diffusion-weighted echo-planar images (5,000–6,500/110; matrix size, 128
x 128; slice thickness, 8 mm; interslice gap, 2 mm; b value, 500;
receiver bandwidth, 32 kHz) along the section-select gradient
(z-axis), and breath-hold unenhanced and contrast-enhanced (0.1
mmol/kg IV gadodiamide, Omniscan, GE Healthcare) T1-weighted 3D fat-suppressed
spoiled gradient-echo images (5.1/1.2; field of view, 320–400 mm; matrix
size, 192 x 160; slice thickness, 4–6 mm; receiver bandwidth, 64
kHz; flip angle, 15°) in the arterial phase (20 seconds) and portal venous
phase (60 seconds). Typical acquisition time was a single breath-hold of 30
seconds to cover the entire liver.
Follow-Up
According to protocol, patients underwent contrast-enhanced and
diffusion-weighted MRI 4–6 weeks after TACE for assessment of tumor
response. Patients with near complete tumor necrosis determined by lack of
enhancement on MRI and an increase in ADC of the lesion did not undergo
additional treatments and underwent follow-up imaging every 6–8 weeks.
Patients with residual enhancement whose clinical perform ance status was
maintained underwent additional TACE treatments.
Image Analysis
MR image processing and ADC maps were generated with a commercially
available workstation (Advantage Windows, GE Health care). Images were
interpreted by consensus of two experienced MRI radiologists in the same
session. Parameters evaluated included change in tumor size, enhancement, and
ADC. For patients who under went more than one TACE cycle, the MR images
obtained after the last cycle were used for comparison.
All target lesions 2 cm or larger in the treated lobe were evaluated; a maximum of four lesions per patient were used to ensure independent sampling. The target lesions were selected by consensus of two radiologists. Target lesions in the treated lobe of the liver were selected. The maximum diameter of the targeted lesions was measured with electronic calipers as proposed in the Response Evaluation Criteria in Solid Tumors (RECIST). Areas of tumor enhancement were considered viable, and areas without enhancement were considered necrotic, as suggested by the European Association for the Study of the Liver [15]. Percentage enhancement was based on enhancement seen on the axial arterial and portal venous phase MR images with the largest tumor size. Complete absence of enhancement was reported as 0%. Enhancement was reported as 25% if there was 25% or less enhancement, 50% if more than 25% and up to 50% enhancement, 75% if more than 50% and up to 75% enhancement, and 100% if greater than 75% enhancement was present.
In cases of lesions that had higher signal intensity than the surrounding liver parenchyma on unenhanced T1-weighted images, subtraction was performed to assess for enhancement. ADC maps were generated from the diffusion-weighted images side by side with the gadolinium-enhanced images, and mean values were recorded by placement of a region of interest (ROI) over the entire treated mass seen on the image with the largest lesion size. ROIs placed on the diffusion-weighted images were automatically generated in the same location on the images with ADC maps. ADC maps of normal-appearing liver, spleen, and par aspinal muscle were generated. Percentage iodized oil deposition on CT was recorded and reported as 25% if 25% or less of the tumor exhibited iodized oil uptake, 50% if more than 25% and up to 50% of the tumor exhibited uptake, 75% if more than 50% and up to 75% of the tumor exhibited uptake, and 100% if 75% or more of the tumor exhibited uptake. For patients who had undergone multiple iodized oil treatments, the mean maximum iodized oil retention in the targeted lesion was recorded.
Statistical Analysis
Statistical analysis was performed with the Stata software package (version
8, Stata). A paired Student's t test was used to compare tumor sizes,
degrees of enhancement, and ADCs before and after TACE to evaluate tumor
response. A paired Student's t test also was used to compare ADCs of
liver, spleen, and muscle before and after treatment. A value of p
< 0.05 was considered to indicate statistical significance.
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Several imaging techniques are used in traditional assessment of tumor response. One of the RECIST is change in tumor size on CT or MRI. Patients who have complete disappearance of all disease are considered responders. Partial response requires a greater than 30% decrease in tumor size. After TACE, however, many lesions do not initially decrease in size. To address this issue, the European Association for the Study of the Liver has officially recommended the use of lesion enhancement on contrast-enhanced CT as the standard factor for determining treatment response after locoregional therapy [15]. Enhanced portions of the tumor are presumed to be viable, whereas unenhanced portions are presumed necrotic. However, accumulation of iodized oil after TACE limits the use of enhancement on contrast-enhanced CT. At our institution we therefore use contrast-enhanced MRI to evaluate enhancement after TACE.
Our data showed that none of the treated lesions was considered a complete responder on the basis of RECIST. Therefore, our results suggest that the RECIST are not useful in determining early tumor response after TACE. Contrast-enhanced MRI depicts areas of tumor enhancement with extracellular contrast agents. Hepatic metastatic lesions of ocular melanoma, however, are already hyperintense on T1-weighted images, and this factor may interfere with accurate determination of contrast enhancement on nonsubtracted images. In this study we saw a significant decrease in enhancement after TACE, indicating that tumor enhancement can be used as a predictor of tumor response.
The mobility of water molecules in tissues is represented by the ADC on diffusion-weighted MRI. This value provides insight into tumor microstructure. Viable tumors contain cells with an intact cell membrane that restricts water mobility and causes low ADCs. Conversely, cellular necrosis increases membrane permeability, which increases the ADC. These characteristics are used to detect cellular necrosis before size regression occurs [17]. Our study showed a significant increase in ADCs of the lesions after treatment, indicating marked cellular necrosis in response to therapy. The ADCs of normal liver tissue, spleen, and muscle showed no significant changes after treatment.
This study had several limitations. First, the patient population was relatively small, so further studies with a larger sample size are needed to confirm our conclusions and to stratify patients into responders and nonresponders. The objective would be to establish a cutoff value between the two groups. A second limitation was possible selection bias, because only patients who underwent MRI before and after treatment were included in the study. Another limitation was the lack of histopathologic correlation of the lesions after chemoembolization. For ethical reasons, we did not obtain histologic correlation in this study. In addition, we could not confirm that the changes in ADC were due only to cellular necrosis and not to oil deposition within the tumor. Our results, however, are in line with those of a previous evaluation of the use of diffusion-weighted imaging after 90Y-microsphere treatment without oil deposition [18]. Changes in ADC occurred only in the targeted tumors, whereas the nontargeted tumors in the contralateral lobe of the liver had no change in ADCs. Therefore, we believe that these changes are due to cellular necrosis resulting from the targeted therapy. Last, we did not perform a reproducibility analysis of our imaging sequence because it was not one of the study objectives. However, our results are in line with those of a previous work [19] that showed an increase in ADC values after locoregional therapy.
Our results indicate that diffusion-weighted MRI can be useful for assessing tumor response after TACE in patients with metastatic ocular melanoma.
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  B. Taouli and D.-M. Koh Diffusion-weighted MR Imaging of the Liver Radiology, January 1, 2010; 254(1): 47 - 66. [Abstract] [Full Text] [PDF]
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