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Published online before print October 24, 2002, 10.1148/radiol.2253011854
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(Radiology 2002;225:766-772.)
© RSNA, 2002

Gastrointestinal Imaging

Detection of Liver Metastases: Comparison of Gadobenate Dimeglumine–enhanced and Ferumoxides-enhanced MR Imaging Examinations1

Chiara Del Frate, MD, Massimo Bazzocchi, MD, Koenraad J. Mortele, MD, Chiara Zuiani, MD, Viviana Londero, MD, Giuseppe Como, MD, Romeo Zanardi, MD and Pablo R. Ros, MD, MPH

1 From the Institute of Radiology, Udine University, Policlinico Universitario a Gestione diretta, via Colugna 50, 33100 Udine, Italy (C.D.F., M.B., C.Z., V.L., G.C., R.Z.); and Department of Radiology, Brigham and Women’s Hospital, Boston, Mass (K.J.M., P.R.R.). From the 2000 RSNA scientific assembly. Received November 20, 2001; revision requested December 19; revision received February 18, 2002; accepted April 16. Address correspondence to C.D.F. (e-mail: iaiacdf@hotmail.com).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To compare gadobenate dimeglumine (Gd-BOPTA)–enhanced magnetic resonance (MR) imaging with ferumoxides-enhanced MR imaging for detection of liver metastases.

MATERIALS AND METHODS: Twenty consecutive patients known to have malignancy and suspected of having focal liver lesions at ultrasonography (US) underwent 1.0-T MR imaging with gradient-recalled-echo T1-weighted breath-hold sequences before, immediately after, and 60 minutes after Gd-BOPTA injection. Subsequently, MR imaging was performed with turbo spin-echo short inversion time inversion-recovery T2-weighted sequences before and 60 minutes after ferumoxides administration. All patients subsequently underwent intraoperative US within 15 days, and histopathologic analysis of their resected lesion-containing specimens was performed. Separate qualitative analyses were performed to assess lesion detection with each contrast agent. Quantitative analyses were performed by measuring signal-to-noise and contrast-to-noise ratios (CNRs) on pre- and postcontrast Gd-BOPTA and ferumoxides MR images. Statistical analyses were performed with Wilcoxon signed rank and Monte Carlo tests.

RESULTS: Sensitivity of ferumoxides-enhanced MR imaging was superior to that of Gd-BOPTA–enhanced MR imaging for liver metastasis detection (P < .05). Ferumoxides MR images depicted 36 (97%) of 37 metastases detected at intraoperative US, whereas Gd-BOPTA MR images depicted 30 (81%) metastases during delayed phase and 20 (54%) during dynamic phase. All six metastases identified only at ferumoxides-enhanced MR imaging were 5–10 mm in diameter. There was a significant increase in CNR between the lesion and liver before and after ferumoxides administration (from 3.8 to 6.8, P < .001) but not before or after Gd-BOPTA injection (from -4.8 to -5.5, P > .05).

CONCLUSION: Ferumoxides-enhanced MR imaging seems to be superior to Gd-BOPTA–enhanced MR imaging for liver metastasis detection.

© RSNA, 2002

Index terms: Gadolinium • Iron • Liver, MR, 761.121411, 761.121412, 761.121413, 761.121416, 761.12143 • Liver neoplasms, metastases, 761.33 • Liver neoplasms, MR, 761.121411, 761.121412, 761.121413, 761.121416, 761.12143 • Magnetic resonance (MR), contrast media, 761.12143


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Magnetic resonance (MR) imaging has become an important tool in clinical liver imaging thanks to the introduction of faster imaging techniques. MR imaging facilitates the detection and characterization of focal liver lesions when other modalities such as computed tomography (CT) and ultrasonography (US) do not yield conclusive findings. Up to 60% of hepatic metastases, especially those smaller than 10 mm, are missed at US or CT, and this substantially affects the effectiveness of surgical and nonsurgical treatments (1–4). Therefore, despite being invasive, intraoperative US and CT during arterial portography have generally been considered the most accurate techniques for the detection of metastases (5).

The advent of liver-specific MR imaging contrast materials, which are agents targeted to enhance hepatocytes or Kupffer cells, has facilitated an increase in the accuracy of MR imaging in liver metastasis detection. The screening of patients with cancer by means of MR imaging with a liver-specific contrast agent has the potential to replace CT during arterial portography as the preoperative imaging examination of choice (2,5).

To our knowledge, ferumoxides (Feridex IV; Berlex Laboratories, Wayne, NJ and Endorem; Guerbet, Aulnay-sous-Bois, France) was the first liver-specific MR imaging contrast agent to be studied in clinical trials and the first such agent for which marketing approval from the United States Food and Drug Administration was obtained (6). Many studies have involved comparisons of the effectiveness of ferumoxides-enhanced MR imaging with that of other imaging modalities, especially CT during arterial portography and intraoperative US (2,7). Although results vary (8,9), ferumoxides-enhanced MR imaging with optimized sequences recently has been shown to have effectiveness equivalent to that of CT during arterial portography (7,10). Results of these studies indicate that ferumoxides is well suited for the preoperative evaluation of hepatic metastases from primary extrahepatic malignancies, especially colorectal cancer. Ferumoxides-enhanced MR imaging has inherent disadvantages, however, such as a relatively long infusion time. Ferumoxides administration has to be performed during a slow (30-minute) infusion with physician supervision. At the Institute of Radiology of Udine University, during this time, one room in the MR service division is occupied, and a nurse has to stay with the patient. This protocol often leads to logistic problems and is time consuming. Moreover, ferumoxides has some minor negative effects—for example, low back pain.

To our knowledge, gadobenate dimeglumine (Gd-BOPTA) (MultiHance, Bracco Diagnostics, Milan, Italy) was the fifth gadolinium chelate to become available in the marketplace; it followed gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany), gadoteridol (ProHance; Bracco Diagnostics), gadoterate (Dotarem; Guerbet, Aulnay-sous-Bois, France), and gadodiamide (Omniscan; Nycomed-Amersham, Oslo, Norway). Although Gd-BOPTA is similar to these agents in terms of pharmacokinetic profile and initial extracellular distribution following intravenous administration, it is different in that a fraction of the administered dose is taken up specifically by functioning hepatocytes (11,12). Gd-BOPTA has been shown to improve the detection of liver lesions, including metastases (13). This contrast agent can potentially enable one to couple the advantages of conventional gadolinium-enhanced MR imaging (for acquisition of dynamic images, which are useful for lesion characterization), with those of liver-specific contrast agents (for acquisition of delayed phase images for lesion detection). The purpose of our study was to compare Gd-BOPTA– and ferumoxides-enhanced MR imaging examinations in the detection of liver metastases.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
Twenty consecutive patients (12 men, eight women; age range, 50–76 years; mean age, 62 years) with surgically proved or biopsy-proved primary malignancies and lesions that were either proven or suspected to be liver metastases at conventional US imaging and who were eligible for surgery underwent Gd-BOPTA– and ferumoxides-enhanced MR imaging examinations. The study was approved by the ethics committee of Udine University, and all patients gave informed consent to be examined for this research after the entire procedure had been fully explained to them.

All patients were referred for surgical resection and underwent intraoperative US with a US imaging unit (model AU5; ESAOTE, Genoa, Italy) within 15 days (range, 8–15 days; mean, 11.85 days) after the last MR imaging examination. Nineteen patients—17 with colorectal carcinoma and two with breast cancer and a single metastatic lesion—underwent surgery for curative purposes. One patient, who had resectable lung adenocarcinoma, had one liver lesion that was suspected to be metastatic at US. Because of its location, the lesion was not accessible at percutaneous biopsy and the patient underwent surgery to confirm the diagnosis. All resected specimens were histopathologically analyzed.

Contrast Agents
In all patients, 0.05 mmol of Gd-BOPTA per kilogram of body weight (ie, 0.1 mL/kg of 0.5 mol/L of the agent) was injected at a rate of 2 mL/sec.

In all patients, 0.075 mL of a suspension of ferumoxides per kilogram of body weight, which corresponded to 15 µmol of iron per kilogram of body weight, was administered. The suspension was diluted in 100 mL of a 5% glucose solution and administered by means of slow intravenous infusion for 30 minutes. All ferumoxides-enhanced MR images were obtained 3–5 days after the Gd-BOPTA–enhanced images were obtained.

MR Imaging
MR images were obtained with a 1.0-T superconductive system (Magnetom Impact; Siemens, Erlangen, Germany) by using a body coil and the following sequences:

Nonenhanced T1-weighted gradient-recalled-echo (GRE) breath-hold sequences were performed in the transverse plane with the following parameters: a repetition time of 148.4 msec in 19 patients and of 200.0 msec in one patient, and in all patients, an echo time of 5.0 msec, a matrix of 80 x 256, one signal acquired, a rectangular field of view of 238 x 380 mm, a section thickness of 8 mm with a 20% intersection gap, and an acquisition time of 14 seconds (for nine sections). Patients were required to hold their breath after an incomplete expiration. The liver was imaged during two or three breath holds, depending on the size of the liver, with a 20% overlap between the volumes to ensure that the entire volume of the liver was covered.

Nonenhanced turbo spin-echo short inversion time inversion-recovery (TSE STIR) T2-weighted sequences were performed in the transverse plane with the following parameters: 5,100/90 (repetition time msec/echo time msec), 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap, and acquisition time of 5 minutes 43 seconds.

Following Gd-BOPTA administration, dynamic MR imaging was performed by using T1-weighted breath-hold sequences during arterial, portal venous, equilibrium, and delayed (ie, 60 minutes after the end of the injection) phases. After ferumoxides administration, the patients underwent MR imaging of the liver with the described T2-weighted TSE STIR sequence.

We decided to perform the Gd-BOPTA–enhanced MR imaging before the ferumoxides-enhanced examination because of the different clearance rates of the two contrast agents. The results of previously performed studies have demonstrated that up to 94% of the injected dose of Gd-BOPTA is excreted in an unchanged form in urine and 2%–4% of the injected dose is excreted in feces within 24 hours (14), whereas the reported half-life of ferumoxides is 3–4 days (6).

Image Evaluation
We performed both a qualitative analysis to assess image quality and lesion depiction and a quantitative analysis to measure signal intensities.

Qualitative image analysis.—The images obtained with each pre- and postcontrast MR imaging sequence and with each contrast agent were evaluated independently by two radiologists (C.D.F., C.Z.) who were not involved in performing or monitoring the MR imaging studies. One radiologist had 3 years of experience in liver MR imaging and the other 10 years of experience. At the time of review, the MR imaging studies were randomly assigned to each radiologist, who was unaware of the results recorded in the clinical report. Each radiologist analyzed the MR studies for image quality and lesion depiction.

Image quality was considered excellent when the liver border was well defined and no motion artifacts were present, good when the liver border was moderately well defined but all anatomic landmarks (ie, aorta, portal vein, and hepatic veins) were well appreciated, and poor when the liver border was poorly defined, substantial motion artifacts were present, and the anatomic landmarks were obscured.

The number of lesions detected with each MR imaging sequence was evaluated. Each lesion was measured and localized to a precise segment of the liver. Each reader was also required to give the image number on which and the level at which each lesion was seen. A lesion was considered to be present only if both observers detected it. A consensus was reached for every case in which the two readers were not in agreement. The readers disagreed about three lesions (described in Results section).

Quantitative image analysis.—Signal intensity measurements were obtained for each patient and for each MR imaging sequence in which a lesion was identified and histopathologically confirmed to be a metastasis. The signal intensity of the metastasis was compared with that of the adjacent normal liver parenchyma, as normalized with the signal intensity of the background noise. One author (G.C.) calculated the signal intensity values of the metastasis and the liver parenchyma by placing a region of interest on the lesion and the adjacent normal hepatic parenchyma. The signal intensity of the background noise was measured by placing a region of interest in the phase-encoding direction ventral to the patient. The regions of interest in the lesions ranged from 0.13 to 0.78 cm2, depending on the size of each lesion, whereas the region of interest was always 0.78 cm2 for both the liver parenchyma and the background noise.

The signal-to-noise ratio for the metastatic lesion (SNRm) and the signal-to-noise ratio for the liver parenchyma (SNRl) were calculated as follows: SNRm = SIm/SDn and SNRl = SIl/SDn, where SIm is the signal intensity of the metastatic lesion; SIl, the signal intensity of the liver parenchyma; and SDn, the SD of the background noise signal intensity.

The contrast-to-noise ratio (CNR) for each lesion, as normalized to SDs of the signal intensities of the metastatic lesion and the liver parenchyma, was calculated as follows: where SDm is the SD of the signal intensity of the metastatic lesion and SDl the SD of the signal intensity of the liver parenchyma.

Statistical Analysis
Because Shapiro-Wilk test results failed to provide sufficient evidence of the normality of the data distributions, we performed statistical analysis by using the Wilcoxon signed rank test for paired observations, with a P value of less than .05 indicating a statistically significant difference. The total number of lesions detected at Gd-BOPTA–enhanced MR imaging was compared with the total number of lesions detected at ferumoxides-enhanced MR imaging to determine whether there was a statistically significant difference in lesion detection between the two MR imaging examinations.

In addition, the CNR between the lesion and liver parenchyma measured at nonenhanced MR imaging was compared with the CNR measured at delayed phase Gd-BOPTA–enhanced MR imaging to demonstrate an eventual improvement in CNR. The same comparison was applied to nonenhanced and ferumoxides-enhanced MR imaging.

Reference Standard
A US-qualified surgeon (accreditation obtained by performing at least 300 intraoperative US examinations a year) compared the MR imaging results of lesion detection with the results obtained at intraoperative US, which was performed immediately before surgical resection with a linear-array broadband 7.5–10.0-MHz US imaging unit (model AU5). All lesions confirmed at intraoperative US were resected and histopathologically confirmed to be metastases. In all cases, the histopathologic findings were consistent with the respective known primary tumor.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
The quality of all images acquired before and after contrast agent administration was considered to be good or excellent. The quality of nonenhanced T1-weighted GRE MR images was good in 12 patients and excellent in eight. The quality of nonenhanced T2-weighted TSE STIR MR images was good in 11 patients and excellent in nine. The quality of T1-weighted GRE MR images obtained during the dynamic phase after Gd-BOPTA administration was good in 14 patients and excellent in six. The quality of T1-weighted GRE MR images obtained during the delayed phase after Gd-BOPTA administration was good in 12 patients and excellent in eight. The quality of T2-weighted TSE STIR MR images obtained after ferumoxides administration was good in six patients and excellent in 14.

Regarding lesion detection, 37 metastases were identified with intraoperative US and histopathologically confirmed. Intraoperative US and surgery revealed metastatic lesions in all patients: one lesion in nine patients, two lesions in six patients, three lesions in four patients, and four lesions in one patient. In each patient, all lesions were located in the same hepatic lobe. The sizes of the lesions ranged from 5 to 32 mm in diameter.

The metastatic lesions, when visible, usually were hypointense at GRE T1-weighted MR imaging. Only one metastasis manifested as an isointense lesion with a hyperintense rim on nonenhanced T1-weighted GRE images, a hypointense lesion on dynamic phase Gd-BOPTA–enhanced T1-weighted GRE MR images, and isointense on delayed phase Gd-BOPTA–enhanced T1-weighted GRE MR images (Fig 1). All metastases were hyperintense on the T2-weighted TSE STIR MR images obtained before and after ferumoxides administration.



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  		Figure 1. Transverse MR images obtained in a 49-year-old man with colorectal carcinoma. (a) Nonenhanced T1-weighted GRE image (200/5, matrix, 80 x 256; number of signals acquired, one; rectangular field of view, 238 x 380 mm; section thickness, 8 mm; intersection gap, 20%) shows a lesion with irregular borders at the dome of the liver. The lesion (arrowhead) is isointense and has a slightly hyperintense rim (arrow). (b, c) T1-weighted GRE images obtained after Gd-BOPTA administration during the (b) arterial and (c) portal venous phases (together constituting the delayed phase) of hepatic enhancement; the lesion is seen better during this dynamic phase. (d) T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase. The depiction of the lesion is not as good as that during the dynamic phase (b and c). The lesion is isointense to the normal liver parenchyma and has a slightly hyperintense rim, as seen during the nonenhanced examination (a). (e) On the nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap), the lesion is hyperintense relative to the normal liver parenchyma. (f) The depiction of the lesion on the T2-weighted TSE STIR image obtained after ferumoxides administration is much better than that on the nonenhanced TSE STIR image (e).

 


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  		Figure 1. Transverse MR images obtained in a 49-year-old man with colorectal carcinoma. (a) Nonenhanced T1-weighted GRE image (200/5, matrix, 80 x 256; number of signals acquired, one; rectangular field of view, 238 x 380 mm; section thickness, 8 mm; intersection gap, 20%) shows a lesion with irregular borders at the dome of the liver. The lesion (arrowhead) is isointense and has a slightly hyperintense rim (arrow). (b, c) T1-weighted GRE images obtained after Gd-BOPTA administration during the (b) arterial and (c) portal venous phases (together constituting the delayed phase) of hepatic enhancement; the lesion is seen better during this dynamic phase. (d) T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase. The depiction of the lesion is not as good as that during the dynamic phase (b and c). The lesion is isointense to the normal liver parenchyma and has a slightly hyperintense rim, as seen during the nonenhanced examination (a). (e) On the nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap), the lesion is hyperintense relative to the normal liver parenchyma. (f) The depiction of the lesion on the T2-weighted TSE STIR image obtained after ferumoxides administration is much better than that on the nonenhanced TSE STIR image (e).

 


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  		Figure 1. Transverse MR images obtained in a 49-year-old man with colorectal carcinoma. (a) Nonenhanced T1-weighted GRE image (200/5, matrix, 80 x 256; number of signals acquired, one; rectangular field of view, 238 x 380 mm; section thickness, 8 mm; intersection gap, 20%) shows a lesion with irregular borders at the dome of the liver. The lesion (arrowhead) is isointense and has a slightly hyperintense rim (arrow). (b, c) T1-weighted GRE images obtained after Gd-BOPTA administration during the (b) arterial and (c) portal venous phases (together constituting the delayed phase) of hepatic enhancement; the lesion is seen better during this dynamic phase. (d) T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase. The depiction of the lesion is not as good as that during the dynamic phase (b and c). The lesion is isointense to the normal liver parenchyma and has a slightly hyperintense rim, as seen during the nonenhanced examination (a). (e) On the nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap), the lesion is hyperintense relative to the normal liver parenchyma. (f) The depiction of the lesion on the T2-weighted TSE STIR image obtained after ferumoxides administration is much better than that on the nonenhanced TSE STIR image (e).

 


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  		Figure 1. Transverse MR images obtained in a 49-year-old man with colorectal carcinoma. (a) Nonenhanced T1-weighted GRE image (200/5, matrix, 80 x 256; number of signals acquired, one; rectangular field of view, 238 x 380 mm; section thickness, 8 mm; intersection gap, 20%) shows a lesion with irregular borders at the dome of the liver. The lesion (arrowhead) is isointense and has a slightly hyperintense rim (arrow). (b, c) T1-weighted GRE images obtained after Gd-BOPTA administration during the (b) arterial and (c) portal venous phases (together constituting the delayed phase) of hepatic enhancement; the lesion is seen better during this dynamic phase. (d) T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase. The depiction of the lesion is not as good as that during the dynamic phase (b and c). The lesion is isointense to the normal liver parenchyma and has a slightly hyperintense rim, as seen during the nonenhanced examination (a). (e) On the nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap), the lesion is hyperintense relative to the normal liver parenchyma. (f) The depiction of the lesion on the T2-weighted TSE STIR image obtained after ferumoxides administration is much better than that on the nonenhanced TSE STIR image (e).

 


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  		Figure 1. Transverse MR images obtained in a 49-year-old man with colorectal carcinoma. (a) Nonenhanced T1-weighted GRE image (200/5, matrix, 80 x 256; number of signals acquired, one; rectangular field of view, 238 x 380 mm; section thickness, 8 mm; intersection gap, 20%) shows a lesion with irregular borders at the dome of the liver. The lesion (arrowhead) is isointense and has a slightly hyperintense rim (arrow). (b, c) T1-weighted GRE images obtained after Gd-BOPTA administration during the (b) arterial and (c) portal venous phases (together constituting the delayed phase) of hepatic enhancement; the lesion is seen better during this dynamic phase. (d) T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase. The depiction of the lesion is not as good as that during the dynamic phase (b and c). The lesion is isointense to the normal liver parenchyma and has a slightly hyperintense rim, as seen during the nonenhanced examination (a). (e) On the nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap), the lesion is hyperintense relative to the normal liver parenchyma. (f) The depiction of the lesion on the T2-weighted TSE STIR image obtained after ferumoxides administration is much better than that on the nonenhanced TSE STIR image (e).

 


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  		Figure 1. Transverse MR images obtained in a 49-year-old man with colorectal carcinoma. (a) Nonenhanced T1-weighted GRE image (200/5, matrix, 80 x 256; number of signals acquired, one; rectangular field of view, 238 x 380 mm; section thickness, 8 mm; intersection gap, 20%) shows a lesion with irregular borders at the dome of the liver. The lesion (arrowhead) is isointense and has a slightly hyperintense rim (arrow). (b, c) T1-weighted GRE images obtained after Gd-BOPTA administration during the (b) arterial and (c) portal venous phases (together constituting the delayed phase) of hepatic enhancement; the lesion is seen better during this dynamic phase. (d) T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase. The depiction of the lesion is not as good as that during the dynamic phase (b and c). The lesion is isointense to the normal liver parenchyma and has a slightly hyperintense rim, as seen during the nonenhanced examination (a). (e) On the nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap), the lesion is hyperintense relative to the normal liver parenchyma. (f) The depiction of the lesion on the T2-weighted TSE STIR image obtained after ferumoxides administration is much better than that on the nonenhanced TSE STIR image (e).

 
Of the 37 metastases identified at intraoperative US and surgery, 18 (49%) were detected at nonenhanced T1-weighted GRE breath-hold MR imaging; 20 (54%), at dynamic phase T1-weighted Gd-BOPTA–enhanced breath-hold GRE MR imaging; and 30 (81%), at delayed phase T1-weighted Gd-BOPTA–enhanced breath-hold GRE MR imaging (Table). Twenty-nine (78%) metastases were detected at nonenhanced T2-weighted TSE STIR MR imaging, whereas 36 (97%) metastases were detected at ferumoxides-enhanced T2-weighted TSE STIR MR imaging (Table).


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  		Liver Metastasis Detection at Gd-BOPTA-enhanced and Ferumoxides-enhanced MR Imaging

 
All 29 of the lesions detected at nonenhanced T2-weighted TSE STIR imaging had also been depicted at delayed phase Gd-BOPTA–enhanced T1-weighted breath-hold GRE MR imaging. In our limited patient population, the delayed phase Gd-BOPTA–enhanced T1-weighted breath-hold GRE sequence was only slightly superior to the nonenhanced T2-weighted TSE STIR sequence: It depicted only one lesion more (Fig 2). Ferumoxides-enhanced T2-weighted TSE STIR MR imaging depicted six lesions more than delayed phase Gd-BOPTA–enhanced T1-weighted breath-hold GRE MR imaging (Fig 3).



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  		Figure 2. Transverse MR images obtained in a 61-year-old man with rectal carcinoma. (a) Nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) shows a 5-mm slightly hyperintense lesion (arrow) in the posterior aspect of the seventh hepatic segment. (b) The lesion (arrow) is better seen on this T2-weighted TSE STIR image obtained after ferumoxides administration. (c) On the T1-weighted GRE image (148.4/5.0, 80 x 256 matrix, one signal acquired, 238 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) obtained after Gd-BOPTA administration during the delayed phase, the lesion (arrow) is hypointense relative to the surrounding liver parenchyma. (d) Nonenhanced T2-weighted TSE STIR image obtained at an upper level in the same patient does not show a lesion. (e) T2-weighted TSE STIR image obtained after ferumoxides administration shows an additional 6-mm hyperintense lesion (arrow). (f) On the T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase, the additional lesion (arrow) depicted in e is hypointense relative to the surrounding liver parenchyma.

 


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  		Figure 2. Transverse MR images obtained in a 61-year-old man with rectal carcinoma. (a) Nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) shows a 5-mm slightly hyperintense lesion (arrow) in the posterior aspect of the seventh hepatic segment. (b) The lesion (arrow) is better seen on this T2-weighted TSE STIR image obtained after ferumoxides administration. (c) On the T1-weighted GRE image (148.4/5.0, 80 x 256 matrix, one signal acquired, 238 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) obtained after Gd-BOPTA administration during the delayed phase, the lesion (arrow) is hypointense relative to the surrounding liver parenchyma. (d) Nonenhanced T2-weighted TSE STIR image obtained at an upper level in the same patient does not show a lesion. (e) T2-weighted TSE STIR image obtained after ferumoxides administration shows an additional 6-mm hyperintense lesion (arrow). (f) On the T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase, the additional lesion (arrow) depicted in e is hypointense relative to the surrounding liver parenchyma.

 


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  		Figure 2. Transverse MR images obtained in a 61-year-old man with rectal carcinoma. (a) Nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) shows a 5-mm slightly hyperintense lesion (arrow) in the posterior aspect of the seventh hepatic segment. (b) The lesion (arrow) is better seen on this T2-weighted TSE STIR image obtained after ferumoxides administration. (c) On the T1-weighted GRE image (148.4/5.0, 80 x 256 matrix, one signal acquired, 238 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) obtained after Gd-BOPTA administration during the delayed phase, the lesion (arrow) is hypointense relative to the surrounding liver parenchyma. (d) Nonenhanced T2-weighted TSE STIR image obtained at an upper level in the same patient does not show a lesion. (e) T2-weighted TSE STIR image obtained after ferumoxides administration shows an additional 6-mm hyperintense lesion (arrow). (f) On the T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase, the additional lesion (arrow) depicted in e is hypointense relative to the surrounding liver parenchyma.

 


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  		Figure 2. Transverse MR images obtained in a 61-year-old man with rectal carcinoma. (a) Nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) shows a 5-mm slightly hyperintense lesion (arrow) in the posterior aspect of the seventh hepatic segment. (b) The lesion (arrow) is better seen on this T2-weighted TSE STIR image obtained after ferumoxides administration. (c) On the T1-weighted GRE image (148.4/5.0, 80 x 256 matrix, one signal acquired, 238 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) obtained after Gd-BOPTA administration during the delayed phase, the lesion (arrow) is hypointense relative to the surrounding liver parenchyma. (d) Nonenhanced T2-weighted TSE STIR image obtained at an upper level in the same patient does not show a lesion. (e) T2-weighted TSE STIR image obtained after ferumoxides administration shows an additional 6-mm hyperintense lesion (arrow). (f) On the T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase, the additional lesion (arrow) depicted in e is hypointense relative to the surrounding liver parenchyma.

 


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  		Figure 2. Transverse MR images obtained in a 61-year-old man with rectal carcinoma. (a) Nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) shows a 5-mm slightly hyperintense lesion (arrow) in the posterior aspect of the seventh hepatic segment. (b) The lesion (arrow) is better seen on this T2-weighted TSE STIR image obtained after ferumoxides administration. (c) On the T1-weighted GRE image (148.4/5.0, 80 x 256 matrix, one signal acquired, 238 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) obtained after Gd-BOPTA administration during the delayed phase, the lesion (arrow) is hypointense relative to the surrounding liver parenchyma. (d) Nonenhanced T2-weighted TSE STIR image obtained at an upper level in the same patient does not show a lesion. (e) T2-weighted TSE STIR image obtained after ferumoxides administration shows an additional 6-mm hyperintense lesion (arrow). (f) On the T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase, the additional lesion (arrow) depicted in e is hypointense relative to the surrounding liver parenchyma.

 


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  		Figure 2. Transverse MR images obtained in a 61-year-old man with rectal carcinoma. (a) Nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) shows a 5-mm slightly hyperintense lesion (arrow) in the posterior aspect of the seventh hepatic segment. (b) The lesion (arrow) is better seen on this T2-weighted TSE STIR image obtained after ferumoxides administration. (c) On the T1-weighted GRE image (148.4/5.0, 80 x 256 matrix, one signal acquired, 238 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) obtained after Gd-BOPTA administration during the delayed phase, the lesion (arrow) is hypointense relative to the surrounding liver parenchyma. (d) Nonenhanced T2-weighted TSE STIR image obtained at an upper level in the same patient does not show a lesion. (e) T2-weighted TSE STIR image obtained after ferumoxides administration shows an additional 6-mm hyperintense lesion (arrow). (f) On the T1-weighted GRE image obtained after Gd-BOPTA administration during the delayed phase, the additional lesion (arrow) depicted in e is hypointense relative to the surrounding liver parenchyma.

 


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  		Figure 3. Transverse MR images obtained in a 70-year-old man with colon carcinoma. (a) Nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) does not show lesions. (b) T2-weighted TSE STIR image obtained after ferumoxides administration shows an 8-mm hyperintense lesion (arrow) in the fourth liver segment. (c) T1-weighted GRE image (148.4/5.0, 80 x 256 matrix, one signal acquired, 238 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) obtained at a comparable level after Gd-BOPTA administration during the delayed phase does not depict the lesion detected after ferumoxides administration (b).

 


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  		Figure 3. Transverse MR images obtained in a 70-year-old man with colon carcinoma. (a) Nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) does not show lesions. (b) T2-weighted TSE STIR image obtained after ferumoxides administration shows an 8-mm hyperintense lesion (arrow) in the fourth liver segment. (c) T1-weighted GRE image (148.4/5.0, 80 x 256 matrix, one signal acquired, 238 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) obtained at a comparable level after Gd-BOPTA administration during the delayed phase does not depict the lesion detected after ferumoxides administration (b).

 


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  		Figure 3. Transverse MR images obtained in a 70-year-old man with colon carcinoma. (a) Nonenhanced T2-weighted TSE STIR image (5,100/90, 120-msec inversion time, 196 x 256 matrix, three signals acquired, 285 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) does not show lesions. (b) T2-weighted TSE STIR image obtained after ferumoxides administration shows an 8-mm hyperintense lesion (arrow) in the fourth liver segment. (c) T1-weighted GRE image (148.4/5.0, 80 x 256 matrix, one signal acquired, 238 x 380-mm rectangular field of view, 8-mm section thickness, 20% intersection gap) obtained at a comparable level after Gd-BOPTA administration during the delayed phase does not depict the lesion detected after ferumoxides administration (b).

 
The two readers agreed with regard to all 18 of the lesions detected at nonenhanced T1-weighted breath-hold GRE MR imaging, all 20 of the lesions visualized at dynamic phase Gd-BOPTA–enhanced T1-weighted breath-hold GRE MR imaging, 29 of the 30 lesions visualized at delayed phase Gd-BOPTA–enhanced T1-weighted breath-hold GRE MR imaging, all 29 of the lesions detected at nonenhanced T2-weighted TSE STIR MR imaging, and 34 of the 36 lesions visualized at ferumoxides-enhanced T2-weighted TSE STIR MR imaging. The sizes of metastatic lesions detected at MR imaging ranged from 5 to 32 mm in diameter (mean diameter, 14 mm). The sizes of the six metastatic lesions detected only after ferumoxides administration ranged from 5 to 10 mm in diameter (mean diameter, 7 mm). Intraoperative US detected only one lesion more than MR imaging. This additional lesion, which was 5 mm in diameter and located on the surface of the liver, was identified in a patient with colon carcinoma in whom MR imaging depicted only one lesion.

In our patient population, there was a statistically significant difference in the number of metastases detected between ferumoxides-enhanced MR imaging and delayed phase Gd-BOPTA–enhanced MR imaging, according to Wilcoxon signed rank test results (z = -2.449 with asymptotic significance, P = .014; Monte Carlo exact significance, P = .032 with 99% CI: 0.025, 0.038). At the time of image review, two small (<5-mm) lesions were considered to be possible metastatic lesions on ferumoxides-enhanced T2-weighted TSE STIR MR images but were not confirmed at intraoperative US. These two false-positive lesions were not mentioned in the clinical report, which was based on the results of examinations performed with all of the MR imaging sequences. No other false-positive lesions were identified with the other sequences.

Quantitative analysis results indicated an increase in CNR (from -4.8 to -5.5) between the lesion and the liver parenchyma when the nonenhanced T1-weighted GRE MR images were compared with the Gd-BOPTA–enhanced T1-weighted GRE MR images acquired during the delayed phase, but the difference was not statistically significant (z = -0.732 with asymptotic significance, P = .464; Monte Carlo exact significance, P = .474 with 99% CI: 0.452, 0.496) (Fig 4). However, a significant increase in CNR between the lesion and liver parenchyma (from 3.8 to 6.8) (z = -4.352 with asymptotic significance, P < .001; Monte Carlo exact significance, P < .001 with 99% CI: 0.00, 0.00) was observed on the T2-weighted TSE STIR images acquired before and after ferumoxides administration (Fig 4).



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  		Figure 4. Bar graph depicts CNRs (C/N) between the lesion and the liver parenchyma at MR imaging before Gd-BOPTA administration (-4.8) and during the delayed phase after Gd-BOPTA administration (-5.5) and at MR imaging before (3.8) and after (6.8) ferumoxides administration. CNRs at nonenhanced T1-weighted GRE MR imaging (box 1), Gd-BOPTA-enhanced delayed phase T1-weighted GRE MR imaging (box 2), nonenhanced T2-weighted TSE STIR MR imaging (box 3), and ferumoxides-nonenhanced T2-weighted TSE STIR MR imaging (box 4) are illustrated. Vertical bars represent standard errors of the mean.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
The results of previous studies (10,15) have shown that surgical resection of liver metastases—those from colorectal carcinoma, in particular—leads to an improved 5-year survival rate. Therefore, accurate detection of hepatic metastatic disease is essential for the optimal treatment of patients.

Several liver-specific contrast agents that are used with MR imaging have been proposed to help improve liver metastasis detection. To our knowledge, ferumoxides, a superparamagnetic iron oxide contrast agent, was the first liver-specific contrast material to be studied in clinical trials and the first such agent for which marketing approval from the United States Food and Drug Administration was obtained (6). Several reports (6–10,16–21) have demonstrated the diagnostic effectiveness of ferumoxides for liver metastasis detection.

More recently, Gd-BOPTA, a hepatobiliary contrast agent, has been proposed for liver lesion detection. To our knowledge, Gd-BOPTA is the first gadolinium-based agent that has been identified to be specifically taken up by functioning hepatocytes after initial distribution to the extracellular compartment and thereby yield an increase in the liver-to-lesion CNR during the delayed phase after it is administered (11,23). This characteristic permits the use of Gd-BOPTA during the delayed phase, in addition to during the dynamic phase, to improve the detection of liver lesions (6,12,13,22).

To our knowledge, no comparison study on the use of these two contrast agents for the detection of liver metastases has been published previously. Therefore, in this study, we assessed lesion detection at Gd-BOPTA-enhanced MR imaging and ferumoxides-enhanced MR imaging in the same patient population, with intraoperative US and surgery as the reference standards. Short intervals between the two MR imaging examinations (3–5 days) and between MR imaging and intraoperative US (15 days) were allowed to eliminate the potential bias associated with lesion growth or new lesion development. In addition, the interval between the two MR imaging examinations was sufficient to negate the potential cross-effects of both contrast agents.

Our study results demonstrate that ferumoxides produces a marked decrease in the signal intensity of the normal liver parenchyma on T2-weighted images, and, owing to the lack of uptake of the agent by metastatic lesions, increases the CNR between the liver and the lesion, from 3.8 to 6.8 (44%), a difference that proved to be highly statistically significant (z = -4.352 with asymptotic significance, P = .00; Monte Carlo significance, P < .001 with 99% CI: 0.00, 0.00). This increased CNR was reflected in the improved liver metastasis detection: from 78% (29 of 37 metastatic lesions) on precontrast T2-weighted TSE STIR MR images to 97% (36 of 37 metastatic lesions) on ferumoxides-enhanced TSE STIR images. These data correlate well with those obtained in previously performed studies (6,7,9,10).

In contrast, there was only a moderate increase in CNR between the liver and the lesion, from -4.8 to -5.5 (13%), on the Gd-BOPTA–enhanced T1-weighted GRE images obtained during the delayed phase, as compared with the CNR on the nonenhanced T1-weighted GRE MR images, and the difference was not statistically significant (P > .05). Reflecting this moderate CNR increase, a moderate increase in liver metastasis detection was demonstrated between the nonenhanced T1-weighted GRE MR images (18 [49%] of 37 metastatic lesions) and the Gd-BOPTA–enhanced T1-weighted MR images obtained during the dynamic (20 [54%] of 37 lesions) and delayed (30 [81%] of 37 lesions) phases. Nevertheless, the effectiveness of delayed phase Gd-BOPTA–enhanced MR imaging for lesion detection seemed to be slightly better than that of nonenhanced T2-weighted TSE STIR imaging (30 [81%] vs 29 [78%] of 37 lesions).

The improvement in liver metastasis detection between delayed phase Gd-BOPTA–enhanced MR imaging and ferumoxides-enhanced MR imaging was demonstrated to be statistically significant (P = .014). On the basis of these data, the use of ferumoxides rather than Gd-BOPTA seems to be recommended for liver metastasis detection.

A limitation of this study, which was specifically designed to investigate the detection of liver metastases, was that we used an extremely limited protocol for the ferumoxides study: We performed only T2-weighted TSE STIR sequences to assess this contrast agent, and this explains the two small false-positive lesions that were identified at ferumoxides-enhanced MR imaging. It is well known that ferumoxides has limited specificity in the detection of very small lesions and that very small cysts or vascular structures may cause interpretation problems (6,9,16). The two false-positive lesions in our study did not affect patient care, because the clinical diagnosis was based on the review of all of the images. When ferumoxides is the only contrast agent used, we recommend a more complete protocol that includes T1- and T2-weighted MR imaging sequences with longer repetition times and the acquisition of images before and after ferumoxides administration.

Another limitation of our study was the small number of patients involved, which was due to the two MR imaging examinations required to compare the two contrast agents. We believe that another limitation was the lack of high-grade MR imaging equipment. With either of these contrast agents, the use of a body coil, with a section thickness of 8 mm and a 20% overlap, may affect the detection of small metastases. Furthermore, the T1-weighted GRE sequences that were optimized for our MR imaging apparatus did not enable us to image the entire liver volume in one acquisition; a 20% overlap between the multiple-breath-hold volumes was used to reduce the potential respiratory misregistration that could affect lesion detection at Gd-BOPTA–enhanced MR imaging.

Because of these limitations, further studies are recommended to confirm our results. The use of state-of-the-art MR imaging equipment with a phased-array coil, three-dimensional GRE sequences, and thinner sections for both T1- and T2-weighted imaging should be considered.

The results of more recent studies (13) of Gd-BOPTA–enhanced MR imaging have shown the potential utility of a double dose of this contrast agent (eg, 0.2 mL/kg of a 0.5 mol/L solution) with a monophasic or biphasic dose regimen in improving the detection of focal liver lesions. We therefore recommend a comparison between ferumoxides-enhanced MR imaging and Gd-BOPTA-enhanced MR imaging with a 0.2 mL/kg-dose of 0.5 mol/L of Gd-BOPTA in the future.

In conclusion, the results of our study, which was designed to investigate the detection of metastases in patients known to have malignancies and suspected of having metastatic hepatic involvement, show that ferumoxides-enhanced MR imaging seems to be superior to Gd-BOPTA–enhanced MR imaging for the detection of liver metastases. However, more data and further research are needed to confirm our results.


   FOOTNOTES
 
Abbreviations: CNR = contrast-to-noise ratio, Gd-BOPTA = gadobenate dimeglumine, GRE = gradient recalled echo, TSE STIR = turbo spin-echo short inversion time inversion recovery

Author contributions: Guarantors of integrity of entire study, C.Z., M.B.; study concepts, C.D.F., K.J.M., V.L., R.Z.; study design, C.D.F., M.B., C.Z., P.R.R.; literature research, G.C., R.Z.; clinical studies, C.D.F., V.L., C.Z.; data acquisition, V.L., G.C., Z.R., C.Z.; data analysis/interpretation, C.D.F., P.R.R., M.B., K.J.M.; statistical analysis, V.L.; manuscript preparation, C.D.F., V.L., C.Z., G.C., R.Z., K.J.M.; manuscript definition of intellectual content, C.Z., M.B., K.J.M., P.R.R.; manuscript editing, C.D.F.; manuscript revision/review, P.R.R., M.B.; manuscript final version approval, all authors.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
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