Primovist enhanced MRI for the detection and evaluation of focal liver lesions

In patients with liver cancer or other liver lesions, liver imaging is crucial
to establish the extent and nature of the tumour(s). These two factors are
essential to define the therapeutic strategy or intervention.
MR imaging has gone through major developments the last decade with an increase
in contrast agents and new MR sequences.
Contrast enhanced MRI has shown to be a very high-quality detection tool for
focal liver lesions, with even higher sensitivities for the detection of focal
liver lesions than CT[5-8]. Recently, new MR contrast agents have been
developed to increase the sensitivity for the detection and characterization of
focal liver lesion. Primovist (Gd-EOB-DTPA, Gadoxetic acid, Bayer Schering
Pharma, Berlin) is one of these new, highly specific hepatocyte-specific MRI
contrast agent for the imaging, detection and characterization of liver
pathology, including liver tumours, cysts, as well as other malignant and
benign lesions. Primovist has a water-soluble compound which is taken up by the
hepatocytes selectively (approximately 30%) and is equally excreted through the
renal and biliary systems in humans*.
Primovist enhances the signal of T1 weighted MR images immediately after
administration. The first phases after Primovist enhancement are similar to
other non-hepatocyte specific agents like Gadovist (Gadobutrol, Bayer Schering
Pharma, Berlin) and include an arterial, portal and late phase. However, there
is an additional effect due to the selective uptake of the contrast agent by
the hepatocytes. Due to the contrast-uptake by the hepatocytes, the signal
intensity of the normal liver parenchyma will increase during the so-called
hepatobiliairy phase 10 and 20 minutes after contrast injection. This results
in specific lesion patterns during the specific phases. E.g. malignant tumours
like metastases or HCC show improved lesion-to-liver contrast (lesions
presenting dark against bright parenchyma) because they do not contain either
hepatocytes or their functioning is hampered*. Furthermore, as this agent is
specific for hepatocytes, it is postulated that lesions such as Focal Nodular
Hyperplasia (FNH) can be better distinguished form lesions such as adenoma.
After administration of Primovist a dynamic phase scan can be performed in
arterial phase, portal-venous phase and equilibrium phase.
In recent years several articles have been published showing the use of
Primovist for the detection and characterization of focal liver lesions. Two
articles from Bluemke et al. and Huppertz et al. used Primovist enhanced MRI
for the detection and characterization of liver metastases. In both articles
MR-Primovist was compared with a plain MR, showing a higher sensitivity and
specificity for both detection and characterization with the MR-Primovist.
Nevertheless, these results are not very useful, since it has been clear that
contrast-enhanced MR-imaging shows improved detection and characterization than
MR-imaging without any contrast. Hammerstingl et al. and Halavaara et al.
reported similar detection and characterization rates for Primovist enhanced MR
and they compared the results with contrast-enhanced CT. As expected, Primovist
enhanced MR showed higher detection and characterization rates than the
contrast-enhanced CT, which is similar to other MR contrast agents. No
articles have been published comparing the current gold standard,
Gadovist-enhanced MR, with the Primovist-enhanced MR. Furthermore, to
determine the actual diagnostic value of MR-Primovist it is most important to
define if MR-Primovist improves patient outcome by determining the correct
treatment. Therefore it is important to demonstrate that if MR-Primovist leads
to higher sensitivities for detection and characterization of focal lesions
than other MR-agents, this actually does result in a higher correct treatment
management. Until now, MR-Primovist was only evaluated for the diagnostic value
of specific patient groups like HCC or CRLM, and the articles only assessed the
change in surgical resection strategy due to adding the Primovist sequences to
plain sequences. Therefore this study proposal is innovative and necessary and
of special interest to the clinical practice.
Apart from the new contrast agents, there are also major advances in MR
sequences, including Diffusion Weighted Imaging (DWI). Diffusion Weighted
Imaging originates from the T2 weighted images and uses the motion of protons
in the extra-cellular space by using large bipolar gradients. Bipolar gradients
suppress the area with large movement of water molecules (diffusion). This
signal is converted to high or low signal intensity on the MR-images. For
example, normal liver parenchyma has a certain motion which correlates to a
large diffusion and therefore low signal on MRI (white), while tumour tissue a
much smaller diffusion and therefore gives a high signal on MRI (dark). The
motion of the extra-cellular protons is called the apparent diffusion
coefficient (ADC). With malignancy, the extra-cellular space is decreased
resulting in a decrease in ADC value. Benign lesions like cysts normally show
an increase in extra-cellular space which results in an increase in ADC value.
The value of the ADC may therefore be used to distinguish between normal liver
parenchyma and focal liver lesions. DWI is an excellent MR tool for the
detection of pathological lesions, and is increasingly applied for tumour
evaluation in the abdomen and pelvis. There are different DWI sequences, with
b=50 s/mm2 and b=500 s/mm2 regularly used. b=50 will provide improved
anatomical information and has a high sensitivity for the detection of lesions.
b=500 improves the specificity for lesion characterization, meaning that
malignant lesions emphasize on this image, while benign lesions do not. There
have been major improvements in the use of MR-DWI for liver imaging and the
current literature shows there is an important role for DWI in the oncological
imaging of the liver.
In conclusion, many articles have been published concerning the application of
Primovist for detection and characterization of focal lesions, the optimal
scanning protocol [18] and the application of Primovist for the detection and
staging of HCC. However, no significant studies have been published comparing
MR-Primovist to extracellular MR contrast agents for lesion detection and
characterization and the actual outcome on treatment management have not been
assessed yet. Furthermore, the 4 major articles about Primovist and the
detection and characterization of focal liver lesions lack the use of a good
reference standard.
In this study we will determine the diagnostic value of MR-Primovist for the
detection and characterization of focal liver lesions on a per-patient and a
per-lesion basis. Furthermore we will determine the accuracy of MR with
Respiratory Triggered DWI (RT-DWI) for the detection and characterization of
focal liver lesions. We will calculate ADC values for the different tumour
types.

To make an efficacy evaluation of Gadolineum Ethoxybenzyl (Gd-EOB)
DTPA-enhanced MR-imaging (Gadoxetic acid, Primovist, Bayer Schering Pharma,
Berlin) and Respiratory Triggered Diffusion Weighted Imaging (DWI) for the
detection and characterization of focal liver lesions

This is a prospective cohort study.

After inclusion, each patient will receive two liver MRI*s: one MRI with
Gadovist enhancement, one MRI with Primovist enhancement. Since all these
patients were referred to the Radiology Department for a Gadovist enhanced MRI
of the liver, only the Primovist enhanced MRI is associated with an extra
burden. The Diffusion Weighted Imaging images do not increase any risk or
burden. Apart from the MRI investigations, each patient will be called by the
study coordinator one week and one month after the Primovist enhanced MRI, to
determine if any (S)AE occurred during the study period.
Primovist is a registered contrast agent with no more side effects than
Gadovist, therefore no more (serious) adverse effects or (serious) adverse
reactions are expected to occur compared to the standard liver MRI with
Gadovist. Bayer Schering Pharma has extensively tested Primovist for its safety
within phase 1,2 and 3 studies1-4.
In 10.3% of patients receiving Primovist AE*s are expected1,2. The most
frequent AE*s that occur are headache and nausea with an incidence of 1.1%,
which is comparable to other Gadolineum contrast agents*. No other AE*s show
any incidence higher than 1.1%*. No deaths are reported in phase 2 and 3
studies due to the administration of Primovist2,*. SAE*s were classified
according to the ICH-GCP definition and included any event resulting in death,
were life-threatening, required inpatient hospitalization/prolonged existing
hospitalization or resulted in persistent significant disability/incapacity or
a congenital birth defect. SAE*s were seen in 3.3% of patients with AE*s and in
0.3% (6/1755) of total population*.
No other investigations, time-consuming events, questionnaires or visits to the
hospital are necessary when participating in this study. Participation in this
study will result in a close and thorough investigation of the patients* liver
disease, although patients do not necessarily benefit from participation.