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 been 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 CT5-8. 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 MRI contrast agent for the
imaging, detection and characterization of liver pathology, including liver
tumors, cysts, as well as other malignant and benign lesions. Primovist has a
water-soluble compound which is taken up by the hepatocytes (approximately 30%)
and is equally excreted renal and biliary in humans*.
Primovist enhances the signal of T1 weighted MR images immediately after
administration. The hepatocytes uptake will increase the signal intensity of
normal liver parenchyma. This results in improved lesion-to-liver contrast
because malignant tumors (metastases, HCC) 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 or HCC. After
administration of Primovist a dynamic phase scans can be performed in arterial
phase, portal-venous phase and equilibrium phase.
Apart from the new contrast agents, there are also major advances in MR
sequences, including Diffusion Weighted Imaging (DWI). DWI is an excellent MR
tool for the detection of pathological lesions, and is increasingly applied for
tumour evaluation in the abdomen and pelvis.
Diffusion Weighted Imaging originates from the T2 weighted images and uses the
motion of protons in the extracellular space by using large bipolar gradients
to differentiate between different tissues. This signal is converted to a 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 tumor tissue a much smaller diffusion and
therefore gives a high signal on MRI (dark). The motion of the extracellular
protons is called the apparent diffusion coefficient (ADC). With malignancy,
the extracellular space is decreased resulting in a decrease in ADV value.
Benign lesions like cysts normally show an increase in extracellular space
which results in an increase in ADV value. The value of the ADC can therefore
be used to distinguish between normal liver parenchyma and focal liver
lesions9,10.
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 don*t.
Respiratory triggered DWI can also be performed after bolus injection of a
contrast agent. In this study we will administer Primovist. We will compare the
sensitivity and specificity for the detection and characterization of focal
liver lesions for contrast enhancement with Primovist alone and for DWI alone.
Furthermore we are especially interested in changes in ADC value between benign
and malignant lesions.

Primary Objective:
Sensitivity, specificity and positive predictive value (PPV) for the detection
and characterization of focal liver lesions using Gd-EOB-DTPA contrast or DWI
with TRON

Secondary Objective(s):
1) Differences between sensitivity, specificity and PPV for the detection and
characterization of benign and malignant lesions
2) Differences between sensitivity, specificity and PPV in the detection
between hypo- and hypervascular lesions
3) Accuracy for the characterization of lesions
4) Differences in apparent diffusion coefficient (ADC) value between benign and
malignant lesions larger than 1 cm

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.
After inclusion in this study, one follow-up MRI scan with Gadovist enhancement
will be performed 6 months after the primary MRI, or 6 months after surgery for
the operable patients, which may differ from the standard follow-up. This
investigation is complementary to this study, although Gadovist is the standard
of care momentarily in the UMC Utrecht.
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*.
Apart from the MRI investigations, each patient will be called by the study
coordinator one month and six months after the Primovist enhanced MRI, to
determine if any (S)AE occurred during the study period.
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.