Primary liver cancers, in particular,
hepatocellular carcinoma (HCC), represent perhaps the most common
malignancy in the world and account for almost 1.25 million deaths
annually. The worldwide geographic variation in incidence is well
known; in the United States, the annual incidence remains relatively
low, with roughly 2,500 cases reported per year. However, a diagnosis
of HCC carries a poor prognosis. Okuda et al reported the results of
a large multi-institutional review of 850 patients with HCC that
demonstrated an overall median survival of 4.1 months. Left
untreated, patients had a rather poor prognosis, with a median
survival of 8.3 months for stage I disease, 2.0 months for stage II,
and 0.7 months for stage III.
Patients who received treatment fared somewhat better. Those with
stage I and stage II disease treated surgically had a median survival
of 21.9 months, while those treated with medical management had a
median survival of 5.0 months. Other researchers have reported 5-year
survival rates ranging from 26% to 40% and 5-year cancer-free rates
The surgical resection of hepatic tumors has historically been a
daunting task, however. Prior to 1970, surgical resection was
associated with mortality rates of 35% to 45%. In contrast, more
recent series have demonstrated considerably lower mortality,
routinely less than 10%.. Yet, despite advances in reducing
operative mortality, hepatic resection still carries significant
morbidity. Complications include wound infection, bile leaks,
bleeding, subphrenic abscess, liver failure, renal failure, pleural
effusions, and pneumothorax; rates of complications vary from 11% to 74%.
In the United States, primary liver cancer represents a minority of
hepatic tumorsonly 2.5% of all new cancers. By far, the
majority of hepatic tumors seen are metastatic lesions, most often of
Again, with colorectal metastases to the liver, surgical resection
has proven to be an effective means of treatment. Patients with
unresected tumors seldom survive beyond 5 years, with a median
survival of 3 to 24 months. In contrast, reports of surgical
resection have demonstrated a 20% to 50% overall 5-year survival rate.[7,8]
Furthermore, resection of recurrent hepatic metastases has proven
beneficial as well. Nearly 80% of patients develop a recurrence of
disease after hepatic resection, and yet, in 35% to 40%, recurrence
is limited to the liver and re-resection may provide long-term survival.[10,11]
Accurate preoperative imaging studies are paramount in determining
appropriate treatment and predicting outcome. The most common imaging
methods include ultrasound, computed tomography (CT),
contrast-enhanced CT (CECT), and/or CT arterial portography (CTAP).
Recent advances in diagnostic imaging have greatly improved the
detection and characterization of hepatic lesions. Advances in CT
include the development of helical scanners that allow for rapid
sequence imaging and dynamic intravenous (IV) contrast enhancement.
Unfortunately, the prognostic abilities of contrast-enhanced CT are
still limited, as evidenced by the fluctuations in management
resulting from the findings of intraoperative ultrasound (IOUS).
This inability to accurately depict lesions preoperatively can have
an enormous impact on patient care, with respect to therapeutic
options and outcome, the patients psychological state, and the
cost of care delivered.
Advances in magnetic resonance imaging (MRI) offer great promise for
improving preoperative imaging capabilities. New imaging techniques,
including fast spin-echo and gradient-echo techniques, permit rapid
breath-hold image acquisition, thus eliminating significant
motion-induced artifact.[13-16] In addition, a number of IV contrast
agents have been developed that enhance the capabilities of MRI,
namely, iron oxide agents and specific hepatobiliary agents.
Three iron oxide contrast agents for liver imaging have been
developed thus far: AMI-25 (Feridex I.V.), SHU-555A (Resovist
Injection), and AMI-227 (Combidex). Feridex I.V. was the first liver
specific contrast agent developed. It uses iron oxide particles as
negative contrast agents to enhance hepatic imaging. Resovist
Injection is a contrast agent similar to Feridex I.V., but it can be
administered by bolus injection rather than infusion. Combidex
differs from the other two iron oxide agents because it consists of
smaller iron-oxide particles. The primary indication for Combidex is
lymph node imaging, but it can also be used for liver imaging.
Feridex I.V. is the only ferumoxides contrast agent currently
available commercially in the U.S. It has been studied extensively,
and its pharmacologic and radiographic properties are well known.
Feridex I.V. is currently administered as a dilute IV infusion over a
30-minute period. Overall, side effects from Feridex I.V. infusion
occur in 10% to 15% of patients and are well tolerated, although
hypotension may still occur in 1% to 2% of patients.
The most common side effects are lower back pain (4%), flushing (2%),
various combined gastrointestinal complaints (5.6%), and an
assortment of other sporadic discomforts. Back pain typically
resolves spontaneously and permits continued contrast infusion.
The theory behind image enhancement with iron oxide contrast agents
rests on the magnetic properties of iron oxide and its affinity for
the reticuloendothelial system. The contrast agent is composed of
crystalline iron oxide particles coated with a surface molecule,
typically a polysaccharide that helps stabilize the particles in
aqueous solution. Paramagnetic ions, such as Fe2+ and Fe3+,
produce domains of spontaneous magnetization when packed closely in
a crystalline structure. The number of domains depends on the
particle size. Larger particles produce multiple domains of
magnetization, while smaller particles produce single domains.
Groups of single-domain particles are particularly susceptible to
external magnetic fields, resulting in super-paramagnetic properties.
When such a field is applied to iron oxide particles, a large
heterogeneous magnetic field results that can be used to enhance MR
images. More specifically, the particles cause increased spin
dephasing upon magnetic resonance (MR) excitation and relaxation,
resulting in a significant reduction in normal liver signal,
especially on T2-weighted images.
Furthermore, iron oxide particles are particularly suited for hepatic
imaging because they are cleared from the blood by phagocytosis. This
results in uptake of the particles by the liver, spleen, bone marrow,
and lymph nodes. Kupffer cells take up iron oxide particles, which
results in a signal loss of T-2 weighted images.
Hepatic tumors, particularly metastatic lesions, cannot take up iron
oxide particles because they either do not contain Kupffer cells or
their activity is reduced. This difference in uptake of contrast
medium results in an improved depiction of metastatic lesions on MR
images (Figure 1).
Comparisons With Other Modalities
Reports of hepatic imaging with ferumoxides have demonstrated its
improved ability to detect focal lesions by increasing the ratio of
lesion-to-background signal intensity. Iron oxide-enhanced MRI has
proven to be more sensitive than unenhanced MRI in detecting focal
hepatic lesions. In a large multicenter trial, iron oxide
enhanced MRI identified 27% more lesions.
Theoretically, iron oxide MRI will improve the detection and
characterization of intrahepatic lesions, resulting in more accurate
staging, more reliable treatment plans and options, and better
selection of surgical candidates. Thus, unnecessary or deleterious
surgery could be avoided, realistic patient expectations maintained,
and medical resources used more efficiently.
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