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 of 55%.[2-4]
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 colorectal origin.
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.