Review Articles
Radioembolization with 90Yttrium Microspheres: A State-of-the-Art Brachytherapy Treatment for Primary and Secondary Liver Malignancies: Part 2: Special Topics

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Yttrium-90 microspheres are increasingly being used as a treatment modality for primary and secondary liver tumors. As these therapies continue to be accepted, it is natural that their application in more complex clinical scenarios will become more common. This article is meant to introduce these controversies and to generate interest and dialogue by the interventional oncology community. This discussion is based on more than 900 90Y radioembolization procedures performed over a 5-year period.

Section snippets

PATIENT SELECTION FOR 90Y VERSUS TACE IN HCC

Patient selection is one of the most frequent areas of debate. The question often arises how to select a patient who might benefit from 90Y versus TACE.

For years, TACE was assumed to provide a survival advantage over supportive care despite several randomized trials with results to the contrary (2, 3, 4, 5, 6). Secondary outcomes such as tumor response, lack of enhancement, and promising survival in comparison with historical untreated control individuals justified the use and adoption of this

RATIONALE FOR USE OF 90Y THERAPY VERSUS TACE IN METASTATIC DISEASE

Although no randomized data support the use of liver-directed therapies such as TACE for metastatic disease to the liver, abundant phase II studies support this indication (16, 17, 18, 19, 20). Response rates ranging from 35% to 100% dispel the notion that metastatic lesions do not respond to arterial treatment given their perceived hypovascularity.

The term “hypovascularity” in reference to metastatic lesions should be further explored. Although it is true that, relative to normal hepatic

COMPLICATIONS OF 90Y INFUSION

Other than the mild postembolization symptoms that may occur after administration of 90Y, the most common complications of radioembolization include nontarget radiation (ie, gastrointestinal ulceration, pancreatitis), radiation pneumonitis, and radiation-induced liver disease (ie, radiation hepatitis) (12, 24, 25, 26, 27, 28, 29). The incidence of nontarget radiation should be minimized if the technical principles described earlier are followed, including aggressive embolization of collateral

PATIENTS WITH INCREASED BILIRUBIN LEVELS: 90Y VERSUS TACE

It can be quite difficult to predict clinical toxicities that might be observed in a patient undergoing TACE. Although risk factors have previously been described, patients who have normal biochemical parameters may still experience treatment toxicities. This is also true of radioembolization.

In the absence of metabolic abnormalities, drug toxicities, or biliary obstruction, patients with increased bilirubin levels, by definition, have compromised hepatocyte function. In patients with HCC, this

LOBAR VERSUS WHOLELIVER TREATMENT

Although much of the early experience with 90Y involved whole-liver infusion, this treatment paradigm is no longer recommended (55, 56). Wholeliver treatment was undertaken because of the limitations in microcatheter technology and imaging. With the advent of 2.3-F and 3-F microcatheters, lobar and segmental infusions are recommended when possible. In addition, significant extrahepatic flow through small vessels can be avoided only with use of lobar or segmental infusions (34, 57). In our

TREATING PATIENTS AFTER RESECTION OR RADIOFREQUENCY ABLATION

The most common scenario involving resection in patients with HCC or colorectal metastases likely involves patients who have already undergone right hepatic lobectomy and in whom disease in the left lobe has now developed. In such cases, the left hepatic artery (and remnant of the right hepatic artery) has usually hypertrophied. The liver should be treated by a lobar approach, with embolization of all collateral vessels, as would be performed in other patients. In this case, the lobes include

TREATING PATIENTS AFTER TACE

The treatment of patients after TACE is an area of very frequent inquiry. The principles of TACE involve the slow and deliberate infusion of a mixture of oil and chemotherapeutic agent, followed by an embolic agent to (i) increase chemotherapy dwell time within the tumor and (ii) minimize systemic toxicity (60). Ideally, if superselective TACE is performed, the tumor vascular bed is saturated with oil/chemotherapy/embolic material while much of the normal parenchyma has been spared. The same is

COMBINATION RF ABLATION AND 90Y

Just as with TACE, there is much interest in combining 90Y therapy with RF ablation. The theory behind this might be to downstage tumors to sizes amenable to RF ablation (≤3 cm) or to create a multimodality approach in the management of liver tumors. Some have advocated the use of RF ablation before radioembolization in an attempt to create a zone of hyperemia and enhanced microsphere uptake. Others have suggested treating the tumors with radioembolization and then administering RF ablation

HEPATICOENTERIC ANASTOMOSES AND BILIARY STENTS

The treatment of patients with previous biliary surgery, hepaticoenteric anastomoses, or biliary stents deserves special mention. It is well recognized that these patients are at high risk for infection after embolic and ablative therapies (84, 85, 86). Given that blood supply to the biliary tree is via the 30-μm peribiliary plexus, 90Y microspheres may potentially flow into and have an effect on the biliary tree. When a patient has received a stent or has undergone surgery with violation and

CYSTIC ARTERY

The cystic artery may occasionally need to be addressed in the treatment of patients with 90Y. The cystic artery may arise from the right, left, proper hepatic artery, or GDA (34). Although the need for prophylactic embolization has never been advocated, our recent experience suggests that prophylactic cystic artery embolization may be considered. This approach is a reaction to two cases of radiation cholecystitis we have encountered among more than 400 patients treated (one case with each type

TREATING PATIENTS ON THE SAME DAY AS PLANNING MESENTERIC ANGIOGRAPHY

Several clinicians have addressed the possibility of treating patients on the same day as the planning mesenteric angiography. For this to be successful, a vial of 90Y (SIR-Spheres or TheraSphere) would have been ordered for that day, and the patient would undergo angiography with coil embolization of vessels, injection of 99mTc-MAA, and imaging in nuclear medicine, and would then return to the angiography suite for 90Y infusion. The shunting fraction and dosimetry calculations would be

RADIATION SEGMENTECTOMY: DOSIMETRY FOR SEGMENTAL OR SUBSEGMENTAL INFUSIONS

As described earlier, the activity of TheraSphere is based on dose required (in Gy) and target volume (in kg). There are cases in which the target tissue is small, there is a feeding vessel to the tumor only, and the 3-GBq activity of TheraSphere is not low enough to deliver 80–150 Gy to the tissue after decay. In such cases, radiation “segmentectomy” is advocated (57, 88). An example best illustrates this. On the basis of the dose decay curve, the lowest activity of TheraSphere available for

HYPERVASCULARITY AND TUMOR-TO-NORMAL UPTAKE RATIO

The therapeutic effect of 90Y microsphere therapy for treatment of liver cancers involves two fundamental principles: (i) most of the tumor blood supply (90%–95%) is derived from the hepatic artery, and (ii) blood flow is preferentially distributed to the tumor relative to normal liver tissue (89, 90, 91). As previously described, this preferential flow permits maximum concentration of the microspheres in the arterioles within the tumor while minimizing radiation exposure to the normal tissue

TREATING A PATIENT WITH INCREASED LUNG SHUNTING

The basic assumption of 90Y infusion and dosimetry is the homogeneous distribution of microspheres throughout the hepatic parenchyma resulting in the same radiation dose to the volume targeted for treatment. However, because tumors are fed almost exclusively by hepatic vasculature and are hypervascular relative to normal parenchyma, this assumption breaks down in a favorable direction. Consequently, hypervascular tumors receive higher doses while normal parenchyma is exposed to minimal

PORTAL VEIN THROMBOSIS: AN EXCLUSIONARY CRITERION?

Increased alkaline phosphatase, aspartate aminotransferase, lactate dehydrogenase, and total bilirubin levels before TACE are associated with increased relative risk for hepatic decompensation (60, 104, 105, 106). In addition, the presence of portal vein thrombosis without cavernous transformation and hepatopetal flow is a well-accepted relative contraindication for percutaneous embolization of liver tumors, despite reports to the contrary (107, 108, 109). Controversy exists concerning whether

IMAGING EVALUATION OF TUMOR RESPONSE IN PATIENTS WITH HCC AND METASTATIC DISEASE: CAUTIONS REGARDING INTERPRETATION

The clinical treatment of patients with metastatic cancer receiving 90Yis different from that for patients with HCC. Aside from demographics, other differentiating features include liver function, tumor markers, chemotherapy, and surgical history, as well as differences in the appearance of tumors within the context of background liver on imaging.

Hepatomas usually arise in diseased liver, a condition characterized by intrinsic hepatocyte dysfunction, often in a background of chronic hepatitis

LONG-TERM FOLLOW-UP

Standard treatment response is assessed and reviewed with the patient 3 months after treatment. At that time, a repeat series of laboratory tests is performed, including liver function, tumor marker measurements, and complete blood count. Cross-sectional imaging including CT or MR imaging, as well as PET, is repeated to assess overall response on the basis of changes in lesion size, enhancement characteristics, or reduction in standard uptake values (112, 113). Although transient changes in

SUMMARY

In most cases of 90Y treatment, patient selection, treatment planning, treatment, and clinical follow-up are relatively straightforward. However, as with any therapeutic endeavor, there are exceptions to the routine. Gastrointestinal and liver-related treatmentemergent complications, although infrequent, should be managed accordingly. Lobar or segmental 90Y infusion beyond major collateral vessels is recommended to minimize deposition of microspheres to nontarget tissue. Prophylactic antiulcer

Acknowledgments

The authors thank the following individuals for their contribution to this review: Beth Oman, Agnieszka Stanisz, Karen Barrett, Krystina Sajdak, Margaret Gilbertsen, and Vanessa Gates. In particular, we would like to thank Angi Courtney for her contribution to this article.

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    R.S. is a consultant for MDS Nordion (Kanata, ON, Canada) and has lectured for Sirtex Medical (Lane Cove, Australia). K.G.T. is Director of Clinical Affairs for MDS Nordion. No research support was provided for this manuscript, and neither manufacturer had any input in this document.

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    Copyright © 2006 Society of Interventional Radiology. Published by Elsevier Inc. All rights reserved.