Radioembolization for liver tumors

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Chapter 84A Radioembolization for liver tumors

Overview

Interventional oncology is a field that is establishing its role in the management of liver tumors. The techniques used in this field are targeted to the tumors to allow delivery of toxic chemotherapeutic, radiotherapeutic, and thermal doses with minimal toxicity to normal structures; this minimizes the systemic toxicity associated with these therapeutic options and allows delivery of doses to the tumor that would not be possible using systemic delivery methods. In this chapter, the general concepts associated with radioembolization and its specific use in different primary and secondary malignancies of the liver will be discussed (Table 84A.1)

History of Radioembolization

External Radiation (See Chapter 84B)

The use of external radiation for liver tumors has traditionally held limited value because of the sensitivity of the normal hepatic parenchyma to the radiation dose (Ingold et al, 1965; Geschwind et al, 2004). A dose greater than 35 Gy has led to the development of a radiation-induced liver disease (RILD); a clinical syndrome of ascites, anicteric hepatomegaly, and elevation of liver enzymes. Conformal-beam therapy, which uses a three-dimensional approach rather than broad axial plane techniques, has been shown to minimize the toxicity to normal hepatic parenchyma (Dawson et al, 1999). However, even when using conformal-beam therapy, the radiation delivered to normal hepatic parenchyma limits the maximum dose that can be delivered to the tumor without compromising safety.

External-beam radiation had limitations in treating liver tumors in specific locations; this includes tumors near the dome of the liver, which carry the risk of exposing the lungs to radiation and increasing the risk of radiation pneumonitis, and tumors in the caudate lobe in close proximity to the porta hepatis, where risk of damage to the major biliary and vascular structures is a consideration. Dose fractionation, dose delivery to the tumor in fractions, is beneficial in targeting radiosensitive and radioresistant malignant cells at different sessions, but multiple treatments are required. The normal tissue complications probability (NTCP) is an important parameter when calculating radiation dose delivery (Dawson et al, 2002), but its use has been challenged (Langer et al, 1998). Respiratory movement must be considered to minimize the incidence of normal tissue complications, although recent advances in the technology of external-beam radiation have been shown to increase safety and efficacy of this technique, such as stereotactic body radiotherapy, proton radiotherapy, and carbon ion radiotherapy; these are establishing the role of external-beam radiotherapy in the management of liver tumors (Dawson & Guha, 2008; Fukumitsu et al, 2009; Nomiya et al, 2008).

Radioembolization

Given the distinct vasculature of hepatic tumors described above, radioembolization provides a mode of delivering localized radiotherapy to the tumor. A radiation dose of up to 150 Gy can be administered, minimizing the complications of external radiation. Radioembolization has been shown to have promising outcomes in primary and secondary hepatic malignancies by numerous investigators.

Radioembolization was first studied by Nolan and Grady (1969) using yttrium-90 oxide (90Y2O3) contained in a metal particle 50 to 100 µm in size. Their study consisted of a small number of patients but showed a favorable response, observed by the reduction in size of palpable masses. The next 90Y study was published in 1982 by Mantravadi and colleagues and studied the effect and distribution of 90Y after whole-liver delivery via the hepatic artery; the authors concluded that patients with hypervascular tumors are much more likely to benefit from this treatment. A dose-escalation study on animals was performed, which formed the basis of the Phase I dose-escalation evaluations in humans (Wollner et al, 1987). Shepherd and colleagues (1992) conducted a Phase I dose-escalation study using 90Y microspheres in 10 patients. Extrahepatic shunting was assessed using technetium-99m–labeled macroaggregated albumin (99mTc-MAA). In contrast to earlier studies, none of the patients in this study experienced hematologic toxicity, a fact that emphasizes the value of assessing angiographic findings and extrahepatic shunting before treatment (Shepherd et al, 1992). The technical aspects of dosimetry, radioassays, safety, and efficacy were discussed by many studies that followed (Andrews et al, 1994; Yan et al, 1993). Lau and colleagues (1994) showed that tumor response was proportional to the dose delivered, with improved survival in patients receiving more than 120 Gy. Recent data on the safety and efficacy of this treatment are discussed below.

90YTTRIUM Microspheres

Pretreatment Evaluation

Pretreatment Angiography and Coil Embolization

Radioembolization requires pretreatment diagnostic mesenteric angiography. The aortogram, superior mesenteric angiogram, and celiac trunk angiogram allow the interventional radiologist an opportunity to study the vascular anatomy of the liver and its surrounding structures in detail. The patency of the portal vein and the presence of arterioportal shunting are assessed. The inadvertent spread of the microspheres is prevented by a meticulous study of the vascular anatomy of the liver and collateral nontarget flow (Covey et al, 2002). Coil embolization of nontarget vessels may be necessary to decrease the unintended deposition of microspheres. Some examples of vessels that may need to be embolized are inferior esophageal, left inferior phrenic, accessory left gastric, supraduodenal, and retroduodenal arteries. The minimal incidence of complications following coil embolization and the grave clinical consequences associated with the inadvertent deposition of microspheres in the stomach, duodenum, or pancreas favor prophylactic coil embolization before radioembolization in select cases.

Available Devices

TheraSphere

TheraSphere (MDS Nordion, Ottawa, ON, Canada) consists of nonbiodegradable glass microspheres with diameters ranging from 20 to 30 µm. It was approved by the Food and Drug Administration (FDA) in 1999 and recently has been approved for use in hepatocellular carcinoma (HCC) patients with portal vein thrombosis (PVT). Vials of six different activities are available; the only difference in the vials is the number of spheres; 1.2 million microspheres are present in a vial with an activity of 3 GBq. Each microsphere has an activity of 2500 Bq at the time of calibration. The activity of the vial varies inversely with the time elapsed after calibration.

Dose Calculation for TheraSphere

The calculation of the dose requires the use of three-dimensional reconstruction of the target site to calculate the volume of the liver to be infused. The volume in cubic centimeters is then used to calculate the mass in grams by multiplying it by a factor of 1.03.

The activity (A) in GBq administered to the target area of the liver, assuming uniform distribution of microspheres (Fig. 84A.1A), is calculated using the following formula:

image

D is the dose administered in Grays, and m is the mass in kilograms. Using this formula, it can be said that a dose of 50 Gy will be administered to 1 kg of tissue if 1 GBq of 90Y is given.

The dose given to the treated mass also depends on the percent residual activity (R) in the vial after treatment and the LSF, which is calculated beforehand. These factors are accounted for in the following formula:

image

SIR-Spheres

SIR-Spheres (Sirtex Medical, Woburn, MA) consist of biodegradable resin microspheres that have a slightly increased diameter and lower specific gravity per microsphere than TheraSphere. The use of SIR-Spheres was approved by the FDA for metastatic colorectal cancer to the liver in 2002. One vial of 3 GBq is available with 40 to 80 million microspheres, with each microsphere measuring from 20 to 60 µm.

As suggested by the small particle size, the embolic effect of the available microscopic spheres is minimal. They are known to lodge in the precapillary arterioles, but their small size also allows deep penetration into the tumor with minimal changes in the vascular supply to the tumor. It has been suggested that hypoxia of the tumors induced by embolization, instead of anoxia, may lead to the release of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1, which may lead to neovascularization of the tumor and subsequent incomplete necrosis and tumor recurrence.

New Concepts

Radiation Segmentectomy

Recently, the concept of radiation segmentectomy has been discussed. This is schematically shown in Figure 84A.1B. The current dosimetry models assume lobar infusion; however, if the tumor is localized to two or fewer liver segments, the interventional radiologist can infuse the dose at the segmental level. This maximizes the dose delivery to the tumor and minimizes delivery of radioactive microspheres to the normal parenchyma (Riaz et al, 2010), an approach that has proven to be a safe and effective method of treatment delivery.

Extended Shelf Life Microspheres

Lewandowski and colleagues (2009b) recently published a report on the concept of extended shelf life microspheres, which can be used for large or multifocal tumors. As stated above, the difference in vials of different activities is the number of microspheres. If the vials of high activities (more microspheres) are allowed to stay on the shelf longer, the activity per microsphere will decrease. This allows the delivery of a higher number of microspheres to larger volumes of the liver with minimal radiotoxicity to the normal parenchyma (Lewandowski et al, 2009b).

Radiation Lobectomy

An animal study concluded that portal fibrosis was seen after the use of radioactive microspheres (Wollner et al, 1988). Gaba and colleagues (2009) recently published a comprehensive analysis on the concept of radiation lobectomy, whereby infusion at the lobar level was used to treat the tumors. Because of fibrosis of the normal parenchyma, decreases in volumes of the treated lobe were seen. Furthermore, compensatory increases in the volumes of the untreated lobes were also observed.