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Recent Advances in Transarterial Therapy of Primary and Secondary Liver Malignancies¹

¹ From the Division of Cardiovascular Intervention, Department of Radiology, Massachusetts General Hospital, Gray 2, 55 Fruit St, GRB-290, Boston, MA 02114. Presented as an education exhibit at the 2006 RSNA Annual Meeting. Received May 16, 2007; revision requested June 13 and received July 19; accepted August 20. S.P.K. and S.W. received funding from Johnson & Johnson (Cordis) and Cook Group; A.T. has no financial relationships to disclose. Address correspondence to S.P.K. (e-mail: skalva{at}partners.org).

	Abstract

Top Abstract Introduction Physiologic Basis of... Indications for Transarterial... Use of Drug-eluting Microspheres Use of Radiation-emitting... Gene Therapy Conclusions References

 
The management of liver malignancies presents many challenges. Few patients with primary hepatocellular carcinoma or metastatic disease of the liver are eligible for surgery, which is the only curative therapeutic option. Because the hepatic tumor burden is often a determinant of eligibility for surgery and is a primary contributor to morbidity and mortality, an increasing number of innovative techniques based on the transarterial administration of liver-directed drug-eluting or radiation-emitting microspheres are being tested for use in cytoreductive and palliative therapy. The delivery of therapy via a transarterial route takes advantage of the fact that hepatic malignancies are primarily supplied by the hepatic artery. The early results of clinical trials are promising; the clinical effectiveness and safety of drug-eluting and yttrium-90–bearing microspheres have been demonstrated; however, further clinical investigation is needed to verify a benefit in survival. Transarterially administered gene therapy holds promise but is still in the early stages of investigation. For all transarterial therapies, the outcome depends heavily on meticulous patient selection, careful preparation and administration of therapy, and early and regular follow-up evaluations by using an interdisciplinary approach.

© RSNA, 2008

	Introduction

Top Abstract Introduction Physiologic Basis of... Indications for Transarterial... Use of Drug-eluting Microspheres Use of Radiation-emitting... Gene Therapy Conclusions References

 
Hepatocellular carcinoma is the most common primary malignancy of the liver, with an annual incidence of more than 1 million worldwide. There are multiple risk factors, including viral infection and alcohol abuse; hepatitis C viral infection accounts for many cases in the United States (1). Surgical resection and liver transplantation are the only curative therapies; unfortunately, only 10% of patients are eligible for surgery (2,3). Hepatocellular carcinoma is associated with a dismal prognosis because most cases are diagnosed at an advanced stage (4). Moreover, the tumors are resistant to chemotherapy (3) and are less vulnerable than normal hepatic parenchyma to radiation therapy (5). In addition, patients frequently have a poor hepatic reserve because of cirrhosis, portal vein thrombosis, or both. The estimated median survival is only 8 months. Most patients die of tumor progression or underlying cirrhosis (1,2).

The liver is also a common site of metastatic disease. For instance, more than 145,000 cases of colorectal cancer are diagnosed each year, and hepatic metastases develop in approximately half of those cases (1,6). The liver is a frequent site of metastases from colorectal cancer because of portal venous drainage of bowel. In most patients, metastases from colorectal cancer affect only the liver; unfortunately, because of the size and number of the lesions at the time of diagnosis, few such patients are candidates for surgical resection or localized therapies such as radiofrequency ablation (6,7) and cryotherapy (8). The first-line therapy for advanced colorectal cancer therefore is systemic chemotherapy or chemotherapy delivered with a hepatic arterial infusion (9,10).

Because of the high mortality associated with untreated primary and secondary hepatic malignancies, an increasing number of innovative therapies are being tested. Transarterial therapies (Table 1) take advantage of the dual blood supply of the liver: The hepatic artery predominantly supplies hepatocellular carcinoma and metastatic deposits, whereas normal liver parenchyma depends primarily on portal venous blood (11). Traditional transarterial therapies are based on the infusion of chemotherapeutic drugs into the hepatic artery either intermittently or through a surgically implanted hepatic artery pump. Such therapies also may include the use of bland embolization to induce tumor ischemia. For example, transarterial chemoembolization (TACE) is a catheter-based technique that combines both regional chemotherapy and embolization to increase the dwell time of cytotoxic agents and induce ischemia in the tumor.

	Physiologic Basis of Transarterial Therapy

Top Abstract Introduction Physiologic Basis of... Indications for Transarterial... Use of Drug-eluting Microspheres Use of Radiation-emitting... Gene Therapy Conclusions References

 
Approximately 80% of the blood supply to hepatocellular carcinoma and hepatic metastases from colorectal cancer arrives via the hepatic artery, whereas three-fourths of the blood supply to normal hepatic parenchyma is portal venous (11). Hence, cytotoxic agents that are infused selectively into the hepatic artery preferentially target tumor cells over normal hepatic tissue. Some hepatic metastases that do not demonstrate significant contrast enhancement at imaging do demonstrate increased uptake after the intraarterial injection of technetium-99m (^99mTc) macroaggregated albumin (MAA), which suggests the hypervascularity of these metastases relative to normal hepatic parenchyma (12–14). In addition, direct infusion via the hepatic artery avoids the first-pass metabolism of chemotherapeutic agents administered orally or intravenously. Indeed, the localized infusion of chemotherapeutic agents via the hepatic artery by using a surgically implanted pump is a method that has been in use for several decades (10).

Conventional TACE therapy, in which arterial inflow is reduced to delay drug washout, enables chemotherapeutic drug concentrations within a tumor that are up to 100 times greater than those achievable with systemic chemotherapy (15–17). Further tumor selectivity is achieved when chemotherapeutic agents (usually a combination of doxorubicin, cisplatin, and mitomycin C) are mixed with lipiodol, an iodized oil that acts as a carrier and that preferentially remains in the tumor because of the absence there of Kupffer cells, the phagocytes that are active in normal parenchyma (15). Several studies demonstrated a positive survival benefit after TACE therapy administered to patients with unresectable hepatocellular carcinoma who had been selected according to specific criteria (18,19). However, although embolic techniques are expected to induce ischemia in tumors, there is evidence that such ischemia may lead to tumor angiogenesis (20). In addition, the plasma levels of chemotherapeutic agents in patients treated with standard TACE therapy are as high as those in patients treated with systemic chemotherapy, and high plasma levels are associated with greater systemic toxic effects. The new therapies currently under investigation with the goal of reducing systemic toxic effects produce lower plasma levels of chemotherapeutic agents (21).

	Indications for Transarterial Therapy

Top Abstract Introduction Physiologic Basis of... Indications for Transarterial... Use of Drug-eluting Microspheres Use of Radiation-emitting... Gene Therapy Conclusions References

 
Surgical resection and liver transplantation are the only curative therapies for hepatocellular carcinoma. In patients who are not surgical candidates with a minimal or no extrahepatic tumor burden, transarterial therapies may be useful for palliative cytoreduction (22); in some patients, the use of transarterial cytoreductive therapies may even help make transplantation feasible (23,24). However, transarterial therapies must be used with caution in patients with hepatic dysfunction from underlying cirrhosis, because these therapies may result in a further deterioration of hepatic function.

The first-line treatment for unresectable hepatic metastases from colorectal cancer is chemotherapy, which may be administered systemically or with a hepatic arterial infusion. Because the progression of hepatic disease contributes significantly to morbidity and mortality, transarterial therapies may be used for palliative or adjuvant therapy, to help stabilize disease or to reduce the hepatic tumor burden (25,26).

	Use of Drug-eluting Microspheres

Top Abstract Introduction Physiologic Basis of... Indications for Transarterial... Use of Drug-eluting Microspheres Use of Radiation-emitting... Gene Therapy Conclusions References

 
Drug-eluting microspheres are made of polyvinyl alcohol hydrogel and are biocompatible, hydrophilic, and nonresorbable. They are specifically designed to sequester doxorubicin hydrochloride from solution (27). The primary advantage of using drug-eluting microspheres for chemotherapy is the sustained release of the chemotherapeutic agent over a long period of time, which contrasts with the more rapid release of the agents from the lipiodol solution in standard TACE therapy (27–29). With a controlled gradual and local release, contact time of the drugs with the tumor is greater and plasma levels of the drugs are lower than those with standard TACE therapy (27–29).

Preprocedural planning with cross-sectional imaging and liver function testing is imperative. Accurate staging of disease by assessing the intrahepatic and extrahepatic tumor burden is crucial to exclude the possibilities of surgical therapy, radiofrequency ablation, and cryotherapy. Cross-sectional imaging can be extremely useful for assessing the hepatic arterial anatomy and portal vein patency.

Pharmacokinetics
Drug loading and elution kinetics are dependent on the particle size. For example, DC Beads (Bio-compatibles UK, Surrey, England) are manufactured in various sizes ranging from 100 to 1200 µm. The maximum single treatment and lifetime doses for doxorubicin are 150 mg and 450 mg per square meter of body surface area, respectively, because of the potential for toxic effects on cardiac function (27,30). For a specific drug concentration, smaller microspheres require less time for drug loading than larger ones do, with a loading efficiency of 99% up to a maximum concentration of 45 mg/mL (27). For a recommended concentration of 25 mg/mL, typical loading times range from 20 to 120 minutes, depending on the microsphere size. Higher drug concentrations require more time for loading. Elution kinetics are similarly affected by microsphere size, with smaller microspheres eluting more quickly than larger ones (27). In an in vitro assessment of drug elution from microspheres loaded at a concentration of 25 mg/mL, the minimum half-life was 150 hours for microspheres with a size of 100–300 µm, and the maximum half-life was 1730 hours for microspheres with a size of 700–900 µm (27). In comparison, in an in vitro assessment of drug elution from a lipiodol emulsion (used as a surrogate for standard TACE therapy), no sustained drug release was demonstrated; the calculated half-life was 1 hour.

A comparison of plasma doxorubicin concentrations after therapy with drug-eluting microspheres as opposed to standard TACE therapy demonstrated that the peak drug concentration as well as the area under the curve is significantly lower after therapy with drug-eluting microspheres than after standard TACE therapy (21). This finding implies a lesser potential for systemic toxic effects with the use of drug-eluting microspheres than with standard TACE therapy.

Preparation and Administration
The microspheres may be loaded with doxorubicin immediately before the procedure. First, the doxorubicin is reconstituted with sterile water, the saline solution in the vial of microspheres is removed, and the doxorubicin solution is added. Drug loading of the microspheres can be monitored by noting the disappearance of the red color of the solution as the microspheres take on a red color. Depending on the microsphere size, drug loading may take 20–120 minutes (for DC Beads) for a doxorubicin concentration of 25 mg/mL (27). An equal volume of a contrast medium is then added before the solution is infused via a catheter into the hepatic artery.

The size of the microspheres and their concentration in the solution should be adjusted according to the tumor volume and the degree of arteriovenous shunting. The doxorubicin dosage also should be adjusted for both body surface area and bilirubin level. Baseline angiography of the celiac, superior mesenteric, and hepatic arteries, as well as indirect portal venography, should be performed to determine the vascular anatomy and assess tumor vascularity. Selective catheterization of the hepatic arterial branches supplying the tumor may be performed to maximize the deposition of drug-eluting microspheres in the tumor and minimize the exposure of normal hepatic parenchyma to chemotherapeutic agents (Fig 1). Administration through the proper hepatic artery is also feasible for treatment of bilobar disease. In patients with variant arterial anatomy, such as a replaced left hepatic artery or a middle hepatic artery, bilobar disease may be treated incrementally by dividing the drug dose and infusing separate portions into the individual hepatic arteries (Fig 2). After the infusion of drug-eluting microspheres, a solution containing bland microspheres (without drugs) may be administered to achieve complete embolization, which is characterized as the cessation of flow in the catheterized vessel.

View larger version (125K): [in this window] [in a new window] [Download PPT slide]   Figure 1a.  Imaging evaluation for planning of transarterial therapy with doxorubicin-eluting microspheres for hepatocellular carcinoma in a 56-year-old man with a hepatitis C viral infection and cirrhosis. (a) Axial T1-weighted fat-saturated magnetic resonance (MR) image obtained after the administration of a gadolinium-based contrast material demonstrates a 4.3-cm arterially enhancing lesion (arrow) in segment VII of the liver and a 1.4-cm lesion with a similar appearance (arrowhead) in segment VIII. There was a third lesion in liver segment VII, as well as right portal vein and right hepatic vein tumor thrombi (not shown). (b) Hepatic angiogram obtained at the level of the proper hepatic artery (arrowhead) depicts a hypervascular lesion (arrows) with an appearance suggestive of hepatocellular carcinoma. Subsequently, 300–500-µm microspheres bearing a dose of 100 mg of doxorubicin were administered.

View larger version (112K): [in this window] [in a new window] [Download PPT slide]   Figure 1b.  Imaging evaluation for planning of transarterial therapy with doxorubicin-eluting microspheres for hepatocellular carcinoma in a 56-year-old man with a hepatitis C viral infection and cirrhosis. (a) Axial T1-weighted fat-saturated magnetic resonance (MR) image obtained after the administration of a gadolinium-based contrast material demonstrates a 4.3-cm arterially enhancing lesion (arrow) in segment VII of the liver and a 1.4-cm lesion with a similar appearance (arrowhead) in segment VIII. There was a third lesion in liver segment VII, as well as right portal vein and right hepatic vein tumor thrombi (not shown). (b) Hepatic angiogram obtained at the level of the proper hepatic artery (arrowhead) depicts a hypervascular lesion (arrows) with an appearance suggestive of hepatocellular carcinoma. Subsequently, 300–500-µm microspheres bearing a dose of 100 mg of doxorubicin were administered.

View larger version (118K): [in this window] [in a new window] [Download PPT slide]   Figure 2a.  Imaging evaluation for planning of doxorubicin-eluting microsphere therapy for hepatocellular carcinoma in a 54-year-old man with a hepatitis C viral infection and cirrhosis. (a) Contrast-enhanced computed tomographic (CT) image of the abdomen demonstrates enhancing lesions (arrows) in both lobes of the liver, findings indicative of hepatocellular carcinoma. (b) Celiac arteriogram depicts an aberrant origin of the right hepatic artery (straight arrow) from the common hepatic artery, as well as termination of the latter in the gastroduodenal artery (arrowhead) and middle hepatic artery (curved arrow). (c) Arteriogram obtained at the level of the left gastric artery (arrowhead) shows a replaced left hepatic artery (arrow). (d, e) Selective angiograms of the right (d) and left (e) hepatic arteries show tumor hypervascularity (arrows). On the basis of these findings, one-half the total dose of 300–500-µm drug-eluting microspheres containing 100 mg of doxorubicin was administered via the right hepatic artery, and the remaining half-dose was split equally between the left and middle hepatic arteries. (f) Contrast-enhanced CT image of the abdomen, obtained 6 weeks after transarterial therapy, depicts areas of necrosis (arrows) in both tumors.

View larger version (140K): [in this window] [in a new window] [Download PPT slide]   Figure 2b.  Imaging evaluation for planning of doxorubicin-eluting microsphere therapy for hepatocellular carcinoma in a 54-year-old man with a hepatitis C viral infection and cirrhosis. (a) Contrast-enhanced computed tomographic (CT) image of the abdomen demonstrates enhancing lesions (arrows) in both lobes of the liver, findings indicative of hepatocellular carcinoma. (b) Celiac arteriogram depicts an aberrant origin of the right hepatic artery (straight arrow) from the common hepatic artery, as well as termination of the latter in the gastroduodenal artery (arrowhead) and middle hepatic artery (curved arrow). (c) Arteriogram obtained at the level of the left gastric artery (arrowhead) shows a replaced left hepatic artery (arrow). (d, e) Selective angiograms of the right (d) and left (e) hepatic arteries show tumor hypervascularity (arrows). On the basis of these findings, one-half the total dose of 300–500-µm drug-eluting microspheres containing 100 mg of doxorubicin was administered via the right hepatic artery, and the remaining half-dose was split equally between the left and middle hepatic arteries. (f) Contrast-enhanced CT image of the abdomen, obtained 6 weeks after transarterial therapy, depicts areas of necrosis (arrows) in both tumors.

View larger version (129K): [in this window] [in a new window] [Download PPT slide]   Figure 2c.  Imaging evaluation for planning of doxorubicin-eluting microsphere therapy for hepatocellular carcinoma in a 54-year-old man with a hepatitis C viral infection and cirrhosis. (a) Contrast-enhanced computed tomographic (CT) image of the abdomen demonstrates enhancing lesions (arrows) in both lobes of the liver, findings indicative of hepatocellular carcinoma. (b) Celiac arteriogram depicts an aberrant origin of the right hepatic artery (straight arrow) from the common hepatic artery, as well as termination of the latter in the gastroduodenal artery (arrowhead) and middle hepatic artery (curved arrow). (c) Arteriogram obtained at the level of the left gastric artery (arrowhead) shows a replaced left hepatic artery (arrow). (d, e) Selective angiograms of the right (d) and left (e) hepatic arteries show tumor hypervascularity (arrows). On the basis of these findings, one-half the total dose of 300–500-µm drug-eluting microspheres containing 100 mg of doxorubicin was administered via the right hepatic artery, and the remaining half-dose was split equally between the left and middle hepatic arteries. (f) Contrast-enhanced CT image of the abdomen, obtained 6 weeks after transarterial therapy, depicts areas of necrosis (arrows) in both tumors.

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 2d.  Imaging evaluation for planning of doxorubicin-eluting microsphere therapy for hepatocellular carcinoma in a 54-year-old man with a hepatitis C viral infection and cirrhosis. (a) Contrast-enhanced computed tomographic (CT) image of the abdomen demonstrates enhancing lesions (arrows) in both lobes of the liver, findings indicative of hepatocellular carcinoma. (b) Celiac arteriogram depicts an aberrant origin of the right hepatic artery (straight arrow) from the common hepatic artery, as well as termination of the latter in the gastroduodenal artery (arrowhead) and middle hepatic artery (curved arrow). (c) Arteriogram obtained at the level of the left gastric artery (arrowhead) shows a replaced left hepatic artery (arrow). (d, e) Selective angiograms of the right (d) and left (e) hepatic arteries show tumor hypervascularity (arrows). On the basis of these findings, one-half the total dose of 300–500-µm drug-eluting microspheres containing 100 mg of doxorubicin was administered via the right hepatic artery, and the remaining half-dose was split equally between the left and middle hepatic arteries. (f) Contrast-enhanced CT image of the abdomen, obtained 6 weeks after transarterial therapy, depicts areas of necrosis (arrows) in both tumors.

View larger version (124K): [in this window] [in a new window] [Download PPT slide]   Figure 2e.  Imaging evaluation for planning of doxorubicin-eluting microsphere therapy for hepatocellular carcinoma in a 54-year-old man with a hepatitis C viral infection and cirrhosis. (a) Contrast-enhanced computed tomographic (CT) image of the abdomen demonstrates enhancing lesions (arrows) in both lobes of the liver, findings indicative of hepatocellular carcinoma. (b) Celiac arteriogram depicts an aberrant origin of the right hepatic artery (straight arrow) from the common hepatic artery, as well as termination of the latter in the gastroduodenal artery (arrowhead) and middle hepatic artery (curved arrow). (c) Arteriogram obtained at the level of the left gastric artery (arrowhead) shows a replaced left hepatic artery (arrow). (d, e) Selective angiograms of the right (d) and left (e) hepatic arteries show tumor hypervascularity (arrows). On the basis of these findings, one-half the total dose of 300–500-µm drug-eluting microspheres containing 100 mg of doxorubicin was administered via the right hepatic artery, and the remaining half-dose was split equally between the left and middle hepatic arteries. (f) Contrast-enhanced CT image of the abdomen, obtained 6 weeks after transarterial therapy, depicts areas of necrosis (arrows) in both tumors.

View larger version (125K): [in this window] [in a new window] [Download PPT slide]   Figure 2f.  Imaging evaluation for planning of doxorubicin-eluting microsphere therapy for hepatocellular carcinoma in a 54-year-old man with a hepatitis C viral infection and cirrhosis. (a) Contrast-enhanced computed tomographic (CT) image of the abdomen demonstrates enhancing lesions (arrows) in both lobes of the liver, findings indicative of hepatocellular carcinoma. (b) Celiac arteriogram depicts an aberrant origin of the right hepatic artery (straight arrow) from the common hepatic artery, as well as termination of the latter in the gastroduodenal artery (arrowhead) and middle hepatic artery (curved arrow). (c) Arteriogram obtained at the level of the left gastric artery (arrowhead) shows a replaced left hepatic artery (arrow). (d, e) Selective angiograms of the right (d) and left (e) hepatic arteries show tumor hypervascularity (arrows). On the basis of these findings, one-half the total dose of 300–500-µm drug-eluting microspheres containing 100 mg of doxorubicin was administered via the right hepatic artery, and the remaining half-dose was split equally between the left and middle hepatic arteries. (f) Contrast-enhanced CT image of the abdomen, obtained 6 weeks after transarterial therapy, depicts areas of necrosis (arrows) in both tumors.

View larger version (160K): [in this window] [in a new window] [Download PPT slide]   Figure 3a.  Complete response of hepatocellular carcinoma in a 49-year-old man after repeat treatment with doxorubicin-eluting microspheres. (a) Axial T1-weighted fat-saturated MR image, obtained after the administration of a gadolinium-based contrast material, demonstrates an arterially enhancing lesion (arrow) that extends into the right portal vein (arrowhead). The size of this solitary lesion (15 cm in the craniocaudal dimension) precluded liver transplantation. (b) Right hepatic arteriogram demonstrates tumor hypervascularity (arrows). Subsequently, an initial infusion of 300–500-µm drug-eluting microspheres containing a dose of 100 mg of doxorubicin was administered. (c) Follow-up MR image of the liver, obtained 1 month after therapy, shows an area lacking enhancement (arrow), a finding indicative of lesion necrosis. The anterior area of enhancement (arrowhead) is suggestive of residual viable tumor. The patient underwent repeat therapy with doxorubicin-eluting microspheres 1 week later. (d) Axial MR image obtained 4 months later shows no enhancement in the tumor (arrows), a finding indicative of necrosis. The tumor size also had decreased to 5 cm. Because of these changes, the patient was eligible for liver transplantation.

View larger version (126K): [in this window] [in a new window] [Download PPT slide]   Figure 3b.  Complete response of hepatocellular carcinoma in a 49-year-old man after repeat treatment with doxorubicin-eluting microspheres. (a) Axial T1-weighted fat-saturated MR image, obtained after the administration of a gadolinium-based contrast material, demonstrates an arterially enhancing lesion (arrow) that extends into the right portal vein (arrowhead). The size of this solitary lesion (15 cm in the craniocaudal dimension) precluded liver transplantation. (b) Right hepatic arteriogram demonstrates tumor hypervascularity (arrows). Subsequently, an initial infusion of 300–500-µm drug-eluting microspheres containing a dose of 100 mg of doxorubicin was administered. (c) Follow-up MR image of the liver, obtained 1 month after therapy, shows an area lacking enhancement (arrow), a finding indicative of lesion necrosis. The anterior area of enhancement (arrowhead) is suggestive of residual viable tumor. The patient underwent repeat therapy with doxorubicin-eluting microspheres 1 week later. (d) Axial MR image obtained 4 months later shows no enhancement in the tumor (arrows), a finding indicative of necrosis. The tumor size also had decreased to 5 cm. Because of these changes, the patient was eligible for liver transplantation.

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 3c.  Complete response of hepatocellular carcinoma in a 49-year-old man after repeat treatment with doxorubicin-eluting microspheres. (a) Axial T1-weighted fat-saturated MR image, obtained after the administration of a gadolinium-based contrast material, demonstrates an arterially enhancing lesion (arrow) that extends into the right portal vein (arrowhead). The size of this solitary lesion (15 cm in the craniocaudal dimension) precluded liver transplantation. (b) Right hepatic arteriogram demonstrates tumor hypervascularity (arrows). Subsequently, an initial infusion of 300–500-µm drug-eluting microspheres containing a dose of 100 mg of doxorubicin was administered. (c) Follow-up MR image of the liver, obtained 1 month after therapy, shows an area lacking enhancement (arrow), a finding indicative of lesion necrosis. The anterior area of enhancement (arrowhead) is suggestive of residual viable tumor. The patient underwent repeat therapy with doxorubicin-eluting microspheres 1 week later. (d) Axial MR image obtained 4 months later shows no enhancement in the tumor (arrows), a finding indicative of necrosis. The tumor size also had decreased to 5 cm. Because of these changes, the patient was eligible for liver transplantation.

View larger version (145K): [in this window] [in a new window] [Download PPT slide]   Figure 3d.  Complete response of hepatocellular carcinoma in a 49-year-old man after repeat treatment with doxorubicin-eluting microspheres. (a) Axial T1-weighted fat-saturated MR image, obtained after the administration of a gadolinium-based contrast material, demonstrates an arterially enhancing lesion (arrow) that extends into the right portal vein (arrowhead). The size of this solitary lesion (15 cm in the craniocaudal dimension) precluded liver transplantation. (b) Right hepatic arteriogram demonstrates tumor hypervascularity (arrows). Subsequently, an initial infusion of 300–500-µm drug-eluting microspheres containing a dose of 100 mg of doxorubicin was administered. (c) Follow-up MR image of the liver, obtained 1 month after therapy, shows an area lacking enhancement (arrow), a finding indicative of lesion necrosis. The anterior area of enhancement (arrowhead) is suggestive of residual viable tumor. The patient underwent repeat therapy with doxorubicin-eluting microspheres 1 week later. (d) Axial MR image obtained 4 months later shows no enhancement in the tumor (arrows), a finding indicative of necrosis. The tumor size also had decreased to 5 cm. Because of these changes, the patient was eligible for liver transplantation.

Liver abscess also reportedly has occurred as a complication of standard TACE therapy in an estimated 4.5% of patients, with a resultant mortality of 13.3% (32,33). The occurrence of liver abscesses after TACE therapy is most common in patients with a bilioenteric anastomosis. Typical prophylactic regimens with antibiotics such as cephalexin have not been proved effective for preventing liver abscesses, although they may reduce the frequency of occurrences of immediate and fatal sepsis (32). However, aggressive prophylactic therapy with broad-spectrum antibiotics in combination with a preprocedural bowel-cleansing regimen appears to prevent liver abscess in patients with bilioenteric anastomoses (34). The available data suggest an improved tumor response with drug-eluting microspheres over that achieved with standard TACE therapy and indicate that the transarterial infusion of drug-eluting microspheres is a potentially effective and safe therapy for unresectable hepatocellular carcinoma. Larger trials are needed to determine whether there is a benefit in survival (21).

	Use of Radiation-emitting Microspheres

Top Abstract Introduction Physiologic Basis of... Indications for Transarterial... Use of Drug-eluting Microspheres Use of Radiation-emitting... Gene Therapy Conclusions References

 
The therapeutic use of external-beam irradiation of the liver has been limited because of the vulnerability of the normal hepatic parenchyma to damage by radiation. Approximately 50% of patients who receive a whole-liver radiation dose of 35 Gy—a dose insufficient to induce tumor cell death—develop radiation-induced liver disease (5,35,36). ⁹⁰Y-bearing microspheres, however, act as point sources of radiation that, when delivered via the hepatic artery, are deposited predominantly within tumor tissue (22). ⁹⁰Y emits beta radiation with a mean energy of 0.94 MeV and mean penetration of 2.5 mm (22). ⁹⁰Y-bearing microspheres can deliver an intratumoral radiation dose of 100–150 Gy, which is highly effective for tumor destruction. In addition, the preferential deposition of the microspheres within the tumor allows selective irradiation of the target rather than normal hepatic parenchyma and thereby reduces the risk of radiation-induced hepatitis.

⁹⁰Y-bearing microspheres are commercially available in two formulations (Table 2). In one of the two, ⁹⁰Y is incorporated into glass microspheres (TheraSphere; MDS Nordion, Ottawa, Ontario, Canada). This formulation was granted an exemption by the FDA in 1999 for use as a humanitarian device in treating unresectable hepatocellular carcinoma. In the other formulation, ⁹⁰Y is incorporated into resin microspheres (SIR-Spheres; Sirtex Medical, Sydney, Australia). This formulation received premarket approval from the FDA in 2002 for use in combination with chemotherapy to treat unresectable hepatic metastases from colorectal cancer.

Patients with hepatic metastases from colorectal cancer usually undergo systemic chemotherapy as a first-line treatment. Before treatment, the performance status of all patients should be graded according to the Eastern Cooperative Oncology Group scheme (Table 3) (38,39). Patients with a compromised performance status (score of 2–4) may incur an increased risk of treatment-related morbidity (38). In addition, a total bilirubin level of more than 1.2 is a marker of impaired hepatic function and a relative contraindication to radioembolization with ⁹⁰Y-bearing microspheres (38).

View larger version (119K): [in this window] [in a new window] [Download PPT slide]   Figure 4a.  Images obtained for planning of 90Y therapy for hepatic metastases from colorectal cancer in a 74-year-old woman show variant hepatic arterial anatomy. To simplify the transarterial administration of the microsphere formulation, coil embolization of the smaller left and middle hepatic arteries was performed via the left gastric artery and common hepatic artery, respectively, before the administration of therapy via the dominant right hepatic artery. (a) Celiac arteriogram demonstrates a middle hepatic artery (straight arrow) and the left hepatic artery (arrowhead), which originates from the left gastric artery (curved arrow). (b) Angiogram at the level of the superior mesenteric artery (arrow) depicts a replaced right hepatic artery (arrowhead). (c) Angiogram shows coil embolization of the left (straight arrow) and middle (arrowhead) hepatic arteries. The 90Y-bearing microspheres were administered at a later date via the right hepatic artery (curved arrow).

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure 4b.  Images obtained for planning of 90Y therapy for hepatic metastases from colorectal cancer in a 74-year-old woman show variant hepatic arterial anatomy. To simplify the transarterial administration of the microsphere formulation, coil embolization of the smaller left and middle hepatic arteries was performed via the left gastric artery and common hepatic artery, respectively, before the administration of therapy via the dominant right hepatic artery. (a) Celiac arteriogram demonstrates a middle hepatic artery (straight arrow) and the left hepatic artery (arrowhead), which originates from the left gastric artery (curved arrow). (b) Angiogram at the level of the superior mesenteric artery (arrow) depicts a replaced right hepatic artery (arrowhead). (c) Angiogram shows coil embolization of the left (straight arrow) and middle (arrowhead) hepatic arteries. The 90Y-bearing microspheres were administered at a later date via the right hepatic artery (curved arrow).

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   Figure 4c.  Images obtained for planning of 90Y therapy for hepatic metastases from colorectal cancer in a 74-year-old woman show variant hepatic arterial anatomy. To simplify the transarterial administration of the microsphere formulation, coil embolization of the smaller left and middle hepatic arteries was performed via the left gastric artery and common hepatic artery, respectively, before the administration of therapy via the dominant right hepatic artery. (a) Celiac arteriogram demonstrates a middle hepatic artery (straight arrow) and the left hepatic artery (arrowhead), which originates from the left gastric artery (curved arrow). (b) Angiogram at the level of the superior mesenteric artery (arrow) depicts a replaced right hepatic artery (arrowhead). (c) Angiogram shows coil embolization of the left (straight arrow) and middle (arrowhead) hepatic arteries. The 90Y-bearing microspheres were administered at a later date via the right hepatic artery (curved arrow).

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   Figure 5a.  Imaging evaluation for planning of 90Y therapy for a hepatic metastasis from colorectal carcinoma in a 48-year-old man. The size of the metastasis had increased during systemic chemotherapy. (a) Axial T1-weighted fat-saturated MR image obtained after the administration of a gadolinium-based contrast material demonstrates a 12-cm enhancing hepatic mass (arrows) adjacent to the porta hepatis. (b) Arteriogram at the level of the common hepatic artery depicts the gastroduodenal artery (curved arrow) and left hepatic artery (straight arrow), but no right hepatic artery. A large tumor blush (arrowheads) is visible. (c) Superior mesenteric arteriogram depicts a replaced right hepatic artery (arrow) that feeds the tumor (arrowheads). (d) Angiogram shows simultaneous catheterization of the right (arrow) and left (arrowhead) hepatic arteries preparatory to the administration of a dose of approximately 27 mCi (1 GBq) of 90Y carried by resin microspheres. One-half that dose was administered via each artery.

View larger version (108K): [in this window] [in a new window] [Download PPT slide]   Figure 5b.  Imaging evaluation for planning of 90Y therapy for a hepatic metastasis from colorectal carcinoma in a 48-year-old man. The size of the metastasis had increased during systemic chemotherapy. (a) Axial T1-weighted fat-saturated MR image obtained after the administration of a gadolinium-based contrast material demonstrates a 12-cm enhancing hepatic mass (arrows) adjacent to the porta hepatis. (b) Arteriogram at the level of the common hepatic artery depicts the gastroduodenal artery (curved arrow) and left hepatic artery (straight arrow), but no right hepatic artery. A large tumor blush (arrowheads) is visible. (c) Superior mesenteric arteriogram depicts a replaced right hepatic artery (arrow) that feeds the tumor (arrowheads). (d) Angiogram shows simultaneous catheterization of the right (arrow) and left (arrowhead) hepatic arteries preparatory to the administration of a dose of approximately 27 mCi (1 GBq) of 90Y carried by resin microspheres. One-half that dose was administered via each artery.

View larger version (124K): [in this window] [in a new window] [Download PPT slide]   Figure 5c.  Imaging evaluation for planning of 90Y therapy for a hepatic metastasis from colorectal carcinoma in a 48-year-old man. The size of the metastasis had increased during systemic chemotherapy. (a) Axial T1-weighted fat-saturated MR image obtained after the administration of a gadolinium-based contrast material demonstrates a 12-cm enhancing hepatic mass (arrows) adjacent to the porta hepatis. (b) Arteriogram at the level of the common hepatic artery depicts the gastroduodenal artery (curved arrow) and left hepatic artery (straight arrow), but no right hepatic artery. A large tumor blush (arrowheads) is visible. (c) Superior mesenteric arteriogram depicts a replaced right hepatic artery (arrow) that feeds the tumor (arrowheads). (d) Angiogram shows simultaneous catheterization of the right (arrow) and left (arrowhead) hepatic arteries preparatory to the administration of a dose of approximately 27 mCi (1 GBq) of 90Y carried by resin microspheres. One-half that dose was administered via each artery.

View larger version (110K): [in this window] [in a new window] [Download PPT slide]   Figure 5d.  Imaging evaluation for planning of 90Y therapy for a hepatic metastasis from colorectal carcinoma in a 48-year-old man. The size of the metastasis had increased during systemic chemotherapy. (a) Axial T1-weighted fat-saturated MR image obtained after the administration of a gadolinium-based contrast material demonstrates a 12-cm enhancing hepatic mass (arrows) adjacent to the porta hepatis. (b) Arteriogram at the level of the common hepatic artery depicts the gastroduodenal artery (curved arrow) and left hepatic artery (straight arrow), but no right hepatic artery. A large tumor blush (arrowheads) is visible. (c) Superior mesenteric arteriogram depicts a replaced right hepatic artery (arrow) that feeds the tumor (arrowheads). (d) Angiogram shows simultaneous catheterization of the right (arrow) and left (arrowhead) hepatic arteries preparatory to the administration of a dose of approximately 27 mCi (1 GBq) of 90Y carried by resin microspheres. One-half that dose was administered via each artery.

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 6a.  Images obtained for therapy planning depict normal hepatic anatomy and the need for extrahepatic vessel embolization in a 63-year-old woman with a colorectal carcinoma metastasis to the liver that progressed during systemic chemotherapy. (a) Arteriogram at the level of the common hepatic artery demonstrates the origin of the gastroduodenal artery (arrow) and the hepatic artery proper (arrowhead). (b) Arteriogram obtained at the level of the common hepatic artery during embolization of the gastroduodenal artery (arrow) depicts the origin of the right gastric artery (arrowhead) distal to that of the gastroduodenal artery. (c) Arteriogram shows embolization performed via the left gastric artery (arrowhead) with a Waltman loop (straight arrow) because of difficulty in achieving direct access to the right gastric artery (curved arrow). (d) Arteriogram obtained at the level of the proper hepatic artery (arrowhead) shows coil embolization of the gastroduodenal artery (curved arrow) and right gastric artery (straight arrows). Extrahepatic vessel embolization was necessary to avoid the reflux of 90Y-bearing microspheres, a complication that might have led to gastrointestinal ulcers.

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 6b.  Images obtained for therapy planning depict normal hepatic anatomy and the need for extrahepatic vessel embolization in a 63-year-old woman with a colorectal carcinoma metastasis to the liver that progressed during systemic chemotherapy. (a) Arteriogram at the level of the common hepatic artery demonstrates the origin of the gastroduodenal artery (arrow) and the hepatic artery proper (arrowhead). (b) Arteriogram obtained at the level of the common hepatic artery during embolization of the gastroduodenal artery (arrow) depicts the origin of the right gastric artery (arrowhead) distal to that of the gastroduodenal artery. (c) Arteriogram shows embolization performed via the left gastric artery (arrowhead) with a Waltman loop (straight arrow) because of difficulty in achieving direct access to the right gastric artery (curved arrow). (d) Arteriogram obtained at the level of the proper hepatic artery (arrowhead) shows coil embolization of the gastroduodenal artery (curved arrow) and right gastric artery (straight arrows). Extrahepatic vessel embolization was necessary to avoid the reflux of 90Y-bearing microspheres, a complication that might have led to gastrointestinal ulcers.

View larger version (141K): [in this window] [in a new window] [Download PPT slide]   Figure 6c.  Images obtained for therapy planning depict normal hepatic anatomy and the need for extrahepatic vessel embolization in a 63-year-old woman with a colorectal carcinoma metastasis to the liver that progressed during systemic chemotherapy. (a) Arteriogram at the level of the common hepatic artery demonstrates the origin of the gastroduodenal artery (arrow) and the hepatic artery proper (arrowhead). (b) Arteriogram obtained at the level of the common hepatic artery during embolization of the gastroduodenal artery (arrow) depicts the origin of the right gastric artery (arrowhead) distal to that of the gastroduodenal artery. (c) Arteriogram shows embolization performed via the left gastric artery (arrowhead) with a Waltman loop (straight arrow) because of difficulty in achieving direct access to the right gastric artery (curved arrow). (d) Arteriogram obtained at the level of the proper hepatic artery (arrowhead) shows coil embolization of the gastroduodenal artery (curved arrow) and right gastric artery (straight arrows). Extrahepatic vessel embolization was necessary to avoid the reflux of 90Y-bearing microspheres, a complication that might have led to gastrointestinal ulcers.

View larger version (126K): [in this window] [in a new window] [Download PPT slide]   Figure 6d.  Images obtained for therapy planning depict normal hepatic anatomy and the need for extrahepatic vessel embolization in a 63-year-old woman with a colorectal carcinoma metastasis to the liver that progressed during systemic chemotherapy. (a) Arteriogram at the level of the common hepatic artery demonstrates the origin of the gastroduodenal artery (arrow) and the hepatic artery proper (arrowhead). (b) Arteriogram obtained at the level of the common hepatic artery during embolization of the gastroduodenal artery (arrow) depicts the origin of the right gastric artery (arrowhead) distal to that of the gastroduodenal artery. (c) Arteriogram shows embolization performed via the left gastric artery (arrowhead) with a Waltman loop (straight arrow) because of difficulty in achieving direct access to the right gastric artery (curved arrow). (d) Arteriogram obtained at the level of the proper hepatic artery (arrowhead) shows coil embolization of the gastroduodenal artery (curved arrow) and right gastric artery (straight arrows). Extrahepatic vessel embolization was necessary to avoid the reflux of 90Y-bearing microspheres, a complication that might have led to gastrointestinal ulcers.

View larger version (69K): [in this window] [in a new window] [Download PPT slide]   Figure 7.  Planar scintigraphy for planning of 90Y therapy in a 49-year-old man with metastatic colorectal carcinoma. Scintigram obtained after an injection of 4.35 mCi (161 MBq) of 99mTc-labeled MAA shows radionuclide activity in the liver and lungs but a noteworthy absence of activity in the gastrointestinal tract. The calculated hepatopulmonary shunt fraction was 10%. The patient was subsequently treated with a low dose of 90Y in a resin microsphere–based formulation.

Dose Calculation
Dose calculation for the administration of the glass microsphere formulation is based on the assumptions of (a) a uniform distribution of microspheres throughout the part of the liver volume that is supplied by the catheterized artery and (b) a nominal target radiation dose of 150 Gy/kg (22,38). The dose to be administered is calculated by using the following equation (3): A_glass = (D · M)/(50 Gy · kg^–1 · GBq^–1), where A_glass is the 90Y activity (in gigabecquerels), D is the nominal target dose (in gray), and M is the liver mass (in kilograms).

The dose calculation for resin microspheres, by contrast, is based on the assumption of a nonuniform distribution of microspheres, with the distribution pattern being influenced by the extent of the tumor burden (22). One of two methods of calculation may be used: In the body surface area method, the dose is calculated on the basis of the body surface area and the extent of the tumor burden in the liver, by using the following equation: A_resin = (BSA – 0.2) + [TV/(TV + LV)], where A_resin is the activity of the ⁹⁰Y content of the microspheres (in gigabecquerels), BSA is the body surface area, TV is the tumor volume, and LV is the liver volume (22). Alternatively, a method based on empirical data may be used (22). If this method is used, the nominal dose is 2 GBq if the tumor involves less than 25% of the total liver volume, 2.5 GBq if the tumor involves 25%–50% of the liver volume, and 3 GBq if the tumor involves more than 50% of the total liver volume. These nominal doses are modified according to the magnitude of the hepatopulmonary shunt fraction, as follows: If the shunt fraction is less than 10%, the nominal dose is administered; if it is 10%–15%, 80% of the nominal dose is administered; and if it is 15%–20%, 60% of the nominal dose is administered.

Delivery
Radioembolization is usually performed as an outpatient procedure. The delivery kit, which is available from the respective manufacturing companies, includes an apparatus that shields the radiation and provides a closed circuit to prevent accidental spills. Whole-liver treatment with ⁹⁰Y-bearing microspheres can be performed at the level of the common or proper hepatic artery, but segmental or lobar infusions are performed with increasing frequency (12), with their primary advantage being a reduction in the risk of reflux of microspheres into the gastroduodenal artery or small perforating vessels (12,39). The avoidance of reflux is particularly important when using resin microspheres, as their greater embolic effect is due to a larger number of microspheres per dose (50 million) compared with glass microspheres (4 million). For whole-liver treatment, Salem and Thurston recommend a "bilobar lobar" infusion in which either the right or the left hepatic artery is catheterized, the microsphere formulation is administered, and then the sequence is repeated with the other hepatic artery (12).

Follow-up Evaluations
Immediately after the therapeutic procedure is completed, planar scintigraphy or single photon emission computed tomography is performed to detect bremsstrahlung from interactions between beta rays and tissue (Fig 8). Postprocedural scintigraphy provides an opportunity to detect any inadvertent extrahepatic deposition of microspheres (43).

View larger version (143K): [in this window] [in a new window] [Download PPT slide]   Figure 8.  Planar scintigraphy performed immediately after the administration of 90Y-bearing microspheres in a 63-year-old woman with hepatic metastases from colorectal cancer. Scintigram shows bremsstrahlung produced by the interaction of beta radiation and tissue, a finding indicative of microsphere deposition. The selective activity depicted throughout the liver, combined with the lack of extrahepatic activity, is indicative of the successful administration of 90Y-bearing microspheres via the proper hepatic artery.

PET may help identify disease response at 1-month follow-up by depicting a decrease in the uptake of FDG by the tumor. Although PET is of limited use for the detection of small new lesions, the use of combined PET/CT may mitigate this limitation (37). In addition, early studies with diffusion-weighted MR imaging demonstrated a posttreatment decrease in the apparent diffusion coefficient of tumors, a finding consistent with treatment-induced cell death both after therapeutic embolization with ⁹⁰Y-bearing microspheres and after standard TACE therapy (46,47).

Serum levels of tumor biomarkers also are assessed at follow-up evaluations, with a reduction in serum values representing a positive tumor response. Increases in serum biomarker values are more difficult to interpret after treatment; they may be due to tumor lysis or to extrahepatic disease progression (45). In patients with hepatocellular carcinoma and a positive response to embolization therapy with ⁹⁰Y-bearing microspheres (with response defined by using the combined criteria of lesion size and necrosis seen at CT), no statistically significant association was found between -fetoprotein values and the combined CT criteria of response (45).

Potential complications of ⁹⁰Y-bearing microsphere therapy include gastrointestinal ulcers, radiation pneumonitis, radiation hepatitis, and radiation cholecystitis. The risk of complications can be minimized with meticulous treatment planning, particularly on the basis of baseline angiography, which may reveal extrahepatic vessels or a cystic artery at risk from reflux of microspheres. Myelosuppression was a reported complication during early experience with ⁹⁰Y microsphere therapy in the 1970s; however, the new resin and glass microspheres devised as radiotherapy delivery vehicles have virtually eliminated the leaching of ⁹⁰Y that presumably led to bone marrow suppression (48,49).

Response of Hepatocellular Carcinoma.— The combined criteria of tumor size change and necrosis may represent the most accurate basis for assessing the response of hepatocellular carcinoma to ⁹⁰Y-bearing microsphere therapy (45). Necrosis may be defined as a lack of enhancement (a change in attenuation by less than 10 HU) after the administration of contrast material at CT (45). In one study of 42 patients with hepatocellular carcinoma treated with ⁹⁰Y-bearing microspheres, the frequency of tumor response was 59% when both RECIST parameters and necrosis were used to define response, compared with 23% with the use of RECIST parameters alone (45). Enhancing nodules that demonstrated growth represented treatment failure, whereas a thin rim of enhancement, which often was transient, likely represented granulation tissue (45).

Response of Metastases from Colorectal Cancer.— A similar study demonstrated that a combination of size and necrosis criteria may be more accurate than size criteria alone for defining tumor response at imaging in patients with hepatic metastases from colorectal cancer (37). FDG uptake by the tumor at PET also may be a very useful indicator of tumor response (Fig 9). In fact, a combination of the criteria of tumor size and necrosis at CT with correlative FDG uptake at PET may be most accurate for determining the response of metastatic disease (37).

View larger version (89K): [in this window] [in a new window] [Download PPT slide]   Figure 9a.  Follow-up imaging for the assessment of tumor response after 90Y-bearing resin microsphere therapy in a 61-year-old woman with hepatic metastases from colorectal cancer. (a) Abdominal contrast-enhanced CT image demonstrates a 4.6 x 3.4-cm hypoattenuating lesion (arrow) in the dome of the liver. Within the lesion, enhancement (attenuation difference after contrast material administration, 39 HU) and a calcification are visible. (b) Coronal image from whole-body FDG PET demonstrates corresponding FDG uptake within the metastasis (arrow). Other foci of increased FDG uptake in the liver (arrowheads) represent additional metastases, which were visible also at CT. (c) Abdominal CT image, obtained 2 months after radioembolization, shows necrosis within the metastasis (arrow), which has decreased in size to 4.2 x 3.4 cm and no longer demonstrates significant enhancement (attenuation difference after contrast material administration, 10 HU). (d) Coronal image from whole-body FDG PET shows no evidence of abnormal metabolic activity in the liver, a finding indicative of local tumor control.

View larger version (103K): [in this window] [in a new window] [Download PPT slide]   Figure 9b.  Follow-up imaging for the assessment of tumor response after 90Y-bearing resin microsphere therapy in a 61-year-old woman with hepatic metastases from colorectal cancer. (a) Abdominal contrast-enhanced CT image demonstrates a 4.6 x 3.4-cm hypoattenuating lesion (arrow) in the dome of the liver. Within the lesion, enhancement (attenuation difference after contrast material administration, 39 HU) and a calcification are visible. (b) Coronal image from whole-body FDG PET demonstrates corresponding FDG uptake within the metastasis (arrow). Other foci of increased FDG uptake in the liver (arrowheads) represent additional metastases, which were visible also at CT. (c) Abdominal CT image, obtained 2 months after radioembolization, shows necrosis within the metastasis (arrow), which has decreased in size to 4.2 x 3.4 cm and no longer demonstrates significant enhancement (attenuation difference after contrast material administration, 10 HU). (d) Coronal image from whole-body FDG PET shows no evidence of abnormal metabolic activity in the liver, a finding indicative of local tumor control.

View larger version (90K): [in this window] [in a new window] [Download PPT slide]   Figure 9c.  Follow-up imaging for the assessment of tumor response after 90Y-bearing resin microsphere therapy in a 61-year-old woman with hepatic metastases from colorectal cancer. (a) Abdominal contrast-enhanced CT image demonstrates a 4.6 x 3.4-cm hypoattenuating lesion (arrow) in the dome of the liver. Within the lesion, enhancement (attenuation difference after contrast material administration, 39 HU) and a calcification are visible. (b) Coronal image from whole-body FDG PET demonstrates corresponding FDG uptake within the metastasis (arrow). Other foci of increased FDG uptake in the liver (arrowheads) represent additional metastases, which were visible also at CT. (c) Abdominal CT image, obtained 2 months after radioembolization, shows necrosis within the metastasis (arrow), which has decreased in size to 4.2 x 3.4 cm and no longer demonstrates significant enhancement (attenuation difference after contrast material administration, 10 HU). (d) Coronal image from whole-body FDG PET shows no evidence of abnormal metabolic activity in the liver, a finding indicative of local tumor control.

View larger version (94K): [in this window] [in a new window] [Download PPT slide]   Figure 9d.  Follow-up imaging for the assessment of tumor response after 90Y-bearing resin microsphere therapy in a 61-year-old woman with hepatic metastases from colorectal cancer. (a) Abdominal contrast-enhanced CT image demonstrates a 4.6 x 3.4-cm hypoattenuating lesion (arrow) in the dome of the liver. Within the lesion, enhancement (attenuation difference after contrast material administration, 39 HU) and a calcification are visible. (b) Coronal image from whole-body FDG PET demonstrates corresponding FDG uptake within the metastasis (arrow). Other foci of increased FDG uptake in the liver (arrowheads) represent additional metastases, which were visible also at CT. (c) Abdominal CT image, obtained 2 months after radioembolization, shows necrosis within the metastasis (arrow), which has decreased in size to 4.2 x 3.4 cm and no longer demonstrates significant enhancement (attenuation difference after contrast material administration, 10 HU). (d) Coronal image from whole-body FDG PET shows no evidence of abnormal metabolic activity in the liver, a finding indicative of local tumor control.

In patients with advanced colorectal metastatic disease that failed to respond to multiple chemotherapeutic regimens, a positive tumor response was demonstrated after ⁹⁰Y-bearing resin microsphere therapy (52). The results of a phase II clinical trial demonstrated that the addition of ⁹⁰Y-bearing resin microsphere treatment to chemotherapy in patients with unresectable colorectal metastases resulted in better median survival than did chemotherapy alone (29.4 months, compared with 12.8 months) (53).

	Gene Therapy

Top Abstract Introduction Physiologic Basis of... Indications for Transarterial... Use of Drug-eluting Microspheres Use of Radiation-emitting... Gene Therapy Conclusions References

 
Other experimental therapies that take advantage of a transarterial approach are in early stages of development. Gene therapy is based on the transfer of DNA or RNA into host tissues, a procedure that may lead to new protein synthesis or to the deactivation of gene expression, with the ultimate goal of inducing tumor lysis, blocking tumor growth, inducing antitumor immunity, activating a prodrug, or inhibiting angiogenesis (54).

Suicide genes encode for proteins that activate innocuous prodrugs into potent antitumor agents (54). Transformed cells that express the suicide gene may exert a so-called bystander effect in which there is diffusion of the gene product into nontransformed cells (55). For example, herpes simplex virus thymidine kinase (HSVtk) can convert ganciclovir into a toxic compound that inhibits nuclear and mitochondrial DNA synthesis and thus produces cell death (54,56,57). Follow-up of patients with hepatocellular carcinoma after direct intratumoral injections of adenovirus carrying the gene for HSVtk showed tumor necrosis in some patients (58). Another example involves pigment epithelium-derived factor (PEDF), which exhibits strong antiangiogenic properties (59). Intratumoral injection of adenovirus carrying the gene for PEDF into a mouse model led to inhibited tumor growth, with an associated decrease in microvascular density within the tumor (59).

The vectors in the examples just described were administered by direct injection into the tumor. However, in an experimental study performed in rats, the hepatic arterial delivery of an Epstein-Barr virus–based vector carrying the gene for interleukin 2, followed by arterial embolization, resulted in higher levels of interleukin 2 expression than either intratumoral injection or portal venous delivery of the vector (60). These results represent the opening of new avenues for transarterial therapy in patients with an unresectable primary or secondary hepatic malignancy.

	Conclusions

Top Abstract Introduction Physiologic Basis of... Indications for Transarterial... Use of Drug-eluting Microspheres Use of Radiation-emitting... Gene Therapy Conclusions References

 
Although unresectable primary and secondary hepatic malignancies are associated with high morbidity and mortality, transarterially delivered therapies hold much promise. Initial results have demonstrated the safety and efficacy of both drug-eluting and ⁹⁰Y-bearing microspheres, but further investigations of survival statistics with these therapies and of the clinical applicability of gene therapy are still needed. When using transarterially delivered therapies, meticulous patient selection and careful planning and execution are imperative and should be carried out with the participation of interventional and diagnostic radiologists, nuclear medicine specialists, and medical, surgical, and radiation oncologists.

	Footnotes

 

Abbreviations: FDA = Food and Drug Administration, FDG = fluorodeoxyglucose, MAA = macroaggregated albumin, RECIST = Response Evaluation Criteria in Solid Tumors, TACE = transarterial chemoembolization

See also the article by Atassi et al (pp 81–99) in this issue.

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Top Abstract Introduction Physiologic Basis of... Indications for Transarterial... Use of Drug-eluting Microspheres Use of Radiation-emitting... Gene Therapy Conclusions References

 

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