Chemoembolization for Hepatocellular Carcinoma

Chemoembolization for Hepatocellular Carcinoma Steven M. Zangan, MD, and Jay Patel, MD

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iver cancer is the fourth-leading cause of cancer-related death in the world and comprises as many as 1 million deaths per year worldwide.1-4 Hepatocellular carcinoma (HCC) has unique geographic, gender, and age distributions determined by specific etiologic factors. HCC is an aggressive disease, with the number of deaths per year caused approximating the incidence throughout the world.5 A variety of important risk factors for the development of HCC has been identified, including hepatitis B carrier state, chronic hepatitis C virus infection, hereditary hemochromatosis, and cirrhosis of almost any cause.6 However, HCC can also occur in patients with no known risk factors.7 The incidence of HCC varies by geographic location and among ethnic groups within the same country, likely because of regional variations in hepatic viruses and environmental pathogens.1 Most hepatomas occur in patients with chronic liver disease or cirrhosis. Patients diagnosed at an early stage may benefit from surgical resection, transplantation, or percutaneous therapy. Although the mainstay of therapy is surgical resection, most patients are not eligible because of tumor extent or underlying liver dysfunction. Because HCC is typically clinically silent during early stages, disease is typically advanced at the time of presentation and only approximately 30%-40% of patients who are evaluated benefit from these treatment options.8 The median survival after late-stage diagnosis ranges between 6 and 20 months.9 Many treatment options have been developed to improve the quality and duration of life for patients with unresectable disease. Although no standard therapy exists, the most commonly used palliative therapies in the United States include systemic therapies and imageguided interventions, such as thermal ablation, transarterial chemoembolization, and selective internal radiation therapy.

Staging of HCC Multiple staging systems have been proposed to predict the prognosis for HCC, although none have been universally

Department of Radiology, University of Chicago Medical Center, Chicago, IL. Address reprint requests to Steven M. Zangan, MD, University of Chicago Medical Center, Department of Radiology, 5841 S. Maryland Ave, MC 2026, Chicago, IL 60637. E-mail: [email protected]

0037-198X/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.ro.2010.10.001

adopted.10-14 Within these schema, 4 features have been recognized as important determinants of survival: the severity of underlying liver disease, tumor size, extension of tumor into adjacent structures, and the presence of metastases.10,11,15-17 The 3 most commonly used systems are the American Joint Committee on Cancer (AJCC) tumor-node-metastases (TNM) classification, the Okuda system, and the Cancer of the Liver Italian Program score (Tables 1-3). A consensus conference on HCC staging held jointly by the AJCC and the American Hepatico-Pancreatico-Biliary Association in 2002 recommended that primary staging for all patients with HCC should be clinical staging, and the Cancer of the Liver Italian Program system was preferred.18 They also recommended secondary staging with the AJCC/Union for International Cancer Control/TNM system for patients undergoing surgery.

Treatment Options Potentially, curative partial hepatectomy or liver transplantation offers the best treatment for HCC. Ideal candidates for resection have a solitary HCC confined to the liver without evidence of invasion of the hepatic vasculature, no evidence of portal hypertension, and well preserved hepatic function (Fig. 1). Long-term relapse free survival rates average 40% or better, and 5-year survival rates as high as 90% are reported in carefully selected patients. Hepatic reserve assessment is vital to selection for resection, with intraoperative mortality twice as high in cirrhotic patients compared with noncirrhotic counterparts. When the future liver remnant is ⬍20% in patients with normal liver function or ⬍40% in cirrhotic patients, portal vein embolization is considered.19 Many patients considered for liver transplantation are unresectable because of the degree of underlying liver dysfunction rather than tumor extent. Orthotopic liver transplantation (OLT) is a suitable option for unresectable patients who have a solitary HCC ⱕ5 cm or up to 3 separate lesions, none of which is larger than 3 cm, no evidence of gross vascular invasion, and no regional nodal or distant metastases. When these selection criteria are strictly applied, excellent overall 3to 4-year overall (75%) and recurrence free survival rates (83%) can be achieved.20 A major problem with OLT is the long waiting time for donor organs, which has necessitated the development of a complex prioritization process, where 105

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106 Table 1 American Joint Committee on Cancer Tumor-NodeMetastasis Staging Stage I

Stage II

Stage IIIA Stage IIIB

Stage IIIC

Stage IVA Stave IVB

T1 (solitary tumor with no vascular invasion) T2 (solitary tumor with vascular invasion or multiple tumors none > 5 cm) T3a (multiple tumors more than 5 cm) T3b (tumor(s) involve a major branch of portal or hepatic vein) T4 (direct invasion of adjacent organs or visceral peritoneum) Any T Any T

N0

M0

N0

M0

N0

M0

N0

M0

Table 3 Cancer Liver Italian Program Scoring system Points 0 Child-Pugh stage Tumor morphology ␣–fetoprotein level, ng/mL Macrovascular invasion

A

1 B

2 C

Uninodular Multinodular Massive (>50% of liver) <400 >400 NA No

Yes

Yes

The total score is derived by adding each of the subscores. Patients with high scores have lower median survival.

N0

M0

N1 Any N

M0 M1

priority for donor organs is given to the most severely ill patients. Thermal ablation consists of killing tumor cells either by freezing them (cryoablation) or heating them (radiofrequency, microwave, or laser ablation). Chemical ablation consists of directly injecting a denaturing agent, such as ethanol or acetic acid, into the tumor. These techniques are reasonable options for patients who do not meet respectability criteria for HCC and yet are candidates for a liver directed procedure based on the presence of disease confined to the liver.

Transarterial Therapy Approximately 80% of the blood supply to hepatomas 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.21 Hence, cytotoxic agents that are infused selectively into the hepatic artery preferentially target tumor cells over normal hepatic tissue. In addition, direct infusion via the hepatic artery avoids the first pass metabolism of chemotherapeutic agents administered orally or intravenously. Conventional transarterial chemoembolization enables chemotherapeutic drug concentrations in the tumor up to 100 times greater than via systemic chemotherapy.22-24 The localized infusion of chemothera-

peutic agents via the hepatic artery by the use of a surgically implanted pump is a method that has been popular for several decades.25 Several variants of transarterial therapy have been used: bland particle embolization, transarterial chemoembolization (TACE) without or with lipiodol (transarterial oily chemoembolization), and transarterial chemotherapy alone or with lipiodol. Lipiodol is an iodized oil that acts as a carrier and preferentially remains in the tumor because of the absence of Kupffer cells, the phagocytes that are active in normal parenchyma.22 Two meta-analysis have failed to show a significant survival difference between bland embolization and TACE, although there was a trend toward longer survival with TACE.26,27 However, most published experience is with TACE, and this procedure has been shown to improve survival in 2 randomized trials involving patients with unresectable HCC.27 As a result, it is the most commonly used technique. There are few randomized trials that have compared different techniques of transarterial therapy. Theoretically, embolization enhances the effect of chemotherapy by causing failure of metabolically active cell membrane pumps, thereby

Table 2 Okuda System Points Tumor size Ascites Albumin level, g/dL Bilirubin level, mg/dL

0

1

<50% of liver No >3 <3

>50% of liver Yes <3 >3

Glossary: stage 1 ⴝ 0 points; stage 2 ⴝ 1-2 points; stage 3 ⴝ 3-4 points.

Figure 1 A 3-cm hepatocellular carcinoma is seen in segment VI of the liver. Note the capsular enhancement. There are no signs of cirrhosis. This patient had excellent functional status and went on to successful surgical resection.

Chemoembolization for HCC

Figure 2 (A) A large hetereogeneously enhancing mass is seen in the caudate lobe on arterial phase CT. (B) Flush aortogram demonstrates a replaced right hepatic artery (arrow) arising from the superior mesenteric artery. (C) The superior mesenteric artery was catheterized to obtain a right hepatic angiogram. Tumor blush is seen in the mass (arrow). (D) Subselective right hepatic angiogram shows the mass to advantage. Note that the medial aspect of the mass fails to show extensive tumor blush. Chemoembolization was performed from this location. (E) Left hepatic angiogram shows segment IV branches arising from the left hepatic artery which feed the mass. These were embolized as well.

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108 overcoming drug resistance.28 However, whether simultaneous or sequential occlusion of the hepatic artery until there is stagnation of blood flow to the tumor results in greater antitumor efficacy than chemotherapy alone has not been proved. The optimal chemotherapeutic agent and best embolization particle (ie, gelatin sponge, degradable starch microspheres, polyvinyl alcohol) have not been established.27,29 Finally, although embolic techniques are expected to induce ischemia in tumors, there is evidence that such ischemia may lead to tumor angiogenesis.30 The authors of a systematic review of arterial embolization techniques27 concluded that TACE provided a survival benefit over no or suboptimal treatment, though the benefit of adding chemotherapy or lipiodol versus bland embolization alone could not be shown. The use of polyvinyl alcohol instead of gelatin sponge required fewer sessions, presumably because polyvinyl alcohol causes permanent or semipermanent arterial occlusion, while gelatin sponge occludes the artery only temporarily.31,32

Recent Advances During the past few years, there has been increasing use of TACE with drug-eluting beads. The chemotherapeutic agent, usually doxorubicin, is contained within the embolic bead, allowing a local, sustained delivery within the tumor. The effect of the chemotherapy is augmented by the ischemic effect of embolization. Plasma concentrations of the chemotherapeutic agent are lower because it is bound to the bead and stays within the tumor. Systemic toxicity is therefore reduced. Early results demonstrate greater necrosis and tumor response in the short term when compared with conventional TACE, although a comparison of various series is difficult because of variation in techniques and heterogeneity in samples.33-39 In the United States, LC beads (AngioDynamics) and Hepaspheres/Quadraspheres (Merit) are commercially available in a variety of sizes and approved as a medical device. The pharmacist typically mixes doxorubicin with the beads using a special technique.

Figure 3 (A) A hypovascular hepatoma is seen in segment II on arterial phase CT. Note the cirrhotic liver and perihepatic ascites. (B) Coronal maximum intensity projection, arterial phase image shows a replaced left hepatic artery (arrow) arising from the left gastric artery. (C) The replaced left hepatic artery (arrow) is shown to advantage on celiac angiogram. (D) Chemoembolization was performed through the replaced left hepatic artery.

Chemoembolization for HCC Radioembolization with Y-90 tagged glass (Therasphere) or resin (SIRsphere) microspheres is safe and effective in patients with unresectable HCC.40-47 However, additional experience is needed to assess long-term disease control and toxicity. In particular, randomized trials are needed to define the safety and role of this technology in the context of other available nonsurgical therapies. Despite multiple studies showing the effectiveness of radioembolization47 it is not commonly used as a first line treatment, in part because of expense. Systemic chemotherapy has not routinely been used for patients with advanced HCC. Hepatomas are relatively chemotherapy refractory. In addition, it can be difficult to gauge benefit from chemotherapy in patients with advanced HCC because survival is most often determined not by tumor aggressiveness or the impact of a systemic treatment, but by the degree of hepatic dysfunction. However, molecularly targeted therapy by the use of sorafenibm, a multitargeted tyrosine kinase inhibitor, appears promising. The multicenter European randomized SHARP trial demonstrated a statistically significant survival benefit for sorafenib over supportive care alone in patients with advanced HCC. Median survival and the time to radiologic progression were nearly 3 months longer with sorafenib than with placebo.48

Patient Selection and Method Once it has been determined that a patient is a candidate for chemoembolization, it is crucial to screen for contraindications to TACE to achieve the desired risk benefit profile. Contraindictions include but are not limited to the following29: portal vein thrombosis, encephalopathy, biliary obstruction, elevated serum bilirubin ⬎ 5 mg/dL, poor liver function, tumor burden involving ⬎50% of the liver, cardiac or renal insufficiency, and uncorrectable coagulopathy. Preoperative imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging is crucial for optimal preprocedure planning. Special attention should be paid to hepatic arterial anatomy because there are commonly anatomic variants that affect the TACE procedure (Figs 2 and 3). No consensus “best” or “standard” chemoembolization protocol exists, and a discussion of the nuances of different protocols is beyond the scope of this article. We will describe the protocol used at our institution. Chemotherapy is typically ordered by the interventional radiologist the day before the procedure. We use a mixture of lipiodol (10 mL) and water-soluble contrast (10 mL) with doxorubicin, 50 mg, cisplatin, 50 mg, and mitomycin, 10 mg. This is followed by administration of embolic microspheres (Embospheres 500700 ␮m) until near complete stasis is achieved. At the time of this writing, the sole U.S. supplier of lipiodol ceased production, resulting in a critical shortage in the United States. Until production and distribution needs could be adequately met by other suppliers, we increased the use of drug eluting beads in our practice. For these cases, on the morning of the procedure, 2 vials of beads (Quadraspheres) are each loaded with 50 mg of doxorubicin. Superselective embolization is

109 then performed until both vials are administered or there is near stasis within the vessel. Mitomycin and cisplatin do not reliably bind the beads and are not used in these cases. Patients are admitted the morning of the procedure, and pertinent laboratory work is reviewed. Peripheral intravenous access is obtained for hydration and medication administration. A bolus of normal saline is administered and then continued as maintenance infusion. Preprocedure antibiotics, antimemetics, and steroids are administered. A Foley catheter is usually placed. Moderate sedation with fentanyl and versed is monitored by the nursing staff. Right common femoral artery access is obtained, and a pigtail catheter is used to obtain an abdominal aortogram, at which time the hepatic arterial anatomy can be ascertained. A variety of 4- or 5-French catheters can be used to select the superior mesenteric artery and angiography is performed to visualize any arterial variants, such as a replaced right hepatic artery and also, to obtain a portal venogram (Fig. 4). The celiac artery is then selected and angiography is performed. We typically then advance the catheter into the common or proper hepatic artery and use a 3-French microcatheter to selectively catheterize the segmental artery as close to the lesion as possible (Fig. 5). Specific microcatheters with a slightly larger inner lumen and shorter overall length have been specifically designed for hepatic chemoembolization and allow easier injection of viscous chemoembolic emulsions. The origins of vessels supplying the gut and gallbladder must be carefully noted to avoid nontarget embolization. When necessary, feeding arteries, typically from the superior mesenteric, phrenic, or intercostal arteries, are also embolized (Fig. 6). After the procedure, patients are admitted to the hospital for observation and pain control, as post embolization syn-

Figure 4 Delayed images from a superior mesenteric angiogram clearly depict the portal venous anatomy.

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Figure 5 (A) The hepatoma in segment II (arrow) enhances on arterial phase CT. (B) The mass (arrow) is faintly seen during left hepatic angiogram. (C) On delayed images, the mass (arrow) enhances avidly. A microcatheter was advanced into the segment II artery and chemoembolization was performed. (D) A noncontrast CT obtained the day following the procedure demonstrates diffuse lipiodol staining of the mass (arrow). (E) Radiofrequency ablation was performed.

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111

Figure 6 (A) T2-weighted magnetic resonance shows a hyperintense mass in the right hepatic lobe. (B) Right T10 intercostal angiogram shows arterial supply to the mass. A microcatheter was advanced distally and chemoembolization was performed. (C) There was also tumor blush (arrows) from the right hepatic artery and this distribution was also treated. (D) Follow-up CT shows lipiodol staining the tumor.

drome occurs in most patients.27 Most patients can be discharged in 24-48 hours. In patients who are also candidates for thermal ablation, we elect to perform the ablation the following day (Fig. 5E).

Complications Serious complications of TACE are uncommon. Liver failure attributable to ischemic damage to the normal liver occurs in ⬍5% of cases.49 Other ischemic complications may include hepatic abscess,50 sterile ischemic and/or chemical cholecystitis, and biliary complications (Fig. 7). Bile duct injury occurs in up to 2% of cases and may result in bilomas or strictures.51 General procedural complications of angiography, such as periprocedural cardiac events, renal insufficiency, hematomas, and femoral artery dissection can also occur but are rare. Treatment related mortality is roughly 2%-3%.52 The most common adverse effect is postembolization syndrome, occurring in 60%-80% of patients.27 Patients typically experience right upper quadrant pain, nausea, low grade fever, and a mild elevation in white blood cell count

and liver enzymes. Symptoms peak at 2-4 days but are selflimited, with full recovery typically occurring within 7-10 days.

Follow-Up Follow-up imaging is determined by institutional protocol, with most centers performing contrast CT or magnetic resonance 4-8 weeks after therapy. On CT follow up, the accumulation pattern of iodized oil can be determined. A focal defect or washout of lipiodol suggests viable tumor, and repeat embolization with special attention to potential accessory arterial supply should be pursued. The size of the lesion typically does not decrease significantly in the short term, therefore, the presence of contrast enhancement is the best clue that viable tumor is present. On magnetic resonance, lipiodol does not significantly affect signal intensity, so contrast enhancement is the best indicator of residual disease. The lesions are often hypointense on T2 because of necrosis. If thermal ablation techniques have also been used, the lesion typically shows an apparent increase in size on early follow

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Figure 7 (A) Contrast-enhanced CT, arterial phase demonstrates a hepatoma in the right lobe (arrow). (B) Right hepatic angiogram shows the tumor blush (arrow). A microcatheter was advanced distally and chemoembolization was performed. (C) The following day, the patient underwent radiofrequency ablation. (D) The patient developed pain, fever, and elevated white blood cell count, and follow-up CT demonstrated an abscess in the right lobe. (E) After percutaneous drainage, the abscess resolved and no residual tumor was seen. This image was obtained 1 year after the initial procedure.

Chemoembolization for HCC up imaging, as a 1-cm ablation margin is ideally achieved. Eventually, the volume of the ablated lesion decreases in size and there is no contrast enhancement.

Conclusions Chemoembolization is an effective treatment for patients with unresectable hepatocellular carcinoma. It is considered the standard of care of intermediate stage HCC.53 Patients should have a patent portal vein, good performance status, and adequate liver function. Serious adverse effects are uncommon and with good supportive medical care, postembolization syndrome is well tolerated.

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