eMedicine Specialties > Radiology > Vascular/Interventional
Chemoembolization, Hepatic
Updated: Apr 3, 2008
Hepatocellular Carcinoma and Liver Metastases
Contrast-enhanced axial CT scan through the liver (same patient as in Images 1-4 in Multimedia) obtained 10 days after chemoembolization shows intensely concentrated lipiodol within the hepatocellular carcinoma. Note the considerable central tumor necrosis.
Hepatocellular carcinoma (HCC) is the most common primary liver tumor worldwide, and its incidence is rising. Most HCCs are associated with cirrhosis. The risk of developing HCC appears to be related to the degree of activity of cirrhosis. The risk is high in patients with macronodular cirrhosis secondary to hemochromatosis and lower in those with alcoholic micronodular cirrhosis. Surgery offers the best prospect of cure, but the resectability of HCC is low.
Depending on the primary site, 30-70% of patients who die of cancer have liver metastasis at autopsy. The most common cause of death from colorectal cancer is liver metastasis. Some success has been achieved in resection of liver metastases with limited-stage disease. Treatment using systemic chemotherapy and radiation therapy is relatively ineffective. The response rate to 5-fluorouracil, the most common single agent used in the treatment of hepatic colorectal metastases, is only 20%. Several groups have explored minimally invasive therapies and found them to be effective in both primary tumors and metastatic tumors. These therapies may ultimately replace surgical resection.
Six minimally invasive techniques are available for treatment of primary and metastatic hepatic neoplasms: (1) transcatheter arterial chemoembolization (TACE); (2) ethanol ablation, or percutaneous ethanol injection (PEI); (3) radiofrequency (RF) ablation; (4) microwave ablation; (5) laser ablation; and (6) cryoablation. TACE has been used the longest (since the mid-1970s), whereas the other therapies have been introduced comparatively recently.1,2
Related eMedicine topics:
Hepatocellular Carcinoma
Primary Biliary Cirrhosis
Incidence, Frequency, and Race
In Japan, HCC is the third most common cancer in men.3 In the United States, approximately 9000 cases occur annually; this incidence is similar to that of Hodgkin disease. HCC is one of the most common visceral tumors, especially in the high-risk populations of Southeast Asia, sub-Saharan Africa, Japan, Greece, and Italy.4
The incidence of HCC is rising worldwide. HCC is more common in men than in women, with a male-to-female ratio of 3-6:1. In areas of low incidence such as the United States and parts of Europe, the average patient age at diagnosis is 60-80 years. However, in areas of high incidence, patients present earlier, typically at the age of 30-50 years. Low-grade fibrolamellar carcinoma is seen in patients aged 20-40 years in whom underlying cirrhosis is absent.
In the United States and Europe, metastatic liver disease is the most common cause of malignancy in the liver; it is 18-40 times more common than primary liver cancer. The true incidence of metastatic liver disease is not known because most figures are based on autopsy series in end-stage malignant disease. However, depending on the primary site, 30-70% of patients who die of cancer have liver metastasis at autopsy.
Natural History
The natural history of HCC in Asia is said to be different from that in Europe and the United States. Although the etiology is multifactorial, the association with hepatitis B and C virus is stronger in Asia and Africa than elsewhere. For patients with HCC, the prognosis is poor without treatment. Okuda et al reported an overall median survival of only 1.6 months.5 In the West, a similar study in unselected patients revealed a median survival of 14 weeks, with only 13% of patients surviving longer than 1 year. Surgery offers the best opportunity for cure, but the resectability rate is low.
HCC is multifocal in 76% of patients, most of whom (81-87%) have underlying cirrhosis. The percentage of patients who are candidates for surgical treatment is 3-30%, depending on the series. In the authors' experience, a rate of 3% is a more accurate figure. Patients with small, uninodular or binodular tumors smaller than 3 cm have the best outcome. For patients undergoing hepatic transplantation, the 3-year survival rate without recurrence is 83%.6 The results of hepatic resection are poor.
A feature of fibrolamellar carcinoma is regional lymph node metastases. Some series suggest that the prognosis of patients with fibrolamellar carcinoma after surgical resection is better than in patients with HCC. Liver metastatic disease is one of the most common medical problems that oncologists face. The liver is particularly prone to metastatic disease, not only because of its dual blood supply but also because of the presence of humoral factors that promote cell growth.
Although the prognosis of patients with metastatic liver disease is usually poor, the use of more aggressive treatment regimens in certain patients, such as those with neuroendocrine tumors and colorectal metastasis, can result in a favorable outcome.7,8
Pathophysiology
Effective chemoembolization of the liver is possible because of 3 circumstances:
- First, the liver has a unique blood supply. The portal vein supplies 75% of the hepatic blood supply, while the hepatic artery supplies the remaining 25%. This backup blood supply allows the occlusion of either vessel without resultant liver infarction.
- Second, 95% of the blood of both primary and metastatic hepatic tumors is derived from the hepatic artery.
- Third, the development of catheter technology allows the superselective placement of catheters for the safe and effective delivery of therapeutic agents to hepatic tumors. Microcatheters can be safely placed, even in the presence of aberrant vessels or a collateral blood supply. In the early 1980s, researchers discovered that when iodized poppy seed oil is injected into the hepatic artery, it remains preferentially in the neovascularity of HCC. Therefore, a vehicle exists for delivering cytotoxic agents to tumor sites in the liver.
A series of animal experiments conducted in Japan, Sweden, and the United States has shown that oil droplets travel through complex vascular routes when oil is injected into the hepatic artery. These droplets flow through the artery and arterioles into the portal venule and sinusoids. They also enter the portal vein via the peribiliary vascular plexus, which provides an avenue for arterioportal communications between the hepatic artery and the portal vein. The mechanism of oil accumulation in the tumor is not fully understood, but it is likely secondary to the siphoning effect of a vascular tumor. After they accumulate, they may be subjected to a slow clearing process. Intra-arterially injected oil is well known to demonstrate preferential flow toward vascular tumors.
The most frequently used cytotoxic drugs for chemoembolization are fluorodeoxyuridine, doxorubicin, cisplatin, and mitomycin. These drugs have been used in the systemic treatment of liver tumors since the 1960s, and they form an important component of the chemoembolization arsenal.
Chemotherapeutic drugs used for chemoembolization all share 2 characteristics: First, when the drug is delivered into the hepatic artery, it is cleared rapidly by the liver. Such clearance accounts for the 100- to 400-fold difference in concentration between the liver and systemic circulation. Second, the drug must be effective primarily at high doses. If the agent is effective at the low doses achieved with systemic administration, there is little point in delivering the drug intra-arterially. A further benefit is gained by regional arterial treatment, which results in lower systemic drug levels, thus reducing toxicity.
Chemotherapeutic agents are usually combined with embolic particles to achieve chemoembolization of hepatic tumors. The aim is to cause ischemia and prolonged contact of the chemotherapeutic agent with the tumor. Such mixtures can dramatically increase the local concentration of the chemotherapeutic agent.
A variety of embolic agents have been used to treat hepatic tumors. The agents used most widely include Gelfoam (Pharmacia, Peapack, NJ), polyvinyl alcohol, and lipiodol.9 Used as pledgets or slurry, Gelfoam is a temporary embolic agent, with recanalization occurring within 2-6 weeks. Polyvinyl alcohol is a permanent embolic agent used alone (carcinoid metastases) or in combination with a chemotherapeutic agent. Lipiodol is an oily contrast agent with an affinity for HCC, making this drug useful diagnostically and therapeutically. Therapeutically, lipiodol is used as a vehicle to deliver a chemotherapeutic agent. Although most chemoembolization therapy applies to HCC, patients with other tumors also may benefit. The role of embolization and chemoembolization in colorectal metastases is not clear.10
A single, controlled, comparison trial of embolization, chemoembolization, and conservative treatment found no significant difference in survival rates between the 3 groups.
In a meta-analysis of randomized controlled trials, Llovet et al found that chemoembolization improves survival in a subset of patients with unresectable HCC and that chemoembolization may be considered the standard treatment for them.11 Tamoxifen does not affect survival of patients with advanced disease.
Carcinoid and islet tumors produce potent hormones, such as serotonin, gastrin, somatostatin, glucagon, adrenocorticotropic hormone, insulin, and other polypeptides.12 The control of symptoms is the primary objective of the therapy because the lifespan of patients is quite long regardless of treatment. However, if medical treatment fails, patients can benefit from hepatic embolization with polyvinyl alcohol, Gelfoam, and/or coils alone or in combination with chemotherapy.13
No consensus exists regarding the type of embolotherapy that is useful in the treatment of neuroendocrine liver metastasis. Both embolization and chemoembolization have been advocated. The primary objective of embolotherapy in treating neuroendocrine liver metastasis is to reduce tumor bulk, reduce hormone levels, and palliate symptoms. Both embolization and chemoembolization can achieve these objectives. A combination of the long-term subcutaneous administration of octreotide acetate, intra-arterial 5-fluorouracil, and tumor chemoembolization has been shown to effectively control progressive liver metastasis and to provide excellent symptomatic palliation in patients with hepatic metastasis from functional carcinoid tumors.14 Interferon therapy for midgut carcinoid liver metastasis appears to be more effective when used in combination with hepatic arterial embolization.15
Ocular melanoma frequently metastasizes to the liver; in such cases, the response rate to chemotherapy is poor. A 46% response rate has been reported after chemoembolization with a combination of cisplatin and polyvinyl alcohol.
Preprocedural Imaging
The imaging strategy in HCC depends on the clinical question to be answered and the treatment options available.
In patients with a known primary malignancy, such as colorectal cancer or islet cell tumors, an initial investigation includes an ultrasonographic examination followed by spiral or multisection 3-phase contrast-enhanced CT scanning (see Images below and Images 1-5 in Multimedia).
Contrast-enhanced axial CT scan through the liver in the portal venous phase in an 88-year-old woman who presented with right upper quadrant discomfort. Scan shows a 13-cm mass occupying the right lobe of the liver; it displaces the portal vein medially. Results of laparoscopic biopsy confirmed the mass to be a well-differentiated hepatocellular carcinoma in a noncirrhotic liver.
Arterial/early capillary phase of a celiac-axis angiogram (same patient as in Image above) shows extensive neovascularity in the mass, with stretching of the vessels around the mass.
Portal venous phase of a celiac-axis angiogram (same patient as in Images above) shows patent splenic and portal veins; therefore, the patient is a suitable candidate for chemoembolization.
Selective hepatic angiogram (same patient as in Images above) obtained after chemoembolization shows a complete shutdown of the neovascularity and pruning of the stretched peripheral vessels.
Contrast-enhanced axial CT scan through the liver (same patient as in Images 1-4 in Multimedia) obtained 10 days after chemoembolization shows intensely concentrated lipiodol within the hepatocellular carcinoma. Note the considerable central tumor necrosis.
MRI and radionuclide scanning are useful in confirming the diagnosis, particularly the diagnosis of benign lesions such as hemangiomas and focal nodular hyperplasia. These lesions are increasingly encountered in the setting of malignant disease. The multiplanar capability of MRI is particularly helpful in determining the exact anatomic location of the lesions. In the setting of HCC, a protocol similar to that used for liver metastasis is performed.
Establishing portal and hepatic vein patency and inferior vena cava invasion is vital.16,17
Preprocedural Preparation and Protocols
Because most patients with HCC have underlying cirrhosis, it is important to use clinical criteria to classify the severity of cirrhosis, which has a considerable bearing on therapeutic decisions. The Child classification system is usually used to stage cirrhosis into group A, group B, or group C. Patients with Child group A disease have the best prognosis; those with Child group C disease have the worst prognosis. The parameters used to stage liver cirrhosis by using the Child classification include serum bilirubin and albumin levels, the presence of ascites, the presence of hepatic encephalopathy, and the patient's nutritional status.
Alternatively, hepatic insufficiency can be staged by using the Hôpital Paul Brousse classification system, and HCC can be staged by using the Okuda staging system.18
Diagnostic imaging depicts not only the primary hepatic disease but also ascites, lymph node metastases, and thrombosis of portal or hepatic veins. Confirming portal vein patency is important because portal vein thrombosis is a relative contraindication to chemoembolization. If portal flow via collateral vessels remains hepatopetal, embolization may be better tolerated. Imaging also plays an important role in evaluating the effectiveness of interventional therapy.
Angiography is an essential part of the workup performed prior to embolization or chemoembolization, although most centers proceed to the embolization procedure if no contraindications are present. Angiography is usually performed by placing a 5F-to-6F catheter through a sheath via the right or left femoral artery. The catheter should be able to accept the insertion of a 3F coaxial microcatheter. A celiac-axis and superior mesenteric angiogram is first obtained to identify common variations in the blood supply to the liver and to check for patency of the portal vein.
According to Michels, the right hepatic artery is aberrant in origin in 26% of cases (replaced, 18%; accessory, 8%), and the left hepatic artery is aberrant in origin in 27% (replaced, 15.5%; accessory, 11.5%).19 The gastroduodenal artery, the duodenal branches of proper hepatic artery, and the cystic artery must all be identified to prevent nontarget embolization. A relatively common finding is reversal of flow in the gastroduodenal artery, resulting from hypervascularity of liver tumors and celiac-axis stenosis. Identifying any parasitic arterial blood supply from adjacent organs, the lumbar and intercostal arteries, and the phrenic arteries is important; for this identification, abdominal aortography is usually required.
Over time, the blood supply must be reassessed because the hepatic arterial supply becomes obliterated, particularly after repeated chemoembolizations. Pathways of collateral flow may develop and contribute to tumor recurrence. Such collateral blood supply may require chemoembolization of branches from the right renal artery and the stomach, as well as the phrenic, intercostal, internal mammary, and colonic arteries. Extra care is required to embolize these arteries safely. Recognizing that not all such vessels can be embolized safely is important. As with any embolization procedure, arterial flow slows with each embolic particle, and the chances of reflux into nontarget blood supply rises.
The Procedure
The catheter is delivered into the feeding artery if catheterized; otherwise, it is injected subselectively into the segment or subsegment of the liver with a tumor. The catheter should always be placed beyond the cystic artery. Before the chemoembolization mixture is delivered intra-arterially, 30-40 mg of 1% lidocaine is injected intra-arterially, with the injection directed at the embolization site. Intra-arterial lidocaine helps reduce embolization-induced pain. If the patient complains of pain or discomfort during the procedure, further aliquots of 2-3 mL of 1% lidocaine may be injected through the catheter. The procedure is completed by performing the embolization by using polyvinyl alcohol with a particle size of 250-400 µm. Patients are observed, and follow-up monitoring is performed according to the protocol.20,21
Treatment protocol for the chemoembolization of HCC
No standard universally agreed-upon protocol has been developed. Chemoembolization involves delivery of a combination of embolic agents (a chemotherapeutic agent and iodized poppy seed oil) into the arterial supply of liver tumors.22 Basically, an emulsion of lipiodol and a cytotoxic drug is used to embolize the tumor; this is followed by particulate embolization. At the authors' institution, a protocol based on the technique used by Bismuth et al has been established.23 To date, the protocol has been used in 280 TACE procedures.
A superselective technique is used as follows:
- Only patients without cirrhosis or those with Child group A or B disease are considered.
- No extrahepatic disease should be demonstrable.
- All patients receive 10 mg of phytonadione intravenously prior to the procedure (the intravenous injection should be administered slowly). Although there is no convincing evidence that phytonadione is useful in these patients, the vitamin is administered on the basis that deficiency frequently occurs in hospitalized patients because of poor diet, recent surgery, parenteral nutrition, and multiple-antibiotic therapy.
- Femoral catheterization and positioning of the catheter are performed in a selective or superselective position.
- Premedication is with lorazepam (Wyeth Laboratories, UK), 0.25 mg/kg orally 1 hour before the procedure. Otherwise, the patient receives nothing by mouth beginning at midnight before the procedure. Lorazepam is used as a premedication to counter anxiety.
- Portal vein patency must be confirmed during the venous phase of celiac or superior mesenteric angiogram.
- The largest tumor is approached first.
- The intra-arterial injection of 30-40 mg of 1% lidocaine is used for analgesia.
- The following is made into an emulsion by repeatedly emptying and filling a syringe over 10 minutes: 10 mL of lipiodol ultrafluid (Mallinckrodt Medical, UK), 5 mL of Omnipaque 300 (Amersham Health, UK; water-soluble contrast aids in emulsifying the mixture), and 50 mg of doxorubicin. Cisplatin is used if doxorubicin is contraindicated.
- Intra-arterial injection is administered under direct visualization to prevent reflux into gastroduodenal or splenic vessels.
- Embolization is performed with Ultra Ivalon, 250-400 µm (Laboratories Nycomed SA).
- Intravenous cefuroxime (750 mg) and metronidazole (500 mg) are administered 3 times per day for 5 days. These antibiotics are given as prophylaxis against septicemia and liver abscess formation.
- Patients are admitted to a high-dependency ward and should be mobilized after 6 hours of bed rest.
- Postoperative analgesia is administered if and when required by the patient.
- All patients receive ranitidine (an H2 antagonist) intravenously 3 times per day until they begin eating.
- Patients are discharged home after 5 days or when their systemic symptoms begin resolving.
- Nonenhanced and enhanced CT examinations are performed 10-14 days following embolization.
- Alpha-fetoprotein levels are evaluated at the 6-week outpatient review.
- If the procedure is successful (>50% lipiodol uptake in necrotic tumor demonstrated on the postprocedural CT scan), the embolization is repeated in 6-8 weeks. If the lipiodol uptake is less than 50%, the authors repeat the CT scan in 6-8 weeks. If the size of the tumor is reduced, repeat TACE may be considered.
- The second TACE treatment should first be performed in previously untreated tumors.
- The third treatment completes a normal course, but further treatments are performed in patients with residual disease.
Treatment protocol for the embolization of carcinoid and islet cell metastases
- Patients must not have hepatic encephalopathy, biliary obstruction, hepatofugal portal flow, tumor load involving more than 50% of the liver, bilirubin levels more than 2 mg/dL, lactic dehydrogenase levels more than 425 U/L, and aspartate aminotransferase levels more than 100 U/L. (However, the tumor-load criterion may not be strictly followed. In one report, part of the liver was embolized on 1 occasion.)
- All patients receive 10 mg of phytonadione intravenously prior to the procedure.
- Premedication is lorazepam, 0.25 mg/kg orally 1 hour before the procedure. Otherwise, the patient receives nothing by mouth beginning at midnight before the procedure.
- Somatostatin analogs are routinely used in active tumors prior to and after embolization to prevent carcinoid crises.
- Femoral catheterization and positioning of the catheter are performed in a selective or superselective position.
- Portal vein patency must be confirmed by obtaining a roadmapping angiogram.
- Intra-arterial injection is administered under direct visualization to prevent reflux into gastroduodenal or splenic vessels.
- Embolization is performed with Ultra Ivalon, 250-400 µm, mixed with 3-4 mL of Omnipaque 300.
- At the authors' institution, 1 lobe or 1 segment of the liver is embolized at a time, depending on the tumor load.
- Intravenous cefuroxime (750 mg) and metronidazole (500 mg) are administered 3 times per day for 5 days.
- Patients are admitted to a high-dependency ward and should be mobilized after 6 hours of bedrest.
- Postoperative analgesia is administered if and when required by the patient.
- All patients receive ranitidine (an H2 antagonist) intravenously 3 times per day until they begin eating.
- Patients are discharged home after 3 days or when their systemic symptoms are resolving.
- CT scans are performed 10-14 days after embolization.
- 5-hydroxyindoleacetic acid (5-HIA) levels are evaluated at the 6-week outpatient follow-up appointment.
- Embolization is repeated in 3-6 months, depending on the response.
The dose of lipiodol used in a large HCC can be individualized according to the blood supply pattern and the tumor diameter, as determined on CT imaging; for example, a patient may have sufficient blood supply, poor blood supply, mixed blood supply, or arteriovenous shunt.24
Complication rates
Reported complication rates vary greatly. In one large series of 351 patients, the reported complications included the following25 :
- Severe postembolization syndrome (15.1%)
- Hepatic injury (30.8%) - Abnormal liver function tests, acute hepatic failure, and hepatic infarction
- Gallbladder infarction (14%)
- Nontarget embolization (4.6%)
- Gastrointestinal bleeding (2.8%)
- Septicemia (2.6%)
- Pulmonary embolism (1.7%)
- Splenic infarction (1.1%)
- Tumor rupture (0.8%)
- Intrahepatic biloma (0.8%)
- Liver abscess (0.3%)
- Spinal cord injury (0.3%)
- Thirty-day mortality (2.6%)
The complication rates in the series by Chung et al appear rather excessive.25 In the series, patients with Child group C disease and cirrhosis were included, and some patients also had portal vein thrombosis. Moreover, whether the procedure was performed superselectively or globally is not clear from reading the article. Other series report a lower complication rate.
One large series describing 2300 chemoembolizations reported a complication rate of 4.4%; the lower rate was related to the use of chemoembolic agents and to the manipulation of the catheter or guidewire.26 The complications included the following:
- Acute hepatic failure (0.26%)
- Liver abscess (0.22%)
- Intrahepatic biloma (0.87%)
- Hepatic infarction (0.17%)
- Multiple intrahepatic aneurysms (0.26%)
- Cholecystitis/gallbladder infarction (0.30%)
- Splenic infarction (0.08%)
- Gastrointestinal mucosal lesion (0.22%)
- Pulmonary embolism/infarction (0.17%)
- Tumor rupture (0.04%)
- Variceal bleeding (0.13%)
- Complications related to catheter manipulation (1.52%)
- Perforation of the celiac axis or its branches (0.17%)
Kothary and associates conducted a retrospective study of 52 high-risk patients to evaluate the safety and efficacy of TACE; patients had an increased serum bilirubin level, a low serum albumin level, poor hepatic reserve, or compromised hepatopetal flow in the portal vein.27 The authors concluded that TACE in high-risk patients does not necessarily incur a higher incidence of morbidity or mortality. They also concluded that patient selection should be based on extent of disease and that tumors should be treated selectively at a segmental level if possible.27
Postprocedural Imaging and Outcome
Follow-up CT scans are obtained approximately 10-14 days after the procedure. An early scan may be acquired if complications, such as nontarget embolization, are suspected. Because the chemotherapeutic agent is mixed with lipiodol, dense opacification associated with necrosis is seen in the tumor. CT scans also demonstrate nontarget embolization and complications such as the development of ascites and pleural effusions. When only polyvinyl alcohol embolization is performed, as in cases of hepatic carcinoid, postembolization CT scans demonstrate only tumor necrosis.28
Follow-up scans obtained 3 months later may show a reduction in tumor size and, in some instances, complete resolution of the liver tumors. Objective response has been reported in 70% of patients, and symptomatic relief has been reported in 90-100% of patients.
Since 1977, TACE has been performed in Japan, where it is regarded as standard treatment for patients with unresectable HCC. In Western nations, the procedure was introduced in the mid-1980s. Conflicting reports have appeared in the literature regarding the efficacy of TACE.
In 1993, Kanematsu et al described the first study comparing hepatic resection in 67 patients with TACE in 20 patients with resectable disease.29 The 1-, 3-, and 5-year cumulative survival rates in 67 patients who underwent resection of the HCC were 89.1%, 74.6%, and 54.6%, respectively. The survival rates in the 20 patients who underwent TACE were 90%, 50%, and 17.50%, respectively. Therefore, surgery offers more favorable results.
In 1994, Yoshikawa conducted a prospective, randomized, controlled trial in 38 patients with unresectable HCC to evaluate the efficacy of TACE versus 4'-epidoxorubicin alone.30 In the TACE group, patients had a better tumor response and prolonged survival (42% vs 12%).
Lin and coworkers evaluated embolization, embolization in conjunction with systemic chemotherapy, and chemotherapy alone in 3 groups of patients.31 Survival in the first 2 groups was significantly better than in the group receiving chemotherapy alone. Vetter and coworkers conducted a prospective study comparing chemoembolization with historical controls.32 They found marked survival benefits with TACE.
Bronowicki and coworkers compared liver transplantation, liver resection, TACE, and conservative treatment in 122 patients with HCC.33 The 5-year probability of survival was close to 45% in each of the 3 treated groups. The probability of cancer recurrence and/or metastatic dissemination was lower after TACE than after surgery.
Bismuth et al (including Sherlock, one of the authors of this article) published their work in the American Journal of Surgery and concluded that TACE in a European setting can achieve results as good as those currently obtained in Japan.23 In a series of 291 patients, they showed that TACE offers considerable benefits in terms of palliation, as confirmed by both reduction in tumor size and the degree of tumor necrosis. At the conclusion of the article, the editors stated, "How best to manage the technically unresectable hepatic tumor troubles every surgeon. This alternative treatment from the clinic of one of the world's best liver surgeons seems like a useful option in highly selected cases."
Pelletier and coworkers conducted a randomly controlled study comparing TACE with supportive care and found no survival advantage in the 2 groups.34 However, several major studies from the Far East (the liver cancer study group of Japan and that of Tang et al35 ) have shown that TACE is an effective treatment in unresectable HCC in terms of increasing the length of survival and the quality of life of patients.
In any review of the literature on TACE, one problem encountered is that the studies are not strictly comparable. Some series involve global embolization rather than selective embolization. Different chemotherapeutic agents, embolic agents, different doses of drugs, and the use of analgesia have been studied. The patient selection criteria also vary. Some series include operable tumors, whereas others include inoperable tumors. Different criteria have been used to classify associated cirrhosis and comorbidity. Although the response to chemoembolization is good, a search for the right combination of chemotherapeutic agents continues.
Comparison of TACE with other techniques
PEI usually is performed in patients with cirrhosis and HCC. PEI is ineffective in liver metastasis. Candidates for ethanol ablation must have tumors with a volume less than 30% of the total volume of the liver. Contraindications for this procedure include portal vein thrombosis, extrahepatic disease, Child group C cirrhosis, a prothrombin time less than 40%, and a platelet count less than 40,000/mm3. PEI is inexpensive, easy to perform, and repeatable. Long-term results of PEI and surgery in the treatment of small to medium-sized HCCs are comparable.
In multiple HCCs, ethanol is less toxic than chemoembolization. PEI is currently considered a reliable alternative to surgery in the management of limited-stage cancer, but unlike TACE, it is not suitable for multifocal advanced disease. Unlike with TACE, necrosis of the capsule and perineoplastic tissue have occurred with PEI.
Shiina and Niwa describe survival rates in 180 patients with inoperable HCC at 1, 2, 3, 4, 5, and 6 years as 82%, 65%, 50%, 41%, 35%, and 31%, respectively.36 They also describe survival rates with a potentially curable HCC treated with PEI in 131 patients at 1, 2, 3, 4, 5, and 6 years as 87%, 70%, 62%, 51%, 43%, and 37%, respectively.
RF ablation is suitable for patients with 4 or fewer primary or metastatic liver tumors 5 cm or smaller. The tumors should be completely surrounded by liver parenchyma, they should be at least 1 cm deep to the liver capsule, and they should be at least 2 cm or more away from major intrahepatic portal and hepatic veins. Subcapsular tumors can be ablated, but in this situation, the procedure causes more pain. RF ablation performed in tumors near the porta hepatis poses an increased risk of injury to the bile ducts and portal vein, and it is generally more painful. Patients with sepsis, severe debility, and coagulopathy usually cannot be treated by using RF.
In a prospective study of small HCCs conducted by Livraghi and associates, the rate of complete ablation was 10% higher with RF ablation than with ethanol ablation.37 Unlike ethanol ablation, RF ablation appears to be effective in treating both HCCs and liver metastases. RF ablation is less toxic than agents used for TACE, and it is better controlled. The main disadvantage of RF ablation is the difficulty in heating normal liver tissue, and hence, tumors have a higher recurrence rate than desired.
Bartolozzi and coworkers investigated the long-term outcome of combined treatment of TACE and PEI in the treatment of HCC.38 The series included 86 patients, all of whom had a single primary tumor larger than 3 cm that was either solitary or was associated with no more than 2 daughter nodules. All patients received treatment with TACE, followed by 4-16 PEI treatments starting 4 weeks after TACE. The overall survival rates at 1, 2, 3, 4, and 5 years were 92%, 83%, 69%, 58%, and 47%, respectively. These figures appear to be more positive than the results achieved with TACE or PEI alone.
In a study by Tanaka et al, combination therapy using PEI and TACE caused complete histologic necrosis in 83% of tumors.39 Combination therapy was also significantly better (P < 0.5) than TACE alone in terms of the rate of primary tumor recurrence found during follow-up examinations.
Kim et al retrospectively analyzed outcomes in 334 consecutive patients who underwent hepatic resection for HCC that was initially judged resectable to assess whether a single session of preoperative TACE affects postoperative outcome.40 The authors concluded that a single session of preoperative TACE for initially resectable HCC worsens the overall survival rate. It may also increase the risk of tumor recurrence in patients in whom tumor necrosis is incomplete.
Sharma et al have shown that TACE for liver-dominant metastasis of stage 4 melanoma is a safe treatment that results in longer survival than has occurred among historical controls.41 Patients with well-defined nodular tumors on angiography fared better than those with infiltrative tumors on angiography.
Huang and associates conducted a randomized, controlled trial of 50 patients with a primary HCC associated with hypersplenism to asses the value of combined treatment of HCC with partial splenic embolization (PSE) and TACE.42 They found no significant difference in the symptoms of post-embolization syndrome and concluded that PSE combined with TACE was more effective and safe than TACE alone for patients with HCC associated with hypersplenism caused by cirrhosis.
A meta-analysis of 4 randomized, controlled trials showed a significant decrease in mortality with the use of multimodality combined treatment (TACE plus percutaneous ablation), as compared with single-modality treatment, in patients with both small and large HCCs. TACE combined with local radiotherapy improved survival in patients with tumor thrombosis of the portal vein in 7 nonrandomized studies. Two randomized controlled trials and 13 nonrandomized studies showed that the use of TACE prior to hepatic resection improves neither survival nor tumor recurrence. Conversely, 2 randomized, controlled trials and 5 comparative studies showed that TACE following hepatectomy confers a survival benefit with reduced HCC recurrence. TACE is also useful to control tumor burden for patients on the waiting list for liver transplantation.43
Marelli et al conducted a systemic review of cohort and randomized studies to evaluate whether specific patient characteristics and/or radiologic transarterial techniques result in better outcomes.44 The authors concluded that no chemotherapeutic agent appeared better than any other. The study showed no evidence of benefit with lipiodol. Gelatin sponge was the most used embolic agent, but PVA particles may be better. TAE appeared to be as effective as TACE.
Multimedia
 | Media file 1:
Contrast-enhanced axial CT scan through the
liver in the portal venous phase in an 88-year-old woman who
presented with right upper quadrant discomfort. Scan shows a
13-cm mass occupying the right lobe of the liver; it displaces
the portal vein medially. Results of laparoscopic biopsy
confirmed the mass to be a well-differentiated hepatocellular
carcinoma in a noncirrhotic liver. |
 | Media file 2: Arterial/early capillary phase of a celiac-axis angiogram (same patient as in Image above) shows extensive neovascularity in the mass, with stretching of the vessels around the mass. |
 | Media file 3:
Portal venous phase of a celiac-axis angiogram
(same patient as in Images above) shows patent splenic and
portal veins; therefore, the patient is a suitable candidate
for chemoembolization. |
 | Media file 4:
Selective hepatic angiogram (same patient as in
Images above) obtained after chemoembolization shows a complete
shutdown of the neovascularity and pruning of the stretched
peripheral vessels. |
 | Media file 5:
Contrast-enhanced axial CT scan through the
liver (same patient as in Images 1-4 in Multimedia)
obtained 10 days after chemoembolization shows intensely
concentrated lipiodol within the hepatocellular carcinoma. Note
the considerable central tumor
necrosis. |
Keywords
minimally invasive therapy of liver tumors, liver chemoembolization, hepatic embolization, liver embolization, embolotherapy, hepatocellular carcinoma, HCC, liver cancer, hepatic cancer, primary hepatic neoplasms, metastatic hepatic neoplasms, transcatheter arterial chemoembolization, TACE, ethanol ablation, percutaneous ethanol injection, PEI, cisplatin, fluorodeoxyuridine, doxorubicin, mitomycin, polyvinyl alcohol, PVA, lipiodol, iodized poppy seed oil, radiofrequency ablation, RF ablation, microwave ablation, laser ablation, cryoablation
More on Chemoembolization, Hepatic |
| References |
References
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Further Reading
Keywords
minimally invasive therapy of liver tumors, liver chemoembolization, hepatic embolization, liver embolization, embolotherapy, hepatocellular carcinoma, HCC, liver cancer, hepatic cancer, primary hepatic neoplasms, metastatic hepatic neoplasms, transcatheter arterial chemoembolization, TACE, ethanol ablation, percutaneous ethanol injection, PEI, cisplatin, fluorodeoxyuridine, doxorubicin, mitomycin, polyvinyl alcohol, PVA, lipiodol, iodized poppy seed oil, radiofrequency ablation, RF ablation, microwave ablation, laser ablation, cryoablation
