DOI: 10.1148/rg.25si055507
RadioGraphics 2005;25:S3-S23
© RSNA, 2005
Staging and Current Treatment of Hepatocellular Carcinoma1
Hollins P. Clark, MD,
W. Forrest Carson, MD,
Peter V. Kavanagh, MD,
Coty P. H. Ho, MD,
Perry Shen, MD and
Ronald J. Zagoria, MD
1 From the Departments of Radiology (H.P.C., W.F.C., P.V.K., R.J.Z.), Internal Medicine (C.P.H.H.), and Surgery (P.S.), Wake Forest University School of Medicine, Meads Hall, 2nd Floor, Medical Center Blvd, Winston-Salem, NC 27157-1088. Presented as an education exhibit at the 2004 RSNA Annual Meeting. Received February 8, 2005; revision requested March 29 and received May 24; accepted May 31. The article discusses an investigational or unlabeled use of a commercial device or pharmaceutical that has not been approved for such purpose by the FDA. TheraSphere® (MDS Nordion, Ottawa, Ontario, Canada) has received humanitarian device exemption approval from the U.S. FDA for treatment of unresectable hepatocellular carcinoma and can be used only in an investigational capacity. SIR-Spheres® (Sirtex Medical, Lake Forest, Ill) has received premarket approval from the FDA for use in combination with hepatic arterial fluorouracil therapy to treat colorectal metastasis to the liver; its use for treatment of primary hepatic neoplastic disease is an off-label application. Likewise, intraarterial administration of cisplatin, doxorubicin, and mitomycin C for treatment of hepatocellular carcinoma constitutes off-label use of these pharmacologic products. All authors have no financial relationships to disclose.
Address correspondence to H.P.C. (e-mail: hclark{at}wfubmc.edu).
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Abstract
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Early-stage hepatocellular carcinoma (HCC) is typically clinically silent, and HCC is often advanced at first manifestation. Without treatment, the 5-year survival rate is less than 5%. The selected treatment depends on the presence of comorbidity; tumor size, location, and morphology; and the presence of metastatic disease. Complete surgical resection followed by hepatic transplantation offers the best long-term survival, but few patients are eligible for this therapy. All other therapies are palliative. Radiofrequency ablation is the preferred method for managing unresectable small HCCs that are few in number. More widespread disease is treated with percutaneous therapies such as chemoembolization and selective internal radiation therapy. Systemic administration of biologic and chemotherapeutic agents is minimally successful in slowing the growth of HCC and typically is used to control symptoms in patients with overwhelming disease. A multidisciplinary approach that includes surgery, systemic therapy, and radiation therapy and that is based on the cooperation of radiation oncologists, interventional and diagnostic radiologists, hepatologists, and pathologists may offer the best chance of a cure or at least a longer and more normal life. To participate effectively in this effort, radiologists must be familiar with staging and treatment options for HCC and with the factors that affect the choice of management method.
© RSNA, 2005
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LEARNING OBJECTIVES FOR TEST 1
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After reading this article and taking the test, the reader will be able to:
- Identify the anatomic and clinical parameters that influence the treatment options and prognosis for patients with hepatocellular carcinoma.
- Discuss the evolving role of image-guided therapies in the treatment of hepatocellular carcinoma.
- Describe the limitations of traditional surgical and medical management of hepatocellular carcinoma.
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Introduction
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Hepatocellular carcinoma (HCC) is the cause of 250,000 deaths worldwide each year. Early HCC is typically clinically silent, and the disease is often well advanced at the first manifestation. Without treatment, there is a 5-year survival rate of less than 5% (1). According to the World Health Organization, by the year 2010, HCC will have surpassed lung cancer as the foremost cause of cancer mortality (2). In the United States alone, the incidence of histologically proved HCC increased from 1.4 of 100,000 people in the 1976–1980 population to 2.4 of 100,000 people in the 1991–1995 population (3). HCC predominantly affects the elderly, and investigators in a recent study of Medicare patients found that the age-adjusted incidence of HCC among individuals 65 years and older had increased from 14.2 per 100,000 in 1993 to 18.1 per 100,000 in 1999 (4). The increasing incidence in this age group may be related to the widespread transmission of viral hepatitis, specifically of types B and C, during the late 1960s and 1970s, when illicit use of intravenous narcotics, needle sharing, unsafe sexual activity, and transfusion of unsafe blood and blood products were common practices (3).
A diagnosis of HCC implies a poor prognosis. Currently, long-term survival is best achieved through surgical management. However, only about 20% of patients are surgical candidates at initial manifestation of HCC (5). Overall survival for patients with unresectable disease is based on tumor stage and size, liver function, and symptoms. Llovet et al (6), in a study of 102 patients with unresectable HCC, determined that survival was 54% at 1 year, 40% at 2 years, and 28% at 3 years. Many treatment options have been developed to improve the quality and duration of life for patients with unresectable HCC. Presently, in the United States, commonly used palliative therapies include systemic therapies, radiofrequency (RF) ablation, transarterial chemoembolization (TACE), and selective internal radiation therapy.
In this article, we review the triage of patients with HCC among the various treatment options (Fig 1) and analyze the capacity of each treatment to prolong and to improve the quality of life. However, this review is only a broad outline. Individual case management and treatment effectiveness are influenced by many intangible and unpredictable factors.
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Figure 1. Flowchart shows the algorithm used for selecting the appropriate treatment for HCC when the principal alternatives are surgical resection (the preferred treatment method), transplantation, RF ablation, TACE, selective internal radiation therapy (SIRT), systemic therapy, and supportive care. Treatment for unresectable HCC is selected on the basis of clinical and imaging findings.
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Staging of HCC
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Cancer staging is an ever-evolving process that is important for both patient management and research advancement. At present, multiple staging systems for HCC are recognized. Several staging systems incorporate various clinical and radiologic parameters into integrated scoring schemes (Okuda, Barcelona Clinic Liver Cancer, and Cancer of the Liver Italian Program [CLIP]). These medical staging systems are most applicable to patients with advanced disease who are not considered candidates for surgery. Systems of staging that are based on the results of pathologic analysis (eg, American Joint Committee on Cancer [AJCC]/Union Internationale Contre le Cancer [UICC] and Liver Cancer Study Group of Japan classification systems) incorporate anatomic and histologic findings at tumor resection (7). Given the heterogeneity of patients with HCC and the small percentage who are surgical candidates, both the clinical and the histopathologic systems of staging are needed. In a 2002 consensus statement, the American Hepato-Pancreato-Biliary Association and the AJCC advocated the use of the CLIP classification system for medical staging because that system has been well validated, is applicable to most patients, and includes easily collected data (8,9). For patients with resectable disease, the AJCC/UICC staging system is most useful, because it too has been validated, it is based on the standard system of tumor, node, and metastasis classification, and it can be applied after resection or transplantation (9,10). At the First International Symposium on Image-guided Therapy for Cancer, in May 2005, Jean-Nicolas Vauthey, MD, chief of the Liver Service in the Department of Surgical Oncology at the University of Texas M. D. Anderson Cancer Center, Houston, Tex, presented a strong argument for acceptance of the AJCC/UICC system because of its capacity to help more accurately predict the prognosis and to direct postoperative adjuvant therapy (7). However, the United Network of Organ Sharing also recognizes the modified tumor, node, and metastasis classification system developed by the American Liver Tumor Study Group for assessment of HCC in patients considered for liver transplantation (Tables 1– 3) (11,12).
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Surgical Treatment
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Complete surgical resection and hepatic transplantation offer the best chance of a cure for HCC. However, surgery is often precluded by extensive disease or poor hepatic functional reserve (Figs 2, 3). Furthermore, patient selection and outcome are inevitably influenced by the skill and experience of the surgeon. Even with surgical resection, the overall 5-year survival is approximately 30% (13).
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Figure 2a. Unresectable HCC in a 48-year-old man. (a) Contrast-enhanced portal phase CT image shows HCC that involves liver segment V (black arrow) and the gallbladder (white arrow). (b) Contrast-enhanced portal phase CT image obtained at a lower level than a shows enlarged portal lymph nodes (arrowhead), which proved to be metastatic disease at histopathologic analysis after fine-needle aspiration performed with endoscopic US guidance. (c) Coronal contrast-enhanced arterial phase CT image depicts both the hepatic mass (arrow) and adenopathy (arrowhead). The patient was not considered a candidate for surgery or local-regional therapy and was referred for systemic therapy.
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Figure 2b. Unresectable HCC in a 48-year-old man. (a) Contrast-enhanced portal phase CT image shows HCC that involves liver segment V (black arrow) and the gallbladder (white arrow). (b) Contrast-enhanced portal phase CT image obtained at a lower level than a shows enlarged portal lymph nodes (arrowhead), which proved to be metastatic disease at histopathologic analysis after fine-needle aspiration performed with endoscopic US guidance. (c) Coronal contrast-enhanced arterial phase CT image depicts both the hepatic mass (arrow) and adenopathy (arrowhead). The patient was not considered a candidate for surgery or local-regional therapy and was referred for systemic therapy.
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Figure 2c. Unresectable HCC in a 48-year-old man. (a) Contrast-enhanced portal phase CT image shows HCC that involves liver segment V (black arrow) and the gallbladder (white arrow). (b) Contrast-enhanced portal phase CT image obtained at a lower level than a shows enlarged portal lymph nodes (arrowhead), which proved to be metastatic disease at histopathologic analysis after fine-needle aspiration performed with endoscopic US guidance. (c) Coronal contrast-enhanced arterial phase CT image depicts both the hepatic mass (arrow) and adenopathy (arrowhead). The patient was not considered a candidate for surgery or local-regional therapy and was referred for systemic therapy.
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Figure 3. Unresectable HCC in a 44-year-old man with hepatitis C. Contrast-enhanced portal phase CT image shows a large and heterogeneously enhancing HCC that involves the entire left hepatic lobe and extends into the right lobe. Parenchymal replacement of more than 50% and preexisting hepatic disease greatly increased the risk of hepatic failure with surgical resection. The patient therefore was referred for selective internal radiation therapy instead of surgery.
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Patient selection greatly affects perioperative and long-term survival. Surgical resection for cure is ideal for small, unifocal tumors and in the absence of vascular invasion, hepatic insufficiency, and clinically significant comorbidities (Fig 4). Fan and colleagues in Hong Kong described attempts to achieve zero perioperative mortality by using the selection criterion of Child-Pugh class A disease, meticulous attention to surgical exposure and ligature, and comprehensive postoperative care to limit fluid overload and initiate early parenteral nutrition (14). Five-year survival for surgical patients with small HCCs (<5 cm in diameter) and limited hepatic dysfunction may approach 60% (15).
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Figure 4a. Small resectable HCC in a 47-year-old woman. (a, b) Contrast-enhanced arterial phase CT images in the axial (a) and coronal (b) planes show an exophytic HCC (arrow) that involves the lateral segment of the left hepatic lobe. (c) Photograph shows the HCC-containing liver specimen that was excised by using a laparoscopic hand-assisted left lateral wedge resection.
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Figure 4b. Small resectable HCC in a 47-year-old woman. (a, b) Contrast-enhanced arterial phase CT images in the axial (a) and coronal (b) planes show an exophytic HCC (arrow) that involves the lateral segment of the left hepatic lobe. (c) Photograph shows the HCC-containing liver specimen that was excised by using a laparoscopic hand-assisted left lateral wedge resection.
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Figure 4c. Small resectable HCC in a 47-year-old woman. (a, b) Contrast-enhanced arterial phase CT images in the axial (a) and coronal (b) planes show an exophytic HCC (arrow) that involves the lateral segment of the left hepatic lobe. (c) Photograph shows the HCC-containing liver specimen that was excised by using a laparoscopic hand-assisted left lateral wedge resection.
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More advanced HCC is less successfully managed with surgery. The only absolute exclusion criterion for surgical intervention is extrahepatic spread of HCC; however, many clinical and morphologic factors may affect the success of surgery and may lead to the choice of an alternative form of management. Most notable among these factors is an association of HCC with cirrhosis (16). The baseline hepatic function influences the purifying and synthesizing capacity of the postoperative organ. Individuals with compromised liver function are less tolerant of partial resection than are those with normal liver function. In general, surgical resection of HCC is limited to patients with Child-Pugh class A disease or those with Child-Pugh class B disease and a well-compensated liver function. Resection in patients with a cirrhotic liver is further complicated by increased perioperative morbidity and mortality, which frequently are due to dysfunction of multiple organ systems, portal hypertension, and inability of the cirrhotic liver to regenerate. Macroscopic or microscopic vascular invasion, which may lead to substantial blood loss during surgery, is also associated with a higher tumor recurrence rate. The importance of these complicating factors is reflected in the various staging systems. Large tumors and multifocal tumors necessitate more extensive resection, but this can be accomplished only in patients with a noncirrhotic liver or with Child-Pugh class A cirrhosis (Figs 5, 6).
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Figure 5a. Large resectable HCC in a 67-year-old man. (a, b) Axial contrast-enhanced portal phase CT image (a) and axial T1-weighted MR image obtained with gadolinium-based contrast material and fat saturation (b) show, in the right hepatic lobe, a large HCC that has invaded the right portal vein (arrow). (c, d) Photographs show the liver specimen excised for removal of the tumor thrombus (arrow in d) en bloc at right hepatic lobectomy. (e) Follow-up axial contrast-enhanced CT image shows the liver margin after partial hepatectomy.
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Figure 5b. Large resectable HCC in a 67-year-old man. (a, b) Axial contrast-enhanced portal phase CT image (a) and axial T1-weighted MR image obtained with gadolinium-based contrast material and fat saturation (b) show, in the right hepatic lobe, a large HCC that has invaded the right portal vein (arrow). (c, d) Photographs show the liver specimen excised for removal of the tumor thrombus (arrow in d) en bloc at right hepatic lobectomy. (e) Follow-up axial contrast-enhanced CT image shows the liver margin after partial hepatectomy.
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Figure 5c. Large resectable HCC in a 67-year-old man. (a, b) Axial contrast-enhanced portal phase CT image (a) and axial T1-weighted MR image obtained with gadolinium-based contrast material and fat saturation (b) show, in the right hepatic lobe, a large HCC that has invaded the right portal vein (arrow). (c, d) Photographs show the liver specimen excised for removal of the tumor thrombus (arrow in d) en bloc at right hepatic lobectomy. (e) Follow-up axial contrast-enhanced CT image shows the liver margin after partial hepatectomy.
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Figure 5d. Large resectable HCC in a 67-year-old man. (a, b) Axial contrast-enhanced portal phase CT image (a) and axial T1-weighted MR image obtained with gadolinium-based contrast material and fat saturation (b) show, in the right hepatic lobe, a large HCC that has invaded the right portal vein (arrow). (c, d) Photographs show the liver specimen excised for removal of the tumor thrombus (arrow in d) en bloc at right hepatic lobectomy. (e) Follow-up axial contrast-enhanced CT image shows the liver margin after partial hepatectomy.
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Figure 5e. Large resectable HCC in a 67-year-old man. (a, b) Axial contrast-enhanced portal phase CT image (a) and axial T1-weighted MR image obtained with gadolinium-based contrast material and fat saturation (b) show, in the right hepatic lobe, a large HCC that has invaded the right portal vein (arrow). (c, d) Photographs show the liver specimen excised for removal of the tumor thrombus (arrow in d) en bloc at right hepatic lobectomy. (e) Follow-up axial contrast-enhanced CT image shows the liver margin after partial hepatectomy.
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Figure 6a. Large resectable HCC in a 47-year-old woman. (a) Axial T1-weighted contrast-enhanced MR image obtained with fat saturation depicts a 13-cm-diameter HCC confined to the right hepatic lobe. (b, c) Photographs obtained during laparotomy and right hepatic lobectomy show HCC at the margin of the liver (b) and the free edge of the left hepatic lobe (c) after argon beam coagulation. (d) Photograph shows the gross specimen after right hepatic lobectomy. (e) Postoperative axial contrast-enhanced CT image shows the surgical margin.
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Figure 6b. Large resectable HCC in a 47-year-old woman. (a) Axial T1-weighted contrast-enhanced MR image obtained with fat saturation depicts a 13-cm-diameter HCC confined to the right hepatic lobe. (b, c) Photographs obtained during laparotomy and right hepatic lobectomy show HCC at the margin of the liver (b) and the free edge of the left hepatic lobe (c) after argon beam coagulation. (d) Photograph shows the gross specimen after right hepatic lobectomy. (e) Postoperative axial contrast-enhanced CT image shows the surgical margin.
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Figure 6c. Large resectable HCC in a 47-year-old woman. (a) Axial T1-weighted contrast-enhanced MR image obtained with fat saturation depicts a 13-cm-diameter HCC confined to the right hepatic lobe. (b, c) Photographs obtained during laparotomy and right hepatic lobectomy show HCC at the margin of the liver (b) and the free edge of the left hepatic lobe (c) after argon beam coagulation. (d) Photograph shows the gross specimen after right hepatic lobectomy. (e) Postoperative axial contrast-enhanced CT image shows the surgical margin.
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Figure 6d. Large resectable HCC in a 47-year-old woman. (a) Axial T1-weighted contrast-enhanced MR image obtained with fat saturation depicts a 13-cm-diameter HCC confined to the right hepatic lobe. (b, c) Photographs obtained during laparotomy and right hepatic lobectomy show HCC at the margin of the liver (b) and the free edge of the left hepatic lobe (c) after argon beam coagulation. (d) Photograph shows the gross specimen after right hepatic lobectomy. (e) Postoperative axial contrast-enhanced CT image shows the surgical margin.
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Figure 6e. Large resectable HCC in a 47-year-old woman. (a) Axial T1-weighted contrast-enhanced MR image obtained with fat saturation depicts a 13-cm-diameter HCC confined to the right hepatic lobe. (b, c) Photographs obtained during laparotomy and right hepatic lobectomy show HCC at the margin of the liver (b) and the free edge of the left hepatic lobe (c) after argon beam coagulation. (d) Photograph shows the gross specimen after right hepatic lobectomy. (e) Postoperative axial contrast-enhanced CT image shows the surgical margin.
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Hepatic transplantation potentially offers a good chance for long-term survival, but transplantation is typically reserved for patients with small tumors and Child-Pugh class C disease, who would not likely tolerate even a limited resection. In a landmark article published in 1996, Mazzaferro et al (17) reviewed their experience with 48 patients with cirrhosis and small unresectable HCCs. They demonstrated the curative effect of transplantation for most patients with three or fewer tumor nodules of less than 3 cm or a solitary HCC of less than 5 cm in diameter, no invasion of blood vessels, and no lymph node involvement (4-year overall and disease-free survival rates were 85% and 92%, respectively). The findings in this and similar investigations led to the creation of the now widely accepted "Milan criteria," an endorsement of the guidelines offered by Mazzaferro and colleagues to help oncologists select patients for transplantation and other methods of disease management (18). This approach has been incorporated into the general algorithm described in this article. However, Yao et al (19) suggested that the selection criteria could be expanded (eg, to include a single tumor with a diameter of 6.5 cm or less, or no more than three lesions with a diameter of 4.5 cm or less and with the total tumor burden being 8.0 cm or less) without a substantial effect on survival outcomes. Likewise, the presence of a living related liver donor may lead to an expansion of the criteria for a few patients. Cadaveric organ availability for transplantation remains a major problem. In the United States, the management of this limited resource rests with the United Network of Organ Sharing, which administers the Organ Procurement and Transplantation Network in accordance with a contract with the Health Resources and Services Administration of the U.S. Department of Health and Human Services. The prioritization process is complex, but it is facilitated in part by the use of the Model for End-stage Liver Disease (MELD) scoring system, which is used to predict mortality for patients with chronic end-stage liver disease. The goal of prioritization is to ensure that sicker patients have preferential access to available organs. Notably, within the present system, stage II HCC classified in accordance with the American Liver Tumor Study Group definitions (one nodule 2.0–5.0 cm; two or three nodules, all <3.0 cm) initially might be assigned an artificially high score based on recognition of the propensity of the disease to progress to an inoperable status, while the three standard MELD markers (total bilirubin and serum creatinine levels and international ratio of prothrombin time) remain relatively low (12,20).
Cross-sectional imaging and image-guided procedures can greatly assist in the surgical management of HCC. Diagnostic radiologists involved in these examinations should be familiar with the common surgical questions so as to optimize their imaging techniques and tailor the subsequent reports to address these issues. Appropriately timed, multiphase contrast material–enhanced imaging is critical to identify the scope of the disease in many patients. Coronal images obtained either with MR imaging or with reformation of CT image data sets can provide a perspective not easily attained with axial images. CT and MR angiography can help to identify atypical vascular anatomy. In contrast, positron emission tomography (PET) with fluorine 18 fluorodeoxyglucose is often unreliable in depicting HCC (21). Radiologic reports should reflect the various anatomic factors that influence disease staging and patient management. By giving special consideration to the Couinaud segmentation of the hepatic anatomy, radiologists can provide information that allows limited resection and maximum preservation of functional hepatocytes. Normal liver parenchyma may be further spared with the use of intraoperative US to define tumor margins.
Interventionalists also contribute to the care of the surgical patient population. Percutaneous ablation and transarterial procedures can potentially stabilize disease in transplantation candidates waiting for donor livers. However, the true benefit of this neoadjuvant preoperative treatment remains unclear. Many transplantation candidates with advanced cirrhotic disease may benefit from a transjugular intrahepatic portosystemic shunt during the wait for an organ. Partial hepatectomy can be complemented with percutaneous ablation to treat residual or recurrent disease in hepatic remnants. Further, the portal vein that perfuses a diseased liver lobe may be selectively embolized prior to resection, to promote liver remnant hypertrophy (Fig 7). However, this intervention involves an increased risk of hepatic failure in patients with advanced cirrhosis, because of their limited capacity to regenerate healthy hepatocytes (22). Finally, a variety of image-guided procedures may be used to manage any complications after partial resection or transplantation.
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Figure 7a. Large resectable HCC in a 73-year-old patient with Child-Pugh class A cirrhosis. (a) Axial contrast-enhanced T1-weighted MR image obtained with fat saturation shows a 9-cm-diameter HCC (arrow) in liver segment VII. The diminutive size of the left hepatic lobe increases the risk of postoperative hepatic failure. (b) Digital subtraction angiogram shows embolization achieved with percutaneous transhepatic access and insertion of coils in branch vessels of the right portal vein to promote left lobe hypertrophy prior to right hepatic lobectomy. (c) Postprocedural contrast-enhanced CT image depicts coils in the right hepatic lobe.
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Figure 7b. Large resectable HCC in a 73-year-old patient with Child-Pugh class A cirrhosis. (a) Axial contrast-enhanced T1-weighted MR image obtained with fat saturation shows a 9-cm-diameter HCC (arrow) in liver segment VII. The diminutive size of the left hepatic lobe increases the risk of postoperative hepatic failure. (b) Digital subtraction angiogram shows embolization achieved with percutaneous transhepatic access and insertion of coils in branch vessels of the right portal vein to promote left lobe hypertrophy prior to right hepatic lobectomy. (c) Postprocedural contrast-enhanced CT image depicts coils in the right hepatic lobe.
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Figure 7c. Large resectable HCC in a 73-year-old patient with Child-Pugh class A cirrhosis. (a) Axial contrast-enhanced T1-weighted MR image obtained with fat saturation shows a 9-cm-diameter HCC (arrow) in liver segment VII. The diminutive size of the left hepatic lobe increases the risk of postoperative hepatic failure. (b) Digital subtraction angiogram shows embolization achieved with percutaneous transhepatic access and insertion of coils in branch vessels of the right portal vein to promote left lobe hypertrophy prior to right hepatic lobectomy. (c) Postprocedural contrast-enhanced CT image depicts coils in the right hepatic lobe.
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Despite recent advances in minimally invasive treatments for HCC, surgical management continues to offer the best chance of long-term survival for eligible patients. Thus, as our understanding of this disease deepens and as the population affected by this disease expands, we must not focus solely on alternatives to surgery but also must develop ways of increasing the number of patients in whom surgery is feasible. Effective disease screening, expanded donor programs, and improved surgical techniques are just a few of the means through which we can achieve this goal.
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RF Ablation
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Several minimally invasive percutaneous techniques are now available to help manage localized solid neoplasms, including primary HCC. Chemical ablation involves the direct infusion into the tumor of a denaturing material such as ethanol or acetic acid. Thermal ablation involves the killing of tissue either by freezing it (as in cryoablation) or heating it (as in RF, microwave, or laser ablation). Percutaneous ethanol injection of HCCs has been used with limited success for many years and is probably the standard with which the other techniques should be compared. However, many institutions around the world have now switched to RF ablation, which appears to enable more effective local control of disease with fewer treatment sessions (23).
RF ablation is performed by using a directed alternating current (460 kHz) to create local ionic agitation, frictional heat, and, ultimately, irreversible cellular damage. Coagulative necrosis is achieved at temperatures that exceed 50°C (24). Radiologists perform the procedure percutaneously and with the use of imaging (typically, CT or US) for guidance. The procedure involves the insertion of a needle-tip electrode with an insulated shaft and an active uninsulated tip into the tumor (Fig 8). RF ablation also may be performed in the operating room by surgeons with laparoscopic guidance. Some surgeons perform RF ablation in conjunction with partial hepatic resection after full laparotomy. Radiologists may assist in such procedures by providing intraoperative US or by performing RF ablation if the surgeon is unfamiliar with the technique.
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Figure 8. RF ablation electrodes. Photograph of a gross bovine liver specimen shows single- and triple-pronged RF ablation electrodes surrounded by charred tissue. The size of in vivo ablation lesions appears similar, but size is affected by the conduction properties of the organ and by the extent of adjacent vascularity.
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RF ablation for the treatment of HCC can be used as a stand-alone therapy or in combination with other treatment methods. As a stand-alone therapy, RF ablation is reserved for treatment of focal or multifocal lesions that are unresectable. RF ablation is not a suitable treatment for diffuse or infiltrative forms of HCC. Although the criteria for the use of RF ablation are not defined absolutely, most physicians select patients on the basis of the lesion size, the number of lesions, and the degree of underlying hepatic impairment. Individual lesions should have a diameter of no more than 5 cm. RF ablation is commonly limited to patients with fewer than three tumors (15). Liver dysfunction in such cases typically corresponds to Child-Pugh class A or B disease. Patients with more advanced liver impairment (Child-Pugh class C) may be candidates for liver transplantation, provided there is no evidence of extrahepatic disease; however, either because of the lack of a donor or because of comorbid conditions, many such patients will receive only chemotherapy and/or supportive care.
Treatment success, in terms of initial technical performance as well as long-term survival, varies with the size of the ablated lesion and the surrounding environment. The reported experience of Buscarini et al (25) in 88 patients shows that complete tumor necrosis is an attainable objective in tumors smaller than 3.5 cm in diameter, although those investigators found that more than one treatment session was necessary in some patients to achieve this goal. In an article about local-regional therapies for HCC, Poon et al (15) cited several RF ablation studies in which complete tumor necrosis was achieved with one treatment session in 80%–90% of tumors smaller than 3–5 cm in diameter. The authors also noted the limited success reported by Livraghi et al (26) with RF ablation for management of larger HCC tumors (mean diameter, 5.4 cm; range, 3.1–9.5 cm) in 126 patients. The success rate for achievement of necrosis in these larger tumors was only 48%. If RF ablation performed with currently available technology is to have a reasonable expectation of success as a stand-alone treatment for HCC, then 5 cm is probably the upper limit for tumor diameter. Furthermore, as with surgical resection, immediate and complete tumor necrosis does not necessarily equate with long-term survival. Despite the uniform achievement of complete necrosis reported by Buscarini et al, the disease-free survival rate in their patient group was 68%, 24%, and 4% at 1, 3, and 5 years, respectively; the overall survival rate was 89%, 62%, and 33% for the same intervals (25).
The anatomic structures surrounding a tumor affect both the risks at RF ablation and the potential for success. HCC in a cirrhotic liver is particularly well suited to treatment with RF ablation, given the hard pseudocapsule that often surrounds such tumors. However, blood flow within adjacent blood vessels can dissipate heat and thereby affect the size and shape of the ablated zone. Caution must be exercised during ablation of tumors that are close to the gallbladder and the large biliary ducts, to avoid significant injury to these structures. In general, treatment of a very peripheral liver tumor involves a remote risk of capsular rupture and adjacent organ injury. A good objective is a 1-cm margin of ablated normal liver tissue around the tumor, the same goal established for most surgical resections. The location of the tumor and the health of the hepatic parenchyma partly determine whether this goal is achieved (Fig 9).
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Figure 9a. RF ablation of subcapsular HCC in an 82-year-old man with Child-Pugh class B cirrhosis. (a) Coronal contrast-enhanced arterial phase CT image depicts a 4.0 x 1.6-cm hypervascular HCC (arrow) in the inferior section of the right hepatic lobe. (b) Axial CT image obtained for guidance during percutaneous RF ablation shows placement of the electrode in the center of the tumor. (c) Coronal contrast-enhanced CT image, obtained 1 month after RF ablation, depicts a good margin of ablated tissue, with no residual tumor (arrow) and no evidence of injury to adjacent structures.
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Figure 9b. RF ablation of subcapsular HCC in an 82-year-old man with Child-Pugh class B cirrhosis. (a) Coronal contrast-enhanced arterial phase CT image depicts a 4.0 x 1.6-cm hypervascular HCC (arrow) in the inferior section of the right hepatic lobe. (b) Axial CT image obtained for guidance during percutaneous RF ablation shows placement of the electrode in the center of the tumor. (c) Coronal contrast-enhanced CT image, obtained 1 month after RF ablation, depicts a good margin of ablated tissue, with no residual tumor (arrow) and no evidence of injury to adjacent structures.
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Figure 9c. RF ablation of subcapsular HCC in an 82-year-old man with Child-Pugh class B cirrhosis. (a) Coronal contrast-enhanced arterial phase CT image depicts a 4.0 x 1.6-cm hypervascular HCC (arrow) in the inferior section of the right hepatic lobe. (b) Axial CT image obtained for guidance during percutaneous RF ablation shows placement of the electrode in the center of the tumor. (c) Coronal contrast-enhanced CT image, obtained 1 month after RF ablation, depicts a good margin of ablated tissue, with no residual tumor (arrow) and no evidence of injury to adjacent structures.
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Advantages of percutaneous RF ablation compared with other local-regional therapies include its repeatability, high local efficacy, sparing of adjacent normal liver tissue, low complication rate, and low cost. Possible complications of RF ablation include pain, nausea, hemorrhage, abscess, tumor seeding of the electrode tract, burns from grounding pads, ascites, pleural effusion, bile duct injury, and thermal injury to adjacent organs (27). Individuals with a choledochoenterostomy have a particularly high risk for developing a postablation abscess (Fig 10). Major complications, which are rare, are minimized and success is maximized by logical patient selection, proper preprocedural management, optimal placement of RF ablation probes, and adequate protection of adjacent organs. Coagulopathy and ascites increase the risk of uncontrollable peritoneal hemorrhage and should be corrected prior to treatment. There should be no active infection. As noted earlier, there are unique risks associated with RF ablation of peripheral tumors. Instillation of sterile water or insufflation with gas to displace the stomach or bowel can lessen the likelihood of injury to the adjacent organs (Fig 11 ). Saline solution should not be used for this purpose, because of its inherent conductive properties. Adjacent organs may be protected also by appropriate variation in the positioning of the patient (eg, placement in decubitus position). Alternatively, RF ablation may be performed with direct visual guidance at open laparotomy.
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Figure 10a. Postablation abscess in a 50-year-old man. (a) Axial unenhanced CT image through segments V and VI of the liver depicts an abscess (arrow) associated with a recent RF ablation site. A percutaneous catheter was placed in the abscess to facilitate healing. (b) Digital subtraction angiogram obtained with infusion of iodinated contrast material via the catheter depicts communication of the abscess with the biliary system (arrow). The patient had a preexistent choledochojejunal anastomosis, which greatly increased the risk for formation of a post–RF ablation abscess.
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Figure 10b. Postablation abscess in a 50-year-old man. (a) Axial unenhanced CT image through segments V and VI of the liver depicts an abscess (arrow) associated with a recent RF ablation site. A percutaneous catheter was placed in the abscess to facilitate healing. (b) Digital subtraction angiogram obtained with infusion of iodinated contrast material via the catheter depicts communication of the abscess with the biliary system (arrow). The patient had a preexistent choledochojejunal anastomosis, which greatly increased the risk for formation of a post–RF ablation abscess.
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Figure 11a. RF ablation of HCC performed after fluid instillation in a 74-year-old woman with Child-Pugh class B cirrhosis. (a) Coronal contrast-enhanced CT image shows a 5 x 4.5-cm HCC (arrow) in liver segment V, directly adjacent to the hepatic flexure of the large bowel. (b) Axial unenhanced CT image obtained to guide ablation shows a 22-gauge needle placed into the right subhepatic space and 150 mL of sterile water (arrow) instilled to displace the bowel from the ablation site. (c) Axial unenhanced CT image obtained during percutaneous RF ablation shows the electrode positioned in the tumor with a right lateral approach. (d) Axial contrast-enhanced CT image obtained immediately after ablation shows a nonenhancing defect (arrow) in the ablation site, a finding consistent with successful RF ablation. No associated bowel injury was identified.
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Figure 11b. RF ablation of HCC performed after fluid instillation in a 74-year-old woman with Child-Pugh class B cirrhosis. (a) Coronal contrast-enhanced CT image shows a 5 x 4.5-cm HCC (arrow) in liver segment V, directly adjacent to the hepatic flexure of the large bowel. (b) Axial unenhanced CT image obtained to guide ablation shows a 22-gauge needle placed into the right subhepatic space and 150 mL of sterile water (arrow) instilled to displace the bowel from the ablation site. (c) Axial unenhanced CT image obtained during percutaneous RF ablation shows the electrode positioned in the tumor with a right lateral approach. (d) Axial contrast-enhanced CT image obtained immediately after ablation shows a nonenhancing defect (arrow) in the ablation site, a finding consistent with successful RF ablation. No associated bowel injury was identified.
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Figure 11c. RF ablation of HCC performed after fluid instillation in a 74-year-old woman with Child-Pugh class B cirrhosis. (a) Coronal contrast-enhanced CT image shows a 5 x 4.5-cm HCC (arrow) in liver segment V, directly adjacent to the hepatic flexure of the large bowel. (b) Axial unenhanced CT image obtained to guide ablation shows a 22-gauge needle placed into the right subhepatic space and 150 mL of sterile water (arrow) instilled to displace the bowel from the ablation site. (c) Axial unenhanced CT image obtained during percutaneous RF ablation shows the electrode positioned in the tumor with a right lateral approach. (d) Axial contrast-enhanced CT image obtained immediately after ablation shows a nonenhancing defect (arrow) in the ablation site, a finding consistent with successful RF ablation. No associated bowel injury was identified.
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Figure 11d. RF ablation of HCC performed after fluid instillation in a 74-year-old woman with Child-Pugh class B cirrhosis. (a) Coronal contrast-enhanced CT image shows a 5 x 4.5-cm HCC (arrow) in liver segment V, directly adjacent to the hepatic flexure of the large bowel. (b) Axial unenhanced CT image obtained to guide ablation shows a 22-gauge needle placed into the right subhepatic space and 150 mL of sterile water (arrow) instilled to displace the bowel from the ablation site. (c) Axial unenhanced CT image obtained during percutaneous RF ablation shows the electrode positioned in the tumor with a right lateral approach. (d) Axial contrast-enhanced CT image obtained immediately after ablation shows a nonenhancing defect (arrow) in the ablation site, a finding consistent with successful RF ablation. No associated bowel injury was identified.
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Although surgery remains the standard of care for the management of small HCCs, this standard may be challenged in the near future, as more results emerge from long-term investigations of RF ablation. Randomized controlled trials are needed to directly compare surgical resection and RF ablation to determine which patient populations benefit most from each form of initial management. Furthermore, the ongoing development and implementation of other minimally invasive techniques will result in an even greater number of alternatives to surgery.
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Chemoembolization and Selective Internal Radiation Therapy
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For many years, interventionalists have derived therapeutic advantages from the dual blood supply to the liver and the propensity for neoplasms to derive their blood supply primarily from the arterial circulation. Various protocols for pharmaceutical infusion and/or arterial embolization via catheter have been developed to help patients who are ineligible for more definitive treatment of hepatic neoplastic disease. HCC tumors designated for catheter-based treatment tend to be large, infiltrative, and/or multifocal. Patients with such tumors often have severe liver dysfunction, and it is only sensible to exclude from eligibility those who cannot tolerate any stress on the surrounding liver. Therefore, patients with Child-Pugh class C disease are usually referred for systemic therapy or supportive care. Other conditions that add substantially to the risk incurred with transarterial therapy include severe thrombocytopenia or leukopenia, cardiac or renal insufficiency, uncorrectable coagulopathy, ascites, portal vein occlusion accompanied by hepatofugal flow, and atypical or diseased arterial anatomy that increases the risk of injury to adjacent gastrointestinal organs from nontarget embolization (Fig 12). In the next section, we briefly describe two transarterial procedures that are commonly used to manage HCC—TACE and selective internal radiation therapy—and discuss several factors that should be considered when selecting the appropriate treatment option.
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Figure 12a. Pretreatment assessment of HCC in a 57-year-old man with Child-Pugh class B cirrhosis. (a, b) Axial contrast-enhanced CT images show a heterogeneously enhancing, infiltrative, multifocal HCC and tumor thrombus in the main portal vein (arrow in b). (c) Late-phase digital subtraction angiogram obtained with hepatic artery access depicts hepatofugal flow in the portal vein (arrow). The large volume of ascites, retrograde portal venous flow, and compromised hepatic function (total bilirubin, >2.0 mg/dL) indicated that the patient was too ill for transarterial therapy. He was referred for systemic therapy.
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Figure 12b. Pretreatment assessment of HCC in a 57-year-old man with Child-Pugh class B cirrhosis. (a, b) Axial contrast-enhanced CT images show a heterogeneously enhancing, infiltrative, multifocal HCC and tumor thrombus in the main portal vein (arrow in b). (c) Late-phase digital subtraction angiogram obtained with hepatic artery access depicts hepatofugal flow in the portal vein (arrow). The large volume of ascites, retrograde portal venous flow, and compromised hepatic function (total bilirubin, >2.0 mg/dL) indicated that the patient was too ill for transarterial therapy. He was referred for systemic therapy.
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Figure 12c. Pretreatment assessment of HCC in a 57-year-old man with Child-Pugh class B cirrhosis. (a, b) Axial contrast-enhanced CT images show a heterogeneously enhancing, infiltrative, multifocal HCC and tumor thrombus in the main portal vein (arrow in b). (c) Late-phase digital subtraction angiogram obtained with hepatic artery access depicts hepatofugal flow in the portal vein (arrow). The large volume of ascites, retrograde portal venous flow, and compromised hepatic function (total bilirubin, >2.0 mg/dL) indicated that the patient was too ill for transarterial therapy. He was referred for systemic therapy.
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Many different pharmaceutical agents and embolization protocols have been used in TACE for the management of unresectable HCC. One commonly used formula contains a mixture of 100 mg cisplatin, 50 mg doxorubicin, and 10 mg mitomycin C in a 1:1 emulsion with a stable iodinated lipid contrast agent, such as ethiodol (Savage Laboratory, Melville, NY), which helps to achieve concentration of the drugs in the tumor vasculature (28). After selective catheterization, this mixture is infused directly into the arterial blood supply to the tumor (Fig 13). A technical controversy that is related to this procedure, as well as to selective internal radiation therapy, is whether such treatments should be complemented with arterial embolization to occlude the blood vessels that supply the neoplasm. The logical and desired result of embolization is tissue ischemia, which leads to hypoxia and cell death in the tumor. Moreover, anoxia causes an increase in tissue permeability and in the local concentration of therapeutic agents. In addition, obstruction of the blood flow inhibits washout of the pharmaceuticals and thus increases the exposure time in the neoplastic tissue (29). However, there is evidence that the hypoxia associated with embolization also promotes new vessel formation in HCC by stimulating the expression of various angiogenic factors (30). In addition, the permanent occlusion of large vessels can preclude subsequent catheter-based treatments. Thus, it remains unclear to what extent arterial embolization should be included in the transarterial management of HCC.
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Figure 13a. Chemoembolization of HCC in a 78-year-old man. (a, b) Axial contrast-enhanced T1-weighted MR image obtained with fat saturation (a) and contrast-enhanced arterial phase CT image (b) depict a 13 x 12-cm heterogeneously enhancing HCC that has nearly replaced the right liver lobe. Because of the extensive liver involvement and comorbidities, the patient was a poor candidate for surgery. (c) Digital subtraction angiogram, obtained with right hepatic artery access via a 3-F microcatheter, shows arteries draped around the large tumor. For therapy, a mixture of cisplatin, doxorubicin, and mitomycin C in a 1:1 emulsion of ethiodol was infused via the same microcatheter and was followed immediately by an infusion of 500–700-µm-diameter polyvinyl alcohol particles to achieve arterial embolization. No additional arterial supply to the tumor was identified. (d) Right hepatic arteriogram, obtained after embolization, shows an accumulation of ethiodol in the tumor bed and decreased arterial blood flow to the tumor. (e) Axial unenhanced CT image obtained just before the patient’s discharge shows a fairly uniform accumulation of ethiodol in the tumor and none in the normal liver tissue, findings that provided assurance that chemotherapy was appropriately administered.
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Figure 13b. Chemoembolization of HCC in a 78-year-old man. (a, b) Axial contrast-enhanced T1-weighted MR image obtained with fat saturation (a) and contrast-enhanced arterial phase CT image (b) depict a 13 x 12-cm heterogeneously enhancing HCC that has nearly replaced the right liver lobe. Because of the extensive liver involvement and comorbidities, the patient was a poor candidate for surgery. (c) Digital subtraction angiogram, obtained with right hepatic arte | |
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Abstract
LEARNING OBJECTIVES FOR TEST...
