CME
Managing localized unresectable hepatocellular carcinoma Jyoti Narang-Master, MS, PA-C; Denise Rizzolo, PA-C, PhD
ABSTRACT Hepatocellular carcinoma is becoming more common, and numerous treatment algorithms are available for this complex disease. This article reviews screening, diagnosis, staging, and management of hepatocellular carcinoma, including various treatments for patients who are not candidates for surgical resection and transplantation. Keywords: hepatocellular carcinoma, unresectable, radiofrequency ablation, Child-Pugh class, transarterial chemoembolization, sorafenib
Learning objectives © BSIP SA / ALAMY
Identify screening and diagnostic strategies for hepatocellular carcinoma. Compare various treatment strategies for managing hepatocellular carcinoma. Describe treatments for patients who are not candidates for surgical resection and transplantation. FIGURE 1. Liver tumor treatment by radiofrequency ablation.
H
epatocellular carcinoma is the fourth most common cancer worldwide and the third most frequent cause of cancer death.1,2 In 2014, the National Cancer Institute (NCI) estimated the incidence and prevalence of new cases of hepatocellular carcinoma and intrahepatic bile duct cancer in the United States at 33,190 and deaths at 23,000.2 Based on a 2009 report, cases of hepatocellular carcinoma are expected to continue to rise 81% by 2020.3 More than 1 million new cases of hepatocellular carcinoma are diagnosed each year worldwide.2 The disease is most common in men; average age at diagnosis is 63.3-6 Hepatitis B accounts for 50% of hepatocellular carcinoma cases, so this cancer is most prevalent in Southeast Asia Jyoti Narang-Master is chief PA for the Department of Surgery at Bellevue Hospital, affiliated with NYU Langone. Denise Rizzolo is an associate professor in the PA program at Seton Hall University in South Orange, N.J., an assistant clinical professor in the Pace completion program in New York City, and practices urgent care in Springfield, N.J. The authors have disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000458854.46279.d8 Copyright © 2015 American Academy of Physician Assistants
JAAPA Journal of the American Academy of Physician Assistants
An electrode is inserted into the tumor via ultrasound guidance, and electrical current produces heat, ablating the tumor.
and in sub-Saharan Africa, where hepatitis B often is transmitted from mother to newborn.3-6 In the United States, hepatocellular carcinoma is becoming increasingly common because of the rise in hepatitis C, which is responsible for 3% to 5% of hepatocellular carcinoma cases.1,2 Together, chronic hepatitis B and chronic hepatitis C account for 30% to 40% of hepatocellular carcinoma cases.1,2 Other risk factors affiliated with hepatocellular carcinoma include: • cirrhosis • alcohol abuse • nonalcoholic fatty liver disease • genetic hemochromatosis • alpha 1-antitrypsin deficiency • autoimmune hepatitis • porphyria cutanea tarda • Wilson disease • smoking • aflatoxin www.JAAPA.com
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
27
CME
Key points Hepatocellular carcinoma is the fourth most common cancer worldwide and the third most frequent cause of cancer death. More than 1 million new cases of hepatocellular carcinoma are diagnosed each year worldwide. Hepatitis B accounts for 50% of hepatocellular carcinoma cases. Patients with unresectable localized hepatocellular carcinoma may be candidates for other types of treatment, including chemoembolization and radiofrequency ablation. The Barcelona Clinic Liver Cancer staging system can provide guidance on which treatment approach to use.
• type 2 diabetes • arsenic in drinking water • exposure to vinyl chloride or thorium dioxide.4,5,7,8 SCREENING AND SURVEILLANCE High-risk patients should be screened for hepatocellular carcinoma then followed with surveillance. Guidelines from the American Association for the Study of Liver Disease (AASLD) recommend surveillance for: • hepatitis B carriers who are Asian men over age 40 years, Asian women over age 50 years, have cirrhosis, or have a family history of hepatocellular carcinoma • black patients with hepatitis B • patients with cirrhosis and hepatitis C, genetic hemochromatosis, or alpha 1-antitrypsin deficiency • patients with stage 4 primary biliary cirrhosis • patients with other cirrhosis.9 The guidelines do not give a recommended age for surveillance in white patients with active hepatitis B.8,9 The benefits of surveillance are uncertain for hepatitis B carriers younger than age 40 years (men) or age 50 years (women), patients with hepatitis C with stage 3 fibrosis, and those with noncirrhotic nonalcoholic fatty liver disease.8 Surveillance, via ultrasound imaging and an alphafetoprotein (AFP) serum level every 6 months, can detect cancer early. On ultrasound, a small hepatocellular carcinoma will appear echogenic because of fat in the cells; other cancers may be seen as hypoechoic or show a target lesion appearance. As a screening test, ultrasound has a sensitivity of 65% to 80% and specificity of more than 90%.5,7-9 The guidelines state that nodules smaller than 1 cm are cirrhotic nodules, and usually not cancer. These nodules should be followed with ultrasound at intervals of 3 months. If no growth has been noted or the lesion is stable over 2 years, baseline surveillance can be continued using the imaging test that first identified the nodules.7,9 Nodules larger than 1 cm found on ultrasound of a cirrhotic liver should undergo a quadruple-phase CT scan or MRI. 28
www.JAAPA.com
DIAGNOSIS If ultrasound imaging raises the suspicion of hepatocellular carcinoma, obtain additional diagnostic tests to characterize the cancer and guide treatment. The diagnosis of hepatocellular carcinoma is highly accurate with CT scans demonstrating the four-phase protocol (contrast-enhanced study): unenhanced, arterial, venous, and delayed. 5 This protocol shows intense arterial enhancement for hepatocellular carcinoma followed by washout in the venous-delayed phases. The arterial enhancement occurs because liver tumors are perfused by the hepatic artery.10 The normal parenchyma is supplied 80% by the portal vein and 20% by the hepatic artery, so the normal parenchyma will enhance in the portal venous phase. Contrast-enhanced MRI also can be used to diagnose hepatocellular carcinoma. MRI has a positive predictive value of 97.4% and specificity of 96.6%.10 CT and MRI also can show appearances of atypical liver lesions (if not indicative of hemangioma), indicating the need for a biopsy to confirm the diagnosis of hepatocellular carcinoma and stratify the treatment recommendations.7 Serum AFP has a sensitivity of 66% and a specificity of 82% as a tumor marker for hepatocellular carcinoma.5,9 Therefore, a hepatic mass with an elevated AFP does not automatically indicate hepatocellular carcinoma—it could be intrahepatic cholangiocarcinoma or metastases from colon cancer.8 Although the most efficient AFP cutoff value indicating liver cancer is 10 to 20 ng/mL, this test has a diagnostic sensitivity of 60%.4 However, an elevated AFP level can be used to monitor for cancer recurrence.2 An AFP concentration of 400 ng/mL or greater is predictive of hepatocellular carcinoma with macrovascular invasion and advanced tumors.5,10 Clinicians should take all imaging results into account when establishing the diagnosis of hepatocellular carcinoma. STAGING CANCER A patient’s degree of cirrhosis is determined by the ChildPugh score, which is based on chemical and biochemical markers including serum albumin and serum bilirubin (Table 1).7 The Barcelona Clinic Liver Cancer system (BCLC) stages a patient’s cancer based on Child-Pugh score, number and size of nodules, cancer symptoms, and liver function.4,5,7 The BCLC also categorizes beneficial therapies by disease stages, from very early through terminal. AN OVERVIEW OF LIVER SURGERY Generally, patients should be in Child-Pugh class A to be candidates for liver resection.2,7 Other variables affecting surgical candidacy include liver function and tumor involvement in relation to the hepatic and portal veins.4 For patients with one tumor and no portal hypertension, surgical resection has an overall survival rate of 90%.5 Successful resection also depends on an adequate liver Volume 28 • Number 1 • January 2015
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Managing localized unresectable hepatocellular carcinoma TABLE 1.
Child-Pugh score7
Scoring: 5-6 points, class A (good operative risk); 7-9 points, class B (moderate operative risk); 10-15 points, class C (poor operative risk) Parameter
1 point
2 points
3 points
Encephalopathy
None
Grade 1 or 2
Grade 3 or 4
Ascites
None
Slight
Moderate
Albumin (g/dL)
>3.5
2.8-3.5
2.3)
Bilirubin (mg/dL)
3
remnant after surgery, and adequate vascular and biliary inflow and outflow.5 Orthotopic liver transplantation, the best curative option for hepatocellular carcinoma, is indicated in patients with limited disease.4,10 The liver is the only organ in the body that regenerates; a transplanted portion will regrow to a normal size liver within a few weeks. However, the shortage of donor livers poses a challenge for patients awaiting liver transplantation.
Adverse reactions to intra-arterial injection of chemotherapy are similar to systemic administration, and include nausea, vomiting, bone marrow depression, alopecia, and renal failure.9 TACE is contraindicated in patients with bilirubin of greater than 3 mg/dL, main portal vein thrombosis, and Child-Pugh class C.5 More than 50% of patients receiving TACE develop postembolization syndrome, which is characterized by fever, abdominal pain, and a moderate degree of ileus.7
TREATING LOCALIZED UNRESECTABLE CANCER This article focuses on treatments for localized unresectable hepatocellular carcinoma. The BCLC staging discussed above can provide guidance on which approach to use.4,5 Treatment algorithms are based on the National Comprehensive Cancer Network guidelines and the AASLD. Treatments include: • transarterial chemoembolization (TACE) • laparoscopic, percutaneous, or open surgical radiofrequency ablation • laparoscopic, percutaneous, or open surgical microwave ablation (Figure 1) • ethanol ablation • combination treatment with medical therapy • sorafenib.4,5,7-10 Studies have concluded that these therapies can improve patient survival rates.5-11
RADIOFREQUENCY ABLATION Radiofrequency ablation uses alternating radiofrequency current to cause frictional heat around an electrode, killing cells by coagulation necrosis. This technique can be used for patients with cirrhosis. The efficacy of radiofrequency ablation is based on factors such as tumor size, number of tumors, tumor location, and proximity of the tumor to
TRANSARTERIAL CHEMOEMBOLIZATION TACE is optimal for patients with large or multifocal hepatocellular carcinoma without vascular invasion or extrahepatic spread, and with proper portal blood flow (Figures 2 to 4).4,5,7-10 Patients with Child-Pugh class A may benefit from this option. This technique entails a catheter placed via the hepatic artery and then advanced to the lobar and segmental branches. Angiography is performed to ensure the safety of the location in delivering the chemoembolic emulsion. Chemotherapy is injected, causing arterial obstruction and stopping blood flow. The chemotherapy agents most commonly used are adriamycin or cisplatin mixed with lipiodol, an oily contrast agent.5,7 JAAPA Journal of the American Academy of Physician Assistants
FIGURE 2. CT scan (arterial phase) of a well-encapsulated,
heterogenous, minimally enhancing mass at the dome of the right hepatic lobe. The mass measured 8.8 x 6.6 cm and was diagnosed as hepatocellular carcinoma. www.JAAPA.com
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
29
CME
FIGURE 3. Coronal section of the same mass as in Figure 2,
also taken at initial diagnosis.
blood vessels and other important structures such as the kidneys, colon, and gallbladder. Radiofrequency ablation offers better results with tumors less than 3 cm in size, due to decreased heat transfer. The 3-year disease-free survival rates are up to 90%.11 Complications occur in 0.9% to 5% of patients, and include peritoneal hemorrhage, bile duct injury, abscess, intestinal perforation, skin burns, and (rarely) tumor seeding.12 MICROWAVE ABLATION Microwave ablation uses high-frequency electromagnetic energy to agitate water molecules, causing frictional heat and coagulation necrosis.12,13 Microwave ablation provides a broader zone of active heating, creating higher temperatures on the targeted zone in less time than radiofrequency ablation. This technique can be used on tumors adjacent to vessels. Multiple antennae are used to deliver high-input power that penetrates deeper into the tissues, so that larger or multifocal tumors can be treated.13 Microwave technology can ablate larger areas more quickly and with less heat transfer and reduced procedural pain compared with radiofrequency ablation. Unlike in radiofrequency ablation, microwave ablation does not require that grounding pads be placed on patients. Microwave ablation can be approached as a percutaneous, laparoscopic, or open surgical procedure.13 Ablation treatment is emerging as an effective technical alternative to surgical resection and is replacing surgery in patients who are not surgical candidates.13 ETHANOL ABLATION Percutaneous ethanol injection was one of the first techniques used to ablate liver tumors.12 This intervention works best for liver tumors less than 2 cm in size, and can be used on tumors near sensitive organs and tissues because no heat transfer occurs.7,9,13 Ethanol injection has a necrosis rate of 90% to 100%; however, the rate is 70% in tumors of 2 to 3 cm and 50% in tumors between 3 and 30
www.JAAPA.com
FIGURE 4. Arteriogram of TACE treatment of the carcinoma
shown in Figure 2.
5 cm.7 The best results are seen in patients in Child-Pugh class A, who have a survival rate of 50% at 5 years.5 SORAFENIB Sorafenib is the first systemic medication proven to extend overall survival in patients with unresectable hepatocellular carcinoma.14 Sorafenib is an oral multikinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and rapidly accelerated fibrosarcoma protein kinase, which are involved in tumor angiogenesis and progression.11,13 The drug comes in 200-mg tablets; the recommended dose is 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal). Common adverse reactions to sorafenib include: • diarrhea (55% of patients) • fatigue (46%) • grade 3 or 4 (severe or life-threatening) adverse reactions, such as severe diarrhea or ulceration (45%) • abdominal pain (31%) • unintended weight loss (30%) • anorexia (29%) • nausea (24%) • hand-foot skin reaction (21%).14,15 A study of sorafenib by Llovet and colleagues followed 602 patients with advanced hepatocellular carcinoma who were randomly assigned to treatment with sorafenib or placebo.15 Patients had not previously undergone systemic treatment, and inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 2 or less (patient is ambulatory but unable to carry out any work activities); Child-Pugh class A; life expectancy of 12 or more weeks; and adequate platelet count, hemoglobin level, prothrombin time, International Normalized Ratio, Volume 28 • Number 1 • January 2015
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Managing localized unresectable hepatocellular carcinoma
hepatic function, albumin level, total bilirubin, and hepatic function. The treatment group (299 patients) received 400 mg of sorafenib twice daily. The study found a median overall survival of 10.7 months in the sorafenib group and 7.9 months in the placebo group (95% CI, 0.55-0.87, P
Managing localized unresectable hepatocellular carcinoma Jyoti Narang-Master, MS, PA-C; Denise Rizzolo, PA-C, PhD
ABSTRACT Hepatocellular carcinoma is becoming more common, and numerous treatment algorithms are available for this complex disease. This article reviews screening, diagnosis, staging, and management of hepatocellular carcinoma, including various treatments for patients who are not candidates for surgical resection and transplantation. Keywords: hepatocellular carcinoma, unresectable, radiofrequency ablation, Child-Pugh class, transarterial chemoembolization, sorafenib
Learning objectives © BSIP SA / ALAMY
Identify screening and diagnostic strategies for hepatocellular carcinoma. Compare various treatment strategies for managing hepatocellular carcinoma. Describe treatments for patients who are not candidates for surgical resection and transplantation. FIGURE 1. Liver tumor treatment by radiofrequency ablation.
H
epatocellular carcinoma is the fourth most common cancer worldwide and the third most frequent cause of cancer death.1,2 In 2014, the National Cancer Institute (NCI) estimated the incidence and prevalence of new cases of hepatocellular carcinoma and intrahepatic bile duct cancer in the United States at 33,190 and deaths at 23,000.2 Based on a 2009 report, cases of hepatocellular carcinoma are expected to continue to rise 81% by 2020.3 More than 1 million new cases of hepatocellular carcinoma are diagnosed each year worldwide.2 The disease is most common in men; average age at diagnosis is 63.3-6 Hepatitis B accounts for 50% of hepatocellular carcinoma cases, so this cancer is most prevalent in Southeast Asia Jyoti Narang-Master is chief PA for the Department of Surgery at Bellevue Hospital, affiliated with NYU Langone. Denise Rizzolo is an associate professor in the PA program at Seton Hall University in South Orange, N.J., an assistant clinical professor in the Pace completion program in New York City, and practices urgent care in Springfield, N.J. The authors have disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000458854.46279.d8 Copyright © 2015 American Academy of Physician Assistants
JAAPA Journal of the American Academy of Physician Assistants
An electrode is inserted into the tumor via ultrasound guidance, and electrical current produces heat, ablating the tumor.
and in sub-Saharan Africa, where hepatitis B often is transmitted from mother to newborn.3-6 In the United States, hepatocellular carcinoma is becoming increasingly common because of the rise in hepatitis C, which is responsible for 3% to 5% of hepatocellular carcinoma cases.1,2 Together, chronic hepatitis B and chronic hepatitis C account for 30% to 40% of hepatocellular carcinoma cases.1,2 Other risk factors affiliated with hepatocellular carcinoma include: • cirrhosis • alcohol abuse • nonalcoholic fatty liver disease • genetic hemochromatosis • alpha 1-antitrypsin deficiency • autoimmune hepatitis • porphyria cutanea tarda • Wilson disease • smoking • aflatoxin www.JAAPA.com
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
27
CME
Key points Hepatocellular carcinoma is the fourth most common cancer worldwide and the third most frequent cause of cancer death. More than 1 million new cases of hepatocellular carcinoma are diagnosed each year worldwide. Hepatitis B accounts for 50% of hepatocellular carcinoma cases. Patients with unresectable localized hepatocellular carcinoma may be candidates for other types of treatment, including chemoembolization and radiofrequency ablation. The Barcelona Clinic Liver Cancer staging system can provide guidance on which treatment approach to use.
• type 2 diabetes • arsenic in drinking water • exposure to vinyl chloride or thorium dioxide.4,5,7,8 SCREENING AND SURVEILLANCE High-risk patients should be screened for hepatocellular carcinoma then followed with surveillance. Guidelines from the American Association for the Study of Liver Disease (AASLD) recommend surveillance for: • hepatitis B carriers who are Asian men over age 40 years, Asian women over age 50 years, have cirrhosis, or have a family history of hepatocellular carcinoma • black patients with hepatitis B • patients with cirrhosis and hepatitis C, genetic hemochromatosis, or alpha 1-antitrypsin deficiency • patients with stage 4 primary biliary cirrhosis • patients with other cirrhosis.9 The guidelines do not give a recommended age for surveillance in white patients with active hepatitis B.8,9 The benefits of surveillance are uncertain for hepatitis B carriers younger than age 40 years (men) or age 50 years (women), patients with hepatitis C with stage 3 fibrosis, and those with noncirrhotic nonalcoholic fatty liver disease.8 Surveillance, via ultrasound imaging and an alphafetoprotein (AFP) serum level every 6 months, can detect cancer early. On ultrasound, a small hepatocellular carcinoma will appear echogenic because of fat in the cells; other cancers may be seen as hypoechoic or show a target lesion appearance. As a screening test, ultrasound has a sensitivity of 65% to 80% and specificity of more than 90%.5,7-9 The guidelines state that nodules smaller than 1 cm are cirrhotic nodules, and usually not cancer. These nodules should be followed with ultrasound at intervals of 3 months. If no growth has been noted or the lesion is stable over 2 years, baseline surveillance can be continued using the imaging test that first identified the nodules.7,9 Nodules larger than 1 cm found on ultrasound of a cirrhotic liver should undergo a quadruple-phase CT scan or MRI. 28
www.JAAPA.com
DIAGNOSIS If ultrasound imaging raises the suspicion of hepatocellular carcinoma, obtain additional diagnostic tests to characterize the cancer and guide treatment. The diagnosis of hepatocellular carcinoma is highly accurate with CT scans demonstrating the four-phase protocol (contrast-enhanced study): unenhanced, arterial, venous, and delayed. 5 This protocol shows intense arterial enhancement for hepatocellular carcinoma followed by washout in the venous-delayed phases. The arterial enhancement occurs because liver tumors are perfused by the hepatic artery.10 The normal parenchyma is supplied 80% by the portal vein and 20% by the hepatic artery, so the normal parenchyma will enhance in the portal venous phase. Contrast-enhanced MRI also can be used to diagnose hepatocellular carcinoma. MRI has a positive predictive value of 97.4% and specificity of 96.6%.10 CT and MRI also can show appearances of atypical liver lesions (if not indicative of hemangioma), indicating the need for a biopsy to confirm the diagnosis of hepatocellular carcinoma and stratify the treatment recommendations.7 Serum AFP has a sensitivity of 66% and a specificity of 82% as a tumor marker for hepatocellular carcinoma.5,9 Therefore, a hepatic mass with an elevated AFP does not automatically indicate hepatocellular carcinoma—it could be intrahepatic cholangiocarcinoma or metastases from colon cancer.8 Although the most efficient AFP cutoff value indicating liver cancer is 10 to 20 ng/mL, this test has a diagnostic sensitivity of 60%.4 However, an elevated AFP level can be used to monitor for cancer recurrence.2 An AFP concentration of 400 ng/mL or greater is predictive of hepatocellular carcinoma with macrovascular invasion and advanced tumors.5,10 Clinicians should take all imaging results into account when establishing the diagnosis of hepatocellular carcinoma. STAGING CANCER A patient’s degree of cirrhosis is determined by the ChildPugh score, which is based on chemical and biochemical markers including serum albumin and serum bilirubin (Table 1).7 The Barcelona Clinic Liver Cancer system (BCLC) stages a patient’s cancer based on Child-Pugh score, number and size of nodules, cancer symptoms, and liver function.4,5,7 The BCLC also categorizes beneficial therapies by disease stages, from very early through terminal. AN OVERVIEW OF LIVER SURGERY Generally, patients should be in Child-Pugh class A to be candidates for liver resection.2,7 Other variables affecting surgical candidacy include liver function and tumor involvement in relation to the hepatic and portal veins.4 For patients with one tumor and no portal hypertension, surgical resection has an overall survival rate of 90%.5 Successful resection also depends on an adequate liver Volume 28 • Number 1 • January 2015
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Managing localized unresectable hepatocellular carcinoma TABLE 1.
Child-Pugh score7
Scoring: 5-6 points, class A (good operative risk); 7-9 points, class B (moderate operative risk); 10-15 points, class C (poor operative risk) Parameter
1 point
2 points
3 points
Encephalopathy
None
Grade 1 or 2
Grade 3 or 4
Ascites
None
Slight
Moderate
Albumin (g/dL)
>3.5
2.8-3.5
2.3)
Bilirubin (mg/dL)
3
remnant after surgery, and adequate vascular and biliary inflow and outflow.5 Orthotopic liver transplantation, the best curative option for hepatocellular carcinoma, is indicated in patients with limited disease.4,10 The liver is the only organ in the body that regenerates; a transplanted portion will regrow to a normal size liver within a few weeks. However, the shortage of donor livers poses a challenge for patients awaiting liver transplantation.
Adverse reactions to intra-arterial injection of chemotherapy are similar to systemic administration, and include nausea, vomiting, bone marrow depression, alopecia, and renal failure.9 TACE is contraindicated in patients with bilirubin of greater than 3 mg/dL, main portal vein thrombosis, and Child-Pugh class C.5 More than 50% of patients receiving TACE develop postembolization syndrome, which is characterized by fever, abdominal pain, and a moderate degree of ileus.7
TREATING LOCALIZED UNRESECTABLE CANCER This article focuses on treatments for localized unresectable hepatocellular carcinoma. The BCLC staging discussed above can provide guidance on which approach to use.4,5 Treatment algorithms are based on the National Comprehensive Cancer Network guidelines and the AASLD. Treatments include: • transarterial chemoembolization (TACE) • laparoscopic, percutaneous, or open surgical radiofrequency ablation • laparoscopic, percutaneous, or open surgical microwave ablation (Figure 1) • ethanol ablation • combination treatment with medical therapy • sorafenib.4,5,7-10 Studies have concluded that these therapies can improve patient survival rates.5-11
RADIOFREQUENCY ABLATION Radiofrequency ablation uses alternating radiofrequency current to cause frictional heat around an electrode, killing cells by coagulation necrosis. This technique can be used for patients with cirrhosis. The efficacy of radiofrequency ablation is based on factors such as tumor size, number of tumors, tumor location, and proximity of the tumor to
TRANSARTERIAL CHEMOEMBOLIZATION TACE is optimal for patients with large or multifocal hepatocellular carcinoma without vascular invasion or extrahepatic spread, and with proper portal blood flow (Figures 2 to 4).4,5,7-10 Patients with Child-Pugh class A may benefit from this option. This technique entails a catheter placed via the hepatic artery and then advanced to the lobar and segmental branches. Angiography is performed to ensure the safety of the location in delivering the chemoembolic emulsion. Chemotherapy is injected, causing arterial obstruction and stopping blood flow. The chemotherapy agents most commonly used are adriamycin or cisplatin mixed with lipiodol, an oily contrast agent.5,7 JAAPA Journal of the American Academy of Physician Assistants
FIGURE 2. CT scan (arterial phase) of a well-encapsulated,
heterogenous, minimally enhancing mass at the dome of the right hepatic lobe. The mass measured 8.8 x 6.6 cm and was diagnosed as hepatocellular carcinoma. www.JAAPA.com
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
29
CME
FIGURE 3. Coronal section of the same mass as in Figure 2,
also taken at initial diagnosis.
blood vessels and other important structures such as the kidneys, colon, and gallbladder. Radiofrequency ablation offers better results with tumors less than 3 cm in size, due to decreased heat transfer. The 3-year disease-free survival rates are up to 90%.11 Complications occur in 0.9% to 5% of patients, and include peritoneal hemorrhage, bile duct injury, abscess, intestinal perforation, skin burns, and (rarely) tumor seeding.12 MICROWAVE ABLATION Microwave ablation uses high-frequency electromagnetic energy to agitate water molecules, causing frictional heat and coagulation necrosis.12,13 Microwave ablation provides a broader zone of active heating, creating higher temperatures on the targeted zone in less time than radiofrequency ablation. This technique can be used on tumors adjacent to vessels. Multiple antennae are used to deliver high-input power that penetrates deeper into the tissues, so that larger or multifocal tumors can be treated.13 Microwave technology can ablate larger areas more quickly and with less heat transfer and reduced procedural pain compared with radiofrequency ablation. Unlike in radiofrequency ablation, microwave ablation does not require that grounding pads be placed on patients. Microwave ablation can be approached as a percutaneous, laparoscopic, or open surgical procedure.13 Ablation treatment is emerging as an effective technical alternative to surgical resection and is replacing surgery in patients who are not surgical candidates.13 ETHANOL ABLATION Percutaneous ethanol injection was one of the first techniques used to ablate liver tumors.12 This intervention works best for liver tumors less than 2 cm in size, and can be used on tumors near sensitive organs and tissues because no heat transfer occurs.7,9,13 Ethanol injection has a necrosis rate of 90% to 100%; however, the rate is 70% in tumors of 2 to 3 cm and 50% in tumors between 3 and 30
www.JAAPA.com
FIGURE 4. Arteriogram of TACE treatment of the carcinoma
shown in Figure 2.
5 cm.7 The best results are seen in patients in Child-Pugh class A, who have a survival rate of 50% at 5 years.5 SORAFENIB Sorafenib is the first systemic medication proven to extend overall survival in patients with unresectable hepatocellular carcinoma.14 Sorafenib is an oral multikinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and rapidly accelerated fibrosarcoma protein kinase, which are involved in tumor angiogenesis and progression.11,13 The drug comes in 200-mg tablets; the recommended dose is 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal). Common adverse reactions to sorafenib include: • diarrhea (55% of patients) • fatigue (46%) • grade 3 or 4 (severe or life-threatening) adverse reactions, such as severe diarrhea or ulceration (45%) • abdominal pain (31%) • unintended weight loss (30%) • anorexia (29%) • nausea (24%) • hand-foot skin reaction (21%).14,15 A study of sorafenib by Llovet and colleagues followed 602 patients with advanced hepatocellular carcinoma who were randomly assigned to treatment with sorafenib or placebo.15 Patients had not previously undergone systemic treatment, and inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 2 or less (patient is ambulatory but unable to carry out any work activities); Child-Pugh class A; life expectancy of 12 or more weeks; and adequate platelet count, hemoglobin level, prothrombin time, International Normalized Ratio, Volume 28 • Number 1 • January 2015
Copyright © 2015 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Managing localized unresectable hepatocellular carcinoma
hepatic function, albumin level, total bilirubin, and hepatic function. The treatment group (299 patients) received 400 mg of sorafenib twice daily. The study found a median overall survival of 10.7 months in the sorafenib group and 7.9 months in the placebo group (95% CI, 0.55-0.87, P
