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Hepatobiliary Cancer
Key Points
Incidence
Globally, hepatobiliary cancer is the sixth most common cause of cancer and the second most common cause of cancer death. In 2018, the expected incidence of hepatobiliary cancer in the United States was 54,410 cases, with 33,990 deaths.
Biological Characteristics
The primary risk factors for hepatocellular carcinoma (HCC) are chronic hepatitis B infection and hepatitis C infection, although liver cirrhosis from any cause increases the risk. The occurrence of cholangiocarcinoma is especially high in patients with primary sclerosing cholangitis. Gallbladder cancer may be related to cholelithiasis.
Staging Evaluation
In addition to a history and physical examination for cancer signs and symptoms, underlying liver disease and liver function need to be considered. The workup includes a complete blood count, liver function tests, and multiphasic liver computed tomography (CT) or magnetic resonance (MR) imaging, and staging chest and pelvis CT. The evaluation of biliary tumors usually also includes endoscopic retrograde cholangiography or MR cholangiopancreatography.
Primary Therapy
For hepatobiliary tumors, the best outcomes are seen in patients who are treated with surgery. Patients with resected early-stage HCC have a 5-year overall survival (OS) of 30% to 50%; 5-year OS for cholangiocarcinoma ranges from 10% to 40% following surgery, with worse outcomes in hilar cancers. Liver transplantation for selected patients with HCC and hilar cholangiocarcinoma is associated with 5-year OS ranging from 70% to 85% (extrahepatic cholangiocarcinoma [EHCC], transplant alone, 5-year OS of 20%-35%). Preoperative concurrent chemoradiotherapy (CRT) plus transplant can result in excellent long-term outcomes (5-year OS of 65%-74%) in carefully selected patients with EHCC who are unresectable with standard surgery. Five-year OS for gallbladder cancer generally ranges from less than 10% to 30%. Percutaneous ablative techniques (such as microwave ablation) and embolization (such as transarterial chemoembolization [TACE]) can also lead to cure in select early- to intermediate-stage HCC. There are multiple prospective trials demonstrating that radiotherapy (RT) may be curative for early to intermediate HCC, with excellent long-term outcomes and acceptable treatment toxicities in selected patients.
Adjuvant Therapy
There is no role for adjuvant therapy following surgery or transplant for HCC. However, for biliary cancers, adjuvant capecitabine improves OS over observation alone. Retrospective database review suggests that adjuvant CRT may reduce the risk of relapse and improve survival, especially in the setting of positive nodes or margins. However, this treatment remains without level 1 evidence.
Locally Advanced Disease
For intermediate HCC, TACE improves survival over best supportive care. For locally advanced HCC involving the vasculature, studies have suggested that survival is improved following TACE plus RT over sorafenib. Local treatments, such as RT for advanced HCC, have excellent local control and the potential for long-term survival. However, prospective evidence is lacking. For locally advanced/unresectable biliary carcinomas, RT plus concurrent chemotherapy (CRT) may lead to sustained local control and higher than expected OS. Preoperative CRT plus liver transplant yields excellent results in carefully selected patients with biliary cancer.
Palliation
For advanced HCC, sorafenib has been shown to improve OS over best supportive care. Low-dose whole-liver RT may reduce pain or discomfort from HCC unsuitable for standard therapies. Gemcitabine plus cisplatin has better OS and progression-free survival than gemcitabine alone in metastatic or locally advanced biliary cancer. Photodynamic therapy combined with stent can provide palliative relief for patients with biliary obstruction from cholangiocarcinoma.
Introduction
Hepatobiliary carcinomas encompass primary cancers of the liver and biliary system. The most common hepatobiliary cancer is hepatocellular carcinoma (HCC), followed by gallbladder cancer (GBCA), extrahepatic cholangiocarcinoma (EHCC), and, finally, intrahepatic cholangiocarcinoma (IHCC). Other cancers of the liver—such as carcinoid tumors, hepatoblastoma, angiosarcoma, and leiomyosarcoma—are rare. In 2018, it was estimated that 42,220 new cases of liver and intrahepatic cancer, with an additional 12,190 gallbladder or other biliary cancer would be diagnosed in the United States.
The best therapy for hepatobiliary tumors is resection; however, only a minority of patients are suitable for surgery owing to locally advanced cancer or impaired liver function. Nonsurgical options for HCC include localized ablative therapies (radiofrequency ablation [RFA], microwave ablation [MWA]), embolotherapies (bland, transarterial chemoembolization [TACE], selective internal radiotherapy [SIRT]), ablative external radiotherapy (stereotactic body radiation therapy [SBRT]), and the oral medication sorafenib. RFA can control HCCs less than 2 to 3 cm, which are not adjacent to large vessels. Multiple prospective clinical trials have demonstrated the use of SBRT for the treatment of both early- and intermediate-stage HCC, with excellent long-term outcomes. However, there are no randomized comparative studies. For intermediate-stage HCC, TACE more than doubles overall survival (OS) compared with best supportive care. It has been suggested that TACE followed by radiotherapy (RT) improves survival over sorafenib. Sorafenib improves survival in HCC unsuitable for locoregional therapies over best supportive care. Lenvatinib was found to be noninferior to sorafenib in the first-line setting and may be an additional treatment option. For progressive HCC on sorafenib, regorafenib improves survival and the role of immunotherapy with checkpoint inhibitors is an area of active investigation. For patients with metastatic or locally advanced biliary carcinoma, gemcitabine plus cisplatin improves median survival compared with gemcitabine alone.
Radiation did not historically play a role in the treatment of hepatobiliary malignancies, largely as a result of low whole-liver radiation tolerance. It was not until conformal RT planning and intensity-modulated radiotherapy (IMRT) that delivery of high doses to focal liver lesions became possible. Charged-particle treatment, such as protons and carbon ions, as well as ablative treatments such as SBRT, are now commonly used to treat select hepatobiliary cancers. Advanced radiation treatment techniques have allowed dose escalation with good local control and higher than expected OS for both HCC and IHCC. Preoperative chemoradiation treatment (CRT) plus liver transplant in carefully selected patients can be a curative option for both IHCC and EHCC. CRT remains an option for unresectable GBCA and select postoperative cases.
Hepatocellular Carcinoma
Epidemiology and Etiology
Globally, hepatobiliary carcinoma is the sixth most common cause of cancer, and the second most frequent cause of cancer death. Incidence has tripled in the United States since 1980, making HCC one of the malignancies with the most rapid increase in incidence. Although relative 5-year survival in the United States has increased from less than 5% in the 1970s to 18% in 2009, death rates have increased by 3% each year since 2000. The increasing diagnosis of HCC is thought to be a result of the hepatitis C epidemic, with obesity and nonalcoholic steatohepatitis (NASH) also contributing to cirrhosis and subsequent HCC.
HCC is twice as common in men as in women. In Asia, southeast Asia, and middle/western and sub-Saharan Africa, HCC is 15 to 100 times more common than in North America, closely tracking the incidence of hepatitis B infection. In the United States, HCC is about four times more common in Asians and two times more common in African Americans than in whites.
The primary risk factor for HCC is chronic viral hepatitis infection. In developing countries, approximately 60% of HCC is caused by the hepatitis B virus (HBV), and 33% is caused by the hepatitis C virus (HCV). In Korea and Taiwan, approximately 90% of patients with HCC are positive for HBV surface antigen (HBsAg). Prospective studies found that HBV carriers have a 200-fold increase in relative risk for HCC. The risk of HCC is increased in patients with HCV, with a 17- to 20-fold relative increase compared with noncarriers. Cirrhosis resulting from nonviral etiologies (including alcohol, NASH, autoimmune chronic active hepatitis, hemochromatosis, and alpha-1-antitrypsin deficiency) is responsible for a substantial proportion of HCC in the United States. NASH results from metabolic syndrome, obesity, insulin resistance, hypertriglyceridemia, and low low-density lipoprotein. Increased free fatty acids in the liver can lead to NF-κB activation, with subsequent inflammation and cirrhosis.
Aflatoxin B, a metabolite of Aspergillus flavus found in stored grain and peanuts in humid parts of Africa and Asia, has been linked with HCC development. A reactive intermediate metabolite of aflatoxin B binds to guanine, which is excised and replaced with thymidine. This mutation is commonly found in the TP53 tumor suppressor gene in HCC occurring in areas of high aflatoxin ingestion.
Prevention and Early Detection
The prevention of HBV infection by vaccination has led to reduced childhood HCC rates in Taiwan after introduction of a nationwide vaccination program in 1986. The incidence of HCC among 6- to 14-year-olds significantly declined from 0.70 to 0.36 per 100,000, with corresponding reductions in mortality. Additional benefit is expected to be realized in the future as the immunized population ages.
Treatment of HCV has traditionally been with interferon (IFN)-based therapy and limited by treatment side effects, including fevers, aches, depression, headache, and fatigue. Introduction of direct-acting antiviral therapies, such as ledipasvir-sofosbuvir, have allowed well-tolerated and curative treatment of chronic HCV. Unfortunately, uptake globally has been low, with drug costs varying from $655 to over US$80,000 per treatment course based on regional pricing.
Liver ultrasound (US) on its own or with alpha-fetoprotein (AFP) has been a useful screening tool to detect early-stage HCC in high-risk populations. Serum AFP has limited utility on its own for screening HCC, even in high-risk populations. In a Chinese trial, approximately 19,000 people were randomized to screening AFP and US every 6 months compared with observation. Mortality from HCC was significantly lower (83/100,000 vs. 132/100,000) and survival was significantly better (5-year OS, 46% vs. 0%) in screened patients. The 2018 National Comprehensive Cancer Network practice guidelines recommend screening patients at high risk for HCC (including patients with cirrhosis and/or HBV), with US and optional AFP every 6 months.
Biological Characteristics and Molecular Biology
HCV has been implicated in the pathogenesis of HCC but without evidence of host genome integration of the viral DNA. Fragments of HBV viral DNA are frequently found within the genome of the HCC, leading to the hypothesis that viral integration activates oncogenes or interferes with tumor suppressor genes. The normal liver of patients with chronic HBV infection shows viral DNA integration early in the course of the disease, suggesting that the HCC may originate from clonal expansion of the affected hepatocytes. The sites of viral DNA integration, however, are not consistent and do not occur near known oncogenes or tumor suppressor genes. The most frequent amplifications of genomic material involve 1q, 8q, 6p, and 17q. Common losses involve 8p, 16q, 4q, and 17p. The viral DNA itself does not contain any known oncogenes. Therefore, if the integration of viral DNA is necessary for carcinogenesis, the mechanism may be caused by genomic instability from deletions and chromosomal rearrangement rather than specific oncogene activation or disruption of tumor suppressor genes.
Hepatocarcinogenesis involves many pathways, including those involving vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), and insulin like growth factor (IGF). VEGF binds to VEGFR, promoting HCC angiogenesis. EGF binds to the epidermal growth factor receptor (EGFR), triggering signal transduction via the RAS/MAPK pathway. HGF binds to the c-MET receptor, upstream of the RAS/MAPK pathway. Activation of the RAS/MAPK pathway leads to HCC growth and proliferation. Hepatocarcinogenesis may be related to the ability of the liver to respond to damage by regeneration. The continuous liver damage seen with chronic hepatitis or cirrhosis leads to increased turnover of hepatocytes. During normal hepatocyte regeneration, proto-oncogene activation and inactivation of suppressor genes occur. Chronic liver damage leads to cellular reproduction, which may allow carcinogenic molecular changes to accumulate without repair. The apparent stepwise progression of small HCCs from regenerating nodules of liver cirrhosis supports this hypothesis.
Pathology and Pathways of Spread
Primary liver tumors can be classified as benign or malignant by their tissue of origin (hepatocyte or biliary). Benign tumors constitute 6% to 12% of all liver tumors and include hepatocellular hyperplasia, adenomas, hepatic cysts, mesenchymal hamartomas or hemangiomas, lipomas, and fibromas. Of all malignant primary tumors, 85% to 95% are of epithelial origin (including HCC, fibrolamellar HCC, cholangiocarcinoma, and hepatoblastoma), whereas 1% to 3% are malignant mesenchymal tumors.
On gross examination, HCC appears as expanding (well-defined margin), infiltrative (poorly defined margin), or multifocal (with multiple tumors throughout the liver). The microscopic appearance of HCC is similar to normal liver both in cytological features and in its plate-like growth. HCC commonly invades adjacent vasculature such as the portal vein, the inferior vena cava (IVC), and sometimes the hepatic vein. It may also invade the diaphragm. Portal nodes are the most likely regional nodes to be involved, but spread to celiac, gastric, and peritoneal nodes may also occur. Nodal metastasis can be found in up to 26% of HCC autopsy cases but distant metastases are uncommon at presentation, mostly involving the abdominal cavity, the lungs, or bone.
Fibrolamellar HCC is a unique subtype that makes up about 5% of the cases in North America. It is associated with the longest survival of HCC subtypes and is typically found in young women. Grossly, fibrolamellar carcinoma is an expanding, sclerosing tumor, characterized by septa of retracted collagenous structures radiating from a central region. On cytological examination, the tumor cells are large and polygonal, with a granular cytoplasm resulting from numerous mitochondria and abundant fibrous stroma arranged in parallel lamellae around nests, cords, and sheets of tumor cells.
Clinical Manifestations, Patient Evaluation, Staging, and Follow-Up
Symptoms and Signs
Outside of those patients whose HCC was detected by screening US, patients with HCC frequently present with right upper abdominal or epigastric pain or discomfort. The pain is usually dull but may be sharp because of tumors causing capsular stretch. Rarely, patients with HCC present with sudden, severe pain related to an acute HCC rupture and bleed. Patients may also present with an enlarging liver mass, increased girth related to ascites, and/or early satiety. Occasionally, HCC in patients with known cirrhosis may cause deterioration of liver function, leading to ascites, variceal bleed, jaundice, or encephalopathy.
The most common physical finding in patients with primary hepatic tumors is hepatomegaly, although this may be variable in HCC given fibrotic shrinkage found in cirrhosis. The liver contour is often smooth but may be nodular from tumor or cirrhosis. Patients with HCC may have a hepatic bruit because of a highly vascular tumor. Splenomegaly is also common in patients with cirrhosis, or from portal hypertension secondary to tumor invasion of the portal vein. Ascites is a particularly ominous finding because it represents either peritoneal tumor involvement, significant hepatic dysfunction resulting from advanced cirrhosis, or vascular tumor invasion. HCC invasion to the hepatic vein may lead to rapid decline in liver function, tense ascites, and tender hepatomegaly.
Laboratory Studies
The goal of the workup of patients with HCC is to define the extent of the tumor and to assess liver function. The workup includes a complete blood count, liver function tests (albumin, bilirubin, and coagulation studies), liver enzymes, and routine biochemistry. Calculation of Child-Pugh (CP) score can be a useful tool for prognosis and treatment options; CP score incorporates bilirubin, albumin, international normalized ratio (INR), and the subjective presence of ascites and encephalopathy. The ALBI score is an objective, simplified model to assess liver function that includes only albumin and bilirubin. It has been found to be a useful tool in hepatic function assessment and expected treatment toxicity. Table 56.1 shows recommended laboratory studies and CP and ALBI score algorithms for HCC.
TABLE 56.1
Diagnostic Tests and Prognostic Scores for Hepatobiliary Cancers
| General | ||||||
| History (including history of jaundice symptoms and hepatic encephalopathy) Physical examination (including assessment for ascites) |
||||||
| Laboratory Studies | ||||||
| Complete blood count Blood chemistries, including liver function studies (albumin, bilirubin) and liver enzymes Coagulation studies (INR) Hepatitis studies (HBsAg, HBsAb, HBcAb, anti-HCV) |
||||||
| Alpha-fetoprotein (if suspicious for hepatocellular or intrahepatic cholangiocarcinoma) Serum CA 19-9, consider CEA and CA-125 (if suspicious for cholangiocarcinoma) |
||||||
| Radiographic Studies | ||||||
| Multiphasic contrast-enhanced liver CT or MR Transhepatic or endoscopic cholangiography (if bile duct blockage is present) |
||||||
| Child–Pugh Score (for Hepatocellular Carcinoma) | ||||||
| Bilirubin (mg/dL) +1 >3.5 +2 2.8-3.5 +3 <2.8 |
Albumin (g/dL) +1 >3.5 +2 2.8-3.5 +3 <2.8 |
INR +1 <1.7 +2 1.7-2.3 +3 >2.3 |
Ascites +1 None +2 Mild (medically managed) +3 Moderate to Severe/Refractory |
Encephalopathy +1 None +2 Grade 1-2 +3 Grade 3-4 |
||
| CLASS A 5-6 points |
CLASS B 7-9 points |
CLASS C 10-15 points |
||||
| Abli Score (for Hepatocellular Carcinoma) | ||||||
| log10 Bilirubin (mcmol/L) x 0.66 + Albumin (g/dL) x -0.085 | ||||||
| GRADE 1 ≤ −2.60 |
GRADE 2 > −2.60 to ≤ −1.39 |
GRADE 3 > −1.39 |
||||
Anti-HCV, Antibody to hepatitis C virus; CT, computed tomography; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; INR, international normalized ratio; MR, magnetic resonance.
Serum AFP is a widely used tumor marker for HCC, with normal values varying by lab (typically 10-20 µg/L or less). AFP levels greater than 400 µg/L (4000 µg/L in patients with hepatitis) are strongly suggestive—but not diagnostic—of HCC. Elevations in AFP between 20 µg/L and 400 µg/L may represent either an exacerbation of hepatitis or HCC. Regression of AFP can be useful in tracking HCC treatment response. However, approximately 10% to 15% of HCCs do not secret AFP.
HCC outcomes in patients with HBV or HCV differ, as does toxicity and tolerability of treatment. High viral load before therapy has been associated with worse survival, and reactivation of HBV has been reported following treatment for HCC. Screening for viral hepatitis should be considered in all at-risk individuals. Approximately 5% to 40% of patients with HCC have a paraneoplastic syndrome, such as hypoglycemia, erythrocytosis, hypercalcemia, or hypercholesterolemia.
Radiographic Studies
Patients with suspected HCC are often evaluated initially with US, which is operator dependent and less helpful in obese patients. The use of Doppler contrast US and harmonic imaging have improved its usefulness. Triphasic computed tomography (CT) and magnetic resonance imaging (MRI) are the primary modalities for imaging-based diagnosis. Serial axial imaging with multiphasic imaging (arterial hepatic, portal venous, and delayed/equilibrium phase) is vital for assessing lesion vascularity, extent of tumor, vascular invasion, and for diagnosis. HCC is hypervascular and typically displays arterial enhancement with washout in venous and delayed phases with capsule appearance ( Fig. 56.1 ). Some have advocated that MRI should be the liver imaging modality of choice in patients with cirrhosis because of the superior contrast resolution and inherent capability of multiplanar evaluation.
The Liver Imaging Reporting and Data System (LI-RADS) criteria is a classification system developed and supported by the American College of Radiology. It is used to estimate the likelihood of HCC in patients with a lesion found in the background of a cirrhotic liver. Lesions are classified by imaging characteristics (size, interval growth, enhancement, washout, and capsule) in a range between LI-RADS 1 (definitely benign) and LI-RADS 5 (definitely HCC). The designation of LI-RADS 5 is considered to be unequivocal and sufficient to render a diagnosis of HCC without a biopsy.
CT of the chest, abdomen, and pelvis is recommended to rule out extrahepatic spread; bone scan can be considered if clinically indicated. Positron emission tomography (PET)/CT has been used to evaluate extrahepatic metastases; however, it is not as sensitive as multiphasic liver CT or MR for evaluating the hepatic extent of tumor.
Diagnosis
Multiphasic CT or MR imaging is most often used to obtain a noninvasive HCC diagnosis with high predictive value, and biopsy can be avoided in most patients. American Association for the Study of Liver Diseases (AASLD) guidelines do not recommend biopsy of lesions greater than 1 cm in at-risk patients if there is classic arterial enhancement and delayed washout (LI-RADS 5 lesion). Biopsy or second imaging modality should be considered in intermediate lesions (LI-RADS 4 or below) or in patients without risk factors but high suspicion for HCC. Repeat imaging is recommended for lesions less than 1 cm. There is a small risk of bleeding, infection, or tumor seeding following percutaneous biopsy. For patients who may be surgical candidates, consider referral to a transplant center prior to biopsy.
Staging.
The eighth edition of the American Joint Committee on Cancer (AJCC) staging manual for HCC is based on size, number, and local and/or vascular invasion ( Table 56.2 ). However, classification by the Barcelona Clinic Liver Cancer (BCLC) staging system with prognostic scoring (including a measure of liver function) is widely used for treatment decision-making ( Fig. 56.2 ).
TABLE 56.2
TNM Classification for Hepatobiliary Cancers
| Primary Tumor: Liver | |
| T0 | No evidence of primary tumor |
| T1 | T1a Solitary tumor ≤ 2 cm |
| T1b Solitary tumor > 2 cm without vascular invasion | |
| T2 | Solitary tumor > 2 cm with vascular invasion, or multiple tumors, none > 5 cm |
| T3 | Multiple tumors, at least one of which is > 5 cm |
| T4 | Single or multiple tumors of any size involving a major branch of the portal vein or hepatic vein, or tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis |
| Primary Tumor: Intrahepatic Bile Duct | |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ (intraductal tumor) |
| T1 | T1a Solitary tumor ≤ 5 cm without vascular invasion |
| T1b Solitary tumor > 5 cm without vascular invasion | |
| T2 | Solitary tumor with intrahepatic vascular invasion or multiple tumors, with or without vascular invasion |
| T3 | Tumor perforating the visceral peritoneum |
| T4 | Tumor involving the local extrahepatic structures by direct invasion |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis present |
| Primary Tumor: Gallbladder | |
| T0 | No evidence of primary tumor. |
| Tis | Carcinoma in situ |
| T1 | T1a Tumor invades the lamina propria |
| T1b Tumor invades the muscular layer | |
| T2 | T2a Tumor invades perimuscular connective tissue on the peritoneal side, without involvement of the serosa (visceral peritoneum) |
| T2b Tumor invades perimuscular connective tissue on the hepatic side, with no extension into the liver | |
| T3 | Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts |
| T4 | Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures |
| N0 | No regional lymph node metastasis |
| N1 | Metastases to one to three regional lymph nodes |
| N2 | Metastases to four or more regional lymph nodes |
| Primary Tumor: Proximal or Perihilar Cholangiocarcinoma (Right, Left, and Common Hepatic Duct) | |
| Tis | Carcinoma in situ/high-grade dysplasia |
| T1 | Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue |
| T2 | T2a Tumor invades beyond the wall of the bile duct to surrounding adipose tissue |
| T2b Tumor invades adjacent hepatic parenchyma | |
| T3 | Tumor invades unilateral branches of the portal vein or hepatic artery |
| T4 | Tumor invades main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement |
| N0 | No regional lymph node metastasis |
| N1 | One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, pancreatoduodenal, and portal vein lymph nodes |
| N2 | Four or more positive lymph nodes from the sites described for N1 |
| Primary Tumor: Distal Extrahepatic Cholangiocarcinoma (From Cystic Duct Insertion Into Common Hepatic Duct) | |
| Tis | Carcinoma in situ/high-grade dysplasia |
| T1 | Tumor invades the bile duct wall with a depth of < 5 mm |
| T2 | Tumor invades the bile duct wall with a depth of 5-12 mm |
| T3 | Tumor invades the bile duct wall with a depth of > 12 mm |
| T4 | Tumor involves the celiac axis, superior mesenteric artery, and/or the common hepatic artery |
| N0 | No regional lymph node metastasis |
| N1 | Metastasis in 1 to 3 regional lymph nodes |
| N2 | Metastasis in 4 or more regional lymph nodes |
| Distant Metastasis | |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
Data from Amin MB, Edge SB, et al. (eds.). AJCC Cancer Staging Manual . 8th ed. American Joint Committee on Cancer, American Cancer Society.
Follow-Up
After transplant, partial hepatectomy or locoregional therapy, imaging, and AFP are recommended every 3 to 6 months for 2 years, and then every 6 to 12 months. Imaging should be triphasic, in the modality (CT or MRI) from diagnosis, so that changes can be followed longitudinally. Given the often multifocal nature of HCC, the treated lesion should be assessed and there should be careful vigilance for new liver lesions.
The most accurate and appropriate method of grading response to radiation treatment is controversial. Response Evaluation Criteria In Solid Tumors (RECIST) or a modified version of RECIST (mRECIST) is commonly used, with the former based on lesion size and the latter based on enhancing component. After SBRT treatment, there are known complex changes in the tumor and surrounding liver parenchyma ; the treated lesion may not measurably shrink but is expected to no longer arterially enhance. RECIST and mRECIST systems have positive predicted value > 76% but poor negative predictive value. This is similar for other response grading systems, such as World Health Organization (WHO) and European Association for the Study of the Liver (EASL) criteria. Given the complexities of HCC and the known challenges in assessing lesion response post-radiotherapy, there is interest in developing new criteria that assess response based on both clinical and radiographic factors.
Treatment of HCV, if present, may be considered after successful treatment of HCC. There is some concern, based on case series, that viral clearance has been correlated to de novo or recurrent HCC, although a case-controlled retrospective study of 71 patients did not find any evidence of this. Of note, reactivation of HBV after RT has also been reported; thus, treatment of active HBV with antiviral therapy is strongly recommended prior to starting RT.
Primary Therapy
Primary therapy for HCC is based on tumor characteristics, liver function, and patient performance status and comorbidities. Fig. 56.2 shows general treatment options based on BCLC stage and includes surgery, local therapies, sorafenib, palliative RT, and best supportive care.
Early-Stage Hepatocellular Carcinoma
Very early–stage and early-stage (BCLC stage O and A) HCC are potentially curable with a variety of therapies. The most established treatments are hepatectomy, liver transplant, and RFA. Resection and transplantation result in the best outcomes, with 5-year OS of 50% to 85%. RFA has excellent outcomes in selected small HCC, with 5-year OS of 33% to 70%. MWA is increasingly used over RFA, as it has similar overall survival, but with better local control (LC) in larger tumors. There is an emerging literature on the use of definitive RT for early-stage HCC with 3-year OS as high as 67%. Stage A patients who are nonsurgical candidates should be primarily treated with local therapy.
Intermediate-Stage Hepatocellular Carcinoma
Intermediate stage (BCLC Stage B) patients can be treated with local therapies in sequence or series if needed upon progression. If resection can be conducted safely, it is associated with the best outcomes. In patients who are unresectable CP-A, regional therapies improve survival. The highest-level data is for TACE, which has been shown to double or triple OS over supportive care alone in randomized trials. Evidence of the benefit of RT is increasing, although there are no published randomized comparative studies. Prognostic factors for patients with unresectable HCC include CP score, AFP level, vascular involvement, the presence of serological markers for HBV or HCV, and overall HCC burden. More patients ultimately develop liver failure because of HCC progression, underlying liver dysfunction, or treatment-induced liver toxicity.
Advanced-Stage Hepatocellular Carcinoma
Advanced-stage (BCLC Stage C) patients with vascular involvement are generally thought to be incurable. Standard of care is sorafenib. An alternative treatment includes a combination of TACE and RT or treatment with RT alone. Virtually all prospective and retrospective radiation studies included only patients with CP-A and CP-B disease. A retrospective review of outcomes in 29 CP-B and CP-C patients showed an overall median survival of 7.9 months but only 2.8 months for those ≥ CP-B8. This suggests that SBRT may have limited benefit for those patients with severely impaired baseline liver function. BCLC stage C patients not amenable to locoregional therapies may benefit from sorafenib or lenvatinib.
Terminal-Stage Hepatocellular Carcinoma
BCLC terminal stage (D) HCC has a poor prognosis; best supportive care is generally recommended. Should performance status or liver function improve, local or systemic therapies can be considered. Many patients develop hepatic pain or discomfort; low-dose palliative RT may be used with the goal of reducing patient pain. In one study, 8 Gy in one fraction to the whole liver resulted in patient-reported improvement of pain in 50% of patients. Other palliative fractionations include 10 Gy in 5 fractions and 21 Gy in 7 fractions. A Canadian randomized trial (NCT02511522) seeks to compare 8 Gy in a single fraction with best supportive care for 60 patients with advanced-stage HCC (including ≤ CP-C10). The primary endpoint is symptomatic improvement of liver cancer pain/discomfort.
Surgical Resection
HCC resection is challenging because most patients have underlying liver dysfunction. The potential for tumor control needs to be balanced against the risk of complications. Tumor location, baseline liver function, and tumor biology should all be considered when making the decision for resection. In patients with cirrhosis considered for resection, portal hypertension is one of the strongest predictors of poor outcome. Surgery should not be offered in patients with manifestations of portal hypertension, including hepatic encephalopathy, gastrointestinal bleeding, ascites, esophageal varices, splenomegaly, platelet count less than 100,000/mm 3 , or a hepatic venous pressure gradient greater than or equal 10 mm Hg. Portal vein embolization (PVE) is sometimes used before hepatectomy to assess the ability of the future liver remnant to hypertrophy following surgery. The ability to hypertrophy after PVE is correlated with lower risk of liver failure postoperatively; lack of hypertrophy has been suggested to be a contraindication to hepatectomy.
Anatomic resections are recommended for HCC provided that adequate remnant liver volume can be preserved. Nonanatomic resections are an option—there is a growing literature on laparoscopic resections. Complications and postoperative liver insufficiency are closely associated with increased mortality following hepatectomy. Modern surgical techniques are associated with operative mortality rates of 1% to 3% and 5-year OS of 40% to 50%. Approximately 40% to 80% of patients relapse. Positive resection margins, microvascular invasion, poorly differentiated HCC, and satellite lesions predict for relapse.
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