Provincial Hepatocellular Cancer Treatment Guidelines As per consensus at the Provincial Upper Gastrointestinal Tract Cancers Guideline Meeting, June 12-13, 2014 Clinical practice guidelines have been developed after multi-disciplinary consensus based on best available literature. As the name suggests, these are to be used as a guide only. These guidelines do not replace physician judgment which is based on multiple factors including, but not limited to, the clinical and social scenario, comorbidities, performance status, age, available resources and funding considerations. The Saskatchewan Cancer Agency disclaims all liability for the use of guidelines except as expressly permitted by the Agency. No portion of these guidelines may be copied, displayed for redistribution to third parties for commercial purposes or any non-permitted use without the prior written permission from the Agency Recommendations for drug treatment presented in the Agency’s guidelines for a cancer site may not reflect provincial cancer drug funding. Please refer to the current Saskatchewan Cancer Agency drug formulary at www.saskcancer.ca for information on cancer drug listing and funding. Benefits and risk of the proposed treatment should be discussed with patient. Participating in clinical trials is encouraged when available. Involvement of a multidisciplinary team is strongly recommended.
Hepatocellular cancer (HCC) represents the sixth most common cancer in the world and the third cause of cancer-related death. It often occurs in the setting of chronic liver disease and cirrhosis. Risk factors include hepatitis B viral infection, chronic hepatitis C virus infection, alcohol, non-alcoholic steatohepatitis associated with morbid obesity and diabetes, plus multiple hereditary metabolic disorders like hemochromatosis.
A. ASSESSMENT AND INVESTIGATIONS
Given the complex nature of hepatocellular cancer management, all patients should be evaluated by a multidisciplinary team including pathologists, radiologists, hepatologists, gastroenterologists, surgeons, medical oncologists, interventional radiologists, radiation oncologists, nuclear medicine specialists, psychiatrists and palliative care specialists (for advanced disease). When a case of hepatocellular cancer is referred to a specialist surgeon, the surgeon should see the patient in 1-2 weeks and discuss it in multidisciplinary conference. If a patient is ready for resection, surgery scheduling should best be targeted within 1 month and should be performed by a specialty-trained surgeon in hepatobiliary surgery at an academic centre. Staging HCC is dependent on the two aspects of the disease, the cancer itself and the commonly associated cirrhosis. The AJCC TNM system is based on pathology. T signifies size/number and invasion into the vessels or adjacent structures, N status describes the number of nodes involved and M indicates metastatic disease. The TNM staging may be helpful in delineating the extent of the cancer but may not be sufficient to help stage the patient. The Barcelona Clinic Liver Cancer (BCLC) staging system (Appendix) incorporates patients and tumour related factors and links them with various treatment options, in patients with HCC and cirrhosis. The system categorizes patients with HCC in to stage 0 and A with early HCC who may benefit from curative therapies, stage B or intermediate and stage C or advanced stage disease who may benefit from palliative treatments and stage D, patients with a very poor life expectancy. The BCLC system may be helpful as a road map used in Page 1 of 10
Saskatchewan Cancer Agency Hepatocellular Cancer Treatment Guidelines
June 2014
the multi-disciplinary discussions. However, it performs very poorly in the advanced stage settings, where it fails to delineate the differences between the sub-groups of patients. In that case, the Cancer of the Liver Italian Program (CLIP) staging system would perform better and would be the recommended system to use especially in the setting of HCV and alcohol etiologies. Despite its limitation, Child-Pugh scoring is commonly used especially in the setting clinical trials. In the special setting of transplant candidates, a MELD (Model for End-Stage Liver Disease) score should be generated (Appendix).
Assessment and diagnostic work-up in patients with suspected HCC include History and physical examination Risk-factors for chronic liver disease Symptoms and signs of chronic liver disease ( jaundice, ascites, splenomegaly, encephalopathy) Performance status and nutritional state History or current abdominal pain (may indicate tumour rupturing) Medications review Laboratory Analysis Etiology of liver disease: Hepatitis B core antibody, hepatitis B Surface Antigen, and Hepatitis C core antibody, iron status, and other tests as clinically indicated. Liver function: prothrombin time, albumin, bilirubin, AST, ALT, GGTP CBC Metabolic profile Tumour marker: serum alpha-fetoprotein Imaging Study Triphasic CT studies for diagnosis and evaluation of tumour extent (number and size of nodules, vascular invasion, extra-hepatic spread). This should include chest, abdomen, and pelvis. MRI can substitute the abdomen/pelvis CT in case of contract allergy despite adequate pre-medication or other applicable reasons. Consider bone scan in symptomatic patients Assessment of portal hypertension if indicated by history, physical examination, or imaging. Upper endoscopy: varices and/or hypertensive gastropathy Before biopsy, evaluate if patient is surgical or transplant candidate. Biopsy is not indicated for patients with a focal lesion in a cirrhotic liver: Who are not candidate for any form of therapy because of serious comorbidity Who have decompensated cirrhosis and are on the waiting list for liver transplantation Who are candidate for resection that can be carried out with an acceptable morbidity and mortality risk
B. MANAGEMENT OF LOCALIZED HCC (CURATIVE TREATMENT) Radical treatments for curative intention include surgical resection, liver transplantation and ablation. There are no randomized trials comparing the efficacy of these approaches. B1. Surgical Approaches Patients with Child A liver function and easily resected lesion, especially those at peripheral segments of liver, such as Segments 2, 3, 4B, 5, 6, should be considered as candidates for surgical resection. Those with Child B7 should be considered selectively. Hepatic resection is controversial in cases of limited and resectable multifocal diseases or major vascular invasion. Patients with Child C or late B are not generally recommended for surgical resection. Page 2 of 10
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Radio-frequency ablation (RFA), trans-arterial chemo-embolization (TACE), Ethanol injection, selective portal vein (PV) embolization may be used pre-operatively in attempt to optimize patient surgical condition. After liver resection, calculated future remnant liver volume should be adequate, i.e. at least 20% without cirrhosis and at least 30 – 40% with Child-Pugh Class A cirrhosis, adequate vascular inflow/outflow and biliary drainage. Usually, two contiguous liver segments with intact vascular inflow and outflow and adequate biliary drainage are preserved. To prevent intrahepatic metastasis, early portal vein control should be considered. Superior and inferior hepatic vena cava and hepato-duodenal ligament slings before liver parenchyma transection as a safeguard in case of massive bleeding, are optional. Electronic devices are the recommended choice for transection of liver parenchyma. Ideal margin is 1 cm from the cancer but at least 1mm is required for clear margin. Cholecystectomy is recommended for each liver resection patient to facilitate possible further local non-surgical management.
B2. Liver transplantation Liver Transplantation should be considered in patients according to Milan Criteria or Alberta Criteria, especially for those with cancer involving central segments (Segments 4A, 7, 8). Milan Criteria: o single lesion ≤ 5cm or o 2 or 3 lesions ≤ 3cm o Both above with no vascular invasion and distance metastasis Alberta Criteria: See table 1 Table 1: Liver transplant criteria for hepatocellular carcinoma patients in Alberta Tumour Criteria Listing Down staging Patient Criteria Age Medical Social
Total tumour volume ≤115 cm3 & alpha-fetoprotein ≤ 400 ng/mL Total tumour volume ≤250 cm3 regardless of alpha-fetoprotein level, who achieve listing criteria & remain stable for 6 months Typically younger than 70 years of age, should have no comorbidities if 65 to 69 years of age No major cardiopulmonary issues, nonsmoker, HIV negative, appropriate nutritional status, etc Adequate support, compliance, appropriate abstinence and rehabilitation if addiction issues*
*Patients being considered for liver transplantation in which alcohol has played a component in the development of liver disease will only be permitted to undergo liver transplantation workup after they fulfill the criteria for listing including abstinence from alcohol (and in some cases, other illicit drugs including marijuana) for six months with certified attendance at an alcohol rehabilitation centre.
B3. Resection versus Transplant Child A patients fitting above liver transplantation criteria should be evaluated by a multidisciplinary team regarding resection or liver transplantation. Liver Transplantation should be considered in patients according to Milan Criteria or Alberta Criteria, especially for those with cancer involving central segments In general, Child’s A with single < 5cm HCC the goal should be liver resection, if possible. The location and extent of resection needed in a patient with Child’s A may determine resection versus transplant. Page 3 of 10
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Child’s B and C should be referred for liver transplant assessment, if not contraindicated.
B3. Loco-regional Therapy (Ablation) All patients with HCC should be evaluated for potential curative therapy (resection or liver transplant). Locoregional therapy should be considered in patients who are not candidates for resection or liver transplant or as a bridging treatment for liver transplant or surgery. Loco-regional therapy is broadly categorized into ablation (radiofrequency, microwave, percutaneous alcohol injection.) and arterially directed therapies (transarterial bland embolization, transarterial chemoembolization, transarterial chemoembolization with drugeluting beads and radioembolization with Yttrium-90 microsphere) [see E1 section]. B3A. Radiofrequency/ Microwave ablation Radiofrequency or microwave ablation (RFA/MWA) is an alternative first line treatment for very early stage HCC (BCLC Stage 0): Single
