Hepatocellular Carcinoma Amr Khayat, MBBS 1

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. It is now the third leading cause of cancer deaths worldwide, with over 500,000 people affected.  Hepatitis and excessive alcohol are the leading causes of HCC. (Hepatitis B or hepatitis C, 20%) or with cirrhosis (about 80%). HCC may present with right upper quadrant pain, weight loss, jaundice, bloating from ascites, and signs of decompensated liver disease.

Microscopically, there are four cytological types: fibrolamellar, pseudoglandular (adenoid), pleomorphic (giant cell) and clear cell. Local expansion, intrahepatic spread, and distant metastases. Serum AFP rise in 40-64%. On CT, HCC can have three distinct patterns of growth: A single large tumor Multiple tumors Poorly defined tumor with an infiltrative growth pattern

Diagnostic Procedures In patients with lesions less than 1 cm, >>>> conservative management with close follow-up and no biopsy is recommended. In patients with 1- to 2-cm lesions, a biopsy should be performed,. Patients with lesions greater than 2 cm, cirrhosis, characteristic imaging studies, and elevated AFP values can be managed without biopsy. Patients with large tumors who are not candidates for resection or transplantation, >>>>>> biopsy is frequently not indicated. Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. Feb 2004;10(2 Suppl 1):S115-20.

Important features that guide treatment include: - Size Spread (stage) Involvement of liver vessels Presence of a tumor capsule Presence of extrahepatic metastases Vascularity of the tumor

AJCC/UICC Classification System The International Union Against Cancer or UICC (French: Union Internationale Contre le Cancer) The American Joint Committee on Cancer (AJCC) 7

Child-Pugh score The Child-Pugh score is used to assess the prognosis of chronic liver disease, mainly cirrhosis. To determine treatment required and the necessity of liver transplantation. The score employs five clinical measures of liver disease. Each measure is scored 1-3, with 3 indicating most severe derangement. The Model for End-Stage Liver Disease, or MELD, is a scoring system for assessing the severity of chronic liver disease. It was initially developed to predict death within three months of surgery in patients that had undergone a transjugular intrahepatic portosystemic shunt (TIPS) procedure.[1]It uses the patient's values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to predict survival. This score is also used by the United Network for Organ Sharing (UNOS) and Eurotransplant for prioritizing allocation of liver transplants. It is calculated according to the following formula:MELD = 3.78[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] + 9.57[Ln serum creatinine (mg/dL)] + 6.43Caveats with the score include:[citation needed]The maximum score given for MELD is 40. All values higher than 40 are given a score of 40If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8, a value of 1.0 is used).Patients with a diagnosis of liver cancer will be assigned a MELD score based on how advanced the cancer is. This staging system is known as the TNM system. T stands for the local extent of the tumor, N stands for the presence or absence of lymph node metastases, and M stands for the presence or absence of distant metastasis (tumor spread to another organ such as the lung in the case of liver cancer). 8

Chronic liver disease is classified into Child-Pugh class A to C, employing the added score from above.

Treatment/Management Surgical resection Liver transplantation Percutaneous ablation Alcohol injection Radiofrequency ablation Transarterial embolization and chemoembolization Chemotherapy. “Radical” “Potentially Curative” “ Palliative ” 10

There is no agreement on a common treatment strategy for patients with HCC worldwide, and several proposals have been published.The three major curative therapies, resection, liver transplantation and percutaneous treatments, compete as first-line treatment option for small single HCC in patients with well-preserved liver function. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. The Lancet 2003; 362: 1907–17. Poon RT, Fan ST, Tsang FH, Wong J. Locoregional therapies for hepatocellular carcinoma: a critical review from the surgeon's perspective. Ann Surg 2002; 235: 466–86. 11

Surgery: Resection and Transplantation Surgery is the mainstay of HCC treatment and achieve the best outcomes in well-selected candidates. Less than 5% patients resectable Factors affecting resectability: Size<5cm number of tumors involvement of major structures hepatic function no extra-hepatic spread no portal hypertension · Requires experienced surgical and supporting team · 5 year survival 60%-70% · 3 year recurrence 45 - 60% Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30: 1434–40. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693–9. 12

Transplantation Milan Criteria : While Waiting : Single HCC ≤5 cm or Up to three nodules ≤3 cm No extra hepatic spread About 10 % qualify for listing The major drawback of transplantation is The scarcity of donors. The long waiting time. While Waiting : Adjuvant therapies whilst on the waiting list are used in most centers to prevent tumor progression. 13

Resection Vs Transplantaion 138 pt with cirrhosis and HCC 85 LT and 53 Resection Child’s A and B Resection Liver Transplantation 83, 57, 50 % 84, 74, 62 % 1, 3, 5-year Survival 70, 44, 31 % 83, 72, 60 % 1, 3, 5-year Disease free Liovet hepatology 1999

Percutaneous Treatments For patients who cannot undergo resection. Complete responses in more than 80% of tumors smaller than 3 cm in diameter, but in 50% of tumors of 3-5 cm in size. 5-year survival rates of 40%-60%. reported in patients with small single tumors, commonly <2 cm in diameter. Although these treatments provide good results, they are unable to achieve response rates and outcomes comparable with surgical treatments. Transarterial Embolization and Chemoembolization is recommended as first line non-curative therapy for non-surgical patients with large/multifocal HCC who do not have vascular invasion or extrahepatic spread. Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 2004; 40: 1352–60. Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 2005; 234: 961–7. Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation. Gastroenterology 2004; 127: S159–66.

Percutaneous Ethanol Injection 207 patients with cirrhosis + HCC < 5 cm · 100% Ethanol Follow up was 25 months No complications 4.3 sessions per patient 88% complete necrosis 1 ,2,3-year survival rates: 90,80,63% Cancer 1992;69:925

Radiofrequency Ablation

BEFORE RF AFTER RF

RFA PEI 96 % 88 % Complete Necrosis 15,3 % 40,4% Progression (3ys) 71,1 % 57,6 % Survival (3ys) PEI (60) RFA (52) 48 (80 %) 47 (90%) Complete Necrosis 4,8 1,2 Mean No. of Sessions Radiology 1999; 210:655 Lin et al. 2004 RFA : More expensive, more complication, more seeding. PEI: More Sessions, less effective in tumors 2cm

Palliative Therapies Primary treatment for unresectable HCC. Embolization agents – usually gelatin or microspheres – may be administered together with selective intra-arterial chemotherapy mixed with lipiodol (chemoembolization). Doxorubicin, mitomycin and cisplatin are the commonly used antitumoral drugs. Arterial embolization achieves partial responses in 15-55% of patients, and significantly delays tumour progression and vascular invasion. # Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004; 127: S179–88. # Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359: 1734–9. # Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 1164–71.

Transarterial Chemoembolization Meta-analysis of 7 randomized controlled trials 2 yr survival: 41% (19-63%) Treatment response: 35% (16-61%) Average no. of sessions: 1-4.5 Risks: Infection Tumor lysis syndrome Hepatic failure Llovel J He aloI2003"37:429

Systemic Treatments A meta-analysis of seven RCTs comparing tamoxifen vs. conservative management, comprising 898 patients, showed neither antitumoral effect nor survival benefit of tamoxifen. Thus, this treatment is discouraged in advanced HCC. Systemic chemotherapy has been tested in nine RCT. The most active agents in vitro and in vivo are doxorubicin and cisplatin. Systemic doxorubicin has been tested in more than 1000 patients within clinical trials and provides partial responses in around 10% of cases, without any evidence of survival advantages . Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429–42. # Fong Y, Kemeny N, Lawrence T. Cancer of the liver and biliary tree. In: De Vita VT, Hellman S, Rosenberg S, eds. Cancer: Principles and Practices of Oncology. Philadelphia, USA: Lippincott Williams and Wilkins, 2001: 1162–204. # Palmer D, Hussain S, Johnson P. Systemic therapies for hepatocellular carcinoma. Expert Opin Investig Drugs 2004; 13: 1555–68.

Chemotherapy Palliative not Curative. Regional (Intra-arterial) better that systemic. Resistant to many agents.

Follow-up Despite optimal treatment, hepatocellular carcinoma continues to have a high recurrence rate. majority of which occur within 2 years. Early recurrence after resection is associated with a dismal prognosis, reducing 5-year survival rates from 70% to 30%. Common extrahepatic sites of metastatic disease include lung, bone, CNS, and adrenal glands.  Factors that increase the likelihood of recurrence include the presence of : multiple foci of hepatocellular carcinoma, liver capsule invasion, tumor size (>5 cm). Vascular invasion, both microscopic and macroscopic. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. Feb 2004;126(2):460-8.

In general, a CT scan at 1 month postresection. Serum alpha-fetoprotein measurements and repeat imaging studies (eg, ultrasound, CT, MRI) every 3-6 months. After 2-3 years, safe to increase the follow-up interval.

Bruix J, Sherman M, 2005: Hepatology 42:1208-1236.

Summary Early-stage hepatocellular carcinoma is typically clinically silent, and HCC is often advanced at first manifestation. Without treatment, the 5-year survival rate is less than 5%. Complete surgical resection followed by hepatic transplantation offers the best long-term survival, but few patients are eligible for this therapy. 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. 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 offer the best chance of a cure or at least a longer and more normal life. 27

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