Treatment of Hepatocellular Carcinoma. Andrew J. Muir, MD MHS Division of Gastroenterology Duke University Medical Center

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1 Treatment of Hepatocellular Carcinoma Andrew J. Muir, MD MHS Division of Gastroenterology Duke University Medical Center

2 Epidemiology of HCC: world The 5 th most common cancer worldwide > 500, 000 new cases/year 626,000 new cases in 2002 The 3 rd most frequent cause of cancer death worldwide females The incidence of HCC is increasing males HCC incidence

3 Epidemiology of HCC: USA The most rapidly increasing form of cancer in the US Hepatitis C epidemic Immigration of populations with high prevalence of chronic Hepatitis B Obesity epidemic and increasing NAFLD Incidence: 15,000-20,000 new cases/year 18,900 cases in 2006 Mainly in patients with cirrhosis Howe et al, J NIH 2001;93(11):824-42

4 Locoregional therapies for HCC Treatment modalities Percutaneous ablation of the tumor Blockage of the tumor blood supply Chemical: injection of chemical substances Thermal: temperature modification Transarterial embolization (TAE) Transarterial chemoembolization (TACE) Percutaneous ethanol Injection (PEI) Radiofrequency ablation (RFA) Cryoablation

5 Percutaneous ethanol injection (PEI) Highly effective for small HCC (< 2 cm) 50% 5-year survival for Child s A patients with successful tumor necrosis (similar to surgical outcome) Low rate of adverse events Inexpensive Requires repeated injections on separate days Shiina et al. AJR 1990;154: Livraghi et al. Radiology 1995;197: Livraghi et al. Cancer 1992;69: Vilana et al. Hepatology 1992;16: Ishii et al. Cancer 1996;77(9): Okada et al. Semin Liver Dis 1999; 19(3): ; Arii et al. Hepatology 2000;32:

6 Radiofrequency ablation (RFA) Laparoscopic, percutaneous, open approach Insertion in the tumor of electrodes that deliver heat around the tip induces tumor necrosis 3 cm necrosis = full ablation of a 2 cm tumor + a cm safety margin

7 RFA HCC before RFA HCC after RFA HCC 7 months after RFA

8 RFA For tumors < 2 cm: RFA has similar efficacy to that of PEI Requires fewer treatment sessions Necrotic effect of RFA is more predictable For tumors > 2 cm: RFA is more effective than PEI in inducing tumor necrosis Better local disease control Better overall survival (comparable to that achieved with resection) At present, RFA has surpassed PEI as a ablative treatment of choice for HCC Drawbacks: Higher cost Higher rate of adverse events (10%): Pleural effusion Peritoneal bleeding Peritoneal seeding Livraghi et al. Radiology 1999;210(3): Lencioni et al. Radiology 2003;228(1): Lin et al. gasrto2004; 127(6):

9 Transarterial embolization (TAE) Angiographic procedure: catheter is advanced into the hepatic artery Lobar and segmental branches (as selective as possible to induce only minimal injury to the surrounding liver) Embolization of hepatic artery: Gelfoam (1 mm cubes) is most frequently used Polyvinyl alcohol, starch microspheres, metallic coils, gelatin, lipiodol, collagen

10 Transarterial chemoembolization (TACE) TAE + a prior injection into the hepatic artery of chemotherapeutic agents mixed with lipiodol = TACE Most commonly used chemotherapeutic agents: Adriamycin, Cis-platin, Mitomycin Hypervascular HCC, before TACE Lipiodol is selectively retained within the tumor increases the exposure of the neoplastic cells to chemotherapy Post-TACE

11 Transarterial chemoembolization (TACE) Indication - First line non-curative therapy for patients with large/multifocal non-surgical HCC if: No PVT, vascular invasion, extrahepatic spread Good functional reserve Survival benefit: 20-60% at 2 years (dependant on tumor stage, liver function, general health status) Curr Opin Gastroenterology, 2003

12 TAE and TACE: treatment response Extensive tumor necrosis is induced in > 50% of patients The residual tumor nests may recover their blood supply and the tumor may continue to grow repeated treatment is required (at regular intervals or on demand) Large liver tumor Llovet at al. Lancet 2002;359: After 5 months necrotic tumor mass, hypertrophy of the reminder of the liver

13 TAE and TACE: contraindications Lack of portal blood flow (PVT, tumor invasion, compression by tumor, hepatofugal flow) The embolization of hepatic artery leaves the portal vein as the sole source of blood supply to the liver If the portal circulation is compromised, arterial embolization increases the risk of liver failure due to ischemic necrosis Decompensated liver disease (Child s B or C): increased risk of liver failure/death due to ischemic liver injury Fan et al. World J Gastroenterol 2001;7: Tazawa et al. J Gastroenterol Hepatol 2001;16: Davidson et al. Transplantation 1994;57:

14 TAE and TACE: side effects Post-embolization syndrome acute ischemia of HCC In > 50% of patients Self-limited in < 48h Fever, abdominal pain, moderate degree of ileus Treatment: 24h NPO, IVF; prophylactic antibiotics (to decrease development of hepatic abscess) are not routinely used Infectious complications (hepatic abscess, cholecystitis) - in the minority of patients Hepatic decompensation Side effects of chemoterapy (in TACE): N/V, BM suppression, alopecia, renal failure

15 Ablative therapies for HCC: summary Tumor size Pro s Con s PEI < 3 cm Low morbidity Multiple sessions RFA < 4-5 cm Fewer sessions Higher morbidity TACE > 5 cm Large tumors Decompensation

16 Down-staging? Downstaging of patients that present initially beyond the conventional limits in order to render them eligible for LT Goal: Decreasing the tumor size and number, so that the HCC meets the UNOS T2 criteria Complete tumor necrosis

17 Milan criteria 1 lesion 5 cm OR 2-3 lesions, each 3 cm 1 lesion 5 cm OR 2-3 lesions, each 3 cm + Absence of macroscopic vascular invasion + absence of macroscopic vascular invasion Absence of extrahepatic spread Absence of extrahepatic spread Mazaferro et al. NEJM 1996;334; Mazaferro et al. NEJM 1996;334;693-99

18 Priority listing for OLT MELD-based UNOS* allocation system (2006): Only patients with T2 lesions are eligible for receiving priority for OLT: Initial MELD score 22 Further MELD score upgrade:10% increase for every 3 months on the waiting list HCC < 2 cm: no priority points for OLT T0 T1 T2 T3 T4a T4b N1 M1 No tumor found One nodule, 1.9 cm One nodule 2-5 cm; 2-3 nodules, all 3 cm One nodule > 5 cm; 2-3 nodules at least one > 3 cm 4 nodules of any size T2-T4a + gross involvement of intrahepatic portal vein (on US, CT, or MRI) Involvement of regional (porta hepatis) LN Metastatic disease, incl. extrahepatic portal or hepatic vein involvement *United Network for Organ Sharing Freeman et al. Am J Transpl 2006;6: Weisner et al. Gastro (5 Suppl 1):S UNOS staging criteria for HCC

19 Down-staging for HCC AASLD 2007, abstract # 163: Yao et al. Excellent longterm outcome following downstagning of HCC prior to liver transplantation: an intention to treat analysis N=61 33 OLT; 2 LDLT Minimum wait: 3 months after downstage 18 unsuccessful downstaging (no response) Survival Overall Post-LT 1 year 87.5% 96.2% 4 years 69.5% 92.1%

20 Radioembolization Selective radiation therapy through intraarterial injection of lipiodol I or Ytrium 90 - labeled microspheres Alone for unresectable HCC or as a neoadjuvant therapy to resection or OLT Mininimally embolic effect (microscopic rather than macroscopic) May be used in patients with branch/partial PVT Well tolerated (low incidence of post-embolization syndrome) Good anti-tumor efficacy activity Encouraging survival Unclear if this is due to the effects of therapy or patients selection unproven effect on survival Sir-spheres Requires complex settings and cannot be easily implemented Kulik et al. Hepatology 2008;47:71-81

21 Systemic treatments for HCC Negligible/marginal anti-tumor activity and no effect on survival Systemic chemotherapy (usually Doxorubicin-based) Selective intra-arterial chemotherapy External radiation Hormonal therapy (tamoxifen, antiandrogens) Octreotide Interferon Systemic treatments of HCC to date have been generally ineffective and not recommended Nerenstone et al. Cancer treat Rev 1988;15:1-31. Okada et al. Hepatogastroenterology 1998; 45(Suppl3): Llovet et al Hepatology 2003;37: Kawai et al. Semin Oncol 1997;24(2 Suppl 6):S6. Raoul et al. Hepatology 1997; 26: Raoul et al. J Nucl Med 1994;35: Carr et al. Liver Transpl 2004;10(2 Suppl1):s107-S110

22 Targeted therapy of HCC: Sorafenib Sorafenib (Nexavar ) is the first targeted therapy to alter the natural history of HCC Small molecule inhibitor: nonselective tyrosine kinase inhibitor with antiangiogenic activity

23 Why targeting angiogenesis in HCC? HCC is hypervascular tumor Increased levels of VEGF have been detected in: HCC as compared to noncancerous liver Serum of patients with HCC Increased VEGF is associated with aggressive HCC behavior, poor prognosis, early relapse post treatment

24 SHARP trial: results Sorafenib prolonged overall survival compared to placebo Median OS:10.7 vs 7.9 months (HR 0.69, p= ) 44% increase in overall survival Sorafenib prolonged time to progression compared to placebo Median TTP: 5.5 vs 2.8 months (HR 0.58, p= ) 73% prolongation in time to progression Sorafenib was well tolerated: side effects Diarrhea, hand-foot syndrome, weight loss, alopecia HTN, bleeding, N/V, myelosuppression, hypophosphatemia, elevated amylase and lipase

25 HCC: multidisciplinary care Interventional Radiologist Transplant surgeon Hepatologist Oncologist Pathologist/ Diagnostic Radiologist

26 Andrew J. Muir, MD MHS Division of Gastroenterology Duke University Medical Center