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Advanced stage HCC management

Advanced stage HCC management. Wenqing Zhang MD, PhD Multimodality Meeting James Graham Brown Cancer Center University of Louisville 03/24/2011. Epidemiology. The 3rd most common cause of death from cancer worldwide The 5th most common cancer in men (523 000 cases, 7.9% of the total)

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Advanced stage HCC management

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  1. Advanced stage HCC management Wenqing Zhang MD, PhD Multimodality Meeting James Graham Brown Cancer Center University of Louisville 03/24/2011

  2. Epidemiology • The 3rd most common cause of death from cancer worldwide • The 5th most common cancer in men (523 000 cases, 7.9% of the total) • The 7th in women (226 000 cases, 6.5% of the total) • Most of the burden: in developing countries • M: F 2.4: 1 • The regions of high incidence(85% HCC are Men): • Eastern and South-Eastern Asia • Middle and Western Africa • also Melanesia and Micronesia/Polynesia (particularly in men) • Low rates HCC in developed regions, with the exception of Southern Europe

  3. Epidemiology • Estimated that 24,120 cases of HCC(17,430 men and 6,690 women) will be diagnosed in 2010 • Estimated 18,910 men and women will die of liver cancer and intrahepatic bile duct in 2010 • High fatality (mortality : incidence ratio : 0.93:1) • Median age at death: 69 ys • Five-year relative survival • 13.2% (WM); 13.5% (WF) • 8.4% (AMM); 12.2%(AMF)

  4. Liver Cancer Incidence and Mortality Worldwide in 2008 • Estimated age-standardised rates (World) per 100,000

  5. Estimated Liver Cancer Incidence Worldwide in 2008 MEN WOMEN GLOBOCAN 2008, International Agency for Research on Cancer

  6. Risk Factors for HCC patients • Protective factors? • White meat may be associated with a reduced risk (NOT red meat) • COFFEE CONSUMPTION  • 2 CUPs/Day reduce HCC by 40%(Meta analysis) • Statins • Hepatitis B carrier state • Chronic hepatitis C virus (HCV) infection • Hereditary hemochromatosis • Environmental toxins  • Flatoxin(microtoxin found in corn, soybeans, and peanuts) • Contaminated drinking water(The blue-green algal toxin Microcystin contamination) • Betel nut chewing • Tobacco and alcohol abuse • Nonalcoholic fatty liver disease and DM • Alpha-1 antitrypsin deficiency  • Hepatic adenoma

  7. Risk Factors for HCC in US Patients Worldwide, 75% to 80% of HCC attributable to: • Chronic HBV (50% to 55%) • HCV (25% to 30%) 100 Known Risk Factor in the US: Viral Hepatitis (N = 691) 80 60 47 Presence of Risk Factor Among HCC Patients (%) 33 40 15 20 5 0 HBV HBV + HCV Neither HCV Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98:2060-2063. El-Serag HB. Gastroenterology. 2004;127:S27-S34. Bosch FX, et al. Gastroenterology. 2004;127:S5-S16.

  8. Staging systems • AJCC : TNM staging system..revised in 2010(7th edition) • Pathologic staging system • The only validated and predict prognosis better than clinical system • Okuda system • Tumor size(50%), Ascites(detectable or not), Albumin(3mg/dl), Bilirubin(3mg/dl) • CLIP score… The Cancer of the Liver Italian Program score • Child-Pugh stage, Tumor morphology, AFP(400mg/dl) and portal vein thrombosis • The Barcelona Clinic Liver Cancer (BCLC) staging classification • Primary lesion, performance status, the presence of constitutional symptoms, vascular invasion and extrahepatic spread, and Okuda stage • The French prognostic classification by The French Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire • Prognostic classification system: Karnofsky PS; Bilirubin >50 mmol/L (>2.9 mg/dL) ; Serum AKP at least twice the ULN; Serum AFP >35 ng/mL ; Ultrasonographic portal obstruction

  9. Which one to choose? • A consensus conference on staging of HCC held jointly by the AJCC and the American Hepatico-Pancreatico-Biliary Association in 2002 recommended: • The primary staging for all patients with HCC should be clinical staging, and the CLIP system was preferred • They also recommended secondary staging with the AJCC/UICC (TNM) staging system for patients undergoing surgery (liver transplantation, resection).

  10. AJCC TAGING CHANGES FROM THE 6th TO THE 7th EDITION

  11. Survival data by stage

  12. Child-Pugh Score

  13. Diagnostic criteria without biopsy • Lesions between 1cm to 2cm • Triphasic imaging study: arterial enhancement and venous washout on 2 imaging modality (CT or MRI or USG or Angiogram ) • Arterial enhancement alone and AFP>200ng/ml(sensitivity 22%, specificity 99%) • Lesions more than 2cm • Triphasic imaging study: arterial enhancement and venous wash out on 1 imaging modality (CT or MRI or USG or Angiogram ) • AFP>200ng/ml • Only arterial enhancement on 2 contrast studies

  14. Classic enhancement on triphasic imaging study

  15. Management of HCC • Only 20-30% of patients are early stage and eligible for surgery resection, local ablation and transplant • High recurrence rate • 70-80% of patients have advanced disease requiring systemic treatment • 5-years survival without treatment only 4 months • NO improvement in 5 years survival in 20 years(<5%)

  16. PVE: Portal vein embolization; RFA: Radiofrequency ablation; PEI: Percutaneous ethanol injection; TACE: Transcatheter arterial chemoembolization. * Suitability of patients with Child-Pugh B cirrhosis for surgical resection is highly controversial. • If not a liver transplantation candidate because disease is outside transplant (Milan) criteria, downstaging therapy (RFA, TACE) could be considered, followed by reassessment for liver transplantation. Δ Systemic therapy options include participation in a clinical trial (preferred) or sorafenib.

  17. HCC– needs a truly integrated multidisciplinary team • No single treatment strategy can be applied to all patients, • Therapy should be tailored to the individual. • Team work: • Gastroenterology • Hepatology, surgery, Transplant surgery, • Interventional and diagnostic radiology, • Medical oncology, Radiation oncology, • Nuclear medicine are • All subspecialties should be involved in the treatment and care of patients with for optimal patient management

  18. Treatment of the early/intermediate stage HCC • Surgical resection is the mainstay of therapy for early stage HCC • Liver transplantation • Radiofrequency ablation (RFA) and microwave ablation • Percutaneous ethanol or acetic acid ablation • Transarterialchemoembolization (TACE) • Cryoablation • Radiation therapy(EBRT or stereotactic, partial/whole liver or SIR-Spheres)

  19. Issues about systemic therapy for advanced stage HCC • A relatively chemotherapy-refractory tumor(over expression of MDR gene, glutathione-S-transferase, heat shock proteins, and mutations in p53) • Underlying liver diseases(cirrhosis)-may be as or more important than HCC itself for pts prognosis • Systemic chemotherapy is usually not well tolerated by patients with significant underlying hepatic dysfunction • Different in etiology of HCC in different population and studies—inconsistence of study results • HCC is a heterogenouse disease at the molecular level • Tumor measurements(Resist to RECIST?) • ONLY for advanced, unresectable HCC on whom liver-directed therapy is not appropriate

  20. Systemic chemotherapy

  21. Conclusion • The combination of gemcitabine plus pegylated liposomal doxorubicin was active and safe in advanced HCC. • Moreover, this treatment induced some complete responses and converted some untreatable HCCs into lesions eligible for resection or transplantation Cancer 2011;117:125–33.

  22. Systemic chemotherapy • Most of them are phase II data • No survival benefits, but very toxic, specially for cirrhotic patients • Play a minor role in the treatment of advanced HCC • Insufficient data to routinely recommend any standard regimen, and no drug or regimen has been approved for the treatment of HCC • Systemic chemotherapy may still be considered for patients whose tumors progress while on sorafenib and whose performance status and baseline liver function are sufficient to tolerate it

  23. Systemic chemotherapy • For patients who are not eligible for clinical trials or if they are not available..consider DOX + Gem or Cis+Gem • Young and healthy patients: more aggressive therapy • Cisplatin, interferon alpha, doxorubicin, and 5-FU (PIAF) • Infusion Doxorubicin and Cisplatin • Older or more frail patients: • Oral Capecitabine or weekly high-dose 5-FU and leucovorin

  24. Systemic chemotherapy • Remember: • Systemic chemotherapy only if patient failed first line therapy AND no clinical trial available OR not a candidate for available clinical trials • Chemotherapy can reactivate viral hepatitis • Maintain antiviral treatment(lamivudine)

  25. Molecularly Targeted therapy • Preclinical studies in hepatocellular tumor suggested possible treatment targets in HCC • Raf/MEK/ERK pathway [1] • Angiogenesis as a target: VEGF augments HCC development and metastasis[2] • EGFR-RAS-MAPK Pathway [3] • Wnt/-Catenin Pathway • PI3K/AKT/mTOR Pathway • IGF signaling • Cell cycle and apoptosis Huynh H, et al. BMC Gastroenterol. 2003;3:19. 2. Yoshiji H, et al. Hepatology. 2004;39:1517-1524. 3. He AR et al. Curr Probl Cancer, March/April 2010: 34(2):131-49 .

  26. Complex Molecular Pathogenesis of HCC Chronicliver damage Hepatocyte regeneration Cirrhosis Genetic alterations HCC Marotta F et al. Clin Ter. 2004;155:187-199. Thorgeirsson SS, et al. Nat Genet. 2002;31:339-346. Wiesenauer CA, et al. J Am Coll Surg. 2004;198:410-421. Wang XW, et al. Toxicology. 2002;181-182:43-47. Feitelson MA, et al. Surg Clin North Am. 2004;84:339-354. Avila MA, et al. Oncogene. 2006;25:3866-3884. • TWO key mechanisms implicated in hepatocarcinogenesis • Liver cirrhosis following tissue damage (infectious or toxic damage) • Mutations occurring in 1 or more oncogenic or tumor suppressor genes

  27. Potential Therapeutic Targets in HCC Avila MA, et al. Oncogene. 2006;25:3866-3884. • Complex molecular pathogenesis suggests multiple potential therapeutic targets, including • Components of Raf/MEK/ERK pathway • EGF/EGFR • VEGF/VEGFR • PDGFR • Several targeted therapies currently under investigation • Gefitinib (EGFR tyrosine kinase inhibitor) • Erlotinib (EGFR tyrosine kinase inhibitor) • Bevacizumab (anti-VEGF monoclonal antibody) • Sorafenib (inhibitor of VEGFR and PDGFR tyrosine kinases, Raf kinase) • Sunitinib(\inhibitor of VEGF, PDGFR, FLT-3, CSF-1R and RET tyrosine kinase)

  28. Sorafenib • An oral multikinase inhibitor • Inhibits tumor cell proliferation via Raf-1 kinase • Exerts antiangiogenic effect by targeting receptor tyrosine kinases • Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109. • Strumberg D, et al. J Clin Oncol. 2005;23:965-972.

  29. Phase II study Conclusions • Interpatient pharmacokinetic differences between Child-Pugh A and B groups were not clinically relevant • Sorafenib equally well tolerated in both subgroups • Of 137 chemotherapy-naive patients: 8 objective responses (2.2 %), 8 minor responses (5.8 %), and 46 (34 %) with stable disease for at least 16 weeks. • Time to progression (TTP) and overall survival • Median TTP: 5.5 months –Median overall survival: 9.2 months • Study served as the basis for a phase III trial of sorafenibmonotherapyvs placebo in patients with advanced HCC Abou-Alfa GK, et al. J Clin Oncol. 2006;24:4293-4300.

  30. SHARP: Phase III Study of Sorafenib in HCC Stratified by macroscopic vascular invasion and/or extrahepatic spread, ECOG PS, geographic region Sorafenib 400 mg PO BID (n = 299) Advanced HCC, Child-Pugh A, ECOG PS 0-2, at least 1 untreated measurable lesion, and no previous systemic treatment (N = 602) Placebo PO BID (n = 303) Llovet JM, et al. N Engl J Med. 2008;359:378-390. Primary endpoints: overall survival and time to symptomatic progression (FHSI8-TSP) Secondary endpoints: TTP by independent review, disease control rate, safety

  31. SHARP: Baseline Characteristics Llovet JM, et al. N Engl J Med. 2008;359:378-390.

  32. The SHARP Trial: Overall Survival 1.00 Sorafenib Median: 10.7 months (95% CI: 9.4-13.3) 0.75 Placebo Median: 7.9 months (95% CI: 6.8-9.1) Probability of Survival 0.50 0.25 HR (S/P): 0.69 (95% CI: 0.55-0.87) P < .001 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Months Since Randomization Llovet JM, et al. N Engl J Med. 2008;359:378-390.

  33. SHARP: TTP by Independent Central Review of Radiologic Progression HR (S/P): 0.58 (95% CI: 0.45-0.74) P < .001 1.00 0.75 Probability of Radiologic Progression Placebo Median: 2.8 months (95% CI: 2.7-3.9) 0.50 Sorafenib Median: 5.5 months (95% CI: 4.1-6.9) 0.25 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months Since Randomization Llovet JM, et al. N Engl J Med. 2008;359:378-390.

  34. SHARP: Response Assessment • Time to symptom progression similar between arms (P = .77) Llovet JM, et al. N Engl J Med. 2008;359:378-390. Llovet JM, et al. ASCO 2007. Abstract LBA1.

  35. SHARP: Treatment-Related Adverse Events Llovet JM, et al. N Engl J Med. 2008;359:378-390.

  36. OS Benefit for Sorafenib in Subgroups According to Baseline Factors Llovet JM, et al. N Engl J Med. 2008;359:378-390.

  37. Phase III Study: Sorafenib vs Placebo in Asian Patients With Advanced HCC Randomized 2:1 and stratified by macroscopic vascular invasion and/or extrahepatic spread, ECOG PS, geographic region Sorafenib 400 mg PO BID (n = 150) Advanced HCC, no previous systemic treatment, ECOG PS 0-2, Child-Pugh A, life expectancy ≥ 12 weeks (N = 226) Placebo PO BID (n = 76) • Baseline characteristics balanced between groups • Primary endpoint not specified • Secondary endpoints: overall survival, TTP, time to symptomatic progression (FSHI8-TSP), disease control rate (RECIST), safety Cheng A, et al. ASCO 2008. Abstract 4509.

  38. Asian Patients With Advanced HCC: Overall Survival 1.00 SorafenibMedian: 6.5 months(95% CI: 5.6-7.6) 0.75 PlaceboMedian: 4.2 months(95% CI: 3.7-5.5) 0.50 Survival Probability 0.25 HR (S/P): 0.68(95% CI: 0.50-0.93)P = .014 0 0 2 4 6 8 10 12 14 16 18 20 22 Months Cheng A, et al. ASCO 2008. Abstract 4509.

  39. Asian Patients With Advanced HCC: Outcomes Time to Symptomatic Progression Time to Progression HR (S/P): 0.90(95% CI: 0.67-1.22)P = .498 HR (S/P): 0.57(95% CI: 0.42-0.79)P < .001 1.00 1.00 SorafenibMedian: 3.5 months(95% CI: 2.8-4.2) SorafenibMedian: 2.8 months(95% CI: 2.6-3.6) 0.75 0.75 0.50 Progression Free Probability 0.50 PlaceboMedian: 3.4 months(95% CI: 2.4-4.1) PlaceboMedian: 1.4 months(95% CI: 1.3-1.5) 0.25 0.25 0 0 0 2 4 6 8 10 12 14 16 18 20 22 0 2 4 6 8 10 12 14 16 18 20 22 Months Months Cheng A, et al. ASCO 2008. Abstract 4509.

  40. Exploratory Subgroup Survival Analyses Favors sorafenib Favors placebo YesNo Age ≥ 65 yrs YesNo MVI YesNo EHS YesNo MVI and/or EHS 01/2 ECOG PS 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 HR for Overall Survival Cheng A, et al. ASCO 2008. Abstract 4509.

  41. Asia-Pacific Study vs SHARP Cheng A, et al. ASCO 2008. Abstract 4509. Llovet JM, et al. N Engl J Med. 2008;359:378-390. • In an Asian population where patients were less hearty, efficacy was maintained • More tumors • Greater hepatic spread • Higher average BLCL stage • Efficacy outcomes were similar between studies including overall survival

  42. Recent clinical trials in the treatment of HCC

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