HEPATOCELLULAR CANCER
 
 
 
 
 
The Child- Pugh classification of liver cirrhosis .  <ul><li>The individual scores are summed and then grouped as: </li></...
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CASE 4  A 51 YEAR OLD MAN WITH UNRESECTABLE LIVER CANCER   <ul><li>HEPATITIS C VIRUS AT 32 YEARS </li></ul><ul><li>DIAGNOS...
CASE 4  A 51 YEAR OLD MAN WITH UNRESECTABLE LIVER CANCER   <ul><li>CURRENT LIVER US REVEALED FOUR NODES OF 23, 18, 12 AND ...
CASE 4  A 51 YEAR OLD MAN WITH UNRESECTABLE LIVER CANCER   <ul><li>THERAPEUTIC RECOMMENDATION: </li></ul><ul><ul><li>SORAF...
Rationale  HCC treatment schedule Llovet JM, &  Bruix J , BCLC.  Lancet,  2003 End Stage Advanced Stage Intermediate Stage...
Sorafenib in HCC: Rationale <ul><li>Raf kinase is overexpressed and activated in HCC 1   </li></ul><ul><li>RAF/MEK/ERK sig...
Sorafenib Targets Both Tumor-Cell Proliferation and Angiogenesis RAS Endothelial cell or Pericyte Angiogenesis : PDGF-  V...
Phase III SHARP Trial Study design <ul><li>Stratification: </li></ul><ul><li>Macroscopic vascular  </li></ul><ul><li>invas...
Phase III SHARP Trial Summary of trial conduct   2 nd  Interim analysis OS  Events: 321 deaths Date: Oct 17 th , 2006 Sora...
Phase III SHARP Trial Overall survival (Intention-to-treat) Sorafenib Median: 46.3 weeks (95% CI: 40.9, 57.9) Survival Pro...
Phase III SHARP Trial Conclusions <ul><li>Sorafenib prolonged overall survival vs placebo  in advanced HCC </li></ul><ul><...
Phase III SHARP Trial Conclusions <ul><li>Sorafenib is the first systemic therapy  to prolong survival in HCC patients </l...
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Medical Students 2011 - A. Cervantes - GASTROINTESTINAL CANCER - Hepatocellular Cancer

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  • Changes Michael Shan: Added medians and HRs Jeff Humphrey/Susan Kelley/Rita: Added 44% increase in OS Lisa Melilli: Changed FHSI-TSP statement to her exact wording Points to Consider Should we add % improvement in TTP? Marius: add “clinically meaningful” to 1 st bullet Howard Snow: add bullet that safety was consistent with TARGETs
  • Changes Susan Kelley/Robert Rosen: Added bullet to tie in MOA story Dimitris: Changed final bullet from “first-line” from “first-systemic Dimitris: Added subbullet on sorafenib clinical benefit in HCC Points to Consider 1. Jim Partyka: 3 rd bullet somewhat overstepping. Consider instead “this study demonstrates that sorafenib is safe and effective in the first-line treatment of HCC”
  • Medical Students 2011 - A. Cervantes - GASTROINTESTINAL CANCER - Hepatocellular Cancer

    1. 1. HEPATOCELLULAR CANCER
    2. 7. The Child- Pugh classification of liver cirrhosis . <ul><li>The individual scores are summed and then grouped as: </li></ul><ul><li><7 = A </li></ul><ul><li>7-9 = B </li></ul><ul><li>>9 = C </li></ul>Score 1 2 3 bilirubin (micromol/l) <34 34-50 >50 albumin (g/l) >35 28-35 <28 PT (seconds prolonged) <4 4-6 >6 encephalopathy none mild marked ascites none mild marked
    3. 22. CASE 4 A 51 YEAR OLD MAN WITH UNRESECTABLE LIVER CANCER <ul><li>HEPATITIS C VIRUS AT 32 YEARS </li></ul><ul><li>DIAGNOSED 5 YEARS AGO OF LIVER CIRRHOSIS BY BIOPSY </li></ul><ul><li>CHILD A STATUS </li></ul><ul><li>PERFORMANCE STATUS 0 </li></ul><ul><li>LIVER US 6 MONTHS AGO NO RELEVANT DATA </li></ul><ul><li>ALFAFETOPROTEIN 75 NG/ML </li></ul>
    4. 23. CASE 4 A 51 YEAR OLD MAN WITH UNRESECTABLE LIVER CANCER <ul><li>CURRENT LIVER US REVEALED FOUR NODES OF 23, 18, 12 AND 38 MM IN BOTH LIVER LOBES </li></ul><ul><li>NO PORTAL VEIN THROMBOSIS </li></ul><ul><li>LIVER TESTS NORMAL VALUES </li></ul><ul><li>CT SCAN REVEALED NO EXTRAHEPATIC DISEASE </li></ul>
    5. 24. CASE 4 A 51 YEAR OLD MAN WITH UNRESECTABLE LIVER CANCER <ul><li>THERAPEUTIC RECOMMENDATION: </li></ul><ul><ul><li>SORAFENIB 400 mg/12 hours </li></ul></ul><ul><ul><ul><li>VS </li></ul></ul></ul><ul><ul><li>CHEMOEMBOLIZATION </li></ul></ul><ul><ul><ul><li>NON CURABLE DISEASE </li></ul></ul></ul><ul><ul><ul><li>RAPID GROWTH </li></ul></ul></ul><ul><ul><ul><li>GOOD PERFORMANCE STATUS </li></ul></ul></ul><ul><ul><ul><li>INTERMEDIATE RISK </li></ul></ul></ul>
    6. 25. Rationale HCC treatment schedule Llovet JM, & Bruix J , BCLC. Lancet, 2003 End Stage Advanced Stage Intermediate Stage Early Stage Surgical Treatments Local Ablation New Agents TACE HCC (30%) Potentially curative treatments 5-yr survival: 50-70% (50-60%) Randomized trials median survival if untreated: 6-16 mo (10%) BSC survival <3 mo
    7. 26. Sorafenib in HCC: Rationale <ul><li>Raf kinase is overexpressed and activated in HCC 1 </li></ul><ul><li>RAF/MEK/ERK signaling pathway is implicated in liver tumorigenesis 1-3 </li></ul><ul><li>Sorafenib, approved in advanced RCC, is the only approved inhibitor of Raf kinase 4 </li></ul><ul><li>Sorafenib is a multikinase inhibitor of RAF, VEGFR, and other kinases 3 </li></ul><ul><li>Sorafenib induces apoptosis in HCC xenograft models 4 </li></ul><ul><li>Sorafenib was active in a Phase II trial of patients with advanced HCC and Child-Pugh class A and B liver function status 5 </li></ul>1. Hwang et al. Hepatol Res . 2. Calvisi et al, Gastroenterology 2006 3. Villanueva et al. Sem Liv Dis 2007 4. Liu et al. Cancer Res . 2006 5. Abou-Alfa et al. J Clin Oncol. 2006.
    8. 27. Sorafenib Targets Both Tumor-Cell Proliferation and Angiogenesis RAS Endothelial cell or Pericyte Angiogenesis : PDGF-  VEGF VEGFR-2 PDGFR-  Paracrine stimulation Mitochondria Apoptosis Tumor cell PDGF VEGF EGF/HGF Proliferation Survival Mitochondria EGF/HGF HIF-2 Autocrine loop Apoptosis ERK RAS MEK RAF Nucleus ERK MEK Wilhelm S et al. Cancer Res. 2004;64:7099-7109. RAF Differentiation Proliferation Migration Tubule formation Sorafenib Sorafenib Nucleus
    9. 28. Phase III SHARP Trial Study design <ul><li>Stratification: </li></ul><ul><li>Macroscopic vascular </li></ul><ul><li>invasion and/or </li></ul><ul><li>extrahepatic spread </li></ul><ul><li>ECOG PS </li></ul><ul><li>Geographical region </li></ul>Sorafenib (n=299) 400 mg po bid continuous dosing <ul><li>Primary end-points: </li></ul><ul><ul><li>Overall survival </li></ul></ul><ul><ul><li>Time to symptomatic progression (FHSI8-TSP) </li></ul></ul><ul><li>Secondary end-points: </li></ul><ul><ul><li>Time to progression (independent review) </li></ul></ul>Placebo (n=303) 2 tablets po bid continuous dosing Randomization N=602
    10. 29. Phase III SHARP Trial Summary of trial conduct 2 nd Interim analysis OS Events: 321 deaths Date: Oct 17 th , 2006 Sorafenib (n=299) Placebo (n=303) 902 patients with HCC screened 602 pts randomized Consent withdrawn: 8% Death: 4% Adverse events: 5% Protocol deviations: 83% 2 did not receive treatment 1 did not receive treatment DMC recomendación Stop RCT
    11. 30. Phase III SHARP Trial Overall survival (Intention-to-treat) Sorafenib Median: 46.3 weeks (95% CI: 40.9, 57.9) Survival Probability Weeks Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88) P =0.00058* 0 80 8 16 24 32 40 48 56 64 72 *O’Brien-Fleming threshold for statistical significance was P=0.0077. Placebo Median: 34.4 weeks (95% CI: 29.4, 39.4) 1.00 0 0.75 0.50 0.25 0 274 241 205 161 108 67 38 12 0 Patients at risk Sorafenib: 0 276 224 179 126 78 47 25 7 2 Placebo: 299 303
    12. 31. Phase III SHARP Trial Conclusions <ul><li>Sorafenib prolonged overall survival vs placebo in advanced HCC </li></ul><ul><ul><li>Median OS, 46 weeks vs 34 weeks </li></ul></ul><ul><ul><li>HR 0.69, P =0.00058 </li></ul></ul><ul><ul><li>44% increase in overall survival </li></ul></ul><ul><li>Sorafenib prolonged time to progression vs placebo </li></ul><ul><ul><li>Median TTP, 24 weeks vs 12 weeks </li></ul></ul><ul><ul><li>HR 0.58, P =0.000007 </li></ul></ul><ul><ul><li>73% prolongation in time to progression </li></ul></ul><ul><li>Sorafenib was well-tolerated with manageable side effects </li></ul>
    13. 32. Phase III SHARP Trial Conclusions <ul><li>Sorafenib is the first systemic therapy to prolong survival in HCC patients </li></ul><ul><li>Sorafenib is the new reference standard for systemic therapy of HCC patients </li></ul>

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