Medical Students 2011 - A. Cervantes - GASTROINTESTINAL CANCER - Hepatocellular Cancer
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Medical Students 2011 - A. Cervantes - GASTROINTESTINAL CANCER - Hepatocellular Cancer
- 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
- 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
- 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Date: Oct 17 th , 2006 Sorafenib (n=299) Placebo (n=303) 902 patients with HCC screened 602 pts randomized Consent withdrawn: 8% Death: 4% Adverse events: 5% Protocol deviations: 83% 2 did not receive treatment 1 did not receive treatment DMC recomendación Stop RCT
- 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
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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”