1. First-line Treatment of Ovarian Cancer: Surgery and Adjuvant Therapy Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium Balkan Masterclass in Clinical Oncology, Dubrovnik, Croatia 2011, 11-15 May

2. Five-year Survival in Ovarian Cancer 30 years of experience Vol. Year Cases Ia IV Overall (n) % 16 1963-68 4588 66.7 5.0 27.3 19 1976-78 6724 72.3 4.5 29.8 21 1982-86 10912 82.3 8.0 35.0 23 1990-92 7059 83.5 11.1 41.6 25 1996-98 4116 89.3 13.4 46.4 26* 1999-01 4911 89.3 18.6 49.7 Int. J Gynecol Obstet 2006 (Suppl 1)

4. Prognostic Factors in Early Ovarian Cancer Stage I Study No. of pts Median Strongest group involved FUP (yr) prognostic factors Vergote et al 1545 3.5 + -10.1 Grade 2001 Zanetta et al 350 9 Grade 1998 Completeness of staging + Norway; + Sweden

8. Bristow et al, 2002

10. Optimal Chemotherapy of Advanced Ovarian Cancer: Historical Perspective Alkylating Cisplatin Carboplatin Paclitaxel Agents     Doxorubicin topotecan?, LPD? gemcitabine?

13. Potential Role of Interval Debulking in OC Suboptimally debulked Study Stage of Chemotherapy No. of Outcome Group disease pts EORTC* IIb-IV 3 x CP II 3 x CP 319 49%  1995/2001 RD > 1 cm vs 6 x CP risk of death GOG III-IV 3 x TP II 3 x TP 550 no risk 2002 RD > 1 cm vs 6 x TP reduction * van der Burg et al (NEJM 1995 [2001]) ° Rose et al (NEJM, 2004)

14. Survival By Treatment 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 p=0.0032 Years O N Number of patients at risk: 122 159 84 40 16 5 Surgery 138 160 64 21 10 4 No Surgery Treatment

15. Biologic Characteristics of Tumor vs Aggressiveness of Surgery in ADOVCA A basis for NACT? Chemosensitive Successful Debulking Survival

18. Vergote et al, N Engl J Med 2010; 363: 943-953

20. Schema New Ovarian Elaborate Trial: NOVEL Trial Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancer FIGO Stage II-IV Conventional TC (c-TC) Paclitaxel 180mg/m 2 , day 1 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80mg/m 2 , days 1,8,15 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles Randomization Stratification; Residual disease: < 1cm, > 1cm FIGO Stage ： II vs. III vs. IV Histology ： clear cell/mucinous vs.serous/others Isohishi et al, ASCO 2008 (abstract #5506) Katsumata et al, Lancet 2009: 374: 1331-1338

21. Dose-dense TC (weekly T, 3-weekly C) ASCO 2008 * /Lancet 2009 PFS dd-TC vs c-TC: HR 0.714 p=0.0015 OS dd-TC vs C-TC: HR 0.735 p=0.0496 *Isohishi et al for JGOG, Katsumata et al. Lancet 2009; 374:1331-8

22. IP Chemotherapy in ADOVCA “Recognition at last” Vermorken JB. Ann Oncol 2006; 17 (suppl. 10): x241-x246

23. IPCT vs IVCT in Advanced Ovarian Cancer Overall survival Investigators No. of Overall survival (mo) year published pts Control arm Exp. Arm Alberts et al, 1996 546 41 49 1 Polyzos et al, 1999 90 25 26 Gadducci et al, 2000 113 51 67 Markman et al, 2001 462 52 63 2 Yen et al, 2001 118 48 43 Armstrong et al, 2006 415 50 66 3 1 p = 0.02; 2 p = 0.05; 3 p = 0.03

24. Pooled Data (all cisplatin studies) HR 0.79 (95% CI : 0.70, 0.89)

26. Targeted Therapies in Ovarian Cancer Target Drug(s) ErbB kinases Gefitinib, erlotinib, lapatinib, canertinib, cetuximab, pertuzumab, matuzumab, trastuzumab MUC1 / PEM Pemtumomab MUC16 (CA 125) Oregovomab mTOR / AKT Temsirolimus, everolimus, deforolimus Apoptosis pathway AEG35156, OGX-011 Angiogenesis Bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, vatalanib Endothelial cells Combretastatin, Oxi4503 Matrix metalloproteinases BAY 12-9566, marimastat

27. Summary of Completed OC Trials with Bevacizumab (B) Trial Rec/Prim Regimen Outcome Toxicity Burger et al 2007 Rec B 15 mg/kg RR 21%, PFS 4.7 mo G 3/4 GI G3 RR  , G4 Prot Cannistra et al 2008 Rec B 15 mg/kg RR 15.9%, PFS 4.4 mo OS 10.7 GIP 11% ATE 6.8% G3 RR  9.1% Micha et al 2007 Prim B 15 mg/kg + TC RR 80% G 3/4 ANC 48.3% G3 RR  11% DVT 11%

31. ICON-7: PFS http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf Accessed 15 October 2010 Academic analysis

35. GOG Ovarian Strategy: GOG 252 IV Paclitaxel 135 mg/m 2 day 1 IP Cisplatin 75 mg/m 2 day 2 IP Paclitaxel 60 mg/m 2 day 8 IV Bevacizumab 15 mg/kg IV Paclitaxel 80 mg/m 2 weekly IP Carboplatin AUC 6 IV Bevacizumab 15 mg/kg IV Paclitaxel 80 mg/m 2 weekly IV Carboplatin AUC 6 q 3 wk IV Bevacizumab 15 mg/kg q 3 wk Bevacizumab q 3 wk Maintenance x 22 Control R A N D O M I Z E Optimal disease (  1 cm residual)

36. GOG Ovarian Strategy: GOG 262 IV Paclitaxel 175 mg/m2 IV Carboplatin AUC 6 +/- IV Bevacizumab 15 mg/kg Control IV Paclitaxel 80 mg/m2 weekly IV Carboplatin AUC 6 q 3 wk +/- IV Bevacizumab 15 mg/kg q 3 wk Bevacizumab q 3 wk Maintenance x 22 R A N D O M I Z E Suboptimal disease (  1 cm residual)