1. Chemotherapy in advanced ovarian cancer Angiolo Gadducci Department of Gynecology and Obstetrics, Unit of Gynecologic Oncology, University of Pisa Rome October 5-6 2007 Mediterranean School of Oncology Highlights in the management of ovarian cancer

2. Integrated therapies in ovarian cancer (OC)  Early stage: Surgery Adjuvant therapy  Advanced stage: Surgery:Primary cytoreduction Interval surgery Second-look Chemotherapy Consolidation/manteinance therapy Recurrent disease: Chemotherapy Surgery

3. Subjects: 8139 patients (6408 deaths) included in 45 trials. Conclusions in term of survival  Platinum based treatment was better than non-platinum regimens (RR= 0.93; 95% CI, 0.83-1.05)  Platinum in combination was better single agent platinum when used as the same doses (RR= 0.85; 95% CI, 0.72-1.00)  CDDP and CBDCA were equally effective RR= 1.05; 95% CI, 0.94-1.18) (B.M.J., 1991) Advanced Ovarian Cancer Trialist Group

4. 49 trials involving 8763 women HR for survival (95% CI) Platinum combination chemotherapy versus single non-platinum0.93 (0.83-1.05) CDDP + non-platinum regimen versus non-platinum regimen0.88 (0.79-0.98) Platinum combination versus single platinum0.91 (0.79-1.05) CDDP versus CBDCA1.02 (0.93-1.12) Advanced Ovarian Cancer Trialists Group 2000 Chemotherapy for advanced OC

5. pathologic response 6-y survival rate PAC 27% 31% PC 21% 25% p value 0.01 <0.02 (1991) Ovarian Cancer Meta-Analysis Project PAC vs PC

6. Overview of the data from:  Advanced Ovarian Cancer Trialist Group  Ovarian Cancer Metanalysis Project Impact of DOX on survival in advanced OC  The addition of DOX improves survival (RR= 0.85; 95% CI = 0.76-0.95, p=0.003) and the size of this benefit is of a similar magnitudo to that of platinum A’Hern and Gore, 1995

7. Patient population: 1526 patients from 132 centres in nine countries. CBDCA CAP 360/ 760 368/766 Deaths Median survival 33 months 33 months 2-year survival 60% 60% HR= 1.00 (95% CI 0.86-1.16) p=0.98 ICON 2: randomised trial of CBDCA versus CAP (CTX, DOX, and CDDP) International Collaborative Ovarian Neoplasm Group Lancet 1998

8. A prognostic model for survival obtained in the meta-analysis included residual disease, age, grade and FIGO stage. A proportional hazard model, fitted the meta-analysis data, was used to construct the expected survival curve for each treatment arm of the ICON 2 trial. Expected survival curves were compared with observed survival curves in the ICON 2 trials. Using the expected survival to explain differences between the results of randomized trials: a case in advanced OC Buyse et al, 2003

9. When this model was applied to the ICON 2 data, there was no difference between the observed and expected curves in the CAP arm. In contrast, the observed survival curve for CBDCA was superior to the expected survival curve. The addition of DOX to platinum-based regimen in OC Buyse et al, 2003

10. The difference between the survivals in ICON 2 and in the meta-analysis may be related to the better results achieved with CBDCA alone at an optimally tolerated dose compared with PC at a CDDP dose of 50-60 mg/m 2. The addition of DOX to platinum-based regimen in OC Buyse et al, 2003

11. . Conclusions Relationship between dose-intensity (mg/m 2 /w) of CDDP, response rate,and survival Bias: analysis performed on trials not designed to assess value of the dose-intensity concept Retrospective analysis of 33 published Trials using CDDP in advanced OC Levin et al, 1989

12. . High dose arm CDDP dose CDDP Survival intensity total dose advantage Kaye et al. 1992 double double yes McGuire et al. 1992 double identical no Colombo et al. 1992 double identical no Conte et al. 1996 double double no Studies designed to explore the dose-response curve of CDDP

15. Authorptsmedian PFSmedian S n (months) (months) Neijt2000 208 TAX 175 mg/m 2 (3-h) + CBDCA AUC 5 16 32 TAX 175 mg/m 2 (3-h) + CDDP 75 mg/m 2 16 30 p= ns p=ns Bookman 2003 840 TAX 175 mg/m 2 (3-h) + CBDCA AUC 7.5 20.7 56.7 TAX 135 mg/m 2 (24-h) + CDDP 75 mg/m 2 19.4 48.8 p= ns p=ns Du Bois 2003798 TAX 185 mg/m 2 (3-h) + CBDCA AUC 6 17.2 43.3 TAX 185 mg/m 2 (3-h) + CDDP 75 mg/m 2 19.1 44.1 p= ns p=ns First Line Chemotherapy : Randomized trials comparing TAX + CBDCA vs CDDP + TAX

17. Vasey P. Proc ASCO 2001;(abstract and oral presentation 804)

18. SCOTROC ASCO 2002: Progression Free Survival Time from randomisation (months) 363024181260 Proportion progression free 1.0.9.8.7.6.5.4.3.2.1 0.0 537 319 320 80 90 0 0 No. of patients ar risk:- PC DC Paclitaxel/Carbo Docetaxel/Carbo Vasey P. Proc ASCO 2002;(abstract and oral presentation 804)

19. SCOTROC: Overall Survival Time from randomisation (months) 363024181260 Proportion alive 1.0.9.8.7.6.5.4.3.2.1 0.0 537 454 449 183 168 0 0 No. of patients ar risk:- PC DC Paclitaxel/Carbo Docetaxel/Carbo Vasey P. Proc ASCO 2002;(abstract and oral presentation 804)

20. PC vs DC Toxicity DCPC Myelosuppression Neurotoxicity Allergy Stomatitis Diarrhea Myalgia/Arthralgia Ozols, ASCO 2001

21. TAX 135 mg/m 2 (24-h) +CDDP 75 mg/m 2 14.0 26.6 CDDP 100 mg/m 2 16.4 30.2 TAX 200 mg/m 2 (24-h) 11.2 26.0 Braccio 1+2 versus 3 p< 0.001 p= ns Braccio 1 versus 2 p= ns p =ns 614 evaluable patients median PFS median S (months) (months) Muggia, 2000 1 st CT : Phase III randomized study of TAX + CDDP vs CDDP vs TAX in stage III-IV with RD > 1 cm: GOG 132

22. First Line Chemotherapy : ICON 3 randomized study 2074 randomized patients Median PFSMedian S months months TAX 175 mg/m 2 (3-h) + CBDCA AUC 5-6 17.3 36.1 CBDCA AUC 5-6 or 16.1 35.4 CDDP 50 mg/m 2 + DOX 50 mg/m 2 + CTX 500 mg/m 2 p=ns International Collaborative Ovarian Neoplasm Group 2002

23. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3  Statistical bias  Different extent of crossover to the taxane-based treatment in the control arm  The use of CBDCA instead of CDDP in the experimental arm  Type of treatment used in the control arm

24. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3  The large effect seen in GOG 111 which maintained at 5- years of follow up excludes the possibility of a type I error.  ICON 3 enrolled 2074 patients and the chance of missing the effect of TAX as large as seen in GOG 111 is only 1%.

25. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 Crossover to taxanes OV 10 48% GOG 132 24% ICON 3 30% (on progression) 6% (before progression)

26. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3  The experimental arm in ICON 3 differ from that of the other trials, because CBDCA was used instead of CDDP and because TAX was given at the dose of 175 mg/m 2 3-h infusion. However, recent randomized studies showed that CBDCA + TAX 3-h infusion can substitute CDDP + TAX 24-h infusion without abrogation of activity

27. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 Control arm GOG 111 CTX 750 mg/m 2 + CDDP 75 mg/m 2 OV 10 CTX 750 mg/m 2 + CDDP 75 mg/m 2 GOG 132CDDP 100 mg/m 2 ICON 3 CDDP 50 mg/m 2 + DOX 50 mg/m 2 + CTX 500 mg/m 2 or CBDCA AUC 5-6

28. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3  The control PC regimen (GOG 111 and OV 10) may be inferior to the control arm used in ICON 3 (PAC or CBDCA) and GOG 132 (high-dose CDDP)  The addition of CTX to CDDP may increase the hematologic toxicity of the regimen, causing excessive treatment delay and dose reduction.  Although there is no evidence of an improvement in survival with higher platinum dose-intensity, the addition of CTX to CDDP may have induced a dose reduction below the minimum standard.

29. Explanations for different results between GOG 111 and OV 10 versus GOG 132 and ICON 3 The lack of benefit associated to platinum/taxane combination in ICON 3 may be due to the superiority of the control arm in this trial compared to the control arms of the previous trials. A meta-analysis with individual patient data from the 4 trials revealed a significant benefit for TAX/platinum-based regimen, which was smaller than that originally expected on the basis of GOG 111.

30. Paclitaxel + Carboplatin (TC) –Accepted standard –“Control Arm” of all recent randomized trials –No other regimen shown to outperform it –Median TTP: 15-18 months –Median OS: <36-40 months Advanced Ovarian Cancer Current accepted Treatment

31. Management of Advanced EOC Search for progress  More active 1 st line regimens  Tailored treatments  IP CT  Maintenance/Consolidation therapy  New treatment strategies (IDS, NACT)  Novel (targeted) agents

32. GOG-182 (ICON 5) Ovarian Cancer III/IV Carboplatin-paclitaxel x 8 OR Carboplatin x 8 Carboplatin-gemcitabine  Carboplatin-paclitaxel x 4 x 4 Carboplatin-Doxil TM -paclitaxel x 8 Carboplatin-topotecan  Carboplatin-paclitaxel x 4 x 4 Carboplatin-paclitaxel-gemcitabine x 8 Control arm selected by institution

33. Bookman MA, ASCO 2006 GOG 182- ICON 5 Trial

34. Phase II trial of the Northeastern German Society of Gynecological Oncology Study population: 105 pts with stage II-IV EOC. CT regimenCBDCA AUC 5 every 3 weeks x 4 cycles followed by TAX 80 mg/m 2 /week x 12 cycles No grade 3 or 4 neurotoxicity and/or nausea/vomiting Grade 3-4:thrombocytopenia, 16%; anemia, 3%; leucopenia, 22% After a median follow-up of 10 months (range 1-27), 20 pts died Median OS: not yet reached Median PFS: 19 months (range: 10-23) Oskay-Oezcelik, ASCO Meeting 2007

35. CBDCA + TAX vs CBDCA + DOXIL in advanced EOC: Preliminary results of phase III MITO-2 trial RANDOMIZATION CBDCA AUC 5 + TAX 175 mg/m 2 CBDCA AUC 5 + DOXIL 30 mg/m 2 every 3 weeks x 6 cycles every 3 weeks x 6 cycles Preliminary data Among 137 pts assigned to CBDCA + DOXIL, 87 were not eligible for response assessment by RECIST Among 50 pts eligible for response assessment, 14 CR and 20 PR were recorded, for a RR of 68% Among 35 pts with not-target lesions, 9 (26%) CR and 18 (51%) PR were observed Pignata, ASCO Meeting 2007

36. ASCO 2007 Educational Session Rare Subtypes of Ovarian Cancer Clear Cell Tumors of the Ovary Toru Sugiyama, Iwate University, Japan Mucinous Ovarian Cancer Martin Gore, Royal Marsden, UK

44. Progress in the management of EOC Evidence-based optimal care of EOC should include: - an accurate surgical staging - a debulking surgery (no macroscopic peritoneal RD, systematic LY ) - IP CT In daily practice, a minority of the pts receive an optimal surgery and NONE is treated with IP CT Tailored treatments should be developed on the basis of clinico- pathological parameters (histology, tumor grade, stage of disease, RD after surgery) Education and training of health professionals might have a major impact on survival

45.  Molecular targeted agents able to interfere with fundamental steps in tumor cell re-growth (i. e. neoangiogenesis and growth factor signaling pathways) should be investigated.  CT based on extreme drug resistance (EDR) assay  CT-based on gene-profiling Conclusions