Neoadjuvant Chemotherapy in Ovarian Cancer

1. Neoadjuvant Chemotherapy in Ovarian Cancer Key issues in trial design

2. Key Issue #1 • What are the most current consensus recommendations on developing large phase III trials in ovarian cancer?

3. 1-A 1: Is there a need to strictly define the extent and type of surgery for patients in first-line trials? • Tissue should be obtained for histopathologic diagnosis to confirm the presence of primary ovarian or peritoneal carcinoma. • Staging should be performed according to FIGO guidelines. For example, this includes at least lymph node sampling and peritoneal staging in early stage invasive disease (FIGO I – IIA). • Up-front maximal surgical effort at cytoreduction with the goal of no residual disease should be undertaken. • Level of Acceptance: 13 / 13

4. 4-A4: Which regimen / kind of regimens can be regarded as standard • comparator for future first-line trials? • Within a given trial the chemotherapy regimen should be standardized and consistent with respect to drugs, dose, and schedule. • The recommended standard comparator for trials on medical treatment in advanced ovarian cancer (FIGO IIB-IV) is carboplatin-paclitaxel • The recommended regimen is carboplatin with a dose of AUC 5 - 7.5 and paclitaxel 175 mg/m²/ 3h given every three weeks for 6 courses • Level of Acceptance: 13 / 13

5. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDSPer protocol population (PP1)

6. GOG 182: OS based on Residual Disease AIOM 2000

7. Multivariate analysis for OS(PP1)

8. Key Issue # 2 • What is the primary hypothesis? • Neoadjuvant chemotherapy will improve OS or PFS

9. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) AIOM 2000

10. GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman, ASCO 2006, #5002

11. GOG 172 – IV vs. IP Overall survival

12. Key Issue # 2 • What is the primary hypothesis? • Neoadjuvant chemotherapy will improve OS or PFS Question # 1: Can we develop a rational superiority trial incorporating neoadjuvant chemotherapy?

13. Key Issue # 2 • What is the primary hypothesis? • Neoadjuvant chemotherapy will improve OS or PFS • Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity

14. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDSSurgical characteristics (PP1)

15. Key Issue # 2 • What is the primary hypothesis? • Neoadjuvant chemotherapy will improve OS or PFS • Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity Question # 2: What is the best trial design based on a primary endpoint of QOL?

16. Key Issue # 2 • What is the primary hypothesis? • Neoadjuvant chemotherapy will improve OS or PFS • Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity • Neoadjuvant chemotherapy will allow more patients to receive optimal surgery and optimal chemotherapy

17. Randomised EORTC-GCG/NCIC-CTG trial on NACT+ IDS versus PDSProtocol Compliance (PP1)

18. GOG 182: Residual Disease after Primary Surgery AIOM 2000

19. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDSSurgical findings and results (PP1) * % calculated on the 306 patients who underwent IDS.

20. Key Issue # 2 • What is the primary hypothesis? • Neoadjuvant chemotherapy will improve OS or PFS • Neoadjuvant chemotherapy will achieve the same survival with a lower operative morbidity • Neoadjuvant chemotherapy will allow more patients to receive optimal surgery and optimal chemotherapy Question # 3: Is there a patient population where this would have an impact on outcome?

21. Key Issue # 3 • Neoadjuvant chemotherapy should be applied to all advanced ovarian cancer patients OR • Neoadjuvant chemotherapy should be only for select populations: • Elderly • Poor performance status • Extensive disease • Medical co-morbidities

22. GOG 182 • Median age on trial 58 (62 in neoadjuvant trial) • Only 14% of patients ≥ 70 • Less than 5% ≥ 75 • Performance status 0, 1, 2 • 15% were stage IV Clearly a large patient population is not being enrolled onto current trials due to advanced age and poor performance status

23. Key Issue # 3: Special Populations • Question # 4: How to best determine extensive disease? • Radiographic, CA-125 • Question # 5: What is the best way to incorporate neoadjuvant chemotherapy into advanced age and poor performance populations? • Endpoints • Inclusive study design

24. Key Issue # 4: Surgical Timing • Question # 6: What is the best timing for surgery in patients undergoing neoadjuvant chemotherapy (3 vs. 6 months)? • Which patients should not undergo surgical intervention?

25. Key Issue # 5: Endpoints • Question # 7: What are the appropriate endpoints and how should they be measured? • OS/PFS • QOL • Surgical morbidity • Response • Clinical • Radiologic • Serum Markers • Surgical complete response

26. Key Issue # 6: Proof-of-Concept designs • Using neoadjuvant chemotherapy for proof-of-concept type studies • Novel strategies • Novel cytotoxic or biologic agents • Molecular mechanisms and biomarkers Question # 8: Can we develop a standard queue for proof-of-concept studies in advanced ovarian cancer patients?