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Neoadjuvant Chemotherapy in Ovarian Cancer Key issues in trial design Key Issue #1 What are the most current consensus recommendations on developing large phase III trials in ovarian cancer? 3rd International Ovarian Cancer Consensus Conference 3rd - 5th September 2004, Black Forest, Germany 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 3rd International Ovarian Cancer Consensus Conference 3rd - 5th September 2004, Black Forest, Germany 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 carboplatinpaclitaxel • 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 Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Per protocol population (PP1) ITT Disabling disease Histology Disease stage CA125/CEA ratio No pelvic mass-FNA Did not start allocated R/ Other Remaining (PP1) PDS N = 361 1 4 3 1 1 13 9 NACT -> IDS N = 357 1 1 2 3 0 5 6 329 339 GOG 182: OS based on Residual Disease AIOM 2000 Multivariate analysis for OS(PP1) P values Optimal debulking 0.0001 Histological type (9 categories) Largest tumor size at randomisation 0.0003 0.0008 Figo Stage (IIIc vs IV) Country (14 categories) 0.0008 0.0014 Age WHO PS Differentiation Grade 0.0020 NS NS Treatment arm NS Key Issue # 2 What is the primary hypothesis? Neoadjuvant chemotherapy will improve OS or PFS NACT + IDS versus PDS: ITT Overall survival 100 90 80 Median survial 70 PDS: 29 months 60 IDS: 30 months 50 HR for IDS:0.98 (0.85, 1.14) 40 30 20 10 0 (years) 0 O N 259 361 251 357 2 4 Number of patients at risk : 183 68 191 56 6 8 16 11 2 1 AIOM 2000 10 Treatment Upfront debulking surgery Neoadjuvant chemotherapy GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 40.4 42.8 39.1 40.2 1.000 0.978 0.972 1.068 1.035 (0.838-1.141) (0.832-1.136) (0.918-1.244) (0.888-1.206) Bookman, ASCO 2006, #5002 GOG 172 – IV vs. IP Overall survival 1.0 0.9 Proportion Surviving 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Treatment IV IP 0.1 0.0 0 12 Censored Failed Total 63 147 210 81 124 205 24 36 48 Months from Randomization 60 72 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? 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 Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical characteristics (PP1) PDS (n = 329) NACT -> IDS (n = 339)* 2,7% 0,6% 8% 2% 1,2% / 0,3% 0,3% / 0,6% Operative time (minutes) 180 180 Red blood cell transfusion 51% 53% Hemorhage Grade 3/4 7% 1% 2,4% 0,3% Postoperative mortality (< 28 days) Postoperative sepsis Fistula (bowel/GU) Venous Gr 3/4 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? 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 Randomised EORTC-GCG/NCIC-CTG trial on NACT+ IDS versus PDS Protocol Compliance (PP1) PDS (n = 329) NACT -> IDS (n = 339) Primary debulking 100 % 0% Interval debulking 19% 90% Second look surgery 5% 4% At least 6 courses CT 83% 86% GOG 182: Residual Disease after Primary Surgery AIOM 2000 Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical findings and results (PP1) Metastases before > 2 cm PDS (n = 329) 95% NACT -> IDS (n = 339)* 68% Metastases before > 10 cm 62% 27% No residual after surgery 21% 53% ≤ 1 cm after surgery 46% 82% * % calculated on the 306 patients who underwent IDS. 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? 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 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 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 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? 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 Key Issue # 6: Proof-of-Concept designs Using neoadjuvant chemotherapy for proof-ofconcept 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?