1. Primary Debulking for Bulky Advanced Stage Ovarian Cancer Ginger J. Gardner, MD Director, Survivorship Program Gynecology Service, Department of Surgery Memorial Sloan-Kettering Cancer Center

2. Ovarian Carcinoma Prognostic FactorsAgeStageGradeHistologyAscitesChemosensitivity Volume of Residual Disease

3. Primary Debulking Surgery for Advanced Stage Disease Bristow, RE, JCO, 20:1248, 2002 Meta-AnalysisMeta-Analysis Medline database 1989 – 1998Medline database 1989 – 1998 Stage III-IV Ovarian CancerStage III-IV Ovarian Cancer 6885 patients6885 patients Multiple linear regression analysisMultiple linear regression analysis **Each 10% increase in maximum cytoreductive surgery was associated with a 5.5% increase in median overall survival **Each 10% increase in maximum cytoreductive surgery was associated with a 5.5% increase in median overall survival

4. % Cytoreduction Median Survival (Months ) Significant survival advantage for women optimally cytoreduced Procedures may include: -En bloc resection of uterus ovaries and pelvic tumor -Omentectomy -Lymphadenectomy -Bowel resection -Diaphragm resection -Splenectomy, Appendectomy Primary Debulking Surgery for Advanced Stage Disease Bristow, RE, JCO, 20:1248, 2002

5. Cytoreductive Surgery for Advanced Stage Disease The Rationale Excision of large tumor mass of poorly perfused, anoxic cells which would otherwise be exposed to sublethal concentration of drug Increase proliferating fraction of cells post-op Removal of 80-90% tumor burden favorable to "fractional cell kill hypothesis" Reduce the opportunity for drug resistance by start- stop chemotherapy approach with neoadjuvant therapy

6. Modified Posterior Pelvic Exenteration

7. Eisenkop, S et al. Obstet Gynecol 1991 Modified Posterior Pelvic Exenteration

8. Ovarian Cancer Stage IIIC Variable extent of Upper Abdominal Disease (UAD) Zivanovic O et al. Gynecol Oncol 2010, 116:351-7

9. Bulky UAD Cephlad to the Greater Omentum Zivanovic O et al. Gynecol Oncol 2010, 116:351-7

10. Splenectomy

11. Splenectomy with Distal Pancreatectomy

12. Diaphragm Peritonectomy

14. Liver and Diaphragm Resection Cut edge of liver Pleural Space

16. Randomized EORTC/NCIC Trial of NACT + IDS vs PDS Randomized EORTC/NCIC Trial of NACT + IDS vs PDS

17. Sept 1998 – Dec 2006Sept 1998 – Dec 2006 670 pts randomized670 pts randomized 59 institutions59 institutions Eligible pts: Stage IIIC-IV disease with ≥2cm upper abdominal diseaseEligible pts: Stage IIIC-IV disease with ≥2cm upper abdominal disease Optimal Debulking (≤1cm)Optimal Debulking (≤1cm) 41.6% PDS41.6% PDS 80.6% IDS80.6% IDS NACT vs PDS Vergote I, et al. NEJM 363:10

18. Median OS 29mos 30mos HR 0.98 (0.84-1.13) NACT vs PDS

19. Complete resection of all macroscopic disease (PDS or IDS) was the strongest independent predictor of OS, p<0.001Complete resection of all macroscopic disease (PDS or IDS) was the strongest independent predictor of OS, p<0.001 Followed by:Followed by: Stage IIIC (vs stage IV), p=0.001Stage IIIC (vs stage IV), p=0.001 Small tumor size at randomization, p=0.001Small tumor size at randomization, p=0.001 Endometrioid histology, p=0.005Endometrioid histology, p=0.005 Younger age, p=0.005Younger age, p=0.005 Predictors of Prolonged Survival Multivariate Analysis Predictors of Prolonged Survival Multivariate Analysis Vergote I, et al. NEJM 363:10

20. PDS Improved OS When Metastatic Implants <5cm PDS Improved OS When Metastatic Implants <5cm Vergote I, et al. NEJM 363:10

21. Summary from Vergote Study Complete gross resection associated with best OS for both PDS and IDSComplete gross resection associated with best OS for both PDS and IDS NACT may be an option for advanced stage ovarian cancer with >5cm distant metastatic implants…NACT may be an option for advanced stage ovarian cancer with >5cm distant metastatic implants… Should NACT be the new standard of care?

22. Questions Remain…. Low rate of primary optimal debulking: 41.6%Low rate of primary optimal debulking: 41.6% Median OS: 30mosMedian OS: 30mos Difficult to enroll good operative candidates onto the surgical trialsDifficult to enroll good operative candidates onto the surgical trials After debulking, the diagnosis changed in 11pts (3.3%) PDS and 7 pts (2.1%) IDS: carcinosarcoma, endometrial ca, GI tumors, LMPs, cervical adenoca, teratoma, rhabdomyosarcoma, pseudomyxomaAfter debulking, the diagnosis changed in 11pts (3.3%) PDS and 7 pts (2.1%) IDS: carcinosarcoma, endometrial ca, GI tumors, LMPs, cervical adenoca, teratoma, rhabdomyosarcoma, pseudomyxoma Histologic grade unknown in 35-45% of casesHistologic grade unknown in 35-45% of cases

23. Acceptance of NACT by SGO Members Acceptance of NACT by SGO Members Dewdney S et al. Gynecol Oncol 2010, 119:18-21 339/1137 (30%) responded339/1137 (30%) responded 98.2% Gynecologic Oncologists98.2% Gynecologic Oncologists 94.6% in United States94.6% in United States 59.2% Academic Practice59.2% Academic Practice 66.7% Male66.7% Male Years in Practice: 39.8% (>15yrs), 22.8% ( 15yrs), 22.8% (<5yrs)

24. Acceptance of NACT by SGO Members Acceptance of NACT by SGO Members Dewdney S et al. Gynecol Oncol 2010, 119:18-21 Rate of Optimal DebulkingRate of Optimal Debulking 42% of GYOs report a 61-80% rate of optimal debulking42% of GYOs report a 61-80% rate of optimal debulking 38.9% of GYOs report a >80% rate of optimal debulking38.9% of GYOs report a >80% rate of optimal debulking Rate of NACTRate of NACT 60% of GYOs give NACT less for <10% of cases60% of GYOs give NACT less for <10% of cases

25. Conclusions -Cytoreduction to > 1 cm residual has no benefit on overall survival -There is a survival benefit associated with cytoreduction to < 1 cm residual -Within the gross residual but < 1 cm category, no gross residual is associated with the longest median survival

26. Role of Maximal Primary Cytoreductive Surgery The Italian Experience Role of Maximal Primary Cytoreductive Surgery The Italian Experience Peiretti M, et al. Gynecol Oncol 2010, 119:259-64

27. Role of Maximal Primary Cytoreductive Surgery The Italian Experience Role of Maximal Primary Cytoreductive Surgery The Italian Experience PFSOS

28. MSKCC Contemporaneous Experience to EORTC Trial Identical inclusion criteria for all patients undergoing primary surgery at MSKCC during same time period (9/98-12/06) Excluded patients with borderline, germ cell, stromal, and advanced carcinoma based solely on microscopic nodal metastasis All pts “eligible” for EORTC trial: 316

29. MSKCC Contemporaneous Experience to EORTC Trial 1998-2006

31. Overall Survival Both Arms of EORTC vs MSKCC MSKCC (optimals + suboptimals) Both EORTC arms Median OS 30 months

32. Quality of Life, Vergote 2010Quality of Life, Vergote 2010 QLQ-C30 global health scores were not significantly different between the NACT and PDS groups at any of the 5 time points evaluatedQLQ-C30 global health scores were not significantly different between the NACT and PDS groups at any of the 5 time points evaluated Even if we consider PDS and NACT OS equivalent, …what about factors? Even if we consider PDS and NACT OS equivalent, …what about factors?

33. Cost Effectiveness, Aletti 2009Cost Effectiveness, Aletti 2009 Surigcal Complexity Score (SCS): 1-3Surigcal Complexity Score (SCS): 1-3 Inpatient costs $21k, $27k, $33k; p<0.001Inpatient costs $21k, $27k, $33k; p<0.001 $4950 / life yr gained for SCS 2 vs 1$4950 / life yr gained for SCS 2 vs 1 $8912 / life yr gained for SCS 3 vs 1$8912 / life yr gained for SCS 3 vs 1 Even if we consider PDS and NACT OS equivalent, …what about factors? Even if we consider PDS and NACT OS equivalent, …what about factors?

34. Intraperitoneal (IP) Chemotherapy Improves Survival Intraperitoneal (IP) Chemotherapy Improves Survival

35. Stage III Ovarian cancer Optimal (<1cm) RANDOMIZE BRCA Analysis DNA Banking Paclitaxel 135 mg/m 2 /24h Cisplatin 75 mg/m 2 q 21 days x 6 Paclitaxel 135 mg/m 2 /24h Cisplatin 100 mg/m 2 IP D2 Paclitaxel 60 mg/m 2 IP D8 q 21 days x 6 Eligibility for IP Treatment on GOG172 Optimal Tumor Debulking Eligibility for IP Treatment on GOG172 Optimal Tumor Debulking

36. GOG 172 Survival Patient Eligibility: Completed Primary Optimal Debulking (≤1cm) Regimen 1 Intravenous Regimen 2 Intraperitoneal Progression-free18.3 mos23.8 mos Overall Survival49.5 mos66.9 mos

37. Advanced Ovarian Cancer CisplatinPaclitaxelMulti-drug Alkeran Alkeran Improving Overall Survival IP therapy (optimal) (optimal) months 12 14 24 37 52 57.4 65.6 0 20 40 60 80 1975198319861996199820032005

38. Primary Debulking for Advanced Ovarian Cancer Summary Primary Debulking for Advanced Ovarian Cancer Summary Large body of retrospective data supports primary debulking surgery, now with median 5yr overall survival.Large body of retrospective data supports primary debulking surgery, now with median 5yr overall survival. Survival benefit includes resection of bulky upper abdominal disease located cephalad to the greater omentum.Survival benefit includes resection of bulky upper abdominal disease located cephalad to the greater omentum. One RCT shows non-inferiority of NACT for large volume distant metastasis (>5cm), but had low median survival, and no benefit for QOL or cost.One RCT shows non-inferiority of NACT for large volume distant metastasis (>5cm), but had low median survival, and no benefit for QOL or cost.

39. Primary Debulking for Advanced Ovarian Cancer Summary Primary Debulking for Advanced Ovarian Cancer Summary MSKCC analysis using the same eligibility criteria demonstrates a longer overall survival.MSKCC analysis using the same eligibility criteria demonstrates a longer overall survival. Eligibility for adjuvant IP chemotherapy is based on optimal tumor debulking status.Eligibility for adjuvant IP chemotherapy is based on optimal tumor debulking status. We should prioritize optimal primary debulking surgery, and use NACT only in selected cases.We should prioritize optimal primary debulking surgery, and use NACT only in selected cases. Our goal is to provide our patients excellence in surgical technique as we continue to expand our chemotherapy repetoire for ovarian cancer.Our goal is to provide our patients excellence in surgical technique as we continue to expand our chemotherapy repetoire for ovarian cancer.

40. Memorial Sloan-Kettering 2011 1884 1985 Thank You! Ginger J. Gardner, MD gardnerg@mskcc.org