1. SURGICAL MANAGEMENT OF PRIMARY EPITHELIAL OVARIAN CANCER Robert P Edwards M.D Professor of Obstetrics, Gynecology, Reproductive Sciences, and Immunology University of Pittsburgh School of Medicine UPMC Cancer Centers Magee-Womens Hospital

2. Ovarian Cancer American Cancer Society Estimates, 2001 0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 160,000 180,000 200,000 BreastUterine Corpus Lung and Bronchus Colon and Rectum Non- Hodgkin’s Lymphoma Estimated New Cancer Cases in US Women Estimated Cancer Deaths in US Women OvarianMelanoma of the Skin Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36.

3. 2010 Gynecologic Cancer US Statistics New CasesDeaths Ovary21,88013,850 Uterine 43,4707,950 Cervix12,2004,210 Vulva3,900920 Vagina2,300780

4. Ovarian Cancer: Staging

5. HISTOLOGY AND CARCINOGENESIS MUELLERIAN METAPLASIA/DYSPLASIA AND INFLAMMATION –PAPILLARY SEROUS – TUBAL DYSPLASIA –ENDOMETRIOD AND CLEAR CELL – ENDOMETRIOSIS –MUCINOUS – PERITONEAL MUCINOUS METAPLASIA –BRENNER TUMORS - UROEPITHELIA

6. How Much Breast and Ovarian Cancer is Hereditary Breast CancerOvarian Cancer 15% - 20% 5% - 10% ASCO 1998 Sporadic Family Cluster Hereditary

7. BRCA 1-Associated Cancers: Lifetime Risk ASCO 1998 Possible increased risk of other cancers (eg, prostrate, colon) Breast cancer 50%-85% (often early age at onset) Second primary breast cancer 40%-60% Ovarian cancer 15%-45%

8. BRCA2-Associated Cancers: Lifetime Risk Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown) Breast cancer (50%-85%) Ovarian cancer (10%-20%) Male breast cancer (6%) ASCO 1998

10. Relative Survival: Ovarian & Breast Cancers Five-Year Relative Survival Rates by Stage at Diagnosis StageOvaryBreast Local93%97% Regional55%76% Distant25%21% All Stages50%84%

11. Ovarian Cancer: Stage Distribution and Survival American Cancer Society 2000 StagePercentSurvival I2495% II665% III5515-30% IV150-20% Overall50%

12. American Cancer Society (www.cancer.org), 2005. Ovarian Cancer: Scope of the Problem In the US 22,220 new cases estimated for 2005 –3% of cancer in women –2nd gynecologic cancer 16,210 deaths estimated for 2005 –Leading cause of death of gynecologic cancers 70% to 75% Stage III or IV at diagnosis Five-year survival: 44% overall –Advanced stage: 29% Most will develop recurrent disease

13. Ovarian Cancer Therapy Proven factors that determine outcome –Surgical staging with optimal surgical effort –Chemotherapy with a platinum agent combination with consideration for peritoneal delivery –Monitoring of progress with frequent examination to determine therapy effectiveness

14. Ovarian Cancer Symptoms Abdominal/pelvic pain Vaginal bleeding Bloating Abdominal distension Irregular menses Change in bowel habits

15. First-Line Therapy – Treatment Considerations

16. First-Line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort

17. What has been the standard of care for the treatment of advanced stage ovarian cancer?

19. NCI Monograph, 1975 ● First to evaluate effect of debulking in stage II-III ovarian cancer patients ● Histologic grade also important prognostic factor Surgical Resection of Tumor Bulk in the Primary Treatment of Ovarian Carcinoma C. Thomas Griffiths Table 2 – Survival, by diameter of largest residual mass Size (cm) Number of PatientsMST (mo) 02939 0-0.52829 0.6-1.51618 >1.52911

20. Ovarian Cancer: Surgical Treatment is more than a hysterectomy Significant survival advantage for women optimally cytoreduced Procedures may include: –En bloc resection of uterus, ovaries and pelvic tumor –Omentectomy –Selective lymphadenectomy –Bowel resection –Removal of diaphragmatic and peritoneal implants –Splenectomy, appendectomy % Cytoreduction Median Survival (Months) Bristow, J., Clin. Oncol. 20: 1248, 2002

21. AJOG, 1994 ● Confirmed the prognostic significance of residual disease in patients with advanced ovarian cancer from GOG protocols 52 and 97

22. JCO, 2002 ● 81 cohorts of stage III/IV ovarian cancer patients evaluated using linear regresssion models ● Each 10% increase in cytoreduction associated with 5.5% increase in median survival ● Platinum dose intensity not significant JCO, 2002

23. Evaluating the Role of Neoadjuvant Chemotherapy in Advanced Ovarian Cancer EORTC 55971 From 1998-2006, 718 randomized between PDS vs. neoadjuvant chemo with IDS after 3 cycles Only 46% optimal in PDS arm Not all patients treated with taxane Morbidity and mortality higher in the PDS arm

24. What new standards have evolved over the past decade for the treatment of advanced stage ovarian cancer?

25. Extensive Upper Abdominal Surgery in Advanced Stage Ovarian Cancer  229 EUAS procedures in 141 patients – diaphragm stripping/resection, splenectomy, partial hepatectomy, distal pancreatectomy  Residual disease  None – 30%  < 1 cm – 60%  > 1 cm – 10%  Mortality 1.4%, grade 3-5 morbidity – 22%  Median survival 57 mos. Chi, Gyn Onc 2010

26. Ovarian Cancer: Survival by Residual Disease Hoskins et al ‘94

27. Theory of Peritoneal Therapy Ovarian Cancer predominantly intraperitoneal disease Dissemination is by exfoliation or “snow globe” phenomena Peritoneal infusion may increase cell kill with less systemic exposures

28. Peritoneal Therapy Regional Perfusion High Drug Concentration Systemic Compartment Low Drug Concentration Locoregional Dedrick 1977

29. Intraperitoneal Chemotherapy offers Survival Advantage in Optimally Debulked Stage III Epithelial Ovarian Carcinoma GOG 172: PFS RR 0.73 GOG 114: PFS RR 0.78 Surv RR 0.81 GOG 104: Survival HR 0.76

30. Bevacizumab Phase II studies –GOG 170 - 2 CR 11 PR /62 patients (21%) PFS 4.7 months –Increased risk of bowel perforations Phase III trial –GOG 218 presented in abstract form –Improved time to recurrence with maintenance

31. NEW THERAPIES MOLECULAR PROFILING MOLECULAR TARGET SCREENS PERSONALIZED APPROACHES REDUCE NUMBER OF CYCLES OF INEFFECTIVE TREATMENTS

32. Distinctive molecular alterations in subtypes high-grade serous PTEN  -catenin ARID1a PPP2R1a KRAS BRAF ERBB2 PIK3CA ZNF217 ARID1aPPP2R1a Others… KRAS Her-2 amp low-grade endometrioid clear cell mucinous p53/Rb pathway BRCA Chromosomal instability Annual Review Pathol 2009, 4:287 Cancer Res 2009, 69:4036 J Natl Can Inst 2003, 95:484 Am J Pathol 2009, 174:1597 Int J Gyn Cancer 2008, 18:487 Am J Surg Pathol 2005, 29:218 Future Oncol 2009, 5: 1641 Wiegand NEJM 20101 Jones science express 2010 McChonechy and Angelsio in press Slide framework courtest of IM Shih