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SURGICAL MANAGEMENT OF PRIMARY EPITHELIAL OVARIAN CANCER

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.

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SURGICAL MANAGEMENT OF PRIMARY EPITHELIAL OVARIAN CANCER

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

  3. 2010 Gynecologic Cancer US Statistics

  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 15% - 20% 5% - 10% 5% - 10% Breast Cancer Ovarian Cancer Sporadic Family Cluster Hereditary ASCO 1998

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

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

  9. Relative Survival: Ovarian & Breast Cancers

  10. Ovarian Cancer: Stage Distribution and Survival American Cancer Society 2000

  11. 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 American Cancer Society (www.cancer.org), 2005.

  12. 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

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

  14. First-Line Therapy – Treatment Considerations

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

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

  17. Surgical Resection of Tumor Bulk in the Primary Treatment of Ovarian Carcinoma C. Thomas Griffiths • First to evaluate effect of debulking in stage II-III ovarian cancer patients • Histologic grade also important prognostic factor NCI Monograph, 1975

  18. 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 Ovarian Cancer: Surgical Treatment is more than a hysterectomy Median Survival (Months) % Cytoreduction Bristow, J., Clin. Oncol. 20: 1248, 2002

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

  20. 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 JCO, 2002

  21. 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

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

  23. 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

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

  25. 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

  26. Peritoneal Therapy Regional Perfusion SystemicCompartment Low Drug Concentration High Drug Concentration Locoregional Dedrick 1977

  27. 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

  28. 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

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

  30. Distinctive molecular alterations in subtypes KRAS Her-2 amp PTEN b-catenin ARID1a PPP2R1a p53/Rb pathway BRCA Chromosomal instability mucinous endometrioid PIK3CA ZNF217 ARID1aPPP2R1a Others… clear cell high-grade serous low-grade Ovarian epithelial carcinoma KRAS BRAF ERBB2 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

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