Dr. Ginger Gardner on Recurrent Ovarian Cancer (SHARE Program)

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On May 22, 2013, SHARE presented "Recurrent Ovarian Cancer: Now What?" The program featured Dr. Ginger Gardner and Dr. Paul Sabbatini of Memorial Sloan-Kettering Cancer Center discussing treatment strategies, as well as new approaches and agents, for managing an ovarian cancer recurrence. Listen to the audio here: www.sharecancersupport.org/gardner

The information in this presentation is not intended to be a substitute for professional medical advice, diagnosis or treatment. The presentation was given on May 22, 2013.

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Dr. Ginger Gardner on Recurrent Ovarian Cancer (SHARE Program)

  1. 1. Recurrent Ovarian Cancer:Recurrent Ovarian Cancer:Surgical OptionsSurgical OptionsGinger J. Gardner, MDGinger J. Gardner, MDAssociate Attending SurgeonAssociate Attending SurgeonDirector, International Fellowship ProgramDirector, International Fellowship Programin Gynecologic Oncologyin Gynecologic OncologyMemorial Sloan-Kettering Cancer CenterMemorial Sloan-Kettering Cancer CenterDivision of Gynecology, Department of SurgeryDivision of Gynecology, Department of Surgery
  2. 2. Ovarian Cancer TreatmentSurgery and Chemotherapy work…
  3. 3. Goals of Primary Surgeryfor Ovarian Cancer1. Establish Tissue Diagnosis2. Identify Histologic Subtype3. Stage of Disease4. Tumor Debulking5. Relieve Symptoms6. Place Intraperitoneal Port (in some cases)
  4. 4. Goals of Primary Surgeryfor Ovarian Cancer1. Establish Tissue Diagnosis2. Identify Histologic Subtype3. Stage of Disease** Tumor Debulking** Relieve Symptoms6. Place Intraperitoneal Port (in some cases)
  5. 5. Ovarian CancerPrognostic FactorsPrognostic FactorsAgeAgeStageStageGradeGradeHistologyHistologyAscitesAscitesChemosensitivityChemosensitivityVolume of Residual DiseaseVolume of Residual Disease
  6. 6. Cytoreductive Surgery forAdvanced Stage DiseaseSurgery is Diagnostic AND Therapeutic– Excision of large tumor mass of poorly perfused,anoxic cells which would otherwise be exposed tosublethal concentration of drug– Increase proliferating fraction of cells post-op– Removal of 80-90% tumor burden favorable to"fractional cell kill hypothesis"– Provides opportunity for IP treatment
  7. 7. Overall Survival by Residual DiseaseHoskins WJ et al. Gynecol Oncol 1992; 47: 159Hoskins WJ et al. Gynecol Oncol 1992; 47: 159
  8. 8. 20222426283032343638400 10 20 30 40 50 60 70 80 90 100% CytoreductionMedianSurvival(Months)Significant survival advantagefor optimally debulkingProcedures may include:-En bloc resection of uterusovaries and pelvic tumor-Omentectomy-Lymphadenectomy-Bowel resection-Diaphragm resection-Splenectomy, AppendectomyCytoreductive Surgery forAdvanced Stage DiseaseBristow, RE, JCO, 20:1248, 2002
  9. 9. Secondary Debulkingand Overall SurvivalTimeProportionSurvivingChi DS et al, Cancer, 2006
  10. 10. Tertiary DebulkingShih, K J Gyn Onc 2010, 117:330-335
  11. 11. Who Will Benefitfrom Secondary Debulking?Chi, DS, Cancer, 2006
  12. 12. Is Restarting the Clockwith Secondary Surgery Enough?Can we do Better??
  13. 13. • Phase III evidence in favor of postoperative IPtherapy• Combination of hyperthermia (heat) and somechemotherapy agents increases drug effectiveness• Increased peritoneal tumor penetration• Intraoperative chemoperfusion: no adhesion barriers• Controlled application under anesthesiaHyperthermic IntraperitonelChemotherapy (HIPEC)…The Chemo Wash
  14. 14. platinum-sensitive recurrent EOCplatinum-free interval >6monthsECOG 0/1no prior chemotherapy for recurrent EOCsecondary cytoreductive surgeryHIPEC (cisplatin 60 mg/m2) HIPEC (cisplatin 80 mg/m2) HIPEC (cisplatin 100 mg/m2)6 cycles postoperative platinum based IV combination chemotherapy*-temporary abdominal closure-closed- abdomen technique-in 3 L of saline solution-90 minutes at 42°C-after HIPEC:irrigation (3 L saline solution)EOC= epithelial ovarian cancer* the use of bevacizumab is allowed; OCEANS study, Aghajanian JCO 2012HIPEC Protocol
  15. 15. Mean cisplatin concentrations during HIPEC in the peritoneal cavity and plasma at 100mg/m² compared to same dose IV administration** Model with 80 mg/m² IV cisplatin administered in 30 minutes; Urien et al. 2004050001000015000200002500030000350000 0.5 1 1.5 2Platinumconcentration[µg/L]Time [h]platinum concentration during HIPECIPPlasma after IPPlasma after ivHIPEC Pharmacokinectics
  16. 16. Patient No. Postoperative IV chemotherapy No. of cycles1 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) 62 Carboplatin AUC 4/ Gemcitabine 1000 mg/m2(days 1 and 8)Bevacizumab 15 mg/kg q 21 days63 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) 64 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) 65 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) 66 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) 67 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) 68 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) 69 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) 610 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) 611 Carboplatin AUC 4/ Gemcitabine 1000 mg/m2(days 1 and 8)Bevacizumab 15 mg/kg q 21 daysongoing12 Carboplatin AUC 5/ Gemcitabine 1000 mg/m2(days 1 and 8) ongoingHIPEC Post-Operative Treatment
  17. 17. • Secondary cytoreduction and HIPEC with cisplatin at 100 mg/m 2isfeasible in patients with platinum sensitive recurrent ovarian cancer• Favorable pharmacokinetic properties of HIPEC with cisplatin areconfirmed at all dose levels, especially at 100 mg/m2• Ability to administer 6 cycles of standard IV platinum-basedchemotherapy after HIPEC does not seem to be compromised• Further randomized trials need to determine the efficacy of HIPEC withcisplatin in comparison to IV chemotherapy alone• Cytoreductive surgery + HIPEC and postoeprative chemotherapy are notcompetitive but can be complementary elements of multimodality treatmentHIPEC Interim Conclusions
  18. 18. • Phase I studies with new drugs and drug combinations adminstered as HIPEC• Quality of life assessment• Cost-effectiveness• Integration of HIPEC-studies into the primary setting• Opportunity for multidisciplinary research collaborations (medicaloncology, anesthesia, colorectal surgery, pharmacology, biostatistics,drug development, nursing)HIPEC Future Directions
  19. 19. How Can WePrevent Ovarian Cancer?
  20. 20. Risk factorRisk factor Relative RiskRelative RiskOlder ageOlder age 33North American/EuropeanNorth American/European 2-52-5High socioeconomic statusHigh socioeconomic status 1.5-21.5-2White raceWhite race 1.51.5NulligravidityNulligravidity 2-32-3InfertilityInfertility 2-52-5Early menarcheEarly menarche 1.51.5Late menopauseLate menopause 1.5-21.5-2History of hysterectomyHistory of hysterectomy 0.5-0.70.5-0.7History of OCP useHistory of OCP use 0.3-0.50.3-0.5Family history OVCAFamily history OVCA 3-43-4Risk Factors for Ovarian Cancer
  21. 21. Risk factorRisk factor Relative RiskRelative RiskOlder ageOlder age 33North American/EuropeanNorth American/European 2-52-5High socioeconomic statusHigh socioeconomic status 1.5-21.5-2White raceWhite race 1.51.5NulligravidityNulligravidity 2-32-3InfertilityInfertility 2-52-5Early menarcheEarly menarche 1.51.5Late menopauseLate menopause 1.5-21.5-2History of hysterectomyHistory of hysterectomy 0.5-0.70.5-0.7History of OCP useHistory of OCP use 0.3-0.50.3-0.5Family history OVCAFamily history OVCA 3-43-4Risk Factors for Ovarian Cancer
  22. 22. Op-Ed ContributorMy Medical ChoiceBy ANGELINA JOLIEPublished: May 14, 2013MY MOTHER fought cancer for almost a decadeand died at 56. She held out long enough tomeet the first of her grandchildren and to holdthem in her arms. But my other children willnever have the chance to know her andexperience how loving and gracious she was.We often speak of “Mommy’s mommy,” and Ifind myself trying to explain the illness that tookher away from us. They have asked if the samecould happen to me. I have always told them notto worry, but the truth is I carry a “faulty” gene,BRCA1, which sharply increases my risk ofdeveloping breast cancer and ovarian cancer.
  23. 23. Hereditary Risk of Ovarian CancerHereditary(~10-15%)SporadicBRCA1 (~70-75%)Other singlegenes (<5%) BRCA2 (~20%)HNPCC(~2%)
  24. 24. BRCA Mutation Carriers• Lifetime risk of ovarian cancer– BRCA1 ~36-46%– BRCA2 ~10-27%• BRCA-associated Ovarian Cancer– Young age, high grade serous histology,advanced stage– 16-21% of high grade serous EOC willhave a BRCA1 or BRCA2 mutation• BRCA-associated Breast CancerKing, et al. Science, 2003.Risch, et al., AmJ Hum Genet, 2001Rubin, et al., Am J Obstet Gynecol, 1998Pal, et al., Cancer, 2005
  25. 25. Risk-Reduction Strategies– Breast• Intensive Surveillance (Mammogram, U/S, MRI)• Chemoprevention (Tamoxifen, Raloxifene,Aromatase Inhibitors)• Risk-Reducing Surgery (Mastectomy,Oophorectomy)– Ovary• Surveillance (Transvaginal U/S, CA125)• Chemoprevention (Oral Contraceptives)• Risk-Reducing Surgery (Tubal Ligation,Oophorectomy)
  26. 26. Semi-Annual (twice/yr):• Pelvic Exam• Pelvic Ultrasound• CA125**Reinforce limitations of screening**Perform until prophylactic salpingo-oophorectomy is completedOvarian Screening in BRCA Patients
  27. 27. MSKCC Experience 1995-2001– 62 BRCA Mutation Carriers Undergoing Surveillance• Mean F/U: 17 months• Twice yearly TV ultrasound and CA125– 22/62 (35%) had at least 1 Abnormal U/S or CA125– 10 with persistent abnormalities that underwent surgery– 5 Ovarian or Fallopian Tube Cancers (4 Stage I or II)– 5 Benign Findings– 2 patients with normal screening were found to cancer atRRSO– 71% Sensitivity 91% SpecificityScheuer L, Kauff N, et al. JCO 2002Ovarian Screening in BRCA Patients
  28. 28. Gilda Radner OCDP Experience 1991-2000– 213 Jewish women with a first or second degree relative withovarian or early onset breast cancer (33 with BRCAmutations)• Mean F/U: 60 months• Annual TV ultrasound and CA125– 8 ovarian, fallopian tube or primary peritoneal ca (7 in BRCAcarriers)• 4 screen detected (1 – Ic; 3 – IIIc)• 4 Interval cancers (1-IIc; 3 – IIIc)Liede A, et al. JCO 2002Ovarian Screening in BRCA Patients
  29. 29. Ovarian Screening in BRCA PatientsAnnual TV ultrasound and CA125Woodward et al. BJOG 2007– 179 women (31 BRCA +) at high risk of ovarian cancer– 29 months f/u– 3 of 4 ovarian cancers were interval (1 – stage IIc; 2 – stage IIIc)– 30 women with abnormal findings under went surgery• 2 cancers detected (1 – stage IIIc ovarian; 1 – endometrialcarcinoma)Hermsen et al. Br J Cancer 2007– 888 BRCA mutation carriers (20 months mean f/u)– 5 of 10 incident cancers were interval– 80% of both screen detected and interval cancers were StageIII/IV
  30. 30. Ovarian Screening in BRCA PatientsConclusions• Equivocal evidence that screening detectsovarian cancer at an early stage.• No evidence that screening results in asurvival benefit in women at inherited risk.• Until further data is available, ovarian cancerscreening should only be thought of as abridge until a women with a BRCA mutationis ready to undergo a RRSO.
  31. 31. Risk-Reducing Salpingo-Oophorectomy(RRSO)The most effective risk-reducing strategyfor women with BRCA 1/2 mutationsKauff & Barakat, J Clin Oncol, 2007
  32. 32. Spread of STIC from the fimbria to the ovarian surface.Site of Origin: Fallopian TubeKurman et al. Hum Path 42: 918-31, 2011
  33. 33. Site of Origin: Fallopian TubeKurman et al. Hum Path 42: 918-31, 2011Implications for Screening: Molecular Signature of FallopianTube/ Uterine WashingsLevine et al. MSKCC/PPG
  34. 34. Conclusions• OCP use reduces risk of Ovarian Cancer• Consider Genetics Evaluation for BRCAmutation among all ovarian cancerpatients, and those with family history• Secondary surgical debulking is availablefor selected patients with recurrent ovariancancer
  35. 35. Conclusions• Heated intraperitoneal chemotherapyprotocols are now available to augmentthe surgical outcome for recurrentdisease.• Surgery may be appropriate in selectedcases of recurrent disease for symptomcontrol.
  36. 36. Ginger J. Gardner, MDGynecologic Cancer SurgeonMemorial Sloan-Kettering Cancer Center

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