Presentation on theme: "Management of Epithelial Ovarian Cancer"— Presentation transcript:
1Management of Epithelial Ovarian Cancer Mohamed Abdulla (M.D.)Department of Clinical OncologyKasr El-Aini School of MedicineCairo UniversityEgyptian Cancer Society Meeting, Demiat Cancer Center – June, 2009
3Magnitude of The Clinical Problem: Steep Survival Gradient of Ovarian Cancer and Stage at DiagnosisStageIIIIIIIVDescriptionConfined to ovariesConfined to pelvisConfined to abdomen/lymph nodesDistant metastasesIncidence20%5%58%17%Survival73%45%21%< 5%1020304050607080IIIIIIIVJelic S, et al Congress of the European Society for Medical Oncology. Mocharnuk R. Available at:
4Magnitude of The Clinical Problem: FDA-Approved Drugs in Ovarian Cancer19781978 Cisplatin1989 Carboplatin1990 Altretamine1992 Paclitaxel1996 Topotecan1999 Liposomal doxorubicin (accelerated)2005 Liposomal doxorubicin (full)2006 Gemcitabine2008
5Magnitude of The Clinical Problem: Stage I/IIEssentially all patients will achieve a clinical CR after surgery and chemotherapy20% to 25% will relapseOptimal stage III> 90% will achieve a clinical CR75% will recurSuboptimal stage III/IV50% will achieve a clinical CR> 90% will recur
6Magnitude of The Clinical Problem: Ovarian Carcinoma--SymptomsAbdominal bloating, increased girth, pressureAbdominal / pelvic painFatigueGI (nausea, gas, constipation, diarrhea)Urinary frequency/ incontinenceWeight loss/ gainShortness of breathVague and often non-gynecologic-- NOT Silent
7Magnitude of The Clinical Problem: Ovarian Carcinoma--SignsPalpable pelvic massAbdominal massAbdominal distensionDecreased breath sounds due to effusionsAdenopathy -- groin, supraclavicularSpreads by local growth, bloodstream and lymphatic routes
8Ovarian Cancer Risk Factors 50 years of age or olderFamilial factorsFamily history of breast, ovarian, or colon cancerPersonal history of breast or colon cancerBRCA (breast cancer) gene mutationHereditary nonpolyposis colon cancer (HNPCC)Other potential risk factorsEarly menarche (younger than 12 years of age)Late menopause (older than 52 years of age)Hormone replacement therapy or fertility drugsFirst pregnancy at older than 30 years of ageInfertility
9endometrial, and ovarian cancers are hereditary How Much Cancer Is Hereditary?~5% to 10% ofbreast, colon,endometrial, and ovariancancers are hereditary90%not hereditary90%not hereditary
10Lifetime Risk of Cancers Associated With Specific Genes BRCA1BRCA2MMR*Breast35-6030-55Ovarian30-4015-256-20Endometrial40-60*MMR (mismatch repair) = HNPCC.Chen S, et al. J Clin Oncol. 2007:25: Aarnio M, et al. Int J Cancer. 1999:81:
11Relative Risk of Ovarian Cancer Ovarian Cancer: Ovulation> 5Durationof OralContraceptiveUse (Yrs)2-3Durationof Breast-Feeding(Mos)12-231-5> 6Numberof TermPregnancies420.00.51.0Relative Risk of Ovarian CancerWhittemore AS, et al. Am J Epidemiol. 1992;136:
12Limiting HRT May Reduce Ovarian Cancer Risk: Estrogen UseNo. of DeathsNo. of Person-YearsRate Ratio (95% CI)*Rate Ratio (95% CI)†Never6892,185,8761.00 (referent)Ever255625,9841.21 ( )1.23 ( )FrequencyCurrent (baseline)62151,8801.45 ( )1.51 ( )Former193474,1031.15 ( )1.16 ( )Current users, yrs< 1031110,3791.07 ( )1.14 ( )≥ 1041,3962.13 ( )2.20 ( )Former users, yrs158416,8231.09 ( )1.10 ( )3557,2811.55 ( )1.59 ( )*Rate ratio estimates adjusted for age and race. †Models adjusted for age at baseline, race, duration of oral contraceptive use, number of live births, age at menopause, body mass index, age at menarche, and tubal ligation.Rodriguez C, et al. JAMA. 2001;285:
13Ovarian Screening Methods for Average-Risk Women CA-125: poor sensitivity in early stage diseaseTransvaginal ultrasound: poor sensitivity in early-stage disease, cannot reliably distinguish benign from malignant changesPelvic exam
14Ovarian Screening Methods for Average-Risk Women (cont’d) Insufficient evidence to recommend population-based screeningLow prevalence of ovarian cancer in general populationNot cost-effectiveDifficult to screen premenopausal womenAppropriate screening is undefined
15Prevention of Ovarian Cancer ChemopreventionOral contraceptive pillsLimit clomifene citrateLimit hormone replacement therapySurgical preventionOophorectomy: 80% risk reduction in high-risk womenBilateral tubal ligation: 72% risk reduction when used with oral contraception1. Finch A, et al. JAMA. 2006;296: Narod SA, et al. Lancet. 2001;357:
16Prophylactic Oophorectomy: Counseling about Risks/Benefits Medical benefitsPrevention of ovarian cancer (unknown risk of peritoneal cancer)Decreases risk of recurrent breast cancerEmotional benefitsRelief from fear of developing ovarian cancerMedical risksLoss of endogenous estrogen (effect on heart, bones, sexual function)Effect of hormone replacement therapy on breast cancer riskEmotional risksIssues around castration
17At What Age Should a Patient Undergo Surgery? Limited data availableDecision often relies on pedigree informationNational Institutes of Health consensus panel recommendation: 35 years of age or older or after childbearing is complete1. JAMA. 1995;273:
19Goals of Therapy: Manage symptomatic patients. Better durability of response.Survival improvement.Maintain Quality of Life.
20GOG 111: Standard of Care Study design Cisplatin 135 mg2 IV over 24 hours +Paclitaxel 75 mg/m2 x 6 cycles(n = 184)Patients with suboptimallydebulked, stage III/IVepithelial ovarian cancerwithin 6 weeks of surgery(N = 386)Cisplatin 75 mg/m2 x 6 cycles +Cyclophosphamide 750 mg/m2 IV(n = 202)McGuire W, et al. N Engl J Med. 1996;334:1-6.
21GOG 111: PFS and OS PFS (P < .001) OS (P < .001) 1.0 1.0 0.9 0.9 0.80.80.70.70.60.6Proportion Surviving Progression Free0.5Proportion Surviving0.50.40.40.184.108.40.206.10.1612182430364248612182430364248Months After Entry Into StudyMonths After Entry Into StudyTreatmentNo. Progression FreeNo. With Treatment FailureTotalMedian PFS, mosCisplatin + cyclophosphamide2817420213Cisplatin + paclitaxel4513918418TreatmentNo. AliveNo. DeadTotalMedian Survival, mosCisplatin + cyclophosphamide6513720224Cisplatin + paclitaxel869818438McGuire W, et al. N Engl J Med. 1996;334:1-6.
22NCCN Guidelines: v2.2009 Stage IA & IB: Grade 1 & 2: Observe. Grade 3: 3-6 Courses Paclitaxel/Carboplatin.Stage IC: 3-6 Courses Paclitaxel/Carboplatin.Stages II, III & IV:Stage II: Intraperitoneal Chemotherapy vs Systemic 6-8 Courses of Paclitaxel/Carboplatin.Stage III (< 1 cm Residual): Intraperitoneal Chemotherapy vs Systemic 6-8 Courses of Paclitaxel/Carboplatin.Stages III (> 1 cm Residual) & IV: Systemic 6-8 Courses of Paclitaxel/Carboplatin.Completion of Surgery.
23New Agents for the Clinical Management of Ovarian Cancer BevacizumabDeathDiagnosisSecondarySurgerySymptomsChemotherapy #1MaintenanceChemo #2Chemo #3+ProgressionStagingPaclitaxel poliglumexOregovomabAbagovomabCanfosfamidePatupilonePhenoxodiolKarenitecinTrabectedin
24GOG 218: Potential New Standard of Care Paclitaxel +Carboplatin + Placebo*Placebo† x 15 monthsPatients with stage III/IV ovarian or primary peritoneal cancer and GOG PS 0-2 entered 1-12 weeks after initial surgery(N = 2000)Placebo† x 15 monthsPaclitaxel +Carboplatin + Bevacizumab*Paclitaxel +Carboplatin + Bevacizumab*Bevacizumab† x 15 months*Beginning in course 2 of chemotherapy.†Beginning in course 7 of chemotherapy.Primary endpoint: PFS measured by RECISTSecondary endpoints: OS, safety, QoL, translational objectives, responseClinicalTrials.gov. NCT
25GC vs TC Induction Regimens Followed by T Consolidation: Study Design Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinomaInduction GCGemcitabine 1000 mg/m2 Days 1, 8+ Carboplatin AUC 5 Day 1x 6 cycles every 21 daysInduction TCPaclitaxel 175 mg/m2 Day 1+ Carboplatin AUC 6 Day 1x 6 cycles q 21 daysClinical CRAnything other than CR(PR, SD, PD)Anything other than CR(PR, SD, PD)Elective T Consolidation TherapyPaclitaxel 135 mg/m2 every 28 days for 12 cyclesSingle-agent crossoverPaclitaxel 175 mg/m2 Day 1Single-agent crossoverGemcitabine 1000 mg/m2 Days 1, 8Gordon A, et al. ASCO Abstract 5536.
26Conventional TC (c-TC) Dose-dense weekly TC (dd-TC) Conventional vs Dose-Dense TC (NOVEL): Study DesignOvarian epithelial, primary peritoneal, or fallopian tube cancer withFIGO stage II-IVStratified byresidual disease ≤ 1 cm vs > 1 cm;FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/othersConventional TC (c-TC)Paclitaxel 180 mg/m2 Day 1 +Carboplatin AUC 6.0 Day 1every 21 days for 6-9 cyclesDose-dense weekly TC (dd-TC)Paclitaxel 80 mg/m2 Days 1, 8, 15 +Carboplatin AUC 6.0 Day 1every 21 days for 6-9 cyclesIsonishi S, et al. ASCO Abstract 5506.
27Proportion Surviving Progression Free Mos From Randomization Conventional vs Dose-Dense TC (NOVEL): PFS1.00.9dd-TC0.8c-TC0.70.6Proportion Surviving Progression Free0.50.40.30.20.10.061218243036424854Mos From RandomizationTreatmentnEventMedian PFS, mosP ValueHR95 %CIc-TC31920017.2dd-TC31216028.0.00150.714Isonishi S, et al. ASCO Abstract 5506.
28Intra-Peritoneal Chemotherapy: Toxicity profile.GOG III :Systemic Paclitaxel/Cisplatin.Intraperitoneal Paclitaxel.Intraperitoneal Cisplatin.ClinicalTrials.gov/ct2/show/NCT August 2008
29Patterns of Recurrence Serologic relapseRising CA-125 only evidence of diseaseLocalized recurrenceDisseminated intraperitoneal diseaseExtraperitoneal metastasesRecurrences can be symptomatic or asymptomatic
30Management of a Rising CA-125 in a Patient Who Is Clinically Disease Free Rising CA-125 is highly predictive of a clinical relapseMedian time of 4-6 months before symptoms develop and/or a clinical recurrence (physical exam or imaging studies) is documented[1,2]Patient/physician preference about instituting chemotherapy is similar (~ 50%)No evidence that delaying chemotherapy until clinical relapse is detrimentalRandomized trial in progress in Europe1. Niloff JM, et al. Am J Obstet Gynecol. 1986;155: Vergote IB, et al. Tumour Biol. 1992;13:
31Role of Secondary Cytoreduction No RCT establishing clinical benefitGynecologic Oncology Group trial in progressEasier to define patients who should not undergo secondary cytoreductionShort disease-free intervalIntraperitoneal carcinomatosis precludes complete resectionAscitesDrug-resistant disease1. ClinicalTrials.gov. Available at: NCT ?term=GOG+cytoreduction&rank=1. Accessed February 4, 2008.
32Platinum-Sensitive Recurrent Ovarian Cancer: Carboplatin is key drugCarboplatin combinations are superior to single-agent carboplatinChoice of carboplatin/gemcitabine vs carboplatin/paclitaxel based on toxicity considerationsResults of carboplatin/PLD vs carboplatin/paclitaxel will be available soon
33Strategies to Improve Outcomes in Platinum-Resistant Disease No evidence that combinations of cytotoxic agents superior to single agentsRCT of canfosfamide + carboplatin vs PLD: negativePLD + trabectedin vs PLD in progressNo RCTs of in vitro sensitivity/resistance assays have shown improvementBiologic agentsBevacizumab? single agent or in combination with chemotherapy
34How Long to Treat Patients With Recurrent Disease? No RCTs in recurrent disease directly address this issueIn previously untreated patients, RCTs have failed to show any benefit for either continuing with the same chemotherapy or switching to a non–cross-resistant regimenIn recurrent disease, the same could be expectedCurrently, this is a personal choice issue with patient/physicianToxicity is keySome patients will choose more therapy as long as there is evidence they are not in a remission—“psychochemotherapy”Benefit of “drug holidays”