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Management of Epithelial Ovarian Cancer Mohamed Abdulla (M.D.) Department of Clinical Oncology Kasr El-Aini School of Medicine Cairo University Egyptian.

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Presentation on theme: "Management of Epithelial Ovarian Cancer Mohamed Abdulla (M.D.) Department of Clinical Oncology Kasr El-Aini School of Medicine Cairo University Egyptian."— Presentation transcript:

1 Management of Epithelial Ovarian Cancer Mohamed Abdulla (M.D.) Department of Clinical Oncology Kasr El-Aini School of Medicine Cairo University Egyptian Cancer Society Meeting, Demiat Cancer Center – June, 2009

2 Magnitude of The Clinical Problem:

3 Jelic S, et al. 2002 Congress of the European Society for Medical Oncology. Mocharnuk R. Available at: http://www.medscape.com/viewarticle/444134. StageIIIIIIIV DescriptionConfined to ovaries Confined to pelvis Confined to abdomen/lymph nodes Distant metastases Incidence20%5%58%17% Survival73%45%21%< 5% 0 10 20 30 40 50 60 70 80 IIIIIIIV Steep Survival Gradient of Ovarian Cancer and Stage at Diagnosis Magnitude of The Clinical Problem:

4 FDA-Approved Drugs in Ovarian Cancer 1978 Cisplatin 1989 Carboplatin 1990 Altretamine 1992 Paclitaxel 1996 Topotecan 1999 Liposomal doxorubicin (accelerated) 2005 Liposomal doxorubicin (full) 2006 Gemcitabine 1978 2008 Magnitude of The Clinical Problem:

5 Stage I/II –Essentially all patients will achieve a clinical CR after surgery and chemotherapy –20% to 25% will relapse Optimal stage III –> 90% will achieve a clinical CR –75% will recur Suboptimal stage III/IV –50% will achieve a clinical CR –> 90% will recur

6 Ovarian Carcinoma--Symptoms Abdominal bloating, increased girth, pressure Abdominal / pelvic pain Fatigue GI (nausea, gas, constipation, diarrhea) Urinary frequency/ incontinence Weight loss/ gain Shortness of breath Vague and often non-gynecologic-- NOT Silent Magnitude of The Clinical Problem:

7 Ovarian Carcinoma--Signs Palpable pelvic mass Abdominal mass Abdominal distension Decreased breath sounds due to effusions Adenopathy -- groin, supraclavicular Magnitude of The Clinical Problem: Spreads by local growth, bloodstream and lymphatic routes

8 Ovarian Cancer Risk Factors 50 years of age or older Familial factors –F–Family history of breast, ovarian, or colon cancer –P–Personal history of breast or colon cancer –B–BRCA (breast cancer) gene mutation –H–Hereditary nonpolyposis colon cancer (HNPCC) Other potential risk factors –Early menarche (younger than 12 years of age) –Late menopause (older than 52 years of age) –Hormone replacement therapy or fertility drugs –First pregnancy at older than 30 years of age –Infertility

9 How Much Cancer Is Hereditary? 90% not hereditary ~5% to 10% of breast, colon, endometrial, and ovarian cancers are hereditary 90% not hereditary

10 Lifetime Risk of Cancers Associated With Specific Genes *MMR (mismatch repair) = HNPCC. Chen S, et al. J Clin Oncol. 2007:25:1329-1333. Aarnio M, et al. Int J Cancer. 1999:81:214-218. Cancer, %BRCA1BRCA2MMR* Breast35-6030-550 Ovarian30-4015-256-20 Endometrial0040-60

11 Whittemore AS, et al. Am J Epidemiol. 1992;136:1212-1220. Duration of Oral Contraceptive Use (Yrs) Duration of Breast- Feeding (Mos) Number of Term Pregnancies 0.00.51.0 0 2 4 > 6 1-5 12-23 0 2-3 > 5 Relative Risk of Ovarian Cancer Ovarian Cancer: Ovulation

12 *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. Estrogen Use No. of Deaths No. of Person-Years Rate Ratio (95% CI)* Rate Ratio (95% CI) Never6892,185,8761.00 (referent) Ever255625,9841.21 (1.05-1.41)1.23 (1.06-1.43) Frequency Current (baseline)62151,8801.45 (1.11-1.88)1.51 (1.16-1.96) Former193474,1031.15 (0.98-1.36)1.16 (0.99-1.37) Current users, yrs < 1031110,3791.07 (0.74-1.54)1.14 (0.79-1.65) 103141,3962.13 (1.48-3.06)2.20 (1.53-3.17) Former users, yrs < 10158416,8231.09 (0.92-1.30)1.10 (0.92-1.31) 103557,2811.55 (1.10-2.18)1.59 (1.13-2.25) Rodriguez C, et al. JAMA. 2001;285:1460-1465. Limiting HRT May Reduce Ovarian Cancer Risk:

13 Transvaginal ultrasound: poor sensitivity in early-stage disease, cannot reliably distinguish benign from malignant changes CA-125: poor sensitivity in early stage disease Pelvic exam Ovarian Screening Methods for Average-Risk Women

14 Insufficient evidence to recommend population- based screening Low prevalence of ovarian cancer in general population Not cost-effective Difficult to screen premenopausal women Appropriate screening is undefined Ovarian Screening Methods for Average-Risk Women (contd)

15 1. Finch A, et al. JAMA. 2006;296:185-192. 2. Narod SA, et al. Lancet. 2001;357:1467-1470. Chemoprevention –Oral contraceptive pills –Limit clomifene citrate –Limit hormone replacement therapy Surgical prevention –Oophorectomy: 80% risk reduction in high-risk women [1] –Bilateral tubal ligation: 72% risk reduction when used with oral contraception [2] Prevention of Ovarian Cancer

16 Medical risks –Loss of endogenous estrogen (effect on heart, bones, sexual function) Effect of hormone replacement therapy on breast cancer risk Emotional risks –Issues around castration Medical benefits –Prevention of ovarian cancer (unknown risk of peritoneal cancer) –Decreases risk of recurrent breast cancer Emotional benefits –Relief from fear of developing ovarian cancer Prophylactic Oophorectomy: Counseling about Risks/Benefits

17 At What Age Should a Patient Undergo Surgery? Limited data available –Decision often relies on pedigree information National Institutes of Health consensus panel recommendation: 35 years of age or older or after childbearing is complete [1] 1. JAMA. 1995;273:491-497

18 Epithelial Ovarian Cancer Standards of Care

19 Goals of Therapy: Manage symptomatic patients. Better durability of response. Survival improvement. Maintain Quality of Life.

20 GOG 111: Standard of Care Study design Cisplatin 135 mg 2 IV over 24 hours + Paclitaxel 75 mg/m 2 x 6 cycles (n = 184) Cisplatin 75 mg/m 2 x 6 cycles + Cyclophosphamide 750 mg/m 2 IV (n = 202) Patients with suboptimally debulked, stage III/IV epithelial ovarian cancer within 6 weeks of surgery (N = 386) McGuire W, et al. N Engl J Med. 1996;334:1-6.

21 GOG 111: PFS and OS McGuire W, et al. N Engl J Med. 1996;334:1-6. TreatmentNo. Progression Free No. With Treatment Failure TotalMedian PFS, mos Cisplatin + cyclophosphamide 2817420213 Cisplatin + paclitaxel4513918418 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months After Entry Into Study Proportion Surviving Progression Free 0624364212183048 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months After Entry Into Study Proportion Surviving 0624364212183048 TreatmentNo. AliveNo. DeadTotalMedian Survival, mos Cisplatin + cyclophosphamide 6513720224 Cisplatin + paclitaxel869818438 PFS (P <.001) OS (P <.001)

22 NCCN Guidelines: v2.2009 Stage IA & IB: 1.Grade 1 & 2: Observe. 2.Grade 3: 3-6 Courses Paclitaxel/Carboplatin. Stage IC: 3-6 Courses Paclitaxel/Carboplatin. Stages II, III & IV: 1.Stage II: Intraperitoneal Chemotherapy vs Systemic 6-8 Courses of Paclitaxel/Carboplatin. 2.Stage III (< 1 cm Residual): Intraperitoneal Chemotherapy vs Systemic 6-8 Courses of Paclitaxel/Carboplatin. 3.Stages III (> 1 cm Residual) & IV: Systemic 6-8 Courses of Paclitaxel/Carboplatin. 4.Completion of Surgery.

23 New Agents for the Clinical Management of Ovarian Cancer Diagnosis Staging Progression Death Secondary Surgery 1.Bevacizumab SymptomsChemotherapy #1MaintenanceChemo #2Chemo #3+ 1.Paclitaxel poliglumex 2.Oregovomab 3.Abagovomab 1.Canfosfamide 2.Patupilone 3.Phenoxodiol 4.Karenitecin 5.Trabectedin

24 GOG 218: Potential New Standard of Care Primary endpoint: PFS measured by RECIST Secondary endpoints: OS, safety, QoL, translational objectives, response *Beginning in course 2 of chemotherapy. Beginning in course 7 of chemotherapy. ClinicalTrials.gov. NCT00262847. Patients with stage III/IV ovarian or primary peritoneal cancer and GOG PS 0-2 entered 1-12 weeks after initial surgery (N = 2000) Paclitaxel + Carboplatin + Placebo* Paclitaxel + Carboplatin + Bevacizumab* Paclitaxel + Carboplatin + Bevacizumab* Placebo x 15 months Bevacizumab x 15 months

25 GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m 2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m 2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m 2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m 2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m 2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days

26 Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m 2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m 2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m 2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506.

27 TreatmentnEventMedian PFS, mosP ValueHR95 %CI c-TC31920017.2 dd-TC31216028.0.00150.7140.581-0.879 Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0123054 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 61842244836 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC

28 Toxicity profile. GOG III : 1.Systemic Paclitaxel/Cisplatin. 2.Intraperitoneal Paclitaxel. 3.Intraperitoneal Cisplatin. Intra-Peritoneal Chemotherapy: ClinicalTrials.gov/ct2/show/NCT00003322. August 2008

29 Serologic relapse –Rising CA-125 only evidence of disease Localized recurrence Disseminated intraperitoneal disease Extraperitoneal metastases Recurrences can be symptomatic or asymptomatic Patterns of Recurrence

30 Rising CA-125 is highly predictive of a clinical relapse –Median 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 detrimental Randomized trial in progress in Europe 1. Niloff JM, et al. Am J Obstet Gynecol. 1986;155:56-60. 2. Vergote IB, et al. Tumour Biol. 1992;13:168-174. Management of a Rising CA-125 in a Patient Who Is Clinically Disease Free

31 No RCT establishing clinical benefit –Gynecologic Oncology Group trial in progress [1] Easier to define patients who should not undergo secondary cytoreduction –Short disease-free interval –Intraperitoneal carcinomatosis precludes complete resection –Ascites –Drug-resistant disease 1. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/ NCT00002568?term=GOG+cytoreduction&rank=1. Accessed February 4, 2008. Role of Secondary Cytoreduction

32 Platinum-Sensitive Recurrent Ovarian Cancer: Carboplatin is key drug Carboplatin combinations are superior to single- agent carboplatin Choice of carboplatin/gemcitabine vs carboplatin/paclitaxel based on toxicity considerations Results of carboplatin/PLD vs carboplatin/paclitaxel will be available soon

33 No evidence that combinations of cytotoxic agents superior to single agents –RCT of canfosfamide + carboplatin vs PLD: negative –PLD + trabectedin vs PLD in progress No RCTs of in vitro sensitivity/resistance assays have shown improvement Biologic agents –Bevacizumab ? single agent or in combination with chemotherapy Strategies to Improve Outcomes in Platinum-Resistant Disease

34 How Long to Treat Patients With Recurrent Disease? No RCTs in recurrent disease directly address this issue In previously untreated patients, RCTs have failed to show any benefit for either continuing with the same chemotherapy or switching to a non–cross-resistant regimen –I–In recurrent disease, the same could be expected Currently, this is a personal choice issue with patient/physician –T–Toxicity is key –S–Some patients will choose more therapy as long as there is evidence they are not in a remissionpsychochemotherapy –B–Benefit of drug holidays


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