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Management of Epithelial Ovarian Cancer

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. Magnitude of The Clinical Problem:. 80. 70. 60. 50. 40. 30. 20. 10.

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Management of Epithelial Ovarian Cancer

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  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. 80 70 60 50 40 30 20 10 0 I II III IV Magnitude of The Clinical Problem: Steep Survival Gradient of Ovarian Cancer and Stage at Diagnosis Jelic S, et al. 2002 Congress of the European Society for Medical Oncology. Mocharnuk R. Available at: http://www.medscape.com/viewarticle/444134.

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

  5. Magnitude of The Clinical Problem: • 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. Magnitude of The Clinical Problem: 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

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

  8. Ovarian Cancer Risk Factors • 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 • 50 years of age or older • Familial factors • Family history of breast, ovarian, or colon cancer • Personal history of breast or colon cancer • BRCA (breast cancer) gene mutation • Hereditary nonpolyposis colon cancer (HNPCC)

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

  11. Ovarian Cancer: Ovulation > 5 Duration of Oral Contraceptive Use (Yrs) 2-3 0 Duration of Breast- Feeding (Mos) 12-23 1-5 > 6 4 Number of Term Pregnancies 2 0 0.0 0.5 1.0 Relative Risk of Ovarian Cancer Whittemore AS, et al. Am J Epidemiol. 1992;136:1212-1220.

  12. Limiting HRT May Reduce Ovarian Cancer Risk: *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;285:1460-1465.

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

  14. Ovarian Screening Methods for Average-Risk Women (cont’d) • 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

  15. Prevention of Ovarian Cancer • 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] 1. Finch A, et al. JAMA. 2006;296:185-192.2. Narod SA, et al. Lancet. 2001;357:1467-1470.

  16. Prophylactic Oophorectomy: Counseling about Risks/Benefits • 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 • 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

  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 mg2 IV over 24 hours + Paclitaxel 75 mg/m2 x 6 cycles (n = 184) Patients with suboptimally debulked, stage III/IV epithelial ovarian cancer within 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.

  21. GOG 111: PFS and OS PFS (P < .001) OS (P < .001) 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 Proportion Surviving Progression Free 0.5 Proportion Surviving 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 Months After Entry Into Study Months After Entry Into Study McGuire W, et al. N Engl J Med. 1996;334:1-6.

  22. NCCN 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.

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

  24. GOG 218: Potential New Standard of Care Paclitaxel + Carboplatin + Placebo* Placebo†x 15 months Patients 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 months Paclitaxel + 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 RECIST • Secondary endpoints: OS, safety, QoL, translational objectives, response ClinicalTrials.gov. NCT00262847.

  25. GC 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 carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days Clinical CR Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) ElectiveT Consolidation Therapy Paclitaxel 135 mg/m2every 28 days for 12 cycles Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Gordon A, et al. ASCO 2008. Abstract 5536.

  26. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stageII vs III vs IV;histology: clear cell/mucinous vs serous/others Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Isonishi S, et al. ASCO 2008. Abstract 5506.

  27. Conventional vs Dose-Dense TC (NOVEL): PFS 1.0 0.9 dd-TC 0.8 c-TC 0.7 0.6 Proportion Surviving Progression Free 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 Mos From Randomization Isonishi S, et al. ASCO 2008. Abstract 5506.

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

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

  30. Management of a Rising CA-125 in a Patient Who Is Clinically Disease Free • 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.

  31. Role of Secondary Cytoreduction • 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.

  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. Strategies to Improve Outcomes in Platinum-Resistant Disease • 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

  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 • In recurrent disease, the same could be expected • Currently, this is a personal choice issue with patient/physician • Toxicity is key • Some patients will choose more therapy as long as there is evidence they are not in a remission—“psychochemotherapy” • Benefit of “drug holidays”

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