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ASCO 2006 Update: Gynecologic Cancers

ASCO 2006 Update: Gynecologic Cancers. Amreen Husain, M.D. Assistant Professor Division of Gynecologic Oncology Stanford University School of Medicine. Overview. Ovarian cancer Benefit of adding a third drug? Intraperitoneal vs. intravenous? Benefit of Prolonged “maintenance” therapy

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ASCO 2006 Update: Gynecologic Cancers

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  1. ASCO 2006 Update: Gynecologic Cancers Amreen Husain, M.D. Assistant Professor Division of Gynecologic Oncology Stanford University School of Medicine

  2. Overview • Ovarian cancer • Benefit of adding a third drug? • Intraperitoneal vs. intravenous? • Benefit of Prolonged “maintenance” therapy • Use of Bevacizumab in ovarian cancer • Endometrial cancer • Adjuvant therapy – radiation vs. chemotherapy? • laparoscopy vs. laparotomy?

  3. Ovarian Cancer Benefit of adding a third cytotoxic agent?

  4. GOG0182-ICON5: Phase III Randomized Trial of Paclitaxel and Carboplatin vs Combinations with Gemcitabine, PEG-Lipososomal Doxorubicin, or Topotecan in Patients with Advanced-Stage Epithelial Ovarian or Primary Peritoneal Carcinoma GOG, MRC, SWOG, ANZGOG, M Negri, and NCI-CTSU Bookman, ASCO 2006

  5. Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m2 (d1) I x8 R A N D O M I Z E Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m2 (d1) Doxil 30 mg/m2 (d1, every other cycle) III x8 Carboplatin AUC 5 (d3) Topotecan 1.25 mg/m2 (d1-3) IV x4 Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m2 (d1) x4 Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m2 (d1) Gemcitabine 800 mg/m2 (d1,8) Carboplatin AUC 6 (d8) Gemcitabine 1 g/m2 (d1,8) V x4 II x8 GOG0182-ICON5: Schema Bookman, ASCO 2006

  6. GOG0182-ICON5: Characteristics

  7. GOG0182-ICON5: Stratification Bookman, ASCO 2006

  8. GOG0182-ICON5: Heme Toxicity * p < 0.001 global test of null hypothesis Bookman, ASCO 2006

  9. GOG0182-ICON5: Non-Heme Toxicity * p < 0.001 global test of null hypothesis Bookman, ASCO 2006

  10. GOG0182-ICON5: Overall Survival Bookman, ASCO 2006

  11. GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman, ASCO 2006

  12. GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman, ASCO 2006

  13. GOG0182-ICON5: Conclusions • The addition of a third cytotoxic agent was associated with increased, but manageable, hematologic toxicity • A third cytotoxic agent was not associated with improved clinical outcomes, including progression-free and overall survival • After more than 25 years, carboplatin remains the dominant agent for treatment of advanced ovarian cancer, with an impact on evaluation of new agents and potential non-platinum alternatives Bookman, ASCO 2006

  14. Ovarian Cancer Intraperitoneal vs. Intravenous chemotherapy?

  15. Intraperitoneal chemotherapy • GOG 172 • N = 416, Stage III, Optimal (<1cm) • Randomized trial • Group 1 • Paclitaxel 135 mg/m2/24h • Cisplatin 75 mg/m2 • q 21 days x 6 • Group 2 • Paclitaxel 135 mg/m2/24h • Cisplatin 100 mg/m2 IP D2 • Paclitaxel 60 mg/m2 IP D8 • q 21 days x 6 • Quality of life: • Greater short term decline • No difference after 12 months Armstrong et al, NEJM 2006

  16. By Treatment Group 1.0 0.9 0.8 0.7 0.6 Proportion Surviving 0.5 0.4 0.3 0.2 l 0.1 IV IP 0.0 0 12 24 36 48 60 Months on Study Figure 2

  17. Wensel ASCO 2006

  18. Baseline Quality of Life and Tolerance for Intraperitoneal Chemotherapy for Advanced Epithelial Ovarian Cancer: A GOG Study • To determine if patient-reported baseline QOL scores are associated with number of IP cycles completed in the GOG 172 • Results – higher FACT-O scores significantly more likely • to complete more IP cycles (OR: 1.27 for every 10 points; 95% CI: 1.11 ~ 1.46; p<0.001), • to tolerate 6 cycles of IP therapy (OR: 1.31 for every 10 points; 95% CI: 1.11 ~ 1.56; p=0.002) • Conclusions – • Baseline QOL associated with tolerance to IP chemotherapy and may be useful in identifying those at risk for serious toxicities Wensel ASCO 2006

  19. Wensel ASCO 2006

  20. Question of abstracts 5004(Markman et al.)Will 12 months of paclitaxel prolong survival in patients with clinical complete remission after primary treatment?

  21. Progression-Free Survival 100% 80% Median At Risk Failed in Months Paclitaxel 12 courses 150 102 22 Paclitaxel 3 courses 146 115 14 60% P=0.01 40% 20% 0% 0 24 48 72 96 Months After Registration

  22. Overall Survival 100% 80% 60% 40% 20% Median At Risk Deaths in Months Paclitaxel 12 courses 150 66 53 Paclitaxel 3 courses 146 80 46 0% 0 24 48 72 96 Months After Registration P=0.27

  23. Increased PFS but: • More time on first line treatment and toxicity • Equal treatment free interval= equal symptoms and toxicity-free survival • Potential for decreased tolerance to subsequent treatment (g 2-3 neuropathy) • No increased in survival

  24. Abstract 5004: Clinical implication PFS=22 mos 1 treatment 12 22 Treatment and PFS = 10 mos PFS=14 mos 1 3 14 Treatment and PFS = 11 mos

  25. Recurrent ovarian - Bevacizumab – multicenter phase II • 44 patients • recurrent / persistent ovarian or primary peritoneal ca • Progression within <6 mos • No more than 3 prior therapies • Response: Overall = 15.9% • CR = 0 • PR = 7 • SD = 11 • Median Duration: 4.2 mos • Toxicity (Grade 3): • 5 htn, 3 MI, 1 CVA, 1 pulm htn, 1 bldg, 5 GI perforation Phase II Bevacizumab 15 mg/kg IV q 3 wks Cannistra, et al, ASCO 2006

  26. GOG 170-D* (N = 63) NCI 5789** (N = 29) Current Study (N = 44) Single agent BV 15 mg/kg q 3 wk BV 10 mg/kg q 2 wks + low dose oral cytoxan Single agent BV 15 mg/kg q 3 wk 42% DDP sensitive up to 2 prior regimens 42% DDP sensitive up to 2 prior regimens Platinum refractory resistant, up to 3 regimens 18% 39% 28% 57% 16% 27.4% Comparison with other trials Study Treatment Prior Treatment Setting Efficacy Results ORR 6-mo PFS

  27. GI Perforations • Five GI perforations observed in this trial • Four occurred within 9 weeks of initiating therapy • Perforation confirmed surgically in 4 cases; 5th developed large pelvic abscess • One fatality out of 5 GIP cases despite surgical intervention • IND Action letter (NIH) - Oct 4, 2005 • Alerted investigators of risk of GI perforations • CTEP database: 144 pts with 1 perforation and 3 fistulas (2.8%) • Total 4+5/144+44= 4.8% risk of perforation

  28. Bevacizumab: Clinical implications • Activity confirmed in relapsed ovarian cancer • Should be avoided in heavily pretreated patients with: • Extensive bowel involvement • Bowel obstruction • Bowel wall thickening

  29. Endometrial cancer • Adjuvant therapy – radiation vs. chemotherapy? • laparoscopy vs. open surgery?

  30. GOG 150 - Uterine Carcinosarcoma • 206 eligible with carcinosarcoma of uterus • Stage I-IV • TAH/BSO • Debulking to <1cm • washings, PA node sampling and omental biopsy optional • 1993-2005 Abdomino (3000 cGy) PelvicRadiation (4980 cGy) Vs. Cisplatin 20 mg/m2/d x 4 d Ifosfamide 1.5 g/m2 x 4 d Mesna 120 mg/m2 IV bolus over 15 minutes then 1.5 g/m2/d IV infusion over 24 hrs. Repeated q 3 weeks x 3 cycles R A N D O M I Z E • Endpoints – • PFS and OS • Toxicity Stage I (31%), II (13%), III (45%), IV (11%) Wolfson, ASCO 2006

  31. CIM improves PFS and OS compared whole abdomino pelvic irradiation • With increased vaginal, decreased distant recurrence • More acute anemia & neuropathy, less chronic GI toxicity • Estimate 5 year survival - • WAI - 34% • CIM - 47%

  32. GOG 150 - Conclusions • Adjuvant chemotherapy is more effective with less long term toxicity than radiotherapy in reducing recurrence and prolonging the survival of patient with optimally debulked uterine CS • Future therapeutic trials for this patient population should consider at least adjunctive vaginal brachytherapy and 3 cycles of CIM as a “control arm” Wolfson, ASCO 2006

  33. Early endometrial ca – laparoscopy GOG LAP2 R A N D O M I Z E • 2616 patients • Clinical stage I/IIA • 2:1 randomization • Lymph node from R & L pelvic/PA • 1996-2005 • Results – • 23% conversion rate for poor exposure, bleeding • Length of stay shorter with laparoscopy, 2 vs 4 days • OR time longer with laparoscopy, 3.3h vs. 2.2h • Fewer G2 or higher morbidity • Acceptable alternative Laparoscopy (n=1696) Laparotomy (n=920) Walker, SGO 2006

  34. Early endometrial ca – laparoscopy GOG LAP2 - QOL • Results – • QOL significantly higher with laparoscopy at 1 wk, 3 wks, and 6 wks after adjusting for baseline scores • No difference at 6 months • OR time longer with laparoscopy, 3.3h vs. 2.2h • no difference in acute peri-operative morbidity or wound complications R A N D O M I Z E • 782 patients • Clinical stage I/IIA • FACT-G – physical, emotional, social well being before, 1,3,6 wks and 6 mos after surgery Laparoscopy (n=524) Laparotomy (n=258) Kornblith et al, SGO 2006

  35. Predicted Probability of Successful Laparoscopy by BMI - Updated % SUCCESSFUL LAPAROSCOPY 74% success BMI

  36. p= 0.010

  37. Laparoscopy is an acceptable alternative to laparotomy for uterine cancer treatment and staging. • Surgeons were encouraged to convert to laparotomy when they encountered metastatic disease. • Conversion to laparotomy is advised when incomplete staging results would yield inadequate information for treatment planning. • Previously reported QOL improvement and decreased hospital stay, fewer grade > 2 complications makes laparascopic staging desirable from a patient perspective. • Survival results are pending.

  38. Review • Ovarian cancer • 3rd agent does not improve outcome • Intraperitoneal therapy for selected patients • Prolonged therapy does not improve outcome. • Endometrial cancer • Laparoscopy is an alternative for selected patients • Adjuvant therapy –chemotherapy better than radiation

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