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

2. Cancer Center Stanford University Gynecologic Cancer Treatment Overview Ovarian cancerOvarian cancer Benefit of adding a third drug?Benefit of adding a third drug? Intraperitoneal vs. intravenous?Intraperitoneal vs. intravenous? Benefit of Prolonged “maintenance” therapyBenefit of Prolonged “maintenance” therapy Use of Bevacizumab in ovarian cancerUse of Bevacizumab in ovarian cancer Endometrial cancerEndometrial cancer Adjuvant therapy – radiation vs. chemotherapy?Adjuvant therapy – radiation vs. chemotherapy? laparoscopy vs. laparotomy?laparoscopy vs. laparotomy?

3. Cancer Center Stanford University Gynecologic Cancer Treatment Ovarian Cancer Benefit of adding a third cytotoxic agent?

4. Cancer Center Stanford University Gynecologic Cancer Treatment 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. Cancer Center Stanford University Gynecologic Cancer Treatment GOG0182-ICON5: Schema R A N D O M I Z E x8 Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m 2 (d1) Doxil 30 mg/m 2 (d1, every other cycle) III x8 Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m 2 (d1) I Carboplatin AUC 6 (d1) 175 mg/m 2 (d1) Paclitaxel 175 mg/m 2 (d1) x4 Carboplatin AUC 6 (d8) Gemcitabine 1 g/m 2 (d1,8) V x4 Carboplatin AUC 5 (d3) Topotecan 1.25 mg/m 2 (d1-3) IV x8 Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m 2 (d1) Gemcitabine 800 mg/m 2 (d1,8) II Bookman, ASCO 2006

6. Cancer Center Stanford University Gynecologic Cancer Treatment GOG0182-ICON5: Characteristics ARM:C+P (n = 864) C+P+G C+P+D (n = 862) CT  CP (n = 861) CG  CP (n = 861) Age (Median) 57.7 y 59.1 y 59.5 y 58.5 y 59.3 y FIGO Stg IV 1º Peritoneal 16.2%13.3%13.3%13.0%13.8%14.5%13.7%12.7%16.3%12.8%

7. Cancer Center Stanford University Gynecologic Cancer Treatment GOG0182-ICON5: Stratification ARM:C+P (n = 864) C+P+G C+P+D (n = 862) CT  CP (n = 861) CG  CP (n = 861) Measurable Interval Surgery 21.6% 7.7% 7.7%22.6% 8.2% 8.2%22.7% 7.7% 7.7%23.3% 7.1% 7.1%24.2% 7.8% 7.8% Bookman, ASCO 2006

8. Cancer Center Stanford University Gynecologic Cancer Treatment GOG0182-ICON5: Heme Toxicity * p < 0.001 global test of null hypothesis Bookman, ASCO 2006

9. Cancer Center Stanford University Gynecologic Cancer Treatment GOG0182-ICON5: Non-Heme Toxicity * p < 0.001 global test of null hypothesis Bookman, ASCO 2006

10. Cancer Center Stanford University Gynecologic Cancer Treatment GOG0182-ICON5: Overall Survival Bookman, ASCO 2006

11. Cancer Center Stanford University Gynecologic Cancer Treatment 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. Cancer Center Stanford University Gynecologic Cancer Treatment 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. Cancer Center Stanford University Gynecologic Cancer Treatment 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. Cancer Center Stanford University Gynecologic Cancer Treatment Ovarian Cancer Intraperitoneal vs. Intravenous chemotherapy?

15. Cancer Center Stanford University Gynecologic Cancer Treatment Intraperitoneal chemotherapy PFSIV 18.3 Months IP 24 Months OSIV 49.7 Months IP 65.6 Months 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. Cancer Center Stanford University Gynecologic Cancer Treatment Figure 2

17. Cancer Center Stanford University Gynecologic Cancer Treatment Wensel ASCO 2006

18. Cancer Center Stanford University Gynecologic Cancer Treatment 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 172To determine if patient-reported baseline QOL scores are associated with number of IP cycles completed in the GOG 172 Results –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 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)to tolerate 6 cycles of IP therapy (OR: 1.31 for every 10 points; 95% CI: 1.11 ~ 1.56; p=0.002) Conclusions –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. Cancer Center Stanford University Gynecologic Cancer Treatment Wensel ASCO 2006

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

21. Cancer Center Stanford University Gynecologic Cancer Treatment Progression-Free Survival 0% 20% 40% 60% 80% 100% 024487296 Months After Registration Paclitaxel 12 courses Paclitaxel 3 courses At Risk 150 146 Failed 102 115 Median in Months 22 14 P=0.01

22. Cancer Center Stanford University Gynecologic Cancer Treatment P=0.27

23. Cancer Center Stanford University Gynecologic Cancer Treatment Increased PFS but: More time on first line treatment and toxicityMore time on first line treatment and toxicity Equal treatment free interval= equal symptoms and toxicity-free survivalEqual treatment free interval= equal symptoms and toxicity-free survival Potential for decreased tolerance to subsequent treatment (g 2-3 neuropathy)Potential for decreased tolerance to subsequent treatment (g 2-3 neuropathy) No increased in survivalNo increased in survival

24. Cancer Center Stanford University Gynecologic Cancer Treatment Abstract 5004: Clinical implication 112treatment 22 Treatment and PFS = 10 mos PFS=22 mos Treatment and PFS = 11 mos 1 14 3 PFS=14 mos

25. Cancer Center Stanford University Gynecologic Cancer Treatment Bevacizumab 15 mg/kg IV q 3 wks Cannistra, et al, ASCO 2006 44 patients recurrent / persistent ovarian or primary peritoneal ca Progression within <6 mos No more than 3 prior therapies P h a s e II II Recurrent ovarian - Bevacizumab – multicenter phase II 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

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

27. Cancer Center Stanford University Gynecologic Cancer Treatment GI Perforations Five GI perforations observed in this trialFive 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, 2005IND 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. Cancer Center Stanford University Gynecologic Cancer Treatment 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. Cancer Center Stanford University Gynecologic Cancer Treatment Endometrial cancer –Adjuvant therapy – radiation vs. chemotherapy? –laparoscopy vs. open surgery?

30. Cancer Center Stanford University Gynecologic Cancer Treatment Abdomino ( Abdomino (3000 cGy) PelvicRadiation ( 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 206 eligible with carcinosarcoma of uterus Stage I-IV TAH/BSO Debulking to <1cm washings, PA node sampling and omental biopsy optional 1993-2005 RANDOMIZE Endpoints –Endpoints – PFS and OSPFS and OS ToxicityToxicity GOG 150 - Uterine Carcinosarcoma Wolfson, ASCO 2006 Stage I (31%), II (13%), III (45%), IV (11%)

31. Cancer Center Stanford University Gynecologic Cancer Treatment Estimate 5 year survival - WAI - 34% CIM - 47% CIM improves PFS and OS compared whole abdomino pelvic irradiationCIM improves PFS and OS compared whole abdomino pelvic irradiation With increased vaginal, decreased distant recurrenceWith increased vaginal, decreased distant recurrence More acute anemia & neuropathy, less chronic GI toxicityMore acute anemia & neuropathy, less chronic GI toxicity

32. Cancer Center Stanford University Gynecologic Cancer Treatment 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 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” Future therapeutic trials for this patient population should consider at least adjunctive vaginal brachytherapy and 3 cycles of CIM as a “control arm” GOG 150 - Conclusions Wolfson, ASCO 2006

33. Cancer Center Stanford University Gynecologic Cancer Treatment Early endometrial ca – laparoscopy GOG LAP2 Laparoscopy (n=1696) Laparotomy(n=920) RANDOMIZE 2616 patients2616 patients Clinical stage I/IIA Clinical stage I/IIA 2:1 randomization 2:1 randomization Lymph node from Lymph node from R & L pelvic/PA R & L pelvic/PA 1996-2005 1996-2005 Walker, SGO 2006 Results – 23% conversion rate for poor exposure, bleeding23% conversion rate for poor exposure, bleeding Length of stay shorter with laparoscopy, 2 vs 4 daysLength of stay shorter with laparoscopy, 2 vs 4 days OR time longer with laparoscopy, 3.3h vs. 2.2h OR time longer with laparoscopy, 3.3h vs. 2.2h Fewer G2 or higher morbidityFewer G2 or higher morbidity Acceptable alternativeAcceptable alternative

34. Cancer Center Stanford University Gynecologic Cancer Treatment Early endometrial ca – laparoscopy GOG LAP2 - QOL Laparoscopy(n=524)Laparotomy(n=258) RANDOMIZE 782 patients782 patients Clinical stage I/IIA Clinical stage I/IIA FACT-G – physical, emotional, social well being before, 1,3,6 wks and 6 mos after surgery FACT-G – physical, emotional, social well being before, 1,3,6 wks and 6 mos after surgery Kornblith et al, SGO 2006 Results – QOL significantly higher with laparoscopy at 1 wk, 3 wks, and 6 wks after adjusting for baseline scoresQOL significantly higher with laparoscopy at 1 wk, 3 wks, and 6 wks after adjusting for baseline scores No difference at 6 months No difference at 6 months OR time longer with laparoscopy, 3.3h vs. 2.2h OR time longer with laparoscopy, 3.3h vs. 2.2h no difference in acute peri- operative morbidity or wound complications no difference in acute peri- operative morbidity or wound complications

35. Cancer Center Stanford University Gynecologic Cancer Treatment 74% success Predicted Probability of Successful Laparoscopy by BMI - Updated % SUCCESSFUL LAPAROSCOPY BMI

36. Cancer Center Stanford University Gynecologic Cancer Treatment

37. Cancer Center Stanford University Gynecologic Cancer Treatment p= 0.010

38. Cancer Center Stanford University Gynecologic Cancer Treatment 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.

39. Cancer Center Stanford University Gynecologic Cancer Treatment Review Ovarian cancerOvarian cancer –3 rd agent does not improve outcome –Intraperitoneal therapy for selected patients –Prolonged therapy does not improve outcome. Endometrial cancerEndometrial cancer –Laparoscopy is an alternative for selected patients –Adjuvant therapy –chemotherapy better than radiation

40. Cancer Center Stanford University Gynecologic Cancer Treatment