The Ohio State University Approach to Advanced Ovarian Cancer Korean Society of Gynecologic Oncology

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1 The Ohio State University Approach to Advanced Ovarian Cancer Korean Society of Gynecologic Oncology April 26, 2013 Larry J. Copeland M.D.

2 Thank You for Your Friendship!

3 The Ohio State University Approach to Ovarian Cancer Accrual to Clinical Trials is Always our Preference 1)Primary Surgery 2)Preferred treatment for early stage disease (Practical application of GOG 157 results) 3)Neoadjuvant therapy (Application of EORTC trial) 4)Role of Intraperitoneal Chemotherapy 5)Role of Maintenance Chemotherapy 6)Role of Bevacizumab (GOG, ICON, and OCEANS results) 7)Secondary tumor reductive surgery 8)Chemotherapy management of recurrent disease

4 Ovarian Carcinoma: Natural History Diagnosis Interval Cytoreduction * Second-Look Progression * Secondary Cytoreduction Death Symptoms * * Chemotherapy #1 * Consolidation * Chemo #2 Chemo #3+ Staging Primary cytoreduction * Cure Supportive Care Slide Modified from original slide of Robert Coleman, M.D.

5 1) Primary Surgery Overall our attitude is to be aggressive with the goal to remove all visible disease

6 Surgical Cytoreduction Rationale for Maximal Reduction: Optim. cytoreduction definition varies: 0.5, 1, 2 cm. Optimal debulking correlates with increases in surgical CR and longer median survival Goal is always No Visible Residual

7 Median Survival (Months) Primary Cytoreduction (Bristow, J Clin Oncol 20:1248, 2002) Meta-analysis: 53 studies ( ) 81 cohorts (Stage III/IV) N = 6885 patients Results Expert centers have high optimal rates Optimal vs. not: 11 mos. (50% increase) Platinum intensity = NS Each 10% in cytoreduction = 5.5% in survival % Cytoreduction Modified Slide: Robert Coleman

8 Sigmoid Right Left Uterus Bladder

9 Retroperitoneal Dissection

10 Intraperitoneal tumor will role with peritoneal dissection. Nodal disease will need to be addressed with lymphadenectomy

11 Surgical Approach Techniques: Retrograde Dissection May Reduce the Need for RS Resection Early Bladder Entry May Protect Bladder Cross-section of Pelvic Dissection Bladder Entry? Retrograde cul de sac entry site from vagina

12 Netter Drawing of Pelvic Retroperitoneum General appearance of pelvis after extensive ovarian tumor debulking, including a rectosigmoid resection Bladder Cervical Stump

13 Surgical Cytoreduction Maximal Reduction - Radical Surgical: Extensive lymphadenectomy Bowel resections Splenectomy Diaphragmatic stripping or resection Partial Hepatic/Gastric resections

14 Surgical Cytoreduction Obstacles to Maximal Surgical Reduction: Patient s performance status,?age Extensive ascites, pleural or pericardial effusions Limiting factors at laparotomy: Extensive infiltration of small bowel mesentery Extensive tumor infiltrating right medial diaphragm Extensive hepatic metastasis

15 Surgical Cytoreduction Controversies of Management and Surgical Intervention: Role of lymphadenectomy in patients with clinically normal nodes and advanced disease Mangioni group - Milan, Italy Panici, JNCI 97:560, patients - stage III/IV, randomized PFS 31.2 mos vs 21.6 months OS 58.7 mos vs 56.3 mos Sites of recurrence were similar Routine LND improves PFS but not OS Ohio State: Variable approach regarding LND if clinically neg.

16 2) Early stage disease In general apply principles of GOG 157, with variations based on toxicity and exploratory data analysis

17 GOG 157: Early Stage Ovarian Cancer I Carboplatin AUC 7.5 Paclitaxel 175mg/m 2 x 6 Epithelial Ovarian Ca Stage I/II II Carboplatin AUC 7.5 Paclitaxel 175 mg/m 2 x 3 Open: Closed: Accrual: Mar-1995 May pts No difference in outcomes: Adjusted - 33% lower recurrence with 6 cycles: HR 0.672, 95% CI Including incomplete staging: HR 0.762, 95% CI Bell J, et al. Gynecol Oncol 102:432-39, 2006

18 GOG 157: Early Stage Ovarian Cancer I Carboplatin AUC 7.5 Paclitaxel 175mg/m 2 x 6 Epithelial Ovarian Ca Stage I/II II Carboplatin AUC 7.5 Paclitaxel 175 mg/m 2 x 3 Exploratory Data Analysis Serous tumors: 6 cycles better than 3 cycles Chan J, et al. Gynecol Oncol 116:301-6, 2010

19 GOG 157: Early Stage Ovarian Cancer I Carboplatin AUC 7.5 Paclitaxel 175mg/m 2 x 6 Epithelial Ovarian Ca Stage I/II II Carboplatin AUC 7.5 Paclitaxel 175 mg/m 2 x 3 Ohio State Application of GOG 157 results: In general give at least 3 cycles with intent to complete 6 cycles, especially with serous tumors. However, with non serous tumors stop between 3 and 6 if neurotoxicity

20 3) Neoadjuvant Chemotherapy In general, the use of neoadjuvant chemotherapy represents the management area most variability amongst our faculty

21 Surgical Cytoreduction Controversies of Management: Role of neoadjuvant chemotherapy (NAC) in patients suspected having extensive disease Most data is retrospective Meta analysis (21 studies) Kang and Nam, Ann Surg Onc 16:2315, 2009 NAC - lower risk of suboptimal sx - OR 0.50 (95CI )

22 Neoadjuvant vs Primary Surgery EORTC-GCG and NCIC CTG - a GCIC Study Vergote I et al. NEJM 2010; 363:943 Eligible Patient Epithelial Ovarian Cancer and Tubal and Peritoneal Stage III C and IV No prior therapy Open: Sept-98 Closed: Dec-06 Enrolled/Randomized: 718/670 pts Primary Cytoreduction (94% had the surgery) Platinum-Chemo X 6 cycles Neoadjuvant Platinum-Chemo X 3 cycles Interval debulking (88% of patients) Platinum-Chemo x 3 cycles

23 Neoadjuvant Study EORTC-GCG and NCIC Treatment arm Median Survival % Resid Periop < 1 cm Mortality (months) Primary Surgery % 2.5% Neoadjuvant Rx % 0.7% Conclusion - Either Mx okay for stage IIIC or IV Vergote et al, NEJM 2010;363

24 Neoadjuvant vs Primary Surgery Eligible Patient Ohio State Approach - Variable: The experienced (Old) tend to do more neoadjuvant chemo The inexperienced (Young) tend to do more primary surgery Primary Cytoreduction Taxane-Platinum Chemo X 6-8 cycles Neoadjuvant Platinum-Chemo X 3-4 cycles Interval debulking Platinum-Chemo x 3-4 cycles

25 4) Role of IP chemotherapy Most patients who have been optimally debulked and who are not eligible for a clinical trial are treated with the OSUspecific IP regimen.

26 GOG 172: Ovarian (optimal III) Epithelial Ovarian Cancer Optimal Stage III No prior therapy I Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 (24 h) II Paclitaxel 135 mg/m 2 (24 h) Cisplatin 100 mg/m 2 IP Paclitaxel 60 mg/m 2 IP (d8) Open: Closed: Accrual: 23-Mar Jan pts Armstrong et al, NEJM, 354:34, 2006

27 Protocol GOG 172 Progression-Free Survival Overall Survival

28 Protocol GOG 172: Toxicity IV IP G4 WBC 14% 31% G3/4 Platelet 4% 12% G3/4 GI 24% 46% G3/4 Renal 1% 6% G3/4 Neuropathy 9% 19% G3/4 Fatigue 5% 17% G3/4 Infection 5% 16% G3/4 Metabolic 7% 27% G3/4 Pain 1% 11% Quality of Life analysis: Wenzel - J Clin Oncol 25:437, 2007 Arms equal after 12 months, except for neurotoxicity.

29 Ovarian (optimal): 172 vs OSU Modification GOG 172 Paclitaxel 135 mg/m 2 (24 h) (d1) Cisplatin 100 mg/m 2 IP (d2) Paclitaxel 60 mg/m 2 IP (d8) OSU Protocol Docetaxel mg/m 2 (d1) Cisplatin 85, mg/m 2 IP (d1) Paclitaxel 60 mg/m 2 IP (d8) NW/UAB Protocol Seamon et al (OSU) Int J Gyn Ca 19:1195, 2009 Berry et al (Northwestern/UAB) Gynecol Oncol 113:63, 2009

30 R A N D O M I Z E GOG 218: Ovarian (III-IV) or Primary Peritoneal Cancer Carboplatin AUC 6 IV plus Paclitaxel 175 mg/m2/3hrs x 6 cycles Placebo x 5 cycles, starting cycle 2 Bevacizumab 15 mg/kg x 5, starting cycle 2 Plus Bevacizumab 15 mg/kg x 5, starting cycle 2 Plus Bevaciz. Q 21 d for 15 months Outcomes Primary: Secondary: Overall Survival PFS and RR Toxicity and QOL Translational Research Largest placebo-controlled Phase III trial in ovarian cancer 1,873 patients Closed to accrual 6-09, FDA registry trial Over 1,500 specimens obtained for biomarker analysis

31 5) Role of Bevacizumab No hesitancy to enroll patients in clinical trial with bevacizuamb. However, if no RCT we tend to not use Bev in front line therapy outside the clinical trial setting Tend to use 10 mg/kg (GOG 218 was 15 mg/kg) More enthusiastic use Bev in recurrent setting

32 Proportion Surviving Progression Free GOG-0218: Investigator-Assessed PFS CP (Arm I) + BEV (Arm II) Patients with event, n (%) Arm I CP (n = 625) 423 (67.7) Arm II CP + BEV (n = 625) 418 (66.9) Median PFS, months Stratified analysis HR (95% CI) One-sided P value (log rank) + BEV BEV maintenance (Arm III) Months Since Randomization ( ) 0.080* Arm III CP + BEV BEV (n = 623) 360 (57.8) ( ) < * Burger RA, et al. J Clin Oncol. 2010;28(18s). Abstract LBA1. *P value boundary =

33 Proportion Surviving GOG-0218: Overall Survival Analysis At time of final PFS analysis (January 2010) CP (Arm I) + BEV (Arm II) + BEV BEV maintenance (Arm III) Patients with events, n (%) Arm I CP (n = 625) Arm II CP + BEV (n = 625) Arm III CP + BEV BEV (n = 623) 156 (25.0) 150 (24.0) 138 (22.2) Median OS, months Stratified analysis HR (95% CI) ( )( ) One-sided P value Months Since Randomization Burger RA, et al. J Clin Oncol. 2010;28(18s). Abstract LBA1.

34 ICON7: Study Design Frontline EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Carboplatin AUC 6* Paclitaxel 175 mg/m 2 Carboplatin AUC 6* Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational Stratification variables: Stage / surgery Time since surgery GCIG group Paclitaxel 175 mg/m 2 Bevacizumab 7.5 mg/kg 12 months No IRC present *Might vary based on GCIG group. Omit cycle 1 bevacizumab if < 4 weeks from surgery. Perren T, et al. Annals Oncol. 2010;21(suppl 8). Abstract LBA4.

35 ASCO 2011

36 Patients (N=484) with Platinum-Sensitive recurrent 1.Epithelial ovarian carcinoma 2.Primary peritoneal carcinoma 3.Fallopian tube carcinoma Phase III: Ovarian Cancer Evaluation of Bevacizumab and Safety (OCEANS) Arm A (n=242) Gemcitabine 1000 mg/m², d 1 & 8 Carboplatin AUC 4, day 1 Placebo IV, day 1 Arm B (n=242) q 21 days x 6 Gemcitabine 1000 mg/m², d 1 & 8 Carboplatin AUC 4, day 1 Bevacizumab 15 mg/kg, day 1 Placebo q21d until PD or unacceptable toxicity Bev q21d until PD or unacceptable toxicity Primary objective: PFS (RECIST) Secondary objective: OR, OS, duration of response, safety Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007)

37 Proportion progression free OCEANS: Primary analysis of PFS CG + PL (n=242) CG + BV (n=242) Events, n (%) 187 (77) 151 (62) Median PFS, months (95% CI) Stratified analysis HR (95% CI) Log-rank p-value 8.4 ( ) 12.4 ( ) ( ) < No. at risk CG + PL CG + BV Months

38 Role of Bevacizumab No hesitancy to enroll patients in clinical trial with bevacizuamb. However, if no RCT we tend to not use Bev in front line therapy outside the clinical trial setting Tend to use 10 mg/kg (GOG 218 was 15 mg/kg) More enthusiastic use Bev in recurrent setting (Most commonly used with Gem/Cis/Bev all 3 drugs days 1 and 15 q 28 days Richardson reference - later)

39 6) Role of Maintenance Chemotherapy Clinical trial experience with mintenance: GOG 178 (Paclitaxel: 3 v 12 cycles) GOG 218, GOG 252, GOG 262 (Bev) GOG 212 (Observation v Paclitaxel v Opaxio) close to completing accrual

40 Maintenance: GOG 178 (SWOG 9701) Evaluation of maintenance therapy after clinical CR to primary surgery and chemotherapy (Tax/Plat) Randomized to 3 or 12 cycles of Taxol DSMC of SWOG closed study prematurely since there was a 7 month difference in PFS (28 vs 21 months), favoring 12 No survival advantage

41 R A N D O M I Z E GOG 212: Ovarian (III-IV) Carboplatin Cisplatin plus Paclitaxel Docetaxel x 6 (5-8) cycles No treatment until clinical progression CT mg/m2 q 28 days Paclitaxel 175 mg/m 2 q 28 days x 12 x 12 Clinical Complete Response 1053 patients enrolled (through April, ) Anticipate closure at within a few months 2013

42 Ohio State Use of Maintenance Chemotherapy GOG 178/SWOG Study GOG 212 Ohio State University: Seldom give maintenance therapy off clinical trial

43 7) Role of Secondary TRS In general will follow the prognostic features resulting in the more favorable outcomes.

44 Secondary Surgical Cytoreduction GOG 213 Currently Open Recurrent Ovarian Cancer: Randomization to Surgery versus Chemo only Slow accrual probably strong selection biases

45 Secondary Surgical Cytoreduction: Factors to Consider Effort and result of primary surgery Who did surgery? What was the effort? Incision/EBL? What was the residual disease status? If not optimally debulked - why Response to primary therapy (Sx + Chemo) Rapidity of normalization of Ca-125 Progression Free Interval

46 Secondary Surgical Cytoreduction: Preoperative Factors to Consider Pathologic features of primary disease Grade? Histologic variant? Patient reserve and general health Age? Nutrition? Medical co-morbidities? Disease profile by examination or imaging Unifocal or Multifocal; Effusions Symptoms Nonsurgical treatment options As an alternative? As an adjuvant?

47 Secondary Cytoreduction OSU - Factors Favoring Efficacy: Extended disease free interval Initial disease limited (stage I vs IIIC) Prior suboptimal debulking secondary to surgeon and not the disease Primary surgical effort not maximal Excellent response to 1 chemotherapy Effective chemotherapy still available

48 8) Second/Third Line Chemo OSU General philosophy for recurrence management: Platinum resistant Non platinum initially (Often weekly paclitaxel with biweekly Bev) Platinum sensitive over 18 mos rerx T/C Platinum sensitive over 12 mos gem/cis/+/-bev Platinum sensitive 6-12 mos non platinum Rx

49 Commonly Cited Trials for Platinum Sensitive Recurrence Clinical Trial Study Drugs P.F. Survival AGO ICON4/AGO CALYPSO OCEANS (ASCO June 2011) Carbo Carbo/Gem Plat Plat/Taxol Plat/Taxol Carbo/Doxil Carbo/Gemcitabine Carbo/Gem/Avastin 5.8 mos 8.6 mos 9 mos 12 mos 9.4 mos 11.3 mos 8.4 mos 12.4 mos

50 Gem/Plat Trial Comparisons Clinical Trial Gem/Plat Regimen Frequency AGO-OVAR Phase III (Platinum sensitive) OCEANS Phase III (Platinum sensitive) Ohio State Univ. Phase II (80% Platinum sensitive, 20% Platinum resistant) Carbo AUC 4 d 1 Gem 1000 mg/m2 d 1 and 8 Carbo AUC 4 d 1 Gem 1000 mg/m2 d 1 and 8 Bev 15 mg/kg d 1 Carbo AUC 3 d 1 and 15 (or Cis 30 mg/m2 d 1 and 15) Gem 1000 mg/m2 d 1 and 15 Bev 10 mg/kg d 1 and 15 Q21 days to progression Q21 days X 6-10 and Bev to progression Q28 days to progression

51 Gem/Plat/+/-Bevacizumab Trial PFS (months) CR% PR% ORR% AGO-OVAR (No Bev) 6-12 mos 7.9 > OCEANS Ohio State U 20% Plat Resistant (Richardson et al, Gynecol Oncol 2008; 111:461-6)

52 The Ohio State University Approach to Advanced Ovarian Cancer Korean Society of Gynecologic Oncology April 26, 2013 Larry J. Copeland M.D. Thank you for your attention!