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An Oncology Exchange Activity

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  1. An Oncology Exchange Activity • Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: • Pre-activity Survey • Located at the front of your syllabus • CME Evaluation with Post-activity Survey • Located at the back of your syllabus

  2. An Oncology Exchange Activity

  3. Disclosures • The relevant financial relationships reported by faculty that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus • The relevant financial relationships reported by the steering committee that they or their spouse/partner have with commercial interests are provided on page 5 of your syllabus • The relevant financial relationships reported by the non-faculty content contributors and/or reviewers that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus

  4. Off-label Discussion Disclosure This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

  5. Learning Objectives • Review the incorporation of guidelines in clinical decision-making to optimize patient outcomes • Evaluate the evidence for personalizing therapy based on genetic mutations and resistance markers • Understand the role of PARP inhibitors and anti-angiogenicagents for platinum-resistant/sensitive recurrent disease • Discuss the integration of ovarian cancer quality measures to improve patient outcomes

  6. Pre-activity Survey • Please take out the Pre-activity Survey from your packet • Your answers are important to us and will be used to help shape future CME activities • It is important that you fill out the information at the top of the form: • Please select the best answer(s) for the questions below: • Degree: _ MD/DO _ Nursing Professional _ PharmD _Other:_____________________________ • Specialty: _ Oncology _ Gynecology _ Surgery _ Internal Medicine _Other:______________________

  7. Pre-activity Survey Question 1 Please rate your level of confidence in personalizing treatment strategies for patients with recurrent ovarian cancer: 1 2 3 4 5 Not confidentExpert

  8. Pre-activity Survey Question 2 Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated benefit in: • HER2/neupositive recurrent ovarian cancer • Platinum-resistant high-grade serous ovarian cancer • p53mutant recurrent ovarian cancer • Women with ovarian cancer and BRCAgermlinemutations

  9. Pre-activity Survey Question 3 In the AURELIA trial, the addition of bevacizumab to chemotherapy for platinum-resistant recurrent ovarian cancer resulted in which of the following outcomes? • A significant improvement in progression-free survival and overall survival by 3.3 months • A significant improvement in progression-free survival and response rates, but not in overall survival • A significant improvement in overall survival and objective response rate, but not in progression-free survival • An increase in objective response rate for the placebo arm • A significant increase in median duration of response by 5 months, objective response rate by 21%, and median progression-free survival by 4 months

  10. Pre-activity Survey Question 4 Which of the following patients with high-grade ovarian cancer should undergo genetic testing for BRCA1/BRCA2? • Patients under the age of 60 • Patients with a significant family history • Patients diagnosed at early stage • All patients

  11. Pre-activity Survey Question 5 Following optimal debulking surgery, a 60-year-old woman receives 6 cycles of carboplatin-paclitaxel. Her CA-125 level following adjuvant chemotherapy remains less than 5 for two years. She then develops bloating and ascites associated with carcinomatosis. What is your treatment recommendation at this time? • Retreat with a platinum-doublet • Non-platinum single agent • Delay treatment until bowel obstruction • Secondary debulking surgery

  12. Goals of TreatmentRelapsed Ovarian Cancer • Prolong Survival • Delay Time to Progression • Control Disease-related Symptoms • Minimize Treatment-related Symptoms • Maintain or Improve Quality of Life

  13. Ovarian CancerHow is Relapse Defined? • Continuous rise in CA-125 • CA-125 above 100 • Radiographic recurrence • Symptomatic recurrence • Physical examination findings • Combination of above

  14. Issues Impacting Therapy for Recurrent Ovarian Cancer • Treatment-free interval • Impact of consolidation/maintenance therapy • Number of prior regimens • Response to prior therapy • Toxicity from prior therapy • Prior use of growth factors • Transfusion requirements • Neuropathy • Volume and site(s) of disease • Ascites/GI symptoms • Potential for secondary surgery • Performance status

  15. Effect of Platinum-Free Interval on Response Rate MarkmanM et al. J ClinOncol.1991;9:389-393; Gore ME et al. GynecolOncol. 1990;36:207-211; Blackledge G et al. Br J Cancer. 1989;59:650-653.

  16. General Approach to Treatment ofRecurrent Disease • Increasing evidence suggests the duration of the PFI alsoinfluences outcomes of non-platinum chemotherapeuticagents/regimens Platinumsensitive Platinum refractory/resistant PFI>6 mos PFI<6 mos Non-platinum treatment Platinumretreatment PFI = progression-free interval.

  17. Ovarian Cancer at First RelapseDefinition of Sensitivity P R I M A R Y T R E A T M E N T 18 12 6 3 0 24 Months Refractory Resistant Sensitive “Very Sensitive” Defined as measurable recurrence, not biochemical (CA-125) recurrence

  18. Platinum-Sensitive Recurrent Ovarian Cancer

  19. What Do We Know about Secondary Debulking? • Surgical endpoint: Complete resection or minimal residual disease? • 8 series >100 patients • EisenkopSM, et al. Cancer. 2000;88(1):144-153. • Scarabelli C, et al. GynecolOncol. 2001;83(3):504-512. • Zang RY, et al. Cancer. 2004;100(6):1152-1161. • Harter P, et al. Ann SurgOncol. 2006;13(12):1702-1710. • Chi DS, et al. Cancer. 2006;106(9):1933-1939. • Oksefjell H, et al. Ann Oncol. 2009;20(2):286-293. • Tian WJ, et al. J SurgOncol. 2010;101(3):244-250. • Sehouli J, et al. J SurgOncol. 2010;102(6):656-662. • Risks of surgery • Identification of surgical candidates

  20. 1. Surgical endpoint: Complete resection or minimal residual disease?AGO DESKTOP OVAR I:Confirming the Surgical Endpoint? No residuals Median OS 45.2 months Residuals >10 mm 0 vs 1-10 mm: HR: 4.17 (CI 2.42 – 7.16); P<.001 0 vs 10+ mm: HR: 3.31 (CI 1.86 – 5.88); P<.001 MedianOS 19.7 months Residuals 1 - 10 mm Median OS 19.6 months CI, confidence interval; HR, hazard ratio; OS, overall survival Harter P, et al. Ann Surg Oncol. 2006;13(12):1702-1710.

  21. 1. Surgical endpoint: Complete resection or minimal residual disease? What Is the Role of Cytoreductive Surgery for Recurrent Ovarian Cancer? • Surgery may be appropriate in selected patients • As yet there is no level I evidence that demonstrates a survival advantage associated with surgical cytoreduction for women with recurrent ovarian cancer • Randomized phase III trials evaluating the role of surgery in recurrent ovarian cancer are a priority • Cytoreductive surgery for women with recurrent ovarian cancer may be beneficial if it results in optimal cytoreduction as defined in A4 (= complete resection) Friedlander M, et al. Int J Gyn Cancer. 2011 ;21(4):771-775.

  22. 2. Risks of surgery AGO-DESKTOP II – Perioperative Morbidity • Study Collective • Patients in intensive care unit 67 (52%) • Days intensive care unit [median] 2 (range: 1-20) • No of patients adm. packed blood cells 55 (44%) • No of ptientss with at least one complication 42 (33%) • Infections requiring antibiotic treatment 31 (24%) • urinary tract 14 (11%) • peritonitis 10 (8%) • pneumonia 4 (3%) • others 7 (5%) • Relaparotomy 14 (11%) • bowel leakage/perforation 6 (5%) • abscess/infection 3 (2%) • bleeding 3 (2%) • fistula 2 (2%) • Thrombosis / Embolism 3 (2%) / 4 (3%) • Other severe complications 12 (9%) • Mortality within 60 days 1 (0.8%) Harter P, et al. Int J GynecolCancer. 2011;21(2):289-295.

  23. 2. Risks of surgery Perioperative Mortality at First Diagnosis and Relapse

  24. 3. Identification of surgical candidatesAGO-DESKTOP II: An International Multicenter GCIG Trial Prospective Validation of a Predictive Score for Resectability in Platinum-Sensitive ROC • DESKTOP II = positive • Positive AGO score predicts complete resection in more than 2 out of 3 pts Frequency of complete resection in AGO-Score positive patients P<.05 DESKTOP Hypothesis Harter P, et al. Int J GynecolCancer. 2011;21(2):289-295.

  25. 3. Identification of surgical candidates Selected Patients – DESKTOP II 08/06 - 03/08: Screening of 516 patients with platinum-sensitive 1st or 2nd relapse in 46 centers 51% (261 patients) AGO score positive 49% (255 patients) AGO score negative 29% (148) surgery 15% (80) surgery 44% (228) surgery Nearby half of patients in dedicated centers undergo surgery for relapse.

  26. 3. Identification of surgical candidates A Frequently Asked Question After DESKTOP II • What was the rate of complete resection in score negative patients? • 63% in a multicenter study • Further selection criteria for surgery by the centers • Underreporting of score negative patients without surgery (~ 30% of score negative pts with surgery)?

  27. 3. Identification of surgical candidates Candidates for Surgery: Time From Randomization to Second-Line Chemotherapy • Rarely relapse diagnosed by symptoms 1.00 Median Early 0.8 months Delayed 5.6 months HR = 0.29 (95% CI 0.24, 0.35) P<.00001 0.75 Proportion Alive Not Started Second-Line Chemotherapy 0.50 0.25 0.00 0 3 6 9 12 15 18 21 24 Months Since Randomization CA-125 elevation 5 months before clinical relapse! Rustin GJ, et al. Lancet. 2010;376(9747):1155-1163.

  28. 1.00 0.75 Proportion Surviving 0.50 0.25 0.00 0 6 12 18 24 30 36 42 48 54 60 Months Since Randomization 3. Identification of surgical candidates In Patients Treated Mainly Without Surgery*… HR = 1.00 (95%CI 0.82-1.22) P = .98 Abs diff at 2 years = 0.1% (95% CI diff = -6.8, 6.3%) Early Delayed Indication for second-line chemo are symptoms and not lab values * only ~ 6% with surgery for recurrent disease Rustin GJ, et al. Lancet. 2010;376(9747):1155-1163.

  29. 3. Identification of surgical candidates Hypothesis: Management of Relapse Depends on Time and Diagnostic Tools Chemo only Tumor Burden Surgery + chemo Ultrasound negative Ultrasound positive „Invisible“ MRI/CT negative MRI/CT positive PET-CT positive ↑ ↑ Time, months ↑ CA125 Symptoms Earlier treatment by improved diagnostic tools and surgical skills?

  30. 3. Identification of surgical candidates Real Benefit by Earlier Diagnosis and Surgery? Diagnosis of 1st relapse by symptoms + ascites → chemotherapy Diagnosis of 1st relapse by CA125+ PET-CT → Surgery + Chemo 2nd relapse

  31. 3. Identification of surgical candidates Aim of Cytoreductive Surgery • Cure - early and “mid” advanced ovarian cancer • Unlikely in surgery for relapse • Palliation of symptoms - eg, ileus, pain • Rarely in selected “ideal” candidates • Prolongation of PFS (only) • Con: hospitalization, complications, surgical risks • Prolongation of OS • Yes, but only if clinically significant • OS after surgery suggests superiority but this may be confounded by earlier start of treatment (and counting days) and by selection of favorable biology

  32. 3. Identification of surgical candidates Cytoreductive Surgery Plus Chemotherapy Versus Chemotherapy Alone for Recurrent EOC AUTHORS’ CONCLUSIONS Implications for practice We found no current evidence from RCTs to guide clinical practice, however the results of an ongoing RCT AGO-OVAR OP.4 are awaited to determine the efficacy of secondary surgical cytoreduction with chemotherapy compared to chemotherapy alone for women with recurrent epithelial ovarian cancer. Galaal K, Naik R, Bristow RE, Patel A, Bryant A, Dickenson HO

  33. 3. Identification of surgical candidates AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4) A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive and AGO score–positive recurrent ovarian cancer Strata: Platinum-free-interval 6-12 mos vs > 12 mos First-line platinum-based chx: yes vs no Cytoreductive surgery Platinum-based chemotherapy* recommended R n=408 No surgery • * Recommended platinum-basedchemotherapyregimen: • - Carboplatin/paclitaxel • Carboplatin/gemcitabine +/- bevacizumab • Carboplatin/pegliposomal doxorubicin • Or other platinum combinations in prospective trials

  34. 3. Identification of surgical candidates GOG-0213: Secondary Cytoreduction + Bevacizumab CarboplatinAUC5 q3w Pretreated platinum-sensitive, EOC, PP or FTC (n = 660) Paclitaxel 175 mg/m2 q3w Surgical candidate No R Bevacizumab 15 mg/kg q3w to PD CarboplatinAUC5 q3w Paclitaxel 175 mg/m2 q3w Yes R Bevacizumab 15 mg/kg Surgery No surgery • Primary endpoint: OS • Stratification: Time to recurrence Open: December 6, 2007 Closed: Ongoing Target accrual: 660 Coleman, et al. 2008

  35. Newly Diagnosed Advanced Ovarian Cancer

  36. Case 1: Platinum-Sensitive“Chemical” Recurrence • Alice, a 60-year-old college professor, underwent TAH and BSO plus omentectomy for stage IIIB epithelial ovarian carcinoma 2 years ago. • Following optimal debulking surgery, she received 6 cycles of IV carboplatin-paclitaxel and tolerated it well. Her Ca-125 level following adjuvant chemotherapy was <5. • She was followed every 3 months with examinations and Ca-125 levels, which were always <5.

  37. Case 1 Treatment Decisions • Six months ago her Ca-125 was slightly higher at 9. Three months later it was 21. Repeat physical examination at this time remains normal, imaging is normal, and this woman is asymptomatic. However, her Ca-125 is now up to 31. • What treatment plan would you recommend for Alice at this time? • What evidence would you cite as the basis for your plan? A PET/CT shows no measurable disease and 6 weeks later the CA125 is now 79. • How would your treatment change if she had three 4-6 cm masses. One in the pelvis and another two in the “residual omentum”?

  38. Case 1 Question 1 Would you recommend secondary debulking surgery? • Yes • No

  39. Aim of Cytoreductive Surgery • Cure - early and “mid” advanced ovarian cancer • Unlikely in surgery for relapse • Palliation of symptoms - eg, ileus, pain • Rarely in selected “ideal” candidates • Prolongation of PFS (only) • Con: hospitalization, complications, surgical risks • Prolongation of OS • Yes, but only if clinically significant • OS after surgery suggests superiority but this may be confounded by earlier start of treatment (and counting days) and by selection of favorable biology

  40. Case 1 Question 2 Which chemotherapy would you recommend? • Carboplatin + paclitaxel • Carboplatin + gemcitabine • Carboplatin + PLD • Carboplatin + paclitaxel + bevacizumab • Carboplatin + gemcitabine + bevacizumab • Carboplatin + PLD + bevacizumab

  41. Randomized Trials in Platinum Sensitive Disease

  42. GCIG CALYPSO Trial Accrual 864 patientsPFS primary endpoint R A N D O M I Z E PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Pujade-Lauraine E et al. J ClinOncol. 2010; 28(20): 3323-3329.

  43. CALYPSO Pujade-Lauraine E et al. J ClinOncol. 2010; 28(20): 3323-3329.

  44. Selected Non-Hematologic Grade 2Toxicities During Treatment *P < 0.001

  45. OCEANS: Study Schema C AUC 4 CG + PL Platinum-sensitive recurrent OCa • Measurable disease • ECOG 0/1 • No prior chemo for recurrent OC • No prior BV (n=484) G 1000 mg/m2, d1 & 8 PL q3w until progression C AUC 4 G 1000 mg/m2, d1 & 8 CG + BV Stratification variables: • Platinum-free interval (6–12 vs >12 months) • Cytoreductive surgery for recurrent disease (yes vs no) BV 15 mg/kg q3w until progression CG for 6 (up to 10) cycles BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer Aghajanian C et al. J ClincOncol 2012; 30(17): 2039-2045.

  46. OCEANS: Primary analysis of PFS 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Months No. at risk CG + BV 242 203 92 33 11 0 CG + PL 242 177 45 11 3 0 Aghajanian C et al. J ClincOncol 2012; 30(17): 2039-2045.

  47. OCEANS: Third Interim OS Analysisa Aghajanianet al. ESMO 2012 1.0 0.8 0.6 0.4 0.2 0.0 Proportion surviving 0 6 12 18 24 30 36 42 48 54 60 Months Number at risk: GC + PL GC + BV 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients)

  48. OCEANS: Select Adverse Events aTwo GI perforations occurred 69 days after last BEV dose. ATE = arterial thromboembolic event; VTE = venous thromboembolic event. Aghajanian C et al. J ClincOncol 2012; 30(17): 2039-2045.

  49. ICON6: Carboplatin +/- Cediranib • Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Recurrence (CT or MRI verified), >6 m from prior platinum • GCIG (AGO, ANZGOG, GEICO, GINECO, NCIC, NSGO) Platinum-based therapy Oral Placebo daily, q 21d Placebo (18 m total) I x 6 2 Platinum-based therapy Oral Cediranib daily, q 21d Placebo (18 m total) II R x 6 3 3 Platinum-based therapy Oral Cediranib daily, q 21d Cediranib (18 m total) III x 6 Open: DEC-2007 Closed: DEC-2011 Target Accrual: 2000 pts (Actual 486) In SEP-2011, primary endpoint changed to PFS, with primary analysis limited between Arms I vs III, and a reduction in overall sample size Adverse events include increased hypertension, diarrhea, hypothyroidism, hemorrhage, proteinuria, and fatigue. LedermannJ. Presented at: European Cancer Congress, 2013. Abstract 10.

  50. ICON6: Overall SurvivalCarboplatin +/- Cediranib 1.00 CediranibCediranib (Maintenance) PlaceboPlacebo (Chemotherapy) Proportion Surviving 0.75 0.50 0.25 0.00 0 6 12 18 24 30 Months On-study LedermannJ. Presented at: European Cancer Congress, 2013. Abstract 10.