ACRIN Gynecologic Committee

1. ACRIN Gynecologic Committee Fall Meeting 2010

2. CT Perfusion Study of Ovarian Cancer ACRIN 6695 Project Team

3. Study Schedule Regimen I: Cycle1 (All cycles 3 weeks in length) Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 RANDOMI ZE Ovarian cancer: suboptimally debulked (e.g. > 1 cm tumor left behind Surgically) Carboplatin AUC 6 IV day 1 every cycle x 6 cycles Paclitaxel 175 mg/m2 IV Day 1 every cycle x 6 cycles Bevacizumab 15 mg/kg IV day 1 every cycle starting cycle 2 and continuing beyond cycle 6 until progression or adverse effects preclude further treatment Regimen II: Cycle1 (All cycles 3 weeks in length) Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Carboplatin AUC 6 IV day 1 every cycle x 6 cycles Paclitaxel 80 mg/m2 IV days 1, 8 and 15 every cycle x 6 cycles Bevacizumab 15 mg/kg IV day 1 every cycle starting cycle 2 and continuing beyond cycle 6 until progression or adverse effects preclude further treatment Perfusion CT intermediate (T1) at end of 1st cycle between 18-21 days Reproducibility Perfusion CT A subgroup of patients will be studied Follow-up RECIST CT scans after cycle 3,6,14,22 After completion of all protocol therapy, every 3 months for 2 years, then every 6 months for 3 years, then annually Baseline RECIST CT scan & Perfusion CT Baseline (T0) At least 3 weeks post surgery and within 4 weeks prior to initiating protocol chemotherapy Perfusion CT (T2) After one week into cycle 2

4. CT Perfusion Study Protocol • Scout to define limits of localization scan • Localization scan • Use site abdominal scan protocol • Define limits of tumor, either 4 or 8 cm slab • If follow-up study, try locate the same tumor slices as the initial baseline study • CT Perfusion scan as per protocol • GE Healthcare scanner - non axial shuttle mode • GE Healthcare scanner – axial shuttle mode • Toshiba Aquilion One scanner • No breath-hold, patient is instructed to breath normally during scan • Contrast dose • 0.7 ml per kg body weight up to a max of 65 ml • Injection rate 3-4 ml per second • Radiation dose • 4 cm coverage : 9.5 mSv • 8 cm coverage : 16.8 mSV

5. CT Perfusion Scan Protocol • 64-slice CT scanner with 40 mm wide detector array without toggling table mode 40 axial scans @ 2.8 - 3 s intervals: 120 kVp; 100 mA; 8 x 5 mm slices; 0.4 s rotation period 0s 3 6 9 12 114 117 120s 1 2 3 4           38 39 40            Inject 300 – 370 mgI/ml contrast 0.8 ml/kg @ 3 – 4 ml/s Effective Dose = 7.2 mSv Skin dose = 150 mGy

6. CT Perfusion Scan Protocol • 64-slice CT scanner with 40 mm wide detector array with toggling table mode 40 passes @ 2.8 - 3 s intervals: 120 kVp; 100 mA; 16 x 5 mm slices; 0.4 s rotation period 0s 3 6 9 12 114 117 120s 1 2 3 4           38 39 40            Inject 300 – 370 mgI/ml contrast 0.8 ml/kg @ 3 – 4 ml/s Effective Dose = 14.3 mSv Skin dose = 150 mGy

7. CT Perfusion Scan Protocol • 128-slice CT scanner with 80 mm wide detector array 40 axial scans @ 2.8 - 3 s intervals: 120 kVp; 100 mA; 16 x 5 mm slices; 0.4 s rotation period 0s 3 6 9 12 114 117 120s 1 2 3 4           38 39 40            Inject 300 – 370 mgI/ml contrast 0.8 ml/kg @ 3 – 4 ml/s Effective Dose = 14.3 mSv Skin dose = 150 mGy

8. CT Perfusion Scan Protocol • 256-slice CT scanner with 120 mm wide detector array 40 axial scans @ 2.8 - 3 s intervals: 120 kVp; 100 mA; 20 x 5 mm slices; 0.4 s rotation period 0s 3 6 9 12 114 117 120s 1 2 3 4           38 39 40            Inject 300 – 370 mgI/ml contrast 0.8 ml/kg @ 3 – 4 ml/s Effective Dose = 17.8 mSv Skin dose = 150 mGy

9. CT Perfusion Scan Protocol • 320-slice CT scanner with 160 mm wide detector array 40 axial scans @ 2.8 - 3 s intervals: 120 kVp; 100 mA; 24 x 5 mm slices; 0.4 s rotation period 0s 3 6 9 12 114 117 120s 1 2 3 4           38 39 40            Inject 300 – 370 mgI/ml contrast 0.8 ml/kg @ 3 – 4 ml/s Effective Dose = 21.4 mSv Skin dose = 150 mGy

10. Average AVG Blood Flow BF BV Blood Volume PS PS Deconvolution with physiol model Example CT Perfusion Scan of Prostate Effective dose 21 mSv Intravenous Injection of Contrast Agent 60-70 ml @ 3-4 ml/s Scan Protocol Each scan: 16 x 5 mm slices @ 80 kVp and 50 mAs 1 scan every 2.8 s 42 scans

11. Primary Objective • To determine whether larger changes in the tumor perfusion parameters (BF, BV, MTT, PS) from baseline T0 to T2 are predictive of higher progression-free survival (PFS) rate at 6 months in patients treated with weekly paclitaxel regimen or every-3-week paclitaxel regimen, who are receiving carboplatin with or without bevacizumab

12. Secondary Objectives • To determine whether larger changes in tumor perfusion parameters from baseline T0 to T1 are predictive of higher progression-free survival (PFS) rate at 6 months in patients treated with weekly paclitaxel regimen or every-3-week paclitaxel regimen, who are receiving carboplatin with or without bevacizumab • To determine whether larger changes in tumor perfusion parameters values from T0 to T1, T0 to T2 and T1 to T2 are predictive of better overall survival in all treatment arms. • To assess the association between changes in tumor perfusion parameters before and after chemotherapy and subsequent best tumor response according to standard anatomic response evaluation criteria (RECIST). • To assess the association between tumor perfusion parameters before chemotherapy and subsequent best tumor response according to standard anatomic response evaluation criteria (RECIST), progression free survival at 6 months and overall survival. • To test the assumption that tumor perfusion parameters are reliable, user-independent and reproducible parameters of tumor microvascular characteristics. A subgroup of 15 patients will have repeat CT Perfusion studies at T1 to achieve this objective

13. Radiation Risk • Radiation Dose • Effective dose • Research plus normal care – 87.2 mSv • Annual background – 3.0 mSv • Cancer induction and fatality risk • BEIR VII report • Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation, National Research Council

14. Questions ?