1. ACRIN Abdominal Committee ACRIN Gynecologic Committee ACRIN 6671 GOG 0233 UPDATE ACRIN PI: M. ATRI GOG PI: M. GOLD

2. ACRIN Gynecologic Committee Lymph Node Evaluation  What is the utility of lymph node evaluation in:  Cervical Carcinoma  Endometrial Carcinoma

3. ACRIN Gynecologic Committee Cervical Carcinoma  Early stage – Any (+) LN  Lymph node metastases high risk factors for recurrence  Identifies population needing adjuvant chemoradiation

4. ACRIN Gynecologic Committee Early Stage Cervical Carcinoma Chemo-RT if one of the following: High Risk: Positive margin, parametrial extension, positive node (87% of CRT vs. 84% of RT) GOG 109 (Peters WA et. al.. J Clinic Oncol 18:1606-1613, 2000)GOG 109 (Peters WA et. al.. J Clinic Oncol 18:1606-1613, 2000) PFS 4-yr PFS 80% vs. 63%; p=0.003 OS 4-yr OS 81% vs. 71%; p=0.007

5. ACRIN Gynecologic Committee Cervical Carcinoma  Early stage – Any (+) LN  Lymph node metastases high risk factors for recurrence  Identifies population needing adjuvant chemoradiation  Locoregionally Advanced – (+) PA LN  Pelvic lymph nodes included in standard pelvic radiation field  Para-Aortic (Abdominal) lymph node metastases results in extended field primary chemoradiation

6. ACRIN Gynecologic Committee Locoregionally Advanced Cervical Carcinoma Risk of lymph node metastases increases with stage Stage % PALN (+) IB11.7 IB211.9 2A2.4-18.2 2B16.7-32.8 3A33.3 3B24.9-31.1 4A12.5-33

7. ACRIN Gynecologic Committee Impact of Para-Aortic Evaluation on Survival Adjusted RR 1.51 (95% CI: 0.99-2.31), p=0.055 Adjusted RR 1.60 (95% CI: 1.03-2.48), p=0.038 Adjusted RR 1.51 (95% CI: 0.99-2.31), p=0.055

8. ACRIN Gynecologic Committee Three-year Progression Free Interval & Overall Survival Importance of Detecting PALN Metastases

9. ACRIN Gynecologic Committee Endometrial Carcinoma  Any (+) Lymph Node  Lymph node metastases high risk factors for recurrence  Identifies population needing adjuvant chemotherapy  Avoids unnecessary post-operative treatment

10. ACRIN Gynecologic Committee Endometrial Carcinoma  Cannot reliably identify who does and does not have LN mets based on pathologic variables  Only 10% of (+) nodes are palpable  37% of nodal mets are < 2 mm  3-5% of “low risk” pts (+) nodes  In LN (+) patients, PALN involved in ~50%, only (+) site 8-17%

11. ACRIN Gynecologic Committee LN Mets in Endometrial Carcinoma Depth of Invasion Grade G1 (N= 180) G2 (N= 288) G3 (N= 153) Endo Only (N= 86) 03%0 Inner 1/3 (N= 281) 3%5%9% Mid 1/3 (N=115) 09%4% Outer 1/3 (N= 139) 11%19%34%

12. ACRIN Gynecologic Committee Distribution of Disease in Node (+) EM Patients Cancer 1987; Gyn Onc 1996; Br J Ca 1997,Gyn Onc 2001,Br J Ca 2002; Am J OB-GYN 2001

13. ACRIN Gynecologic Committee Endometrial Carcinoma  PALN failure reduced from 39 to 13% in pts undergoing LN resection (Corn, Int J RBP 1992;24:223)  Failure to sample systematically PLN/PALN leads to increased retroperitoneal failures (Chaung, Gyn Onc 1995;58:189)  Less failures, improved PFS/OS in patients undergoing PALND (Mariani, Gyn Onc 2000;76:348)

14. ACRIN Gynecologic Committee Survival Benefit Associated with Extensive Lymphadenectomy High Risk: Stage IB Grade 3 Stage IC Stage II Stage III Stage IV 5-Year DS Survival 1-8 Nodes:90.4% 9-16 Nodes:91.3% ≥16 Nodes:94.0% 0 50100 150200 100 75 0 Time (months) Percent Survival (%) (p=0.048) 1-8 Nodes 9-16 Nodes ≥16 Nodes Chan et al, Cancer 2006

15. ACRIN Gynecologic Committee Endometrial Carcinoma  GOG 33 - 621 Clinical Stage I patients  153 pts w/ G3 18% (+)PLN & 11% (+)PALN  97 pts w/ Cervical involvement 16% (+)PLN & 14% (+)PALN  GOG 210 – Restricted enrollment 947 patients  129 (13.6%) Stage IIIC  51 (5.4%) Stage IVB  University of Oklahoma – 607 staged patients  47 (8%) w/ (+) Lymph Nodes 43% (+)PLN / 40% (+)P&PALN / 17% (+)PALN

16. ACRIN Gynecologic Committee ACOG Practice Bulletin Management of Endometrial Cancer Number 65, August 2005 “Most women with endometrial cancer benefit from systematic surgical staging” “Staging is prognostic and facilitates targeted therapy to maximize survival and minimize the effects of under- treatment and over-treatment” “Retroperitoneal lymph node assessment is a critical component of surgical staging and is associated with improved survival” “Palpation of the retroperitoneum is an inaccurate measure and cannot substitute for surgical dissection of nodal tissue” Reaffirmed 2009

17. ACRIN Gynecologic Committee  COMBIDEX MRI review  Update on ACRIN6671/GOG0233 OUTLINE

18. ACRIN Gynecologic Committee  Interim analysis after 30 positive patients  Sensitivity > 60% to continue  Combidex provider stopped providing the agent in October 2009  New Amendment to include endometrial cancer  ACRIN/GOG approval to review Combidex MRI data COMBIDEX MRI REVIEW Study Protocol Requirement

19. ACRIN Gynecologic Committee COMBIDEX MRI REVIEW Study Protocol Requirement  Seven central readers  Initial training on 3 test cases  Submission and approval of forms  Two step review  Combidex insensitive sequence review Data submission and query  All sequence review

20. ACRIN Gynecologic Committee REVIEW PROCESS  5 NA, 2 European readers  All academic abdominal imagers  5/7 had experience with USPIO review  Effect of experience  3 at ACRIN headquarter, 4 at their institutions  Review process complete  Abstract submission to ASCO 2011

21. ACRIN Gynecologic Committee COMBIDEX MRI REVIEW Challenges (N: 33 Patients)  Reader selection  Handful of experienced readers  2 of more experienced readers dropped out/replaced  Difficult to bring reviewers to ACRIN headquarter  Difficult to entice them to meet timelines (5 months)  Long review process [3 days (3x8hrs)]

22. ACRIN Gynecologic Committee IMAGING REVIEW Literature  Pubmed & Google Scholar  Keywords  Imaging review  Imaging review and clinical trial  radiology review study  Off-site vs. On-site imaging review

23. ACRIN Gynecologic Committee NUMBER OF ARTICLES0 Tumour Size Measurement in an Oncology Clinical Trial: Comparison Between Off-site and On-site Measurements Clinical Radiology, 58:311

24. ACRIN Gynecologic Committee IMAGING REVIEW Questions  On-site vs. Off-site  Reviewer fatigue  Familiarity with PACS system  Role of experience  Role of sub-specialization  Reviewer accountability

25. ACRIN Gynecologic Committee IMAGING REVIEW Questions Role of experience Role of fatigue Accountability PACS system Combination of Rev. Compare half days Authorship ACRIN vs. Commercial

26. ACRIN Gynecologic Committee Evidence of disease outside of the pelvis or abdominal nodal region amenable to biopsy or sampling (i.e. intrahepatic, pulmonary, or thoracic or supraclavicular lymphadenopathy on PET/CT) No evidence of disease outside of the pelvis or abdominal nodal region amenable to biopsy or sampling (i.e. intrahepatic, pulmonary, or thoracic or supraclavicular lymphadenopathy on PET/CT) SCHEMA (ENDOMETRIUM) AdvancedLymph adenopathy not amenable to surgery Endometrial cancer patients eligible for lymphadenectomy Grade 3 endometrioid; clear-cell, serous papillary, or carcinosarcoma (any grade); and Grade 1 or 2 endometrioid with cervical stromal involvement overt on clinical examination or confirmed by endocervical curettage Pre-operative PET/CT Scan of the abdomen and pelvis and chest

27. ACRIN Gynecologic Committee Evidence of disease outside of the pelvis or abdominal nodal region on PET/CT No evidence of disease outside of pelvis or abdominal nodal region on PET/CT Lymphadenectomy abandoned, Chemotherapy Protocol for Advanced /Recurrent Disease Bx ( + ) Biopsy of metastatic disease outside of the pelvis or abdominal nodal region by FNA, core biopsy, or surgical biopsy Bx ( -) AdvancedLymph adenopathy not amenable to surgery Chemo-Radiation Therapy to start within four weeks of enrollment into the study Total abdominal hysterectomy, bilateral salpingo-oopherectomy, and abdominal & pelvic lymph node sampling SCHEMA (ENDOMETRIUM) Standard institutional treatment

28. ACRIN Gynecologic Committee ACRIN 6671/GOG 0233 UPDATE  Required sample size  Cervix165  Endometrium215  Number of accruing centers???  Number of accrued patients  Cervix?  Endometrium?

29. ACRIN Gynecologic Committee DISCUSSION  Possibility of review during accrual  Suggestions to increase accrual