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ACRIN 6671 GOG 0233 UPDATE ACRIN PI: M. ATRI GOG PI: M. GOLD

ACRIN 6671 GOG 0233 UPDATE ACRIN PI: M. ATRI GOG PI: M. GOLD. Lymph Node Evaluation. What is the utility of lymph node evaluation in: Cervical Carcinoma Endometrial Carcinoma. Cervical Carcinoma. Early stage – Any (+) LN Lymph node metastases high risk factors for recurrence

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ACRIN 6671 GOG 0233 UPDATE ACRIN PI: M. ATRI GOG PI: M. GOLD

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  1. ACRIN 6671 GOG 0233 UPDATEACRIN PI: M. ATRIGOG PI: M. GOLD

  2. Lymph Node Evaluation • What is the utility of lymph node evaluation in: • Cervical Carcinoma • Endometrial Carcinoma

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

  4. 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) PFS OS 4-yr PFS 80% vs. 63%; p=0.003 4-yr OS 81% vs. 71%; p=0.007 • GOG 109 (Peters WA et. al. . J Clinic Oncol 18:1606-1613, 2000)

  5. 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. Locoregionally Advanced Cervical Carcinoma Risk of lymph node metastases increases with stage

  7. 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. Importance of Detecting PALN Metastases Three-year Progression Free Interval & Overall Survival

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

  10. 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. LN Mets in Endometrial Carcinoma

  12. 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. 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. Survival Benefit Associated withExtensive Lymphadenectomy 1-8 Nodes 9-16 Nodes ≥16 Nodes 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% 100 Percent Survival (%) 75 (p=0.048) 0 150 200 50 100 0 Time (months) Chan et al, Cancer 2006

  15. 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. ACOG Practice BulletinManagement of Endometrial CancerNumber 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. OUTLINE • COMBIDEX MRI review • Update on ACRIN6671/GOG0233

  18. COMBIDEX MRI REVIEWStudy Protocol Requirement • 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

  19. COMBIDEX MRI REVIEWStudy 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. 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. COMBIDEX MRI REVIEWChallenges (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. IMAGING REVIEWLiterature • Pubmed & Google Scholar • Keywords • Imaging review • Imaging review and clinical trial • radiology review study • Off-site vs. On-site imaging review

  23. NUMBER OF ARTICLES 0 Tumour Size Measurement in an Oncology Clinical Trial: Comparison Between Off-site and On-site MeasurementsClinical Radiology, 58:311

  24. IMAGING REVIEWQuestions • On-site vs. Off-site • Reviewer fatigue • Familiarity with PACS system • Role of experience • Role of sub-specialization • Reviewer accountability

  25. IMAGING REVIEWQuestions • Combination of Rev. • Compare half days • Authorship • ACRIN vs. Commercial • Role of experience • Role of fatigue • Accountability • PACS system

  26. Pre-operative PET/CT Scan of the abdomen and pelvis and chest 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) Advanced Lymph adenopathy not amenable to surgery SCHEMA (ENDOMETRIUM) 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

  27. Total abdominal hysterectomy, bilateral salpingo-oopherectomy, and abdominal & pelvic lymph node sampling Biopsy of metastatic disease outside of the pelvis or abdominal nodal region by FNA, core biopsy, or surgical biopsy Bx (-) Bx (+) Lymphadenectomy abandoned, Chemotherapy Protocol for Advanced /Recurrent Disease Chemo-Radiation Therapy to start within four weeks of enrollment into the study SCHEMA (ENDOMETRIUM) Advanced Lymph adenopathy not amenable to surgery 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 Standard institutional treatment

  28. ACRIN 6671/GOG 0233 UPDATE • Required sample size • Cervix 165 • Endometrium 215 • Number of accruing centers ??? • Number of accrued patients • Cervix ? • Endometrium ?

  29. DISCUSSION • Possibility of review during accrual • Suggestions to increase accrual

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