ACRIN 6671 GOG 0233 UPDATE

ACRIN PI: M. ATRI GOG PI: M. GOLD

ACRIN Abdominal Committee

ACRIN Gynecologic Committee

Lymph Node Evaluation

What is the utility of lymph node evaluation in:
Cervical Carcinoma Endometrial Carcinoma

ACRIN Gynecologic Committee

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

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)
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)

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
ACRIN Gynecologic Committee

Locoregionally Advanced Cervical Carcinoma

Risk of lymph node metastases increases with stage

Stage IB1 IB2 2A 2B 3A 3B 4A

% PALN (+) 1.7 11.9 2.4-18.2 16.7-32.8 33.3 24.9-31.1 12.5-33

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

ACRIN Gynecologic Committee

Importance of Detecting PALN Metastases

Three-year Progression Free Interval & Overall Survival

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

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%

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)

Inner 1/3 (N= 281) Mid 1/3 (N=115) Outer 1/3 (N= 139)

0
3% 0

3%
5% 9%

0
9% 4%

11%

19%

34%

ACRIN Gynecologic Committee

Distribution of Disease in Node (+) EM Patients

70 60 50 40 30 20 10 0 Pelvic Only Pel + PALN PALN only
ACRIN Gynecologic Committee

Creasman Schorge
Onda

McMeekin Otsuka
Katz

Any PALN

Cancer 1987; Gyn Onc 1996; Br J Ca 1997,Gyn Onc 2001,Br J Ca 2002; Am J OB-GYN 2001

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)
ACRIN Gynecologic Committee

Survival Benefit Associated with Extensive Lymphadenectomy

100 Percent Survival (%)

1-8 Nodes 9-16 Nodes 16 Nodes

75

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 0 50

(p=0.048)
150 100 Time (months) 200

ACRIN Gynecologic Committee

Chan et al, Cancer 2006

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

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 undertreatment 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 ACRIN Gynecologic Committee

OUTLINE

COMBIDEX MRI review Update on ACRIN6671/GOG0233

ACRIN Gynecologic Committee

COMBIDEX MRI REVIEW Study 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
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

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
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)]
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

ACRIN Gynecologic Committee

NUMBER OF ARTICLES

0
Tumour Size Measurement in an Oncology Clinical Trial: Comparison Between Off-site and On-site Measurements Clinical Radiology, 58:311
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

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

ACRIN Gynecologic Committee

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

Pre-operative PET/CT Scan of the abdomen and pelvis and chest

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)
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)

Advanced Lymph adenopathy not amenable to surgery

SCHEMA (ENDOMETRIUM)
No evidence of disease outside of pelvis or abdominal nodal region on PET/CT Evidence of disease outside of the pelvis or abdominal nodal region on PET/CT Advanced Lymph adenopathy not amenable to surgery

Total abdominal hysterectomy, bilateral salpingo-oopherectomy, and abdominal & pelvic lymph node sampling

Biopsy of metastatic disease Bx (-) outside of the pelvis or abdominal nodal region by FNA, core biopsy, or surgical biopsy
Bx (+)

Lymphadenectomy Chemo-Radiation Therapy abandoned, Chemotherapy to start within four weeks Standard institutional treatment Protocol for Advanced of enrollment into the /Recurrent Disease study
ACRIN Gynecologic Committee

ACRIN 6671/GOG 0233 UPDATE

Required sample size
Cervix Endometrium 165
215

Number of accruing centers Number of accrued patients

Cervix Endometrium
ACRIN Gynecologic Committee

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DISCUSSION

Possibility of review during accrual Suggestions to increase accrual

ACRIN Gynecologic Committee