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 1.51 (95% CI: 0.99-2.31), p=0.055
ACRIN Gynecologic Committee
Adjusted RR 1.60 (95% CI: 1.03-2.48), p=0.038
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)
0
3%
0
Inner 1/3
(N= 281)
3%
5%
9%
Mid 1/3
(N=115)
0
9%
4%
Outer 1/3
(N= 139)
11%
19%
34%
ACRIN Gynecologic Committee
Distribution of Disease in Node (+) EM Patients
70
60
50
Creasman
Schorge
40
Onda
30
McMeekin
Otsuka
20
Katz
10
0
Pelvic Only Pel + PALN PALN only
Any PALN
Cancer 1987; Gyn Onc 1996; Br J Ca 1997,Gyn Onc 2001,Br J Ca 2002; Am J OB-GYN 2001
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)
ACRIN Gynecologic Committee
Survival Benefit Associated with
Extensive Lymphadenectomy
Percent Survival (%)
100
1-8 Nodes
9-16 Nodes
≥16 Nodes
75
(p=0.048)
0
0
50
150
100
Time (months)
ACRIN Gynecologic Committee
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%
200
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
• Combination of Rev.
• Role of fatigue
• Compare half days
• Accountability
• Authorship
• PACS system
• 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
Total abdominal hysterectomy,
bilateral salpingo-oopherectomy,
and abdominal & pelvic lymph
node sampling
Evidence of disease
outside of the pelvis or
abdominal nodal region on
PET/CT
Advanced
Lymph
adenopathy
not
amenable to
surgery
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
institutionalProtocol
treatment
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
?
?
???
DISCUSSION
 Possibility of review during accrual
 Suggestions to increase accrual
ACRIN Gynecologic Committee