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

ACRIN Abdominal Committee

ACRIN Gynecologic Committee

ACRIN 6671 GOG 0233 UPDATE

ACRIN PI: M. ATRIGOG 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 Identifies population needing adjuvant

chemoradiation


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


Cervical Carcinoma

Early stage – Any (+) LN Lymph node metastases high risk factors for


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


Locoregionally Advanced Cervical Carcinoma

Risk of lymph node metastases increases with stage

StageStage % PALN (+)% PALN (+)

IB1IB1 1.71.7

IB2IB2 11.911.9

2A2A 2.4-18.22.4-18.2

2B2B 16.7-32.816.7-32.8

3A3A 33.333.3

3B3B 24.9-31.124.9-31.1

4A4A 12.5-3312.5-33


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=0.038Adjusted RR 1.51 (95% CI: 0.99-2.31), p=0.055


Three-year Progression Free Interval & Overall Survival

Importance of Detecting PALN Metastases


Endometrial Carcinoma

Any (+) Lymph Node Lymph node metastases high risk factors for


chemotherapy Avoids unnecessary post-operative treatment



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%


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%


Distribution of Disease in Node (+) EM Patients

0

10

20

30

40

50

60

70

Pelvic Only Pel + PALN PALN only Any PALN

Creasman

Schorge

Onda

McMeekin

Otsuka

Katz

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



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)


Survival Benefit Associated withExtensive Lymphadenectomy

High Risk:Stage IB

Grade 3Stage ICStage IIStage IIIStage IV

5-Year DS Survival1-8 Nodes: 90.4%9-16 Nodes: 91.3%≥16 Nodes: 94.0%

0 50 100 150 200

100

75

0

Time (months)

Per

cen

t S

urv

ival

(%

)

(p=0.048)

1-8 Nodes9-16 Nodes≥16 Nodes

Chan et al, Cancer 2006



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


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


COMBIDEX MRI review

Update on ACRIN6671/GOG0233

OUTLINE


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 REVIEWStudy Protocol Requirement


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


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


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)]


IMAGING REVIEWLiterature

Pubmed & Google Scholar

Keywords Imaging review

Imaging review and clinical trial

radiology review study

Off-site vs. On-site imaging review


NUMBER OF ARTICLES

00Tumour Size Measurement in an Oncology Clinical Trial: Comparison Between Off-site and On-site MeasurementsClinical Radiology, 58:311


IMAGING REVIEWQuestions

On-site vs. Off-site Reviewer fatigue

Familiarity with PACS system

Role of experience

Role of sub-specialization

Reviewer accountability


IMAGING REVIEWQuestions

• Role of experience

• Role of fatigue

• Accountability

• PACS system

• Combination of Rev.

• Compare half days

• Authorship

• ACRIN vs. Commercial


Evidence of disease outside Evidence of disease outside of the pelvis or abdominal of the pelvis or abdominal nodal region amenable to nodal region amenable to biopsy or sampling (i.e. biopsy or sampling (i.e.

intrahepatic, pulmonary, or intrahepatic, pulmonary, or thoracic or supraclavicular thoracic or supraclavicular

lymphadenopathy on lymphadenopathy on PET/CT)PET/CT)

No evidence of disease outside of No evidence of disease outside of the pelvis or abdominal nodal the pelvis or abdominal nodal region amenable to biopsy or region amenable to biopsy or

sampling (i.e. intrahepatic, sampling (i.e. intrahepatic, pulmonary, or thoracic or pulmonary, or thoracic or

supraclavicular lymphadenopathy supraclavicular lymphadenopathy on PET/CT)on PET/CT)

SCHEMA (ENDOMETRIUM)SCHEMA (ENDOMETRIUM)

AdvancedAdvancedLymphLymph

adenopathy adenopathy notnot

amenable to amenable to surgery surgery

Endometrial cancer patients eligible for lymphadenectomyEndometrial cancer patients eligible for lymphadenectomyGrade 3 endometrioid; clear-cell, serous papillary, or carcinosarcoma Grade 3 endometrioid; clear-cell, serous papillary, or carcinosarcoma

(any grade); and Grade 1 or 2 endometrioid with cervical stromal (any grade); and Grade 1 or 2 endometrioid with cervical stromal involvement overt on clinical examination involvement overt on clinical examination

or confirmed by endocervical curettage or confirmed by endocervical curettage

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


Evidence of disease outside Evidence of disease outside of the pelvis or abdominal of the pelvis or abdominal nodal region on PET/CTnodal region on PET/CT

No evidence of disease outside ofNo evidence of disease outside ofpelvis or abdominal nodal region pelvis or abdominal nodal region

on PET/CTon PET/CT

Lymphadenectomy Lymphadenectomy abandoned, Chemotherapy abandoned, Chemotherapy

Protocol for Advanced Protocol for Advanced

/Recurrent Disease/Recurrent Disease

Bx (+)

Biopsy of metastatic disease Biopsy of metastatic disease outside of the pelvis or outside of the pelvis or

abdominal nodal region by abdominal nodal region by FNA, core biopsy, or surgical FNA, core biopsy, or surgical

biopsybiopsy

Bx (-)

AdvancedAdvancedLymphLymph

adenopathy adenopathy notnot

amenable to amenable to surgerysurgery

Chemo-Radiation Therapy Chemo-Radiation Therapy to start within four weeks to start within four weeks

of enrollment into the of enrollment into the studystudy

Total abdominal hysterectomy, Total abdominal hysterectomy, bilateral salpingo-oopherectomy, bilateral salpingo-oopherectomy,

and abdominal & pelvic lymph and abdominal & pelvic lymph node samplingnode sampling

SCHEMA (ENDOMETRIUM)SCHEMA (ENDOMETRIUM)

Standard institutional treatmentStandard institutional treatment


ACRIN 6671/GOG 0233 UPDATE

Required sample size Cervix 165 Endometrium 215

Number of accruing centers ??? Number of accrued patients

Cervix ? Endometrium ?


DISCUSSION

Possibility of review during accrual

Suggestions to increase accrual

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

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