ACRIN 6690
“A Prospective, Multicenter Comparison of
Multiphase Contrast-Enhanced CT (MCECT) and
Multiphase Contrast-Enhanced MRI (MCEMR)
for Diagnosis of Hepatocellular Carcinoma
and Liver Transplant Allocation”
Christoph Wald, M.D. Ph.D. , Lahey Clinic
Associate Professor of Radiology,
Tufts University School of Medicine
Background
• HCC and ESLD patient compete for deceased donor
liver transplants
• Imaging based HCC diagnosis can lead to exception
MELD points
• Performance of imaging under current UNOS/OPTN
policy was found to be poor (1)
• National consensus process and conference defined
new draft policy in 2008 (2)
• Details of draft policy form basis for trial hypotheses
• Trial tests new policy performance in real life clinical
setting
(1) Freeman, R. B., A. Mithoefer, et al. (2006). "Optimizing staging for hepatocellular carcinoma before liver transplantation: A retrospective
analysis of the UNOS/OPTN database." Liver Transpl 12(10): 1504-1511.
(2) Pomfret, E. A., K. Washburn, Wald, C. et al. (2010). "Report of a national conference on liver allocation in patients with hepatocellular
carcinoma in the United States." Liver Transpl 16(3): 262-278.
Hypotheses
• Modern imaging can accurately diagnose and stage HCC in
ESLD patients
• Focal liver lesions can be accurately assigned to premalignant and malignant diagnostic categories
• The false positive rate in the malignant lesion category can be
reduced from current unacceptable levels by utilizing the
criteria proposed in the new OPTN/UNOS liver imaging policy.
• MRI is the superior cross-sectional imaging method for
diagnosing HCC
• Imaging with CT or MRI can diagnose residual or recurrent
viable HCC after focal ablative therapy
New Draft UNOS/OPTN Classification System*
• Attemtps standardization of:
–
–
–
–
–
Equipment
Protocol
Diagnostic criteria
Nodule classification & terminology
Reader qualification
• Adopted for this trial to test new draft policy
*Pomfret, E. A., K. Washburn, Wald, C. et al. (2010). "Report of a national conference on liver allocation in patients
with hepatocellular carcinoma in the United States." Liver Transpl 16(3): 262-278.
UNOS/OPTN Class 0-4
[nondiagnostic – benign - pre-malignant]
UNOS/OPTN Class 5 - HCC
Application of draft imaging criteria
Primary Aim
• Compare sensitivity of multiphase contrastenhanced CT with multiphase contrast-enhanced
MR for diagnosing HCC.
• Primary analysis at the lesion level using core
laboratory imaging interpretations.
• A secondary analysis will be performed at the
patient level.
Secondary Aims
• Compare the PPV of CT to that of MRI for diagnosing HCC.
[Primary analysis at lesion level using core laboratory interpretations.
Secondary analysis at the patient level]
• Compare the lesion-level sensitivity and PPV of CT and MRI [as
interpreted by radiologists at the respective transplant centers]
• Compare sensitivity and specificity of MCE-CT versus MRI for
residual or recurrent HCC after local ablative therapy.
[Reference standard: explant path workup or Bx]
• Determine accuracy of imaging-based diagnosis/staging of HCC
with OPTN liver imaging criteria compared with explant path
diagnosis/staging
• Explore whether the comparisons of sensitivity and PPV are
affected by stratifying patients by AFP level (elevated vs normal)
• Assess sensitivity and PPV of MRI and CT interpreted at the
participating sites vs core lab interpretations [blinded, single
modality]
Other trial design features
• Cyclical serial imaging (CT and MR) ensures that
images are obtained ≤90 days to liver explant
• Single modality readers at sites strongly encouraged
to avoid cross-contamination
• Last imaging time point will be correlated 1:1 with
explant pathology
Trial Logistics Overview
Subject Enrollment: 440 participants
• This study will enroll from 11 UNOS/OPTN regions:
Quota of participants proportional to contribution of the
region to the national total of patients transplanted with HCCexception points.
• 32 sites are currently targeted and have received the
protocol and site participation packet.
– 16 sites have submitted the protocol specific
application (5 of the applications have been approved)
– 10 sites submitted test images
• Expected Activation: mid-late October 2010; based on site
readiness (IRB etc)
Trial Overview
After enrollment, centers must acquire MCE-imaging with the
complementary modality no later than 30 days after the
SOC imaging study [if initial diagnosis was made on CT, then MRI
or if initial diagnosis was made on MRI, then CT]
Subsequently, participants will undergo cyclical imaging with
both modalities in accordance with the 90-day update
UNOS requirement for HCC-exception points
Site Participation
• Test Image Qualification:
– Review and quality assessment at ACRIN Core lab
of:
3 MCE-CT scans and
3 MCE-MRI scans
sagittal and coronal reformats
– The qualifying scans are retrospectively selected at
centers
– Must have been performed on patients with HCC
– Must have been obtained during the previous 12
months on scanners of the vendor, model and
software platform intended for use in the trial.
Schema
HCC diagnosis by baseline CT or MRI
(SOC imaging at participating center)
Listing for liver transplantation with HCC-exception points and
enrolled in study
Local ablative
therapy
Complement imaging within 30 days of initial imaging
(SOC and complement CT and MRI imaging to be performed)
Imaging
Repeat serial imaging every 90 days
(CT and MRI)
Transplant surgery
Explant pathology analysis
(SOC + complement imaging, no less
than 28 days and no more than 60
days after completion of ablation)
Study Procedures
• Serial MCE-MR and MCE-CT imaging will be performed
at baseline within 30 days of the corresponding SOC
imaging at the expense of the trial to achieve the study
objectives.
• If a participant undergoes local ablative therapy after
enrollment, this study protocol requires imaging with both
CT and MRI 28 to 60 days after completion of treatment.
• Serial SOC and study-related complementary scans will
be performed at least every 90 days as required by the
UNOS guidelines for HCC-exception point updates.
Inclusion Criteria
• Must have at least one focal liver nodule compatible with
imaging diagnosis of T2 stage HCC (OPTN Class 5B liver
lesion) on MCE-CT and/or MCE-MRI
• Radiologic stage must be within Milan criteria*
• Patient must be listed on the regional OPTN/UNOS liver
transplant waitlist with HCC-exception MELD points
*Mazzaferro, V., E. Regalia, et al. (1996). "Liver transplantation for the treatment of small hepatocellular carcinomas
in patients with cirrhosis." N Engl J Med 334(11): 693-699.
Exclusion Criteria (selection)
• Radiologic disease stage beyond Milan criteria
[Evidence of extrahepatic tumor, or unifocal tumor mass > 5 cm in diameter
or multifocal tumors 4 or more in number, or multiple (3 or less) HCC with at
least one tumor exceeding 3 cm diameter]
• Any prior local ablative therapy to liver; prior
systemic [sorafenib] therapy
• Renal impairment [eGFR< 60 mL/min/1.73 m2 obtained within 28
days prior to registration]
• Not suitable to undergo MRI with an extracellular
gadolinium-based contrast agent that does not have
dominant hepatobiliary excretion
• [other…]
Explant Pathology Correlation
• Local pathologists will be provided with MPR images per their
preference for correlation
• Presence of a radiologist at time of explant analysis is strongly
encouraged
• All liver slices will be photographed on both sides and images
submitted to ACRIN
• Must identify, [photo-]document and sample all Class 4 and 5 lesions
described on imaging for 1:1 correlation
• Tumors will be designated with unique identifiers to allow one-to-one
correlation of radiologic and microscopic diagnoses on a per-nodule
basis.
• If no lesion is identified pathologically at the site of a radiologic lesion,
the segmental area of the radiologic lesion will be extensively
sampled according to the judgment of the local pathologist
End
• Questions?
Other opportunities
• Optional Eovist subtrial
• Radiation concern / MRI SOC
?Institutional perspective vs overall
[national] perspective