ACRIN 6690

1. 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

2. 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 • 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. • 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.

3. Hypotheses • Modern imaging can accurately diagnose and stage HCC in ESLD patients • Focal liver lesions can be accurately assigned to pre-malignant 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

4. 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.

5. UNOS/OPTN Class 0-4 [nondiagnostic – benign - pre-malignant]

6. UNOS/OPTN Class 5 - HCC

7. Application of draft imaging criteria

8. Compare sensitivity of multiphase contrast-enhanced 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. Primary Aim

9. 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] Secondary Aims

10. 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

11. 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 HCC-exception 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 Logistics Overview

12. 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 Trial Overview

13. Test Image Qualification: Review and quality assessment at ACRIN Core lab of:3 MCE-CT scans and3 MCE-MRI scanssagittal 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. Site Participation

14. 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 (SOC + complement imaging, no less than 28 days and no more than 60 days after completion of ablation) Repeat serial imaging every 90 days (CT and MRI) Transplant surgery Explant pathology analysis

15. 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. Study Procedures

16. 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 Inclusion Criteria *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.

17. 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…] Exclusion Criteria (selection)

18. 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 Explant Pathology Correlation

19. End • Questions?

20. Other opportunities • Optional Eovist subtrial • Radiation concern / MRI SOC ?Institutional perspective vs overall [national] perspective