ACRIN 6673 MULTICENTER FEASIBILITY STUDY OF PERCUTANEOUS RADIOFREQUENCY ABLATION OF HEPATOCELLULAR CARCINOMA IN CIRRHOTIC PATIENTS Final Report from Central Review Data

6673 RFA of HCC Protocol Team – Gerald Dodd, III, MD (Principal Investigator) – Fenghai Duan, PhD (Statistician) – Damian Dupuy, MD (Radiologist) – Glenn Halff, MD (Surgical Oncologist) – David Lu, MD (Radiologist) – Shahla Masood, MD (Central Pathologist) – Anthony Shields, MD, PhD (Oncologist)

6673 RFA of HCC ACRIN Staff – Lisa Cimino (Imaging) – Vincent Girardi (Biostatistician) – Jeremy Gorelick (Biostatistician) – Donna Hartfeil (Project Manager) – Benjamin Herman (Biostatistician) – Mary Kelly-Trunan (Regulatory) – Anthony Levering (Imaging) – Robin McCall (Imaging) – Maria Oh, (Protocol Development) – Josephine Schloesser (Regulatory) – Chris Steward (Regulatory) – Tina Taylor (Data Manager)

6673 RFA of HCC University of Texas, Health Science Center, San Antonio / Gerald Dodd, III, MD University of California, Los Angeles / David Lu, MD Rhode Island Hospital / Damian Dupuy, MD Hospital of the University of Pennsylvania / Aalpen Patel, MD University of Massachusetts Medical Center, Worcester / Sri Shankar, MD Cedar Sinai Medical Center / Peter Julien, MD and Frank Moser, MD Mayo Clinic, Rochester / Matthew Callstrom, MD, PhD Medical College of Wisconsin / Sean Tutton, MD University of Wisconsin / Fred Lee, MD University of Texas, MD Anderson / Kamran Ahrar, MD University of North Carolina / Robert Dixon, MD University of Alabama, Birmingham / J. Kevin Smith, MD Scott and White Clinic and Hospital, Texas / Mark Montgomery, MD University of California, Davis / John McGahan, MD 14 Participating Centers

6673 RFA of HCC Primary study objective: To estimate the proportion of patients undergoing solitary or repetitive percutaneous RFA treatment sessions whose livers have no identifiable tumor by CT scan at 18 months following initiation of therapy

6673 RFA of HCC Some secondary study objectives: –Aim: Effects of tumor size, local recurrence, remote occurrence, whether or not repeated RFA, etc. on success rate at 18-month Notations: –Local intrahepatic tumor: tumor was treated but seen again at the ablated site – Remote intrehepatic tumor: new tumor was seen but remote from the ablated site(s).

6673 RFA of HCC Enrollment Criteria –Cirrhosis –MELD Score < 15 –HCC = 1-3 tumors < 3cm, or 1 tumor > 3 and < 5cm –No previous treatment for HCC

6673 RFA of HCC Treatment –Percutaneous radiofrequency ablation Ablations permitted from enrollment through 15th month Single vendor RFA unit (Covidien) Standardized ablation protocol

6673 RFA of HCC Follow-up –3 phase CT Prior to treatment Immediately after ablation Every 3-months through 18 months post ablation

6673 RFA of HCC Central review –To determine the presence/absence of tumor –Scans were divide into two equal batches and were reviewed by one of the two central readers. –Discrepancy from the local read were adjudicated by the other central reader.

6673 RFA of HCC Results –45 Eligible patients enrolled 29 men, 16 women Average age 61 (range, 40 to 81) –Number of tumors 1 = 39 2 = 4 3 = 2

6673 RFA of HCC Results –Patient status 33 dropped out prior to completion 12 patients completed study

6673 RFA of HCC Results –Patient status 33 dropped out prior to completion –15 were transplanted –5 died –5 withdrew from the study –7 started nonprotocol treatment –1 developed an extrahepatic tumor

6673 RFA of HCC Results –Patient status 15 were transplanted –4 had tumor on last CT »2 had a local tumor »2 had a remote tumor –11 had no tumor

6673 RFA of HCC Results –Patient status 5 patients died –2 had tumor on last CT and was the cause of death for 2 of those –3 had no tumor 7 patients had non-protocol treatment –7 had tumor on last CT –0 had no tumor

6673 RFA of HCC Results –Patient status 12 patients completed study –8 = 1 ablation –2 = 2 ablations –2= 3 ablations

6673 RFA of HCC Results –Patient status 12 patients completed study –Tumor status on 18 month CT »10 = no tumor at treated sites (83%) »8 = tumor free (67%) »2 = local intrahepatic tumor (17%) »4 = remote intrahepatic tumor (33% )

6673 RFA of HCC Results –Aim: control disease at 18 months Out of 45 patients, 8 patients who completed study without tumor –success rate = 8/45 (18%) (95% Exact CI: 0.08, 0.32) Only 12 patients who made it to 18 months –success rate = 8/12 (67%) (95% Exact CI: 0.35, 0.90)

6673 RFA of HCC Results –Aim: control disease at 18 months or successful bridge to transplant Including the previous 8 tumor-free patients at 18 months plus 15 patients who made it to transplant –success rate = 23/45(51%) (95% Exact CI: 36%, 66%)

6673 RFA of HCC Results

6673 RFA of HCC Results –Local tumor control Out of 60 ablated tumors, 36 were never seen again. –Local control rate = 36/60 (60%) (95% Exact CI: 0.47, 0.72)

6673 RFA of HCC Results Median time to recurrence is 12 months (95% CI: 6 – 18 months)