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Adjuvant Therapy for Hepatocellular Carcinoma after Curative Resection or Transplant: Why Don’t We Do It?. Carl R. Schmidt, MD, MSCI Assistant Professor of Surgery. Objectives. Describe outcomes in HCC Rationale for adjuvant therapy Patient selection for adjuvant therapy
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Adjuvant Therapy for Hepatocellular Carcinoma after Curative Resection or Transplant: Why Don’t We Do It? Carl R. Schmidt, MD, MSCI Assistant Professor of Surgery
Objectives Describe outcomes in HCC Rationale for adjuvant therapy Patient selection for adjuvant therapy Adjuvant therapy strategies
Outcomes in HCC – Poor! Survival N=164 Recurrence N=164 Cha JACS 2003
Choosing the best treatment strategy for HCC HCC ECOG 0, Child-Pugh A ECOG 0-2, Child-Pugh A-B ECOG > 2, Child-Pugh C Very early stage Early stage Intermediate stage Advanced stage Terminalstage Single < 5 cm, 2-3 ≤ 3 cm, ECOG 0 Single < 2 cm N1 or M1 Vascular invasion Extrahepatic disease Multifocal disease Single 3 nodules ≤ 3 cm Portal HTN/bilirubin OLT candidate Increased Normal No Yes Sorafenib Resection Liver transplant Ablate TACE “Curative” treatments Symptomatic (unless OLT) Llovet JNCI 2008 Bruix Hepatology 2005 Not included: single tumor > 5 cm – resection or TACE
Choosing the best treatment strategy for HCC HCC ECOG 0, Child-Pugh A ECOG 0-2, Child-Pugh A-B ECOG > 2, Child-Pugh C Very early stage Early stage Intermediate stage Advanced stage Terminalstage Single < 5 cm, 2-3 ≤ 3 cm, ECOG 0 Single < 2 cm N1 or M1 Vascular invasion Extrahepatic disease Multifocal disease Single 3 nodules ≤ 3 cm Portal HTN/bilirubin OLT candidate Increased Normal No Yes Sorafenib Resection Liver transplant Ablate TACE Symptomatic (unless OLT) Surgical treatments: applicable overall to 10% to 15% of HCC at first diagnosis and 2% to 5% of recurrent HCC Nonsurgical treatments: applicable overall to 65% to 75% of HCC at first diagnosis and 50% to 70% of recurrent HCC
Multifocal tumors 1/5 alive at 3 years N=300, HCC > 10 cm 5 centers of excellence Pawlik Archives 2005
Major Vascular Invasion 23% alive at 5 years if minimal or no fibrosis N=100, HCC with major vascular invasion 5 centers of excellence Pawlik Surgery 2004
Objectives Describe outcomes in HCC Rationale for adjuvant therapy Patient selection for adjuvant therapy Adjuvant therapy strategies
Recurrence is Not Always Local Lower risk after resection? High Risk after TACE Schmidt Curr Op in Org Trans 2010 Only three months later!
The Field Effect of Cirrhosis Hoshida NEJM 2008 • Genes and outcome • N = 133 good • N = 73 poor • Normal liver not tumor tissue • Liver fx – good • Inflamm - poor
Circulating Tumor Cells Yang Hepatobiliary Pancreat Dis Int. 2005 Ghossein Clin Can Res 1999
CTCs and metastatic disease Portal vein thrombosis Extrahepatic disease Tumor > 5 cm Multiple tumor nodules Yang Hepatobiliary Pancreat Dis Int. 2005
Objectives Describe outcomes in HCC Rationale for adjuvant therapy Patient selection for adjuvant therapy Adjuvant therapy strategies
Which HCC are High Risk? Size > 5 cm Major vascular invasion Poorly differentiated histology Infiltrating phenotype What about molecular phenotype?
Molecular Biology is Important 15% who might be candidates for adjuvant therapy after transplant Dvorchik Liver Transplantation 2008 Fractional allelic imbalance (Pitt) LOH in tumor suppressor genes Increased recurrence after transplant
Tumor Biology and Therapy Tushar Patel’s lab used 81 human HCC’s Gene signature associated with vascular invasion Computational bioinformatics reveals 3 potential candidates for therapy Braconi Cancer 2005
Objectives Describe outcomes in HCC Rationale for adjuvant therapy Patient selection for adjuvant therapy Adjuvant therapy strategies
Adjuvant Regional Therapy • Prospective RCT • One dose 131I-Lipiodol (arterial) 6 weeks after resection HCC • Randomization stopped early due to benefit • Median TTR 19 vs 7 months (P=0.01) • OS 67% vs 36% at 5 years (P=0.04) Lau Ann Surg 2008
Adjuvant Chemotherapy • Gemcitabine and cisplatin after resection • Improved DSS 32% to 78% at 3 years • Retrospective • Adjuvant doxorubicin after transplant • HCC > 5 cm • Bridging triple drug TACE prior • 5-year survival 44%
Active Biologic Therapies • Interferon-alpha • Sorafenib • S-1 (dehydropyrimidine dehydrogenase inhibitor) • HSV-TK (virus)
Sorafenib Clinical Trials: Two open at OSU for adjuvant sorafenib STORM – after “curative” resection or ablation SPACE – with TACE P.I. Mark Bloomston Llovet NEJM 2009
S-1 and Interferon-α S1 - oral DPD inhibitor N = 12 patients with metastatic HCC OS 1-year = 62% Response = 25% Nakamura Cancer 2008
HSV-TK N = 45 HCC > 5cm Liver transplant (LT) vs. LT + adjuvant ADV-TK RFS 3 yrs 44% vs. 9% OS 3 yrs 70% vs. 20% Li Clin Cancer Res 2007
Summary • There are safe and efficacious adjuvant therapies available to patients with high risk HCC after resection or transplant • The most promising strategies include regional and biologic therapies
Conclusions • Advances in adjuvant therapies are critical to improving outcomes in HCC after potentially curative therapies, and we might already consider some of these approaches • Prospective trials are critical for evaluation of each new therapy to guide patient selection and to demonstrate efficacy
Adjuvant Therapy for Hepatocellular Carcinoma after Curative Resection or Transplant: Why Don’t We Do It? Carl R. Schmidt, MD, MSCI Assistant Professor of Surgery