Adjuvant Therapy for Hepatocellular Carcinoma after Curative Resection or Transplant: Why Don

1
Adjuvant Therapy for Hepatocellular Carcinoma
after Curative Resection or Transplant Why Dont
We Do It?

• Carl R. Schmidt, MD, MSCI
• Assistant Professor of Surgery

2
Objectives

• Describe outcomes in HCC
• Rationale for adjuvant therapy
• Patient selection for adjuvant therapy
• Adjuvant therapy strategies

3
Outcomes in HCC Poor!
Survival N164
Recurrence N164
Cha JACS 2003
4
Choosing the best treatment strategy for HCC
HCC
ECOG 0-2, Child-Pugh A-B
ECOG gt 2, Child-Pugh C
ECOG 0, Child-Pugh A
Terminalstage
Intermediate stage
Very early stage
Early stage
Advanced stage
Single lt 5 cm, 2-3 3 cm, ECOG 0
Single lt 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
Liver transplant
Ablate
TACE
Resection
Curative treatments
Symptomatic (unless OLT)
Llovet JNCI 2008 Bruix Hepatology 2005
Not included single tumor gt 5 cm resection or
TACE
5
Choosing the best treatment strategy for HCC
HCC
ECOG 0-2, Child-Pugh A-B
ECOG gt 2, Child-Pugh C
ECOG 0, Child-Pugh A
Terminalstage
Intermediate stage
Very early stage
Early stage
Advanced stage
Single lt 5 cm, 2-3 3 cm, ECOG 0
Single lt 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
Liver transplant
Ablate
TACE
Resection
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
6
Multifocal tumors
1/5 alive at 3 years
N300, HCC gt 10 cm 5 centers of excellence
Pawlik Archives 2005
7
Major Vascular Invasion
23 alive at 5 years if minimal or no fibrosis
N100, HCC with major vascular invasion 5
centers of excellence
Pawlik Surgery 2004
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Objectives

• Describe outcomes in HCC
• Rationale for adjuvant therapy
• Patient selection for adjuvant therapy
• Adjuvant therapy strategies

9
Recurrence is Not Always Local
Lower risk after resection?
High Risk after TACE
Schmidt Curr Op in Org Trans 2010
Only three months later!
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The Field Effect of Cirrhosis

• Genes and outcome
• N 133 good
• N 73 poor
• Normal liver not tumor tissue
• Liver fx good
• Inflamm - poor

Hoshida NEJM 2008
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Circulating Tumor Cells
Yang Hepatobiliary Pancreat Dis Int. 2005
Ghossein Clin Can Res 1999
12
CTCs and metastatic disease
Portal vein thrombosis Extrahepatic disease Tumor
gt 5 cm Multiple tumor nodules
Yang Hepatobiliary Pancreat Dis Int. 2005
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Objectives

• Describe outcomes in HCC
• Rationale for adjuvant therapy
• Patient selection for adjuvant therapy
• Adjuvant therapy strategies

14
Which HCC are High Risk?

• Size gt 5 cm
• Major vascular invasion
• Poorly differentiated histology
• Infiltrating phenotype
• What about molecular phenotype?

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Molecular Biology is Important

• Fractional allelic imbalance (Pitt)
• LOH in tumor suppressor genes
• Increased recurrence after transplant

15 who might be candidates for adjuvant therapy
after transplant
Dvorchik Liver Transplantation 2008
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Tumor Biology and Therapy

• Tushar Patels lab used 81 human HCCs
• Gene signature associated with vascular invasion
• Computational bioinformatics reveals 3 potential
  candidates for therapy

Braconi Cancer 2005
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Objectives

• Describe outcomes in HCC
• Rationale for adjuvant therapy
• Patient selection for adjuvant therapy
• Adjuvant therapy strategies

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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 (P0.01)
• OS 67 vs 36 at 5 years (P0.04)

Lau Ann Surg 2008
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Adjuvant Chemotherapy

• Gemcitabine and cisplatin after resection
• Improved DSS 32 to 78 at 3 years
• Retrospective
• Adjuvant doxorubicin after transplant
• HCC gt 5 cm
• Bridging triple drug TACE prior
• 5-year survival 44

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Active Biologic Therapies

• Interferon-alpha
• Sorafenib
• S-1 (dehydropyrimidine dehydrogenase inhibitor)
• HSV-TK (virus)

21
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
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S-1 and Interferon-a

• S1 - oral DPD inhibitor
• N 12 patients with metastatic HCC
• OS 1-year 62
• Response 25

Nakamura Cancer 2008
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HSV-TK

• N 45 HCC gt 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
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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

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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

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Adjuvant Therapy for Hepatocellular Carcinoma
after Curative Resection or Transplant Why Dont
We Do It?

• Carl R. Schmidt, MD, MSCI
• Assistant Professor of Surgery