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Current role of adjuvant treatment after curative treatment of HCC

Current role of adjuvant treatment after curative treatment of HCC. Joint Hospital Surgical Grand Round Dr Arthur M. Y. Fung Caritas Medical Centre 19 th October, 2013. Overview. Only 10-30% of HCC are amenable to surgical resection 1 50-90% of post-op death is due to recurrent disease 2

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Current role of adjuvant treatment after curative treatment of HCC

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  1. Current role of adjuvant treatment after curative treatment of HCC Joint Hospital Surgical Grand Round Dr Arthur M. Y. Fung Caritas Medical Centre 19th October, 2013

  2. Overview • Only 10-30% of HCC are amenable to surgical resection1 • 50-90% of post-op death is due to recurrent disease2 • Sources of recurrence • Early recurrence (<2yr): intrahepatic metastasis of primary tumour • Late recurrence (>2yr): multicentric de-novo carcinogenesis • Objective of adjuvant treatment • Eradicate residual microscopic HCC foci • Prevent de-novo carcinogenesis 1. Zhong JH, Li H, Li LQ, You XM, Zhang Y, Zhao YN, et al. Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials. Eur J Surg Oncol. 2012 Apr;38(4):286-95. doi: 10.1016/j.ejso.2012.01.006. Epub Jan 24. 2. Lau WY, Lai EC, Lau SH. The current role of neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for hepatocellular carcinoma: a systematic review. Hepatobiliary Pancreat Dis Int. 2009 Apr;8(2):124-33.

  3. Treatment modalities covered • Transcatheter arterial chemoembolization • Intra-arterial lipiodol-Iodine-131 • Interferon • Nucleoside analogue

  4. Transcatheter arterial chemoembolization in HCC with portal vein tumour thrombus Peng BG, He Q, Li JP, Zhou F. Adjuvant transcatheter arterial chemoembolization improves efficacy of hepatectomy for patients with hepatocellular carcinoma and portal vein tumor thrombus. Am J Surg. 2009 Sep;198(3):313-8. doi: 10.1016/j.amjsurg.2008.09.026. Epub 9 Mar 12.

  5. Transcatheter arterial chemoembolization Zhong C, Guo RP, Li JQ, Shi M, Wei W, Chen MS, et al. A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for Stage III A hepatocellular carcinoma. J Cancer Res Clin Oncol. 2009 Oct;135(10):1437-45. doi: 10.007/s00432-009-0588-2. Epub 2009 May 1.

  6. Transarterial chemo-embolization

  7. Chen X, Zhang B, Yin X, Ren Z, Qiu S, Zhou J. Lipiodolized transarterial chemoembolization in hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol. 2013 May;139(5):773-81. doi: 10.1007/s00432-012-1343-7. Epub 2013 Feb 3.

  8. TACE • Subgroup benefits • Portal vein tumour thrombus (Peng et al.) • Stage IIIA HCC (Zhong et al.) • >5cm tumour with high risk features, recurrence within 2 years (Chen et al.) • Role • Early detection and treatment of residual tumour • ↓early recurrence • Overall survival benefit? • Conclusion: further trials needed

  9. Intra-arterial lipiodol – Iodine - 131

  10. DFS OS Lau WY, Leung TWT, Ho SKW, Chan M, Machin D, Lau J, et al. Adjuvant intra-arterial lipiodol-iodine-131 for resectable hepatocellular carcinoma: a prospective randomised trial. The Lancet. 1999;353(9155):797-801. Lau WY, Lai EC, Leung TW, Yu SC. Adjuvant intra-arterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial-update on 5-year and 10-year survival. Annals of surgery. 2008 Jan;247(1):43-8. PubMed PMID: 18156922.

  11. Chua TC, Saxena A, Chu F, Butler SP, Quinn RJ, Glenn D, et al. Hepatic resection with or without adjuvant iodine-131-lipiodol for hepatocellular carcinoma: a comparative analysis. Int J Clin Oncol. 2011 Apr;16(2):125-32. doi: 10.1007/s10147-010-0143-9.

  12. Interferon Adverse effects: Fever Chills Fatigue Myalgia Headache Leukocytopenia Thrombocytopenia Rare adverse effects: Elevated ALT Alopecia Depression Hyperthyroidism Delays cirrhosis Prevents 2nd tumour Inhibits micrometastasis

  13. Antiviral therapy - Interferon • Systematic review by Zhong et al. 2012 • 8 RCTs • Post-curative treatment (resection or local ablation) • Treatment group: 3-10 million units of IFN (intramuscular) • 2-year tumour recurrence and overall survival Zhong JH, Li H, Li LQ, You XM, Zhang Y, Zhao YN, et al. Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials. Eur J Surg Oncol. 2012 Apr;38(4):286-95. doi: 10.1016/j.ejso.2012.01.006. Epub Jan 24.

  14. Characteristics of included studies • ≥50% with cirrhosis • Mixed HBV and HCV population

  15. 2-year recurrence RR = 0.84 (95% CI 0.73 – 0.97, P = 0.02) • 2-year overall survival RR = 1.15 (95% CI 1.07 – 1.22, P< 0.001)

  16. Interferon – individual studies • Relative risk of death for interferon treatment = 0.42 (95% CI, 0.17–1.05; P0.063) • DFS • Fewer recurrence at 6 months in stage III/IVa • Non-significant overall Lo CM, Liu CL, Chan SC, Lam CM, Poon RT, Ng IO, et al. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg. 2007 Jun;245(6):831-42.

  17. OS • Stage I/II: no benefit • Stage III/IVA: improved 5-year survival from 24% to 68% (p = 0.038) • Multivariate analysis found pTNM stage was the only significant prognostic factor for survival • Side effects • 3/31 stopped • 22/31 required dose reduction

  18. Peg-interferon + Ribavirin on HCV related HCC Hsu YC, Ho HJ, Wu MS, Lin JT, Wu CY. Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma. Hepatology. 2013 Jul;58(1):150-7. doi: 10.1002/hep.26300. Epub 2013 May 15. Mortality Recurrence

  19. Interferon • Generalizability is in doubt • Systematic review: mixed HBV & HCV population • Lo et al. with HBV predominant population: only stage III/IVa benefit? • HCV related HCC: favourable • Further RCTs should target HBV & HCV population separately

  20. Nucleoside Analogue OS DFS

  21. Stage I, II tumours Stage III tumours DFS OS Chan AC, Chok KS, Yuen WK, Chan SC, Poon RT, Lo CM, et al. Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma. Arch Surg. 2011 Jun;146(6):675-81. doi: 10.1001/archsurg.2011.125.

  22. Without major vascular invasion With major vascular invasion OS DFS

  23. Wu C-Y. Association Between Nucleoside Analogues and Risk of Hepatitis B Virus–Related Hepatocellular Carcinoma Recurrence Following Liver Resection. Jama. 2012;308(18):1906.

  24. Controversial, benefit only in DFS / OS Harmful Beneficial

  25. Bring home message • TACE: areas of further RCTs • Portal vein tumour thrombus • Stage IIIA HCC • >5cm tumour with high risk features, recurrence within 2 years • I-131: beneficial, but need larger RCTs • Interferon • Beneficial for HCV • Separate HBV & HCV studies are needed • Nucleoside analogue • Beneficial for HBV • Clarify its role in early vs. advanced stage HCC

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