Time-to-Interventional Failure as a New Surrogate Measure for Survival Outcomes after Resection of Hepatocellular Carcinoma

  • Junichi ShindohEmail author
  • Yusuke Kawamura
  • Yuta Kobayashi
  • Norio Akuta
  • Masahiro Kobayashi
  • Yoshiyuki Suzuki
  • Kenji Ikeda
  • Masaji Hashimoto
2019 SSAT Plenary Presentation



This study sought to investigate the clinical impact of repeated interventions for recurrent hepatocellular carcinoma (HCC) and to establish a new surrogate measure for survival: the time-to-interventional failure (TIF).


Based on a retrospective review of 1158 patients who underwent curative resection for HCC, the abilities of recurrence-free survival (RFS) and TIF, which was defined as the elapsed time from resection to unresectable/unablatable recurrence, to predict overall survival (OS) were compared.


Within a median follow-up period of 84.9 months, 676 (59.0%) recurrence events occurred, 78.1% of which were resectable/ablatable recurrences. Of these, 99.1% of the patients underwent repeated treatments. TIF had a stronger correlation than RFS (r = 0.921 vs. r = 0.631) in prediction of OS. Patients who underwent curative-intent treatment (i.e., resection or ablation) for recurrence showed significantly better survival outcomes compared with those who underwent non-curative treatment (e.g., TACE, chemotherapy) (median OS, 89.1 months vs. 55.0 months; P < 0.0001). This tendency was constant across the AJCC stages and multivariate analysis confirmed that curative-intent treatment is associated with improved survival after initial recurrence (hazard ratio, 0.55; 95% CI, 0.37–0.81; P = 0.003).


OS after HCC resection is more strongly dependent on TIF than on RFS. Aggressive curative-intent interventions for recurrent HCC may prolong survival regardless of the cancer stage.


Hepatocellular carcinoma Surgery RFA TACE Survival 


Author Contribution

Study design: Shindoh, Kawamura

Acquisition of data: All authors

Analysis and interpretation of data: Shindoh, Kawamura, Kobayashi Y

Drafting the manuscript: All authors

Final approval: All authors


This study is supported by the institutional research grand for clinical study at Toranomon Hospital.

Compliance with Ethical Standards

The Institutional Review Board of Toranomon Hospital approved this study protocol (No. 1438).

Conflict of Interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011 Mar;53(3):1020–2.CrossRefGoogle Scholar
  2. 2.
    Kudo M, Izumi N, Kokudo N, Matsui O, Sakamoto M, Nakashima O, et al. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Digestive diseases. 2011;29(3):339–64.CrossRefGoogle Scholar
  3. 3.
    Belghiti J, Panis Y, Farges O, Benhamou JP, Fekete F. Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg. 1991 Aug;214(2):114–7.CrossRefGoogle Scholar
  4. 4.
    Grazi GL, Ercolani G, Pierangeli F, Del Gaudio M, Cescon M, Cavallari A, et al. Improved results of liver resection for hepatocellular carcinoma on cirrhosis give the procedure added value. Ann Surg. 2001 Jul;234(1):71–8.CrossRefGoogle Scholar
  5. 5.
    Imamura H, Matsuyama Y, Miyagawa Y, Ishida K, Shimada R, Miyagawa S, et al. Prognostic significance of anatomical resection and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma. Br J Surg. 1999 Aug;86(8):1032–8.CrossRefGoogle Scholar
  6. 6.
    Kakazu T, Makuuchi M, Kawasaki S, Miyagawa S, Hashikura Y, Kosuge T, et al. Repeat hepatic resection for recurrent hepatocellular carcinoma. Hepatogastroenterology. 1993 Aug;40(4):337–41.Google Scholar
  7. 7.
    Nakajima Y, Ko S, Kanamura T, Nagao M, Kanehiro H, Hisanaga M, et al. Repeat liver resection for hepatocellular carcinoma. J Am Coll Surg. 2001 Mar;192(3):339–44.CrossRefGoogle Scholar
  8. 8.
    Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 2002 Mar;235(3):373–82.CrossRefGoogle Scholar
  9. 9.
    Mise Y, Hasegawa K, Shindoh J, Ishizawa T, Aoki T, Sakamoto Y, et al. The Feasibility of Third or More Repeat Hepatectomy for Recurrent Hepatocellular Carcinoma. Ann Surg. 2015 Aug;262(2):347–57.CrossRefGoogle Scholar
  10. 10.
    Meniconi RL, Komatsu S, Perdigao F, Boelle PY, Soubrane O, Scatton O. Recurrent hepatocellular carcinoma: a Western strategy that emphasizes the impact of pathologic profile of the first resection. Surgery. 2015 Mar;157(3):454–62.CrossRefGoogle Scholar
  11. 11.
    Yang W, Chen MH, Wang MQ, Cui M, Gao W, Wu W, et al. Combination therapy of radiofrequency ablation and transarterial chemoembolization in recurrent hepatocellular carcinoma after hepatectomy compared with single treatment. Hepatol Res. 2009 Mar;39(3):231–40.CrossRefGoogle Scholar
  12. 12.
    Oba M, Hasegawa K, Matsuyama Y, Shindoh J, Mise Y, Aoki T, et al. Discrepancy between recurrence-free survival and overall survival in patients with resectable colorectal liver metastases: a potential surrogate endpoint for time to surgical failure. Ann Surg Oncol. 2014 Jun;21(6):1817–24.CrossRefGoogle Scholar
  13. 13.
    Makuuchi M, Kosuge T, Takayama T, Yamazaki S, Kakazu T, Miyagawa S, et al. Surgery for small liver cancers. Semin Surg Oncol. 1993 Jul-Aug;9(4):298–304.CrossRefGoogle Scholar
  14. 14.
    Kobayashi Y, Kiya Y, Sugawara T, Nishioka Y, Hashimoto M, Shindoh J. Expanded Makuuchi's criteria using estimated indocyanine green clearance rate of future liver remnant as a safety limit for maximum extent of liver resection. HPB (Oxford). 2019 Jan 30.Google Scholar
  15. 15.
    Shindoh J, Kawamura Y, Kobayashi Y, Kiya Y, Sugawara T, Akuta N, et al. Platelet-Albumin Score as a Sensitive Measure for Surgical Risk Prediction and Survival Outcomes of Patients with Hepatocellular Carcinoma. J Gastrointest Surg. 2019 Jan;23(1):76–83.CrossRefGoogle Scholar
  16. 16.
    Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017 Jul;11(4):317–70.CrossRefGoogle Scholar
  17. 17.
    Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003 Dec 6;362(9399):1907–17.CrossRefGoogle Scholar
  18. 18.
    Kudo M, Trevisani F, Abou-Alfa GK, Rimassa L. Hepatocellular Carcinoma: Therapeutic Guidelines and Medical Treatment. Liver Cancer. 2016 Nov;6(1):16–26.CrossRefGoogle Scholar
  19. 19.
    Chan AC, Poon RT, Cheung TT, Chok KS, Chan SC, Fan ST, et al. Survival analysis of re-resection versus radiofrequency ablation for intrahepatic recurrence after hepatectomy for hepatocellular carcinoma. World J Surg. 2012 Jan;36(1):151–6.CrossRefGoogle Scholar
  20. 20.
    Song KD, Lim HK, Rhim H, Lee MW, Kim YS, Lee WJ, et al. Repeated Hepatic Resection versus Radiofrequency Ablation for Recurrent Hepatocellular Carcinoma after Hepatic Resection: A Propensity Score Matching Study. Radiology. 2015 May;275(2):599–608.CrossRefGoogle Scholar
  21. 21.
    Ho CM, Lee PH, Shau WY, Ho MC, Wu YM, Hu RH. Survival in patients with recurrent hepatocellular carcinoma after primary hepatectomy: comparative effectiveness of treatment modalities. Surgery. 2012 May;151(5):700–9.CrossRefGoogle Scholar
  22. 22.
    Wang DY, Liu L, Qi XS, Su CP, Chen X, Liu X, et al. Hepatic Re-resection Versus Transarterial Chemoembolization for the Treatment of Recurrent Hepatocellular Carcinoma after Initial Resection: a Systematic Review and Meta-analysis. Asian Pac J Cancer Prev. 2015;16(13):5573–8.CrossRefGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2019

Authors and Affiliations

  • Junichi Shindoh
    • 1
    • 2
    Email author
  • Yusuke Kawamura
    • 3
  • Yuta Kobayashi
    • 1
  • Norio Akuta
    • 3
  • Masahiro Kobayashi
    • 3
  • Yoshiyuki Suzuki
    • 3
  • Kenji Ikeda
    • 3
  • Masaji Hashimoto
    • 1
  1. 1.Hepatobiliary-pancreatic Surgery Division, Department of Gastroenterological SurgeryToranomon HospitalTokyoJapan
  2. 2.Okinaka Memorial Institute for Medical DiseaseTokyoJapan
  3. 3.Department of HepatologyToranomon HospitalTokyoJapan

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