Tumor Biology

, Volume 37, Issue 7, pp 9301–9310 | Cite as

Total tumor volume predicts survival following liver resection in patients with hepatocellular carcinoma

  • Mu-xing Li
  • Hong Zhao
  • Xin-yu Bi
  • Zhi-yu Li
  • Zhen Huang
  • Yue Han
  • Jian-guo Zhou
  • Jian-jun Zhao
  • Ye-fan Zhang
  • Wen-qiang Wei
  • Dong-bin Zhao
  • Jian-qiang Cai
Original Article


Assessing the prognosis of patients with hepatocellular carcinoma (HCC) by the number and size of tumors is sometimes difficult. The main purpose of the study was to evaluate the prognostic value of total tumor volume (TTV), which combines the two factors, in patients with HCC who underwent liver resection. We retrospectively reviewed 521 HCC patients from January 2001 to December 2008 in our center. Patients were categorized using the tertiles of TTV. The prognostic value of TTV was assessed. With a median follow-up of 116 months, the 1-, 3-, and 5-year overall survival (OS) rates of the patients were 93.1 , 69.9, and 46.3 %, respectively. OS was significantly differed by TTV tertile groups, and higher TTV was associated with shorter OS (P < 0.001). Multivariate analysis revealed that TTV was an independent prognostic factor for OS. Larger TTV was significantly associated with higher alpha-fetoprotein level, presence of macrovascular invasion, multiple tumor lesions, larger tumor size, and advanced tumor stages (all P < 0.05). Within the first and second tertiles of TTV (TTV ≤ 73.5 cm3), no significant differences in OS were detected in patients within and beyond Milan criteria (P = 0.183). TTV-based Cancer of the Liver Italian Program (CLIP) score gained the lowest Akaike information criterion value, the highest χ 2 value of likelihood ratio test, and the highest C-index among the tested staging systems. Our results suggested that TTV is a good indicator of tumor burden in patients with HCC. Further studies are warranted to validate the prognostic value of TTV.


Total tumor volume Tumor burden Hepatocellular carcinoma Prognosis 



Hepatocellular carcinoma


Liver resection


Total tumor volume


Hepatitis B virus


Hepatitis C virus






Barcelona Clinic Liver Cancer stage


Cancer of the Liver Italian Program


Akaike information criterion



This study was funded by the National High-Tech R&D (863) Program of China (2015AA020408), the National Natural Science Foundation of China (81201967), the Beijing Natural Science Foundation (7144238), and Beijing Nova Program (No. 2009A69).

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: a Cancer J Clin. 2015;65(1):5–29.Google Scholar
  2. 2.
    Singal AG, El-Serag HB. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin Gastroenterol Hepatol. 2015;13(12):2140–51.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55.CrossRefPubMedGoogle Scholar
  4. 4.
    de Martel C, Maucort-Boulch D, Plummer M, Franceschi S. World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma. Hepatology. 2015;62(4):1190–200.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Santi V, Buccione D, Di Micoli A, Fatti G, Frigerio M, Farinati F, et al. The changing scenario of hepatocellular carcinoma over the last two decades in Italy. J Hepatol. 2012;56(2):397–405.CrossRefPubMedGoogle Scholar
  6. 6.
    Altekruse SF, McGlynn KA, Dickie LA, Kleiner DE. Hepatocellular carcinoma confirmation, treatment, and survival in surveillance, epidemiology, and end results registries, 1992–2008. Hepatology. 2012;55(2):476–82.CrossRefPubMedGoogle Scholar
  7. 7.
    Bolondi L, Burroughs A, Dufour JF, Galle PR, Mazzaferro V, Piscaglia F, et al. Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis. 2012;32(4):348–59.PubMedGoogle Scholar
  8. 8.
    Zhong JH, Ke Y, Gong WF, Xiang BD, Ma L, Ye XP, et al. Hepatic resection associated with good survival for selected patients with intermediate and advanced-stage hepatocellular carcinoma. Ann Surg. 2014;260(2):329–40.CrossRefPubMedGoogle Scholar
  9. 9.
    Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology. 2002;35(3):519–24.CrossRefPubMedGoogle Scholar
  10. 10.
    Nathan H, Hyder O, Mayo SC, Hirose K, Wolfgang CL, Choti MA, et al. Surgical therapy for early hepatocellular carcinoma in the modern era: a 10-year SEER-Medicare analysis. Ann Surg. 2013;258(6):1022–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Fonseca AL, Cha CH. Hepatocellular carcinoma: a comprehensive overview of surgical therapy. J Surg Oncol. 2014;110(6):712–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Mazzaferro V, Lencioni R, Majno P. Early hepatocellular carcinoma on the procrustean bed of ablation, resection, and transplantation. Semin Liver Dis. 2014;34(4):415–26.CrossRefPubMedGoogle Scholar
  13. 13.
    Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamamoto J, Kosuge T, Saiura A, Sakamoto Y, Shimada K, Sano T, et al. Effectiveness of hepatic resection for early-stage hepatocellular carcinoma in cirrhotic patients: subgroup analysis according to Milan criteria. Jpn J Clin Oncol. 2007;37(4):287–95.CrossRefPubMedGoogle Scholar
  15. 15.
    Ng KK, Vauthey JN, Pawlik TM, Lauwers GY, Regimbeau JM, Belghiti J, et al. Is hepatic resection for large or multinodular hepatocellular carcinoma justified? Results from a multi-institutional database. Ann Surg Oncol. 2005;12(5):364–73.CrossRefPubMedGoogle Scholar
  16. 16.
    Toso C, Meeberg G, Hernandez-Alejandro R, Dufour JF, Marotta P, Majno P, et al. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: a prospective validation. Hepatology. 2015;62(1):158–65.CrossRefPubMedGoogle Scholar
  17. 17.
    Toso C, Trotter J, Wei A, Bigam DL, Shah S, Lancaster J, et al. Total tumor volume predicts risk of recurrence following liver transplantation in patients with hepatocellular carcinoma. Liver Transpl. 2008;14(8):1107–15.CrossRefPubMedGoogle Scholar
  18. 18.
    Macaron C, Hanouneh IA, Lopez R, Aucejo F, Zein NN. Total tumor volume predicts recurrence of hepatocellular carcinoma after liver transplantation in patients beyond Milan or UCSF criteria. Transplant Proc. 2010;42(10):4585–92.CrossRefPubMedGoogle Scholar
  19. 19.
    Lee YH, Hsia CY, Hsu CY, Huang YH, Lin HC, Huo TI. Total tumor volume is a better marker of tumor burden in hepatocellular carcinoma defined by the Milan criteria. World J Surg. 2013;37(6):1348–55.CrossRefPubMedGoogle Scholar
  20. 20.
    Edge SB. American Joint Committee on Cancer. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.Google Scholar
  21. 21.
    A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology. 1998;28(3):751–5.Google Scholar
  22. 22.
    Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(3):329–38.CrossRefPubMedGoogle Scholar
  23. 23.
    Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer. 1985;56(4):918–28.CrossRefPubMedGoogle Scholar
  24. 24.
    Hosmer DW, Hosmer T, Le Cessie S, Lemeshow S. A comparison of goodness-of-fit tests for the logistic regression model. Stat Med. 1997;16(9):965–80.CrossRefPubMedGoogle Scholar
  25. 25.
    Newson RB. Comparing the predictive powers of survival models using Harrell’s C or Somers’ D. Stata J. 2010;10(3):339–58.Google Scholar
  26. 26.
    Forster MR. Key concepts in model selection: performance and generalizability. J Math Psychol. 2000;44(1):205–31.CrossRefPubMedGoogle Scholar
  27. 27.
    Jung YK, Jung CH, Seo YS, Kim JH, Kim TH, Yoo YJ et al. BCLC stage B is a better designation for single large hepatocellular carcinoma than BCLC stage A. Journal of gastroenterology and hepatology. 2015.Google Scholar
  28. 28.
    Nanashima A, Tobinaga S, Kunizaki M, Miuma S, Taura N, Takeshita H, et al. Strategy of treatment for hepatocellular carcinomas with vascular infiltration in patients undergoing hepatectomy. J Surg Oncol. 2010;101(7):557–63.CrossRefPubMedGoogle Scholar
  29. 29.
    Bertino G, Neri S, Bruno CM, Ardiri AM, Calvagno GS, Malaguarnera M, et al. Diagnostic and prognostic value of alpha-fetoprotein, des-gamma-carboxy prothrombin and squamous cell carcinoma antigen immunoglobulin M complexes in hepatocellular carcinoma. Minerva Med. 2011;102(5):363–71.PubMedGoogle Scholar
  30. 30.
    Lee YH, Hsu CY, Huang YH, Su CW, Lin HC, Hsia CY, et al. Alpha-fetoprotein-to-total tumor volume ratio predicts post-operative tumor recurrence in hepatocellular carcinoma. J Gastrointest Surg. 2013;17(4):730–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. The Cancer of the Liver Italian Program (CLIP) investigators. Hepatology. 2000;31(4):840–5.Google Scholar
  32. 32.
    Marrero JA, Kudo M, Bronowicki JP. The challenge of prognosis and staging for hepatocellular carcinoma. Oncologist. 2010;15 Suppl 4:23–33.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Mu-xing Li
    • 1
  • Hong Zhao
    • 1
  • Xin-yu Bi
    • 1
  • Zhi-yu Li
    • 1
  • Zhen Huang
    • 1
  • Yue Han
    • 2
  • Jian-guo Zhou
    • 1
  • Jian-jun Zhao
    • 1
  • Ye-fan Zhang
    • 1
  • Wen-qiang Wei
    • 3
  • Dong-bin Zhao
    • 1
  • Jian-qiang Cai
    • 1
  1. 1.Department of Abdominal Surgical Oncology, Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College (CAMS and PUMC)BeijingPeople’s Republic of China
  2. 2.Department of Interventional Therapies, Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College (CAMS and PUMC)BeijingPeople’s Republic of China
  3. 3.Department of Cancer EpidemiologyCancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS and PUMC)BeijingPeople’s Republic of China

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