Complex treatment of hepatocellular carcinoma at early (BCLC-A) and intermediate (BCLC-B) stages

Аim. Evaluation of the effectiveness of hepatocellular carcinoma treatment at early BCLC-A and intermediate BCLC-B stages by the combined use of liver resections and locoregional therapy.

Materials and methods. The study included 142 patients with hepatocellular carcinoma. At the BCLC-A stage – 46 observations, at the BCLC-B stage – 96 observations. Chronic hepatitis and cirrhosis of various etiologies were detected in 58 (40.8%) patients. Liver resection of various volumes, transarterial chemoembolization and radiofrequency ablation were used for treatment. With the tumor progression and the ineffectiveness of locoregional therapy, targeted therapy was prescribed.

Results. Four groups of patients were identified depending on treatment tactics. In group 1, 28 patients underwent radical liver resections; in group 2, 37 patients underwent preoperative transarterial chemoembolization and liver resection. In group 3, 63 patients underwent therapeutic transarterial chemoembolization and radiofrequency ablation. In group 4, 14 patients underwent transarterial chemoembolization followed by hepatic arterial infusion of chemotherapy and targeted therapy. Overall survival in groups 1 and 2 significantly exceeds survival rates in groups 3 and 4. The median overall survival in groups 1–4 was 39, 37.5, 19.5, and 7.5 months (p_1–3 = 0.0001 ; p_1–4 = 0.0009, p_2–3 = 0.018 , p _2–4 = 0.001). The cumulative one, three and five year survival rates in groups 1 and 2 did not significantly differ (87.8% and 80.0%, 82.5% and 75.0%, 68.2% and 58.0%, 54.5% and 41.0%, respectively, p1–2 = 0.076). However, group 1 consisted exclusively of patients with BCLC-A stages with solitary tumors less than 6.5 cm in diameter, group 2 included large BCLC-A tumors and multiple tumors BCLC-B stages (67.6%).

Conclusion. For the treatment of patients with hepatocellular carcinoma BCLC-A and BCLC-B stages, a multimodal approach should be applied, including differential use and a rational combination of regional chemotherapy and resection techniques, taking into account the functional state of the liver.

1. European Association for the Study of the Liver, European Organization for Research and Treatment of Cancer. EASLEORTC Clinical Practice Guidelines: management of hepatocellular carcinoma. J. Hepatol. 2012; 56 (4): 908–943. PMID: 22424438. https://doi.org/10.1016/j.jhep.2011.12.001

2. Chen M.S., Li J.Q., Zheng Y., Guo R.P., Liang H.H., Zhang Y.Q., Lin X.J., Lau W.Y. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann. Surg. 2006; 243 (3): 321–328. PMID: 16495695. PMCID: PMC1448947. https://doi.org/10.1097/01.sla.0000201480.65519.b8

3. Huang J., Yan L., Cheng Z., Wu H., Du L., Wang J., Xu Y., Zeng Y. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann. Surg. 2010; 252 (6): 903–912. PMID: 21107100. https://doi.org/10.1097/SLA.0b013e3181efc656

4. Lee H.W., Lee J.M., Yoon J.H., Kim Y.J., Park J.W., Park S.J., Kim S.H., Yi N.J., Suh K.S. A prospective randomized study comparing radiofrequency ablation and hepatic resection for hepatocellular carcinoma. Ann. Surg. Treat. Res. 2018; 94 (2): 74–82. PMID: 29441336. PMCID: PMC5801331. https://doi.org/10.4174/astr.2018.94.2.74

5. Siddique O., Yoo E.R., Perumpail R.B., Perumpail B.J., Liu A., Cholankeril G., Ahmed A. The importance of a multidisciplinary approach to hepatocellular carcinoma. J. Multidiscip. Healthc. 2017; 10: 95–100. https://doi.org/10.2147/JMDH.S128629

6. Zhaohui Z., Shunli S., Bin C., Shaoqiang L., Yunpeng H., Ming K., Lijian L., Gang P.B. Hepatic resection provides survival benefit for selected intermediate-stage (BCLC-B) hepatocellular carcinoma patients. Cancer Res. Treat. 2019; 51 (1): 65–72. https://doi.org/10.4143/crt.2018.038

7. Choi S.H., Choi G.H., Kim S.U., Park J.Y., Joo D.J., Ju M.K., Kim M.S., Choi J.S., Han K.H., Kim S.I. Role of surgical resection for multiple hepatocellular carcinomas. World J. Gastroenterol. 2013; 19 (3): 366–374. https://doi.org/10.3748/wjg.v19.i3.366

8. Zhong J.H., Ke Y., Gong W.F., Xiang B.D., Ma L., Ye X.P., Peng T., Xie G., Li L. Hepatic resection associated with good survival for selected patients with intermediate and advancedstage hepatocellular carcinoma. Ann. Surg. 2014; 260 (2): 329–340. https://doi.org/10.1097/SLA.0000000000000236

9. Zhu S.L., Ke Y., Peng Y.C., Ma L., Li Н., Li L.Q., Zhong J.H. Comparison of long-term survival of patients with solitary large hepatocellular carcinoma of BCLC stage a after liver resection or transarterial chemoembolization: a propensity score analysis. PLoS ONE. 2014; 9 (12): e115834. https://doi.org/10.1371/journal.pone.0115834

10. Bellissimo F., Pinzone M.R., Cacopardo B., Nunnari G. Diagnostic and therapeutic management of hepatocellular carcinoma. World J. Gastroenterol. 2015; 21 (42): 12003–12021. https://doi.org/10.3748/wjg.v21.i42.12003

11. Bruix J., Gores G.J., Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014; 63 (5): 844–855. PMID: 24531850. https://doi.org/10.1136/gutjnl-2013-306627

12. Zlokachestvennye opuholi [specvypusk zhurnala]: prakticheskie rekomendacii Rossijskogo obshchestva klinicheskoj onkologii. Lekarstvennoe lechenie zlokachestvennyh opuholej. Podderzhivayushchaya terapiya v onkologii pod redakciej V.M. Moiseenko [Malignant tumors [special issue of the journal]: practical recommendations of the Russian Society of Clinical Oncology. Drug therapy of malignant tumors. Maintenance therapy in oncology, edited by V.M. Moiseenko]. Moscow: All-Russian public organization “Russian Society of Clinical Oncology”, Moscow, 2019. 776 p. (In Russian)

13. Bruix J., Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011; 53 (3): 1020–1022. PMID: 21374666. PMCID: PMC3084991. https://doi.org/10.1002/hep.24199

14. Dutkowski P., Linecker M., DeOliveira M., Mu llhaupt B., Clavien P.A. Challenges to liver transplantation and strategies to improve outcomes. Gastroenterology. 2015; 148 (2): 307–323. PMID: 25224524. https://doi.org/10.1053/j.gastro.2014.08.045

15. Kow A.W.C. Transplantation versus liver resection in patients with hepatocellular carcinoma. Transl. Gastroenterol. Hepatol. 2019; 17; 4:33. eCollection 2019. PMID: 31231700. PMCID: PMC6556690. https://doi.org/10.21037/tgh.2019.05.06

16. Yang H.J., Lee J.H., Lee D.H., Yu S.J., Kim Y.J., Yoon J.H., Kim H.C., Lee J.M., Chung J.W., Yi N.J., Lee K.W., Suh K.S., Lee H.S. Small single-nodule hepatocellular carcinoma: comparison of transarterial chemoembolization, radiofrequency ablation, and hepatic resection by using inverse probability weighting. Radiology. 2014; 271 (3): 909–918. PMID: 24520944. https://doi.org/10.1148/radiol.13131760

17. Raza A., Sood G.K. Hepatocellular carcinoma review: Current treatment, and evidence-based medicine. World J. Gastroenterol. 2014; 20 (15): 4115–4127. PMID: 24764650. PMCID: PMC3989948. https://doi.org/10.3748/wjg.v20.i15.4115

18. Qi X., Wang D., Su C., Li H., Guo X. Hepatic resection versus transarterial chemoembolization for the initial treatment of hepatocellular carcinoma: a systematic review and metaanalysis. Oncotarget. 2015; 6 (21): 18715–18733. https://doi.org/10.18632/oncotarget.4134

19. Meguro M., Mizuguchi T., Nishidate T., Okita K., Ishii M., Ota S., Ueki T., Akizuki E., Hirata K. Prognostic Roles of preoperative α-fetoprotein and des-γ-carboxy prothrombin in hepatocellular carcinoma patients. World J. Gastroenterol. 2015; 21 (16): 4933–4945. PMID: 25945007. PMCID: PMC4408466. https://doi.org/10.3748/wjg.v21.i16.4933

20. Rungsakulkij N., Suragul W., Mingphruedhi S., Tangtawee P., Muangkaew P., Aeesoa S. Prognostic factors in patients with HBV-related hepatocellular carcinoma following hepatic resection. Infect. Agent. Cancer. 2018; 13 (20): 1–13. PMID: 29930697. PMCID: PMC5994073. https://doi.org/10.1186/s13027-018-0192-7

21. Zhang D.Z., Wei X.D., Wang X.P. Comparison of hepatic resection and transarterial chemoembolization for solitary hepatocellular carcinoma. World J. Gastroenterol. 2015; 21 (15): 4635–4643. https://doi.org/10.3748/wjg.v21.i15.4635

22. Chang W.T., Kao W.Y., Chau G.Y., Su C.W., Lei H.J., Wu J.C., Hsia C.Y., Lui W.Y., King K.L., Lee S.D. Hepatic resection can provide long-term survival of patients with non-early-stage hepatocellular carcinoma: extending the indication for resection? Surgery. 2012; 152 (5): 809–820. PMID: 22766361. https://doi.org/10.1016/j.surg.2012.03.024

23. Bolondi L., Burroughs A., Dufour J.F., Galle P.R., Mazzaferro V., Piscaglia F., Raoul J.L., Sangro B. Heterogeneity of patients with intermediate (BCLC-B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis. 2012; 32 (4): 348–359. PMID: 23397536. https://doi.org/10.1055/s-0032-1329906

24. Adhoute X., Penaranda G., Raoul J.L., Bourliere M. Hepatocellular carcinoma scoring and staging systems. Do we need new tools? J. Hepatol. 2016; 64 (6): 1449–1450. PMID: 26912407. https://doi.org/10.1016/j.jhep.2016.01.038

25. Arizumi T., Ueshima K., Iwanishi M., Minami T., Chishina H., Kono M., Takita M., Kitai S., Inoue T., Yada N., Hagiwara N., Ida H.,Minami Y., Sakurai T., Kitano M., Nishida N., Kudo M. Validation of a modified substaging system (Kinki Criteria) for patients with intermediate-stage hepatocellular carcinoma. Oncology. 2015; 89 (Suppl 2): 47–52. PMID: 26584036. https://doi.org/10.1159/000440631

26. Ciria R., Lopez-Cillero P., Gallardo A.B., Cabrera J., Pleguezuelo M., Ayllon M.D., Luque A., Zurera L., Espejo J.J., Rodríguez-Perálvarez M., Montero J.L., de la Mata M., Briceño J. Optimizing the management of patients with BCLC stage-B hepatocellular carcinoma: modern surgical resection as a feasible alternative to transarterial chemoemolization. Eur. J. Surg. Oncol. 2015; 41 (9): 1153–1161. PMID: 26118317. https://doi.org/10.1016/j.ejso.2015.05.023

27. Farinati F., Vanin V., Giacomin A., Pozzan C., Cillo U., Vitale A., Di Nolfo A.M., Del Poggio P., Benvegnu L. , Rapaccini G., Zoli M., Borzio F., Giannini E.G., Caturelli E., Trevisani F., Italian Liver Cancеr (ITA.LI.CA) group. BCLC stage B hepatocellular carcinoma and transcatheter arterial chemoembolization: a 20-year survey by the Italian Liver Cancer group. Liver Int. 2015; 35 (1): 223–231. PMID: 25074434. https://doi.org/10.1111/liv.12649

28. Kudo M., Arizumi T., Ueshima K., Sakurai T., Kitano M., Nishida N. Subclassification of BCLC B stage hepatocellular carcinomа and treatment strategies: proposal of modified Bolondi's subclassification (Kinki Criteria). Dig. Dis. 2015; 33 (6): 751–758. PMID: 26488473. https://doi.org/10.1159/000439290

29. Yin L., Li H., Li A.J., Lau W.Y., Pan Z.Y., Lai E.C., Wu M.C., Zhou W.P. Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan Criteria: a RCT. J. Hepatol. 2014; 61 (1): 82–88. PMID: 24650695. https://doi.org/10.1016/j.jhep.2014.03.012

30. Virshke E.R., Kosyrev V.Yu., Dolgushin B.I. Hepatocellular carcinoma BCLC B: looking for the best treatment. Interventional radiological technologies in the treatment of patients with HCC. Zlokachestvennye opuholi = Malignant tumors. 2016; 4 (special issue 1): 26–28. (In Russian)

31. Ni J.Y., Liu S.S., Xu L.F., Sun H.L., Chen Y.T. Meta-analysis of radiofrequency ablation in combination with transarterial chemoembolization for hepatocellular carcinoma. World J. Gastroenterol. 2013; 19 (24): 3872–3888. PMID: 23840128. PMCID: PMC3699038. https://doi.org/10.3748/wjg.v19.i24.3872

32. Hsu C.Y., Huang Y.H., Hsia C.Y., Su C.W., Lin H.C., Loong C.С., Chiou Y.Y., Chiang J.H., Lee P.С., Huo T.I., Lee S.D. A new prognostic model for hepatocellular carcinoma based on total tumor volume: The Taipei Integrated Scoring system. J. Hepatol. 2010; 53 (1): 108–117. https://doi.org/10.1016/j.jhep.2010.01.038

33. Yau T., Tang V.Y., Yao T.J., Fan S.T., Lo C.M., Poon R.T. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology. 2014; 146 (7): 1691–1700. e3. https://doi.org/10.1053/j.gastro.2014.02.032

34. Pugh R.N.H., Murray-Lyon I.M., Dawson J.L., Pietroni M.C., Williams R. Transsection of the oesophagus for bleeding oesophageal variceas. Brit. J. Surg. 1973; 60 (8): 648–652. PMID: 4541913. https://doi.org/10.1002/bjs.1800600817

35. Faybik P., Hetz H. Plasma disappearance rate of indocyanine green in liver dysfunction. Transplant. Proc. 2006; 38 (3): 801–802. PMID: 16647475. https://doi.org/10.1016/j.transproceed.2006.01.049

36. Mukherjee S., Rogers M.A., Buniak B. Comparison of indocyanine green clearance with Child's-Pugh score and hepatic histology: a multivariate analysis. Hepatogastroeneterology. 2006; 53 (67): 120–123. PMID:16506389.

37. Oellerich M., Burdelski M., Lautz H.U., Binder L., Pichlmayr R. Predictors of one-year pretransplant survival in patients with cirrhosis. Hepatology. 1991; 14 (6): 1029–1034. PMID: 1959850.

38. Dzidzava I.I., Slobodyanik A.V., Kudryavtseva A.V., Zheleznyak I.S., Kotiv B.N., Alent'yev S.A., Lazutkin M.V., Soldatov S.A. The Results of СТ-Volumetry and Clearance Test with Indocyanine Green as Indications for Preoperative Portal Vein Embolization. Annaly khirurgicheskoy gepatologii = Annals of HPB Surgery. 2016; 21 (3): 34–46. https://doi.org/10.16931/1995-5464.2016334-46 (In Russian)

39. Guo Z., Zhong Y., HuB., Jiang J.H., Li L.Q., Xiang B.D. Hepatic resection or transarterial chemoembolization for hepatocellular carcinoma within Milan criteria: a propensity score matching analysis. Medicine (Baltimore). 2017; 96 (51): e8933.PMID: 29390426 PMCID: PMC5758128. https://doi.org/10.1097/MD.0000000000008933