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Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally advanced hepatocellular carcinoma with intrahepatic metastasis

Abstract

Purpose

Although sorafenib has been approved for treating advanced hepatocellular carcinoma (HCC), its high cost, frequent adverse events, and unsatisfactory efficacy remain unresolved. We evaluated the efficacy and safety of the combination treatment of localized concurrent chemoradiation therapy (CCRT) for locally advanced HCC with portal vein thrombosis (PVT) and transarterial chemoembolization (TACE) for intrahepatic metastasis.

Methods

Between January 2006 and June 2011, 30 patients with HCC with portal vein invasion and intrahepatic metastasis were enrolled. After TACE for intrahepatic metastasis, localized CCRT (45 Gy over 5 weeks with conventional fractionation and hepatic artery infusional chemotherapy using 5-fluorouracil as a radiosensitizer, administered during the first and fifth weeks of radiotherapy) was used to treat main HCC with PVT. The modified response evaluation criteria in solid tumors (mRECIST) were used to evaluate tumor response.

Results

The median age of the patients (26 men, 4 women) was 51 years. Objective response rates were 30.0 % (9/30) and 32.1 % (9/28) in the intention-to-treat and per protocol analyses, respectively. The median progression-free survival (PFS) and overall survival (OS) were 4.5 and 9.8 months, respectively. Baseline α-fetoprotein (AFP) correlated significantly with PFS (P = 0.008), whereas baseline AFP, completion of the protocol, and overall radiological response influenced OS significantly (all P < 0.05). All adverse events were predictable and manageable with conservative care.

Conclusions

Combination treatment of localized CCRT and TACE was effective and tolerable in patients with locally advanced HCC with PVT and intrahepatic metastasis. This protocol may be an alternative option when sorafenib cannot be prescribed.

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References

  1. Kudo M (2010) The 2008 Okuda lecture: management of hepatocellular carcinoma: from surveillance to molecular targeted therapy. J Gastroenterol Hepatol 25(3):439–452. doi:10.1111/j.1440-1746.2009.06207.x

    PubMed  Article  CAS  Google Scholar 

  2. Yuen MF, Hou JL, Chutaputti A, Asia Pacific Working Party on Prevention of Hepatocellular C (2009) Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol 24(3):346–353. doi:10.1111/j.1440-1746.2009.05784.x

    PubMed  Article  Google Scholar 

  3. Kim SU, Kim YR, Kim do Y, Kim JK, Lee HW, Kim BK, Han KH, Chon CY, Moon YM, Ahn SH (2007) Clinical features and treatment outcome of advanced hepatocellular carcinoma with inferior vena caval invasion or atrial tumor thrombus. Korean J Hepatol 13(3):387–395

    PubMed  Article  Google Scholar 

  4. Han KH, Seong J, Kim JK, Ahn SH, Lee do Y, Chon CY (2008) Pilot clinical trial of localized concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma with portal vein thrombosis. Cancer 113(5):995–1003. doi:10.1002/cncr.23684

    PubMed  Article  CAS  Google Scholar 

  5. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, Group SIS (2008) Sorafenib in advanced hepatocellular carcinoma. The New England Journal of Medicine 359(4):378–390. doi:10.1056/NEJMoa0708857

    PubMed  Article  CAS  Google Scholar 

  6. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10(1):25–34. doi:10.1016/s1470-2045(08)70285-7

    PubMed  Article  CAS  Google Scholar 

  7. Bruix J, Sherman M, American Association for the Study of Liver D (2011) Management of hepatocellular carcinoma: an update. Hepatology (Baltimore, Md) 53(3):1020–1022. doi:10.1002/hep.24199

  8. Trevisani F, De Notariis S, Rossi C, Bernardi M (2001) Randomized control trials on chemoembolization for hepatocellular carcinoma: is there room for new studies? J Clin Gastroenterol 32(5):383–389

    PubMed  Article  CAS  Google Scholar 

  9. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J (2002) Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology (Baltimore, Md) 35(5):1164–1171. doi:10.1053/jhep.2002.33156

    Google Scholar 

  10. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sola R, Rodes J, Bruix J, Barcelona Liver Cancer G (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359(9319):1734–1739. doi:10.1016/s0140-6736(02)08649-x

    PubMed  Article  Google Scholar 

  11. Park JY, Ahn SH, Yoon YJ, Kim JK, Lee HW, Lee do Y, Chon CY, Moon YM, Han KH (2007) Repetitive short-course hepatic arterial infusion chemotherapy with high-dose 5-fluorouracil and cisplatin in patients with advanced hepatocellular carcinoma. Cancer 110(1):129–137. doi:10.1002/cncr.22759

    PubMed  Article  Google Scholar 

  12. Robertson JM, Lawrence TS, Dworzanin LM, Andrews JC, Walker S, Kessler ML, DuRoss DJ, Ensminger WD (1993) Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 11(7):1286–1293

    CAS  Google Scholar 

  13. Seong J, Keum KC, Han KH, Lee DY, Lee JT, Chon CY, Moon YM, Suh CO, Kim GE (1999) Combined transcatheter arterial chemoembolization and local radiotherapy of unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 43(2):393–397

    PubMed  Article  CAS  Google Scholar 

  14. Park JW (2005) Hepatocellular carcinoma in Korea: introduction and overview. The Korean journal of gastroenterology 45(4):217–226

    PubMed  Google Scholar 

  15. Seong J, Park HC, Han KH, Chon CY, Chu SS, Kim GE, Suh CO (2003) Clinical results of 3-dimensional conformal radiotherapy combined with transarterial chemoembolization for hepatocellular carcinoma in the cirrhotic patients. Hepatology Research: The Official Journal of the Japan Society of Hepatology 27(1):30–35

    Article  Google Scholar 

  16. Lencioni R, Llovet JM (2010) Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 30(1):52–60. doi:10.1055/s-0030-1247132

    PubMed  Article  CAS  Google Scholar 

  17. Kim DY, Ryu HJ, Choi JY, Park JY, Lee DY, Kim BK, Kim SU, Ahn SH, Chon CY, Han KH (2012) Radiological response predicts survival following transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma. Aliment Pharmacol Ther 35(11):1343–1350. doi:10.1111/j.1365-2036.2012.05089.x

    PubMed  Article  CAS  Google Scholar 

  18. Ando E, Yamashita F, Tanaka M, Tanikawa K (1997) A novel chemotherapy for advanced hepatocellular carcinoma with tumor thrombosis of the main trunk of the portal vein. Cancer 79(10):1890–1896

    PubMed  Article  CAS  Google Scholar 

  19. Shim JH, Lee HC, Kim SO, Shin YM, Kim KM, Lim YS, Suh DJ (2012) Which response criteria best help predict survival of patients with hepatocellular carcinoma following chemoembolization? A validation study of old and new models. Radiology 262(2):708–718. doi:10.1148/radiol.11110282

    PubMed  Article  Google Scholar 

  20. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ, Panel of Experts in HCCDCT (2008) Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer Institute 100(10):698–711. doi:10.1093/jnci/djn134

    PubMed  Article  Google Scholar 

  21. Cuesta L, Betlloch I, Toledo F, Latorre N, Monteagudo A (2011) Severe sorafenib-induced hand-foot skin reaction. Dermatol Online J 17(5):14

    PubMed  CAS  Google Scholar 

  22. Lee HC (2008) Systemic chemotherapy of hepatocellular carcinoma—Korean experience. Oncology 75(Suppl 1):114–118. doi:10.1159/000173432

    PubMed  Article  CAS  Google Scholar 

  23. Park HC, Seong J, Han KH, Chon CY, Moon YM, Suh CO (2002) Dose-response relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 54(1):150–155

    PubMed  Article  Google Scholar 

  24. Ando E, Tanaka M, Yamashita F, Kuromatsu R, Yutani S, Fukumori K, Sumie S, Yano Y, Okuda K, Sata M (2002) Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. Cancer 95(3):588–595. doi:10.1002/cncr.10694

    PubMed  Article  Google Scholar 

  25. Yamakado K, Nakatsuka A, Ohmori S, Shiraki K, Nakano T, Ikoma J, Adachi Y, Takeda K (2002) Radiofrequency ablation combined with chemoembolization in hepatocellular carcinoma: treatment response based on tumor size and morphology. Journal of Vascular and Interventional Radiology JVIR 13(12):1225–1232

    PubMed  Article  Google Scholar 

  26. Fujiyama S, Tanaka M, Maeda S, Ashihara H, Hirata R, Tomita K (2002) Tumor markers in early diagnosis, follow-up and management of patients with hepatocellular carcinoma. Oncology 62(Suppl 1):57–63

    PubMed  Article  CAS  Google Scholar 

  27. Shim JH, Lee HC, Won HJ, Shin YM, Kim KM, Lim YS, Suh DJ (2012) Maximum number of target lesions required to measure responses to transarterial chemoembolization using the enhancement criteria in patients with intrahepatic hepatocellular carcinoma. J Hepatol 56(2):406–411. doi:10.1016/j.jhep.2011.04.028

    PubMed  Article  Google Scholar 

  28. Iwasa S, Ikeda M, Okusaka T, Ueno H, Morizane C, Nakachi K, Mitsunaga S, Kondo S, Hagihara A, Shimizu S, Satake M, Arai Y (2011) Transcatheter arterial infusion chemotherapy with a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. Jpn J Clin Oncol 41(6):770–775. doi:10.1093/jjco/hyr037

    PubMed  Article  Google Scholar 

  29. Nagano H, Wada H, Kobayashi S, Marubashi S, Eguchi H, Tanemura M, Tomimaru Y, Osuga K, Umeshita K, Doki Y, Mori M (2011) Long-term outcome of combined interferon-alpha and 5-fluorouracil treatment for advanced hepatocellular carcinoma with major portal vein thrombosis. Oncology 80(1–2):63–69. doi:10.1159/000328281

    PubMed  Article  CAS  Google Scholar 

  30. Siringo S, Burroughs AK, Bolondi L, Muia A, Di Febo G, Miglioli M, Cavalli G, Barbara L (1995) Peptic ulcer and its course in cirrhosis: an endoscopic and clinical prospective study. J Hepatol 22(6):633–641

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065) and by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (0620390).

Conflict of interest

None to declare from all authors.

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Corresponding author

Correspondence to Jinsil Seong.

Additional information

M. S. Park and S. U. Kim are co-first authors of this article, and have contributed equally.

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280_2012_1993_MOESM1_ESM.jpg

Supplementary figure 1. CT findings of PR (A), SD (B), and PD (C) after localized CCRT and TACE (arterial phase). A: After treatment, the diameter of main HCC with PVT showing arterial enhancement significantly decreased (PR) and intrahepatic metastatic HCCs showed compact lipiodolization (CR, white arrow). A hemangioma was noted at segment 4. B: Although intrahepatic metastatic lesion showed compact lipiodolization after treatment (CR, white arrow), the diameter of main HCC with PVT showing arterial enhancement did not decreased (from 7.5 to 7.2 cm; 4.0% decrease; SD) enough to meet the criteria of PR. Thus, overall response was SD. C: After treatment, the diameter of main HCC with PVT showing arterial enhancement increased (from 11.8 to 14.5 cm; 22.4% increase; PD) although intrahepatic metastatic lesion showed compact lipiodolization (CR, white arrow). Thus, overall response was PD. (JPEG 131 kb)

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Park, M.S., Kim, S.U., Park, J.Y. et al. Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally advanced hepatocellular carcinoma with intrahepatic metastasis. Cancer Chemother Pharmacol 71, 165–173 (2013). https://doi.org/10.1007/s00280-012-1993-9

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  • DOI: https://doi.org/10.1007/s00280-012-1993-9

Keywords

  • Chemoport
  • Concurrent chemoradiation
  • Hepatocellular carcinoma
  • Modified RECIST
  • Radiation
  • Transarterial chemoembolization