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Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma

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Abstract

Purpose

Sorafenib improves overall survival and time to progression of advanced hepatocellular (aHCC) patients such as demonstrated in 2 phase III trials. However, aHCC patients’ outcome is still poor despite these results. In order to improve the efficacy of systemic treatment for aHCC, we evaluated the combination of sorafenib plus 5-fluorouacil infusion in a phase II trial.

Methods

Patients with aHCC not eligible for loco-regional therapies, Child-Pugh A-B, ECOG-PS 0-1, and without history of anti-cancer systemic treatment were enrolled. Treatment schedule was: sorafenib 400 mg/bid continuously and continuum infusion of 5-fluorouracil 200 mg/sqm/daily day 1–14 every 3 weeks.

Results

Thirty-nine patients were enrolled: ECOG-PS 0-1: 29-10, Child-Pugh A-B: 36-3. Grade 3/4 (%) toxicities included: diarrhea 5.1/0, mucositis 20.5/2.6, hand foot skin reaction 20.5/0, skin rash 10.5/0, hypertension 10.3/0, hyperbilirubinemia 5.1/2.6, glutamic-oxaloacetic transaminase increase 10.3/0, glutamic-pyruvic transaminase increase 7.7/0, cardiac toxicity (one heart failure, two atrial fibrillation cases) 7.7/0, and bleeding (melena) in 2.6/0. One partial response was observed. Stable disease was obtained in 46.2% of patients with a median duration of 16.2 months. Median time to progression was 8 months (CI 95% = 5.7–10.4), and median overall survival was 13.7 months (CI 95% = 9.5–17.9).

Conclusions

The results show an encouraging disease control rate, time to progression, and overall survival. The combination of sorafenib and 5-fluorouracil was feasible, and the side effects were manageable for patients carefully selected for liver function and performance status.

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References

  1. (1967) Malignant hepatoma-controlled therapeutic trials. South African primary liver cancer research group. Initial report. S Afr Med J 41:309–314

  2. Abou-Alfa GK, Johnson P, Knox J, Davidenko I, Lacava J, Leung T, Mori A, Le Berre M, Voliotis D, Saltz L (2008) Final results from a phase II (PhII), randomized, double-blind study of sorafenib plus doxorubicin (S + D) versus placebo plus doxorubicin (P + D) in patients (pts) with advanced hepatocellular carcinoma (AHCC). Gastrointestinal cancers symposium meeting abstract, 128

  3. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24:4293–4300

    Article  PubMed  CAS  Google Scholar 

  4. Awada A, Gil T, Whenham N, Van Hamme J, Besse-Hammer T, Brendel E, Delesen H, Joosten MC, Lathia CD, Loembe BA, Piccart-Ghebart M, Hendlisz A Safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors: results of a phase 1 Trial. J Clin Pharmacol

  5. Chang YS, Adnane J, Trail PA, Levy J, Henderson A, Xue D, Bortolon E, Ichetovkin M, Chen C, McNabola A, Wilkie D, Carter CA, Taylor IC, Lynch M, Wilhelm S (2007) Sorafenib (BAY 43–9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 59:561–574

    Article  PubMed  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 10:25–34

    Article  PubMed  CAS  Google Scholar 

  7. Davis HL Jr, Ramirez G, Ansfield FJ (1974) Adenocarcinomas of stomach, pancreas, liver, and biliary tracts. Survival of 328 patients treated with fluoropyrimidine therapy. Cancer 33:193–197

    Article  PubMed  Google Scholar 

  8. Falkson G, Moertel CG, Lavin P, Pretorius FJ, Carbone PP (1978) Chemotherapy studies in primary liver cancer: a prospective randomized clinical trial. Cancer 42:2149–2156

    Article  PubMed  CAS  Google Scholar 

  9. Figer A, Moscovici M, Bulocinic S, Radu P, Astmon J, Shmuely E, Laba O, Gadish D, Brendel E, Schwartz B (2004) Phase I trial of BAY 43-9006 in combination with 5-fluorouracil (5-FU) and leucovorin (LCV) in patients with advanced refractory solid tumors. Ann Oncol 15:iii87–iii88

    Google Scholar 

  10. Figer AMM, Bulocinic S, Radu P, Astmon J, Shmuely E, Laba O, Gadish D, Brendel E, Schwartz B (2004) Phase I trial of BAY 43-9006 in combination with 5-fluorouracil (5-FU) and leucovorin (LCV) in patients with advanced refractory solid tumors. Ann Oncol 15: iii87–88

    Google Scholar 

  11. Garcia MJA, Ward EM, Center MM, Hao Y, Siegel RL, Thun MJ (2007) Global cancer facts & figures 2007. American Cancer Society, Atlanta

    Google Scholar 

  12. Hsu CH, Wong CCY, Yao T, Tang V, Chan P, Chiu J, Fan S, Poon R (2010) Efficacy and tolerability of sorafenib in elderly patients with advanced hepatocellular carcinoma. J Clin Oncol 28:e14522 abstr

    Google Scholar 

  13. Hsu CH, Shen YC, Lin ZZ, Chen PJ, Shao YY, Ding YH, Hsu C, Cheng AL Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma. J Hepatol 53:126–131

  14. Infante JR, Jones SF, Bendell JC, Greco FA, Yardley DA, Lane CM, Spigel DR, Hainsworth JD, Burris III HA A drug interaction study evaluating the pharmacokinetics and toxicity of sorafenib in combination with capecitabine. Cancer Chemother Pharmacol

  15. Joensuu H, De Braud F, Grigagni G, De Pas T, Spitalieri G, Coco P, Spreafico C, Boselli S, Toffalorio F, Bono P, Jalava T, Kappeler C, Aglietta M, Laurent D, Casali PG Vatalanib for metastatic gastrointestinal stromal tumour (GIST) resistant to imatinib: final results of a phase II study. Br J Cancer

  16. Johnson PJ (2003) Are there indications for chemotherapy in hepatocellular carcinoma? Surg Oncol Clin N Am 12:127–134

    Article  PubMed  Google Scholar 

  17. Kee KM, Wang JH, Lee CM, Chen CL, Changchien CS, Hu TH, Cheng YF, Hsu HC, Wang CC, Chen TY, Lin CY, Lu SN (2007) Validation of clinical AJCC/UICC TNM staging system for hepatocellular carcinoma: analysis of 5, 613 cases from a medical center in southern Taiwan. Int J Cancer 120:2650–2655

    Article  PubMed  CAS  Google Scholar 

  18. Kennedy PS, Lehane DE, Smith FE, Lane M (1977) Oral fluorouracil therapy of hepatoma. Cancer 39:1930–1935

    Article  PubMed  CAS  Google Scholar 

  19. Lee SJ, Lee J, Park SH, Park JO, Park YS, Kang WK, Yim DS, Lim HY Phase 1 trial of S-1 in combination with sorafenib for patients with advanced hepatocellular carcinoma. Invest New Drugs

  20. Lencioni R, Llovet JM Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 30:52–60

  21. Link JS, Bateman JR, Paroly WS, Durkin WJ, Peters RL (1977) 5-Flourouracil in hepatocellular carcinoma: report of twenty-one cases. Cancer 39:1936–1939

    Article  PubMed  CAS  Google Scholar 

  22. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66:11851–11858

    Article  PubMed  CAS  Google Scholar 

  23. Llovet JM (2005) Updated treatment approach to hepatocellular carcinoma. J Gastroenterol 40:225–235

    Article  PubMed  Google Scholar 

  24. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ (2008) Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 100:698–711

    Article  PubMed  Google Scholar 

  25. 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 (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  PubMed  CAS  Google Scholar 

  26. Luporini G, Labianca R, Pancera G (1993) Medical treatment of hepatocellular carcinoma. J Surg Oncol (Suppl 3):115-118

  27. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP (2006) The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 45:529–538

    Article  PubMed  Google Scholar 

  28. Prete SD, Montella L, Caraglia M, Maiorino L, Cennamo G, Montesarchio V, Piai G, Febbraro A, Tarantino L, Capasso E, Palmieri G, Guarrasi R, Bianco M, Mamone R, Savastano C, Pisano A, Vincenzi B, Sabia A, D’Agostino A, Faiola V, Addeo R Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study. Cancer Chemother Pharmacol 66:837–844

  29. Sawaki A, Nishida T, Doi T, Yamada Y, Komatsu Y, Kanda T, Kakeji Y, Onozawa Y, Yamasaki M, Ohtsu A Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor. Cancer

  30. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  31. Ueshima K, Kudo M, Tanaka M, Kumada T, Sakurai T, Chung H, Hagiwara S, Minami Y, Inoue T, Yada N, Kitai S, Takita M, Hayaishi S (2011) Phase I study of sorafenib in combination with low-dose cisplatin and fluorouracil intra-arterial infusion chemotherapy. J Clin Oncol (Suppl 29)

  32. Villanueva A, Minguez B, Forner A, Reig M, Llovet JM Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy. Annu Rev Med 61:317–328

  33. Wilhelm S, Chien DS (2002) BAY 43–9006: preclinical data. Curr Pharm Des 8:2255–2257

    Article  PubMed  CAS  Google Scholar 

  34. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109

    Article  PubMed  CAS  Google Scholar 

  35. Yau T, Chan P, Cheung FY, Lee AS, Yau TK, Choo SP, Lau J, Wong JS, Fan ST, Poon RT (2009) Phase II trial of sorafenib with capecitabine and oxaliplatin (SECOX) in patients with locally advanced or metastatic hepatocellular carcinoma. Eur J Cancer Suppl 7:20–21

    Article  Google Scholar 

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Acknowledgments

Bayer Pharma S.p.A, Milan, Italy founded this research. We thank Dr Clare Paterson and Donna Voeller who helped editing the paper.

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Authors and Affiliations

  1. Department of Oncology, Transplant and New Advances in Medicine, BIOS, University of Pisa, 67 Via Roma, 56126, Pisa, Italy

    Iacopo Petrini

  2. Medical Oncology, Pisa University Hospital, Pisa, Italy

    Monica Lencioni, Miriam Ricasoli, Mauro Iannopollo, Cinzia Orlandini & Sergio Ricci

  3. Gastroenterology Unit, Pisa University Hospital, Pisa, Italy

    Filippo Oliveri

  4. Department of Diagnostic and Interventional Radiology, Pisa University, Pisa, Italy

    Carlo Bartolozzi

Authors
  1. Iacopo Petrini
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  2. Monica Lencioni
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  3. Miriam Ricasoli
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  4. Mauro Iannopollo
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  5. Cinzia Orlandini
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  6. Filippo Oliveri
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  8. Sergio Ricci
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Corresponding author

Correspondence to Iacopo Petrini.

Additional information

ClinicalTrials.gov ID: NCT00619541.

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Petrini, I., Lencioni, M., Ricasoli, M. et al. Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 69, 773–780 (2012). https://doi.org/10.1007/s00280-011-1753-2

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  • DOI: https://doi.org/10.1007/s00280-011-1753-2

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