Summary
The purpose of this study was to evaluate the efficacy of postoperative adjuvant chemotherapy with FOLFOX regimen on the outcome after LT for HCC patients who did not meet the Milan criteria. Ninety-five consecutive HCC patients with liver cirrhosis undergoing LT were enrolled. Fifty-eight who did not meet the Milan criteria were randomized to open-label treatment with or without adjuvant chemotherapy after LT (n = 29/group). The FOLFOX chemotherapy protocol comprised 3-week cycles of oxaliplatin 100 mg/m2 on day 1, leucovorin (calcium folinate, CF) 200 mg/m2 on day 1 followed by 3-day, and 5-fluorouracil (5-FU) 2000 mg/m2 as a 48-h continuous infusion, for up to six courses in the 1st year after transplantation. Median survival was extended by 4.57 months by combination chemotherapy. The 1- and 3-year survival rates were 89.7% and 79.3% with chemotherapy versus 69.0% and 62.1% without chemotherapy. The cumulative 1-year survival was significantly increased by chemotherapy (log-rank test, P = 0.043). The 6-month tumor-free survival rate was 24.1% higher with chemotherapy than without. The recurrence rate after LT was significantly different between the two groups at 6 months (P = 0.036), but not at 3 years (P = 0.102). The chemotherapy regimen was generally well tolerated. Post-LT adjuvant chemotherapy with oxaliplatin/5-FU/CF could not prevent tumor recurrence post-LT but may contribute to improve the survival of HCC patients who do not meet the Milan criteria. These results should be verified in a larger sample with a longer follow-up period.
Similar content being viewed by others
References
Bosch FX, Ribes J, Borras J (1999) Epidemiology of primary liver cancer. Semin Liver Dis 19:271–285
Poon RTP, Fan ST, Wong J (2000) Risk factors prevention and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg 232:10–24
Coelho GR, Vasconcelos KF, Vasconcelos JB et al (2009) Orthotopic liver transplantation for hepatocellular carcinoma: one center’s experience in the Northeast of Brazil. Transplant Proc 41:1740–1742
Hertl M, Cosimi AB (2005) Liver transplantation for malignancy. Oncologist 10:269–281
Varona MA, Del Pino JM, Barrera M et al (2009) Hepatocellular carcinoma and liver transplantation: a 12-year experience. Transplant Proc 41:1005–1008
Chen GH (2009) Liver transplantation in China: retrospect and prospect. Chin Med J 122:2229–2230
Fernandez JA, Robles R, Marin C et al (2003) Can we expand the indications for liver transplantation among hepatocellular carcinoma patients with increased tumor size? Transplant Proc 35:1818–1820
Chu F, Morris DL (2006) Single centre experience of liver resection for hepatocellular carcinoma in patients outside transplant criteria. Eur J Surg Oncol 32:568–572
Mazzaferro V, Regalia E, Doci R et al (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693–699
Yao FY, Ferrell L, Bass NM et al (2002) Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 8:765–774
Gondolesi GE, Roayaie S, Muñoz L et al (2004) Adult living donor liver transplantation for patients with hepatocellular carcinoma: extending UNOS priority criteria. Ann Surg 239:142–149
Coriat R, Mir O, Cessot A et al (2010) Feasibility of oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX-4) in cirrhotic or liver transplant patients: experience in a cohort of advanced hepatocellular carcinoma patients. Invest New Drugs Aug 27 [Epub ahead of print]
Shimoda M, Ghobrial RM, Carmody IC et al (2004) Predictors of survival after liver transplantation for hepatocellular carcinoma associated with Hepatitis C. Liver Transpl 10:1478–1486
Marsh JW, Dvorchik I, Subotin M et al (1997) The prediction of risk of recurrence and time to recurrence of hepatocellular carcinoma after orthotopic liver transplantation: a pilot study. Hepatology 26:444–450
Gondolesi GE, Roayaie S, Muñoz L et al (2006) Adjuvant chemotherapy for prevention of recurrence of invasive hepatocellular carcinoma after orthotopic liver transplantation. Transplant Proc 38:2495–2498
Kwok PC, Lam TW, Lam PW et al (2003) Randomized controlled trial to compare the dose of adjuvant chemotherapy after curative resection of hepatocellular carcinoma. J Gastroenterol Hepatol 18:450–455
Ono T, Yamanoi A, El N et al (2001) Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials. Cancer 91:2378–2385
Hsieh CB, Chou SJ, Shih ML et al (2008) Preliminary experience with gemcitabine and cisplatin adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma. Eur J Surg Oncol 34:906–910
**a Y, Qiu Y, Li J et al (2010) Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol 17:3137–3144
Xu J, Zhong Y, Weixin N et al (2007) Preoperative hepatic and regional arterial chemotherapy in the prevention of liver metastasis after colorectal cancer surgery. Ann Surg 245:583–590
Ragnhammar P, Hafström L, Nygren P et al (2001) Swedish council of technology assessment in health care. A systematic overview of chemotherapy effects in colorectal cancer. Acta Oncol 40:282–308
Trojan J, Lubomierski N, Lehnert T et al (2008) Neoadjuvant treatment with cetuximab, 5-Fluorouracil, folinic Acid and oxaliplatin in unresectable retroperitoneal recurrent colon cancer. Z Gastroenterol 46:776–779
Poggi G, Quaretti P, Minoia C et al (2008) Transhepatic arterial chemoembolization with oxaliplatin-eluting microspheres (OEM-TACE) for unresectable hepatic tumors. Anticancer Res 28:3835–3842
Uhm JE, Park JO, Lee J et al (2009) A phase II study of oxaliplatin in combination with doxorubicin as first-line systemic vchemotherapy in patients with inoperable hepatocellular carcinoma. Cancer Chemother Pharmacol 63:929–935
Li S, Niu Z, Tian H et al (2007) Treatment of advanced hepatocellular carcinoma with gemcitabine plus oxaliplatin. Hepatogastroenterology 54:218–223
Van Cutsem E, Van de Velde C, Roth A et al (2008) Expert opinion on management of gastric and gastro-oesophageal junction adenocarcinoma on behalf of the European Organisation for Research and Treatment of Cancer (EORTC)-gastrointestinal cancer group. Eur J Cancer 44:182–194
Wang GQ, Wan DS, Zhou ZW et al (2007) Efficacy and toxicity of FOLFOX6 regimen in treating colorectal cancer patients with liver metastasis. Ai Zheng 26:411–414
Raimondo ML, Burroughs AK (2002) Single-agent immunosuppression after liver transplantation: what is possible? Drugs 62:1587–1597
Tobinai K, Kohno A, Shimada Y et al (1993) Toxicity grading criteria of the Japan Clinical Oncology Group. Jpn J Clin Oncol 23:250–257
Yang BS, Ma YJ, Wang Y et al (2007) Protective effect and mechanism of stronger neo-minophagen C against fulminant hepatic failure. World J Gastroenterol 133:462–466
Alp MH, Hickman R (1987) The effect of prostaglandins, branched-chain amino acids and other drugs on the outcome of experimental acute porcine hepatic failure. J Hepatol 4:99–107
Sutcliffe R, Maguire D, Murphy P et al (2005) Detection and clinical significance of bone marrow micrometastases in patients undergoing liver transplantation for hepatocellular carcinoma. Transplantation 80:88–94
Olthoff KM, Rosove MH, Shackleton CR et al (1995) Adjuvant chemotherapy improves survival after liver transplantation for hepatocellular carcinoma. Ann Surg 221:734–743
Huang J, He X, Chen G et al (2002) Liver transplantation at the Sun Yat-Sen University of Medical Sciences in China. Chin Med J 115:543–548
Roayaie S, Frischer JS, Emre SH et al (2002) Long term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinoma larger than 5 centimeters. Ann Surg 235:533–539
Qin S, Bai Y, Ye S et al (2010) Thongprasert, Y. Chao, K, Phase III study of oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) versus doxorubicin as palliative systemic chemotherapy in advanced HCC in Asian patients, Journal of Clinical Oncology. 2010 ASCO Annual Meeting Proceedings. 28 suppl (May 20 Supplement) 4008
Cheng A-L, Kang Y-K, Chen Z et al (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
Lee JO, Kim DY, Lim JH et al (2009) Palliative chemotherapy for patients with recurrent hepatocellular carcinoma after liver transplantation. J Gastroenterol Hepatol 24:800–805
Vexler AM, Mou X, Gabizon AA et al (1995) Reduction of the systemic toxicity of cisplatin by intra-arterial hepatic route administration for liver malignancies. Int J Cancer 60:611–615
Boucher E, Corbinais S, Brissot P et al (2002) Treatment of hepatocellular carcinoma (HCC) with systemic chemotherapy combining epirubicin, cisplatinum and infusional 5-fluorouracil (ECF regimen). Cancer Chemother Pharmacol 50:305–308
Al-Batran SE, Atmaca A, Hegewisch-Becker S et al (2004) Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol 22:658–663
Louvet C, André T, Tigaud JM et al (2002) Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 20:4543–4548
Gerard JP, Chapet O, Nemoz C et al (2003) Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 phase II trial. J Clin Oncol 21:1119–1124
Pettengell R, Aapro M, Brusamolino E et al (2009) Implications of the European Organisation for Research And Treatment Of Cancer (EORTC) guidelines on the use of granulocyte colony-stimulating factor (G-CSF) for lymphoma care. Clin Drug Investig 29:491–513
Liongue C, Wright C, Russell AP et al (2009) Granulocyte colony-stimulating factor receptor: stimulating granulopoiesis and much more. Int J Biochem Cell Biol 41:2372–2375
Author information
Authors and Affiliations
Corresponding author
Additional information
Qing Zhang and Hong Chen authors contributed equally to this work
Rights and permissions
About this article
Cite this article
Zhang, Q., Chen, H., Li, Q. et al. Combination adjuvant chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin after liver transplantation for hepatocellular carcinoma: a preliminary open-label study. Invest New Drugs 29, 1360–1369 (2011). https://doi.org/10.1007/s10637-011-9726-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-011-9726-1