Hepatic arterial chemotherapy with raltitrexed and oxaliplatin versus standard chemotherapy in unresectable liver metastases from colorectal cancer after conventional chemotherapy failure (HEARTO): a randomized phase-II study

  • Francois GhiringhelliEmail author
  • Julie Vincent
  • Leila Bengrine
  • Christophe Borg
  • Jean Louis Jouve
  • Romaric Loffroy
  • Boris Guiu
  • Julie Blanc
  • Aurélie Bertaut
Original Article – Clinical Oncology



Hepatic arterial infusion (HAI) of chemotherapy could be used in patients with liver-only metastatic colorectal cancer (mCRC) to fight against chemoresistance. We previously reported the efficacy of raltitrexed plus oxaliplatin (HAI) in a retrospective series. We performed a randomized two-stage phase-II study to evaluate the efficacy of HAI of the combination of raltitrexed and oxaliplatin in refractory mCRC with only liver metastases in comparison with standard of care.

Patients and methods

Eligible patients had unresectable mCRC and were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were randomized between HAI raltitrexed (3 mg/m2 over 1 h) followed by oxaliplatin (130 mg/m2 over 2 h) every 3 weeks and standard of care in a 2:1 ratio. A total of 57 patients (38 in the experimental arm and 19 in the standard of care arm) were to be included. The main objective was to demonstrate 6-month PFS of 45% by intention-to-treat analysis in the experimental arm, compared to theoretical PFS of 20%, with a unilateral alpha risk of 5% and beta risk of 10%.


After inclusion of 27 patients, the trial was terminated due to insufficient accrual. In the experimental arm, 11 and 4 patients experienced grade 3 and 4 toxicities, respectively. The most frequent grade 3–4 toxicities were neutropenia, liver toxicity, and abdominal pain. Median progression-free survival was 6.7 months (95% Confidence Interval; 3.9–7.2) in the HAI group and 2.2 months (95% CI 1.2–4.3) with standard of care [HR 0.32 (95% CI 0.14–0.76), p = 0.01]. Median overall survival did not differ between the two groups, at 11.2 months (95% CI 4.8–17.6) for the HAI group and 11.9 months (95% CI 2.8–14.3) for standard of care [HR 0.86 (95% CI 0.36–2.04), p = 0.73].


Although stopped prematurely, this randomized trial provides evidence for the benefit and safety of HAI of a combination of raltitrexed and oxaliplatin in liver-only mCRC with chemoresistant disease.


Colorectal cancer Liver metastasis Hepatic arterial infusion Oxaliplatin Raltitrexed 


Author contributions

FG and AB were the main authors of the manuscript. They were involved in the conception, design and coordination of the study as well as in data analysis, interpretation of results, and drafting of the manuscript. JV, LB, JLJ, CB, BG, and RL participated in the collection and analysis of data. JB performed statistical analysis. All authors contributed to the interpretation of data and critically revised the manuscript. All authors read and approved the final manuscript.


INCA-PHRC-2009. Funding has been received form Institut National Du Cancer with Grand No. 2019.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval

This study was prospective and approved by the Ethics Review Committee od Dijon (CCP EST 1).

Informed consent

All participants provided written informed consent to participate.

Availability of data and materials

The data sets generated and analyzed during the current study were not approved for public release by the Ethics Committee, but are available from the corresponding author on reasonable request.


  1. Ackerman NB (1974) The blood supply of experimental liver metastases. IV. Changes in vascularity with increasing tumor growth. Surgery. 75:589–596Google Scholar
  2. Adam R, Wicherts DA, de Haas RJ et al (2009) Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 27:1829–1835CrossRefGoogle Scholar
  3. Boige V, Malka D, Elias D et al (2008) Hepatic arterial infusion of oxaliplatin and intravenous LV5FU2 in unresectable liver metastases from colorectal cancer after systemic chemotherapy failure. Ann Surg Oncol 15:219–226CrossRefGoogle Scholar
  4. Bouchahda M, Adam R, Giacchetti S et al (2009) Rescue chemotherapy using multidrug chronomodulated hepatic arterial infusion for patients with heavily pretreated metastatic colorectal cancer. Cancer 115:4990–4999CrossRefGoogle Scholar
  5. Cocconi G, Cunningham D, Van Cutsem E et al (1998) Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 16:2943–2952CrossRefGoogle Scholar
  6. D’Angelica MI, Correa-Gallego C, Paty PB et al (2015) Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes. Ann Surg 261:353–360CrossRefGoogle Scholar
  7. Del Freo A, Fiorentini G, Sanguinetti F et al (2006) Hepatic arterial chemotherapy with oxaliplatin, folinic acid and 5-fluorouracil in pre-treated patients with liver metastases from colorectal cancer. Vivo. 20:743–746Google Scholar
  8. Ducreux M, Ychou M, Laplanche A et al (2005) Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 23:4881–4887CrossRefGoogle Scholar
  9. Feliu J, Castanon C, Salud A et al (2005) Phase II randomised trial of raltitrexed-oxaliplatin vs raltitrexed-irinotecan as first-line treatment in advanced colorectal cancer. Br J Cancer 93:1230–1235CrossRefGoogle Scholar
  10. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J et al (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49:1374–1403CrossRefGoogle Scholar
  11. Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–386CrossRefGoogle Scholar
  12. Fiorentini G, Rossi S, Dentico P et al (2004) Oxaliplatin hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: a phase I-II clinical study. Anticancer Res 24:2093–2096Google Scholar
  13. Fiorentini G, Cantore M, Rossi S et al (2006) Hepatic arterial chemotherapy in combination with systemic chemotherapy compared with hepatic arterial chemotherapy alone for liver metastases from colorectal cancer: results of a multi-centric randomized study. Vivo. 20:707–709Google Scholar
  14. Folprecht G, Grothey A, Alberts S, Raab HR, Kohne CH (2005) Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 16:1311–1319CrossRefGoogle Scholar
  15. Gunasekara NS, Faulds D. Raltitrexed. A review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer. Drugs. 1998;55:423-435Google Scholar
  16. Guo JH, Zhang HY, Gao S et al (2017) Hepatic artery infusion with raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis. World J Gastroenterol 23:1406–1411CrossRefGoogle Scholar
  17. Hendlisz A, Van den Eynde M, Peeters M et al (2010) Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol 28:3687–3694CrossRefGoogle Scholar
  18. Kemeny NE, Niedzwiecki D, Hollis DR et al (2006) Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 24:1395–1403CrossRefGoogle Scholar
  19. Kemeny N, Capanu M, D’Angelica M et al (2009) Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 20:1236–1241CrossRefGoogle Scholar
  20. Kern W, Beckert B, Lang N et al (2001) Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer. Ann Oncol 12:599–603CrossRefGoogle Scholar
  21. Khouri C, Guiu B, Cercueil JP, Chauffert B, Ladoire S, Ghiringhelli F (2010) Raltitrexed and oxaliplatin hepatic arterial infusion for advanced colorectal cancer: a retrospective study. Anticancer Drugs 21:656–661CrossRefGoogle Scholar
  22. Levasseur LM, Slocum HK, Rustum YM, Greco WR (1998) Modeling of the time-dependency of in vitro drug cytotoxicity and resistance. Cancer Res 58:5749–5761Google Scholar
  23. Levi FA, Boige V, Hebbar M et al (2016) Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV. Ann Oncol 27:267–274CrossRefGoogle Scholar
  24. Lim A, Le Sourd S, Senellart H et al (2017) Hepatic Arterial infusion chemotherapy for unresectable liver metastases of colorectal cancer: a multicenter retrospective study. Clin Colorectal Cancer. 16:308–315CrossRefGoogle Scholar
  25. Mancuso A, Giuliani R, Accettura C et al (2003) Hepatic arterial continuous infusion (HACI) of oxaliplatin in patients with unresectable liver metastases from colorectal cancer. Anticancer Res 23:1917–1922Google Scholar
  26. Ridge JA, Bading JR, Gelbard AS, Benua RS, Daly JM (1987) Perfusion of colorectal hepatic metastases. Relative distribution of flow from the hepatic artery and portal vein. Cancer 59:1547–1553CrossRefGoogle Scholar
  27. Rougier P, Laplanche A, Huguier M et al (1992) Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 10:1112–1118CrossRefGoogle Scholar
  28. Therasse P, Arbuck SG, Eisenhauer EA et al (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. 92:205–216CrossRefGoogle Scholar
  29. Toso C, Pinto Marques H, Andres A et al (2017) Liver transplantation for colorectal liver metastasis: survival without recurrence can be achieved Liver Transpl. 23:1073–1076CrossRefGoogle Scholar
  30. Van Cutsem E, Cervantes A, Adam R et al (2016) ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 27:1386–1422CrossRefGoogle Scholar
  31. Volovat SR, Volovat C, Negru SM, Danciu M, Scripcariu V (2016) The efficacy and safety of hepatic arterial infusion of oxaliplatin plus intravenous irinotecan, leucovorin and fluorouracil in colorectal cancer with inoperable hepatic metastasis. J Chemother 28:235–241CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medical Oncology, Centre Georges-François LeclercUniversity of Bourgogne Franche ComtéDijonFrance
  2. 2.University of Burgundy and Franche ComtéDijonFrance
  3. 3.University Hospital of Besançon and CIC-BT506BesançonFrance
  4. 4.University Hospital of DijonDijonFrance
  5. 5.University Hospital of MontpellierMontpellierFrance
  6. 6.Unit of Methodology and BiostatisticsCentre Georges-François LeclercDijonFrance

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