A randomized phase II trial of hepatic arterial infusion of oxaliplatin plus raltitrexed versus oxaliplatin plus 5-fluorouracil for unresectable colorectal cancer liver metastases

Ai-Wei Feng, Jian-Hai Guo, Song Gao, Fu-Xin Kou, Shao-Xing Liu, Peng Liu, Hui Chen, Xiao-Dong Wang, Hai-Feng Xu, Guang Cao, Xu Zhu, Ai-Wei Feng, Jian-Hai Guo, Song Gao, Fu-Xin Kou, Shao-Xing Liu, Peng Liu, Hui Chen, Xiao-Dong Wang, Hai-Feng Xu, Guang Cao, Xu Zhu

Abstract

Background: The purpose was to compare the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin plus raltitrexed (TOMOX) to those of oxaliplatin plus 5-fluorouracil (FOLFOX) for unresectable colorectal cancer liver metastases (CRCLM).

Methods: Patients with unresectable CRCLM were randomly assigned to receive HAI of TOMOX or FOLFOX. The primary end points were progression-free survival (PFS) measured from the date of randomisation until the date of disease progression and objective response rate (ORR). The secondary end points were overall survival (OS) measured from the date of randomisation until the date of death from any cause, disease control rate (DCR), and adverse events.

Results: 113 patients were randomly assigned. With a median follow-up of 39.5 months, the PFS was 5.8 months [95% CI, 4.838-6.762]) and 4.6 months [95% CI, 3.419-5.781; P = 0.840], and the median OS was 17.6 months [95% CI, 13.828-21.372] and 13.1 months [95% CI, 11.215-14.985; P = 0.178] for the FOLFOX and TOMOX arm, respectively. The ORR were 26.1% vs 22.4% and DCR were 80.4% vs 71.4% in the FOLFOX and TOMOX arms. The most common severe adverse event was elevation of liver enzymes and pain, which did not differ in the two arms.

Conclusion: HAI chemotherapy was effective for unresectable CRCLM. HAI of FOLFOX has similar efficacy to TOMOX, and HAI of TOMOX had shorter arterial infusion time.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT02557490" title="See in ClinicalTrials.gov">NCT02557490.

Keywords: 5-fluorouracil; colorectal cancer; hepatic arterial infusion; liver metastases; oxaliplatin; raltitrexed.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Feng, Guo, Gao, Kou, Liu, Liu, Chen, Wang, Xu, Cao and Zhu.

Figures

Figure 1
Figure 1
Trial Profile.
Figure 2
Figure 2
OS since randomization for patients receiving HAI of FOLFOX or TOMOX.
Figure 3
Figure 3
PFS since randomization for patients receiving HAI of FOLFOX or TOMOX.

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2021) 71:209–49. doi: 10.3322/caac.21660
    1. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. . Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol: Off J Am Soc Clin Oncol (2009) 27:3677–83. doi: 10.1200/jco.2008.20.5278
    1. Kemeny NE, Melendez FD, Capanu M, Paty PB, Fong Y, Schwartz LH, et al. . Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol: Off J Am Soc Clin Oncol (2009) 27:3465–71. doi: 10.1200/jco.2008.20.1301
    1. Goere D, Deshaies I, de Baere T, Boige V, Malka D, Dumont F, et al. . Prolonged survival of initially unresectable hepatic colorectal cancer patients treated with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases. Ann Surg (2010) 251:686–91. doi: 10.1097/SLA.0b013e3181d35983
    1. D’Angelica MI, Correa-Gallego C, Paty PB, Cercek A, Gewirtz AN, Chou JF, et al. . 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 (2015) 261:353–60. doi: 10.1097/SLA.0000000000000614
    1. Lévi FA, Boige V, Hebbar M, Smith D, Lepère C, Focan C, et al. . 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 (2016) 27:267–74. doi: 10.1093/annonc/mdv548
    1. Ackerman NB. The blood supply of experimental liver metastases. IV Changes Vasc Increasing Tumor Growth Surg (1974) 75:589–96.
    1. Kemeny NE, Niedzwiecki D, Hollis DR, Lenz H-J, Warren RS, Naughton MJ, et al. . 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 (2006) 24:1395–403. doi: 10.1200/jco.2005.03.8166
    1. Gallagher DJ, Capanu M, Raggio G, Kemeny N. Hepatic arterial infusion plus systemic irinotecan in patients with unresectable hepatic metastases from colorectal cancer previously treated with systemic oxaliplatin: a retrospective analysis. Ann Oncol (2007) 18:1995–9. doi: 10.1093/annonc/mdm405
    1. Cercek A, Boucher TM, Gluskin JS, Aguilo A, Chou JF, Connell LC, et al. . Response rates of hepatic arterial infusion pump therapy in patients with metastatic colorectal cancer liver metastases refractory to all standard chemotherapies. J Surg Oncol (2016) 114:655–63. doi: 10.1002/jso.24399
    1. Lim A, Le Sourd S, Senellart H, Luet D, Douane F, Perret C, et al. . Hepatic arterial infusion chemotherapy for unresectable liver metastases of colorectal cancer: A multicenter retrospective study. Clin Colorectal Cancer (2017) 16:308–15. doi: 10.1016/j.clcc.2017.03.003
    1. Ensminger WD, Rosowsky A, Raso V, Levin DC, Glode M, Come S, et al. . A clinical-pharmacological evaluation of hepatic arterial infusions of 5-fluoro-2’-deoxyuridine and 5-fluorouracil. Cancer Res (1978) 38:3784–92.
    1. Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, et al. . Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med (1999) 341:2039–48. doi: 10.1056/nejm199912303412702
    1. Groot Koerkamp B, Sadot E, Kemeny NE, Gonen M, Leal JN, Allen PJ, et al. . Perioperative hepatic arterial infusion pump chemotherapy is associated with longer survival after resection of colorectal liver metastases: A propensity score analysis. J Clin Oncol: Off J Am Soc Clin Oncol (2017) 35:1938–44. doi: 10.1200/jco.2016.71.8346
    1. Hohn DC, Stagg RJ, Friedman MA, Hannigan JF, Jr., Rayner A, Ignoffo RJ, et al. . A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the northern California oncology group trial. J Clin Oncol: Off J Am Soc Clin Oncol (1989) 7:1646–54. doi: 10.1200/jco.1989.7.11.1646
    1. Kemeny NE, Jarnagin WR, Capanu M, Fong Y, Gewirtz AN, Dematteo RP, et al. . Randomized phase II trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer. J Clin Oncol: Off J Am Soc Clin Oncol (2011) 29:884–9. doi: 10.1200/JCO.2010.32.5977
    1. Cercek A, D’Angelica M, Power D, Capanu M, Gewirtz A, Patel D, et al. . Floxuridine hepatic arterial infusion associated biliary toxicity is increased by concurrent administration of systemic bevacizumab. Ann Surg Oncol (2014) 21:479–86. doi: 10.1245/s10434-013-3275-0
    1. Goéré D, Benhaim L, Bonnet S, Malka D, Faron M, Elias D, et al. . Adjuvant chemotherapy after resection of colorectal liver metastases in patients at high risk of hepatic recurrence. Ann Surg (2013) 257:114–20. doi: 10.1097/SLA.0b013e31827b9005
    1. Ghiringhelli F, Vincent J, Bengrine L, Borg C, Jouve JL, Loffroy R, et al. . 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. J Cancer Res Clin Oncol (2019) 145:2357–63. doi: 10.1007/s00432-019-02970-8
    1. Guo JH, Zhang HY, Gao S, Zhang PJ, Li XT, Chen H, et al. . Hepatic artery infusion with raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis. World J Gastroenterol (2017) 23:1406–11. doi: 10.3748/wjg.v23.i8.1406
    1. Lakatos E. Sample sizes based on the log-rank statistic in complex clinical trials. Biometrics (1988) 44:229–41. doi: 10.2307/2531910
    1. Lakatos E. Designing complex group sequential survival trials. Stat Med (2002) 21:1969–89. doi: 10.1002/sim.1193
    1. Boige V, Malka D, Elias D, Castaing M, De Baere T, Goere D, et al. . Hepatic arterial infusion of oxaliplatin and intravenous LV5FU2 in unresectable liver metastases from colorectal cancer after systemic chemotherapy failure. Ann Surg Oncol (2008) 15:219–26. doi: 10.1245/s10434-007-9581-7
    1. Tsimberidou AM, Leick MB, Lim J, Fu S, Wheler J, Piha-Paul SA, et al. . Dose-finding study of hepatic arterial infusion of oxaliplatin-based treatment in patients with advanced solid tumors metastatic to the liver. Cancer Chemother Pharmacol (2013) 71:389–97. doi: 10.1007/s00280-012-2014-8
    1. Huang M, Yang Y, Zhu X, Chen Z, Zhang W, Wang C, et al. . A prospective phase II study of raltitrexed combined with s-1 as salvage treatment for patients with refractory metastatic colorectal cancer. Asia Pac J Clin Oncol (2021) 17:513–21. doi: 10.1111/ajco.13511
    1. Longo-Muñoz F, Argiles G, Tabernero J, Cervantes A, Gravalos C, Pericay C, et al. . Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial. Clin Trans Oncol: Off Publ Fed Span Oncol Soc Natl Cancer Inst Mex (2017) 19:227–35. doi: 10.1007/s12094-016-1528-7
    1. Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. . Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med (2015) 372:1909–19. doi: 10.1056/NEJMoa1414325
    1. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. . Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet (Lond Engl) (2013) 381:303–12. doi: 10.1016/s0140-6736(12)61900-x
    1. Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. . Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol (2015) 16:619–29. doi: 10.1016/s1470-2045(15)70156-7
    1. Venook AP, Niedzwiecki D, Lenz H-J, Innocenti F, Mahoney MR, O’Neil BH, et al. . CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol (2014) 32:LBA3–LBA. doi: 10.1200/jco.2014.32.18_suppl.lba3
    1. Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, et al. . Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: The open-label, randomized, phase III TAILOR trial. J Clin Oncol: Off J Am Soc Clin Oncol (2018) 36:3031–9. doi: 10.1200/jco.2018.78.3183
    1. Karapetis CS, Jonker D, Daneshmand M, Hanson JE, O’Callaghan CJ, Marginean C, et al. . PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer–results from NCIC CTG/AGITG CO. 17 Clin Cancer Res: an Off J Am Assoc Cancer Res (2014) 20:744–53. doi: 10.1158/1078-0432.ccr-13-0606
    1. Pietrantonio F, Petrelli F, Coinu A, Di Bartolomeo M, Borgonovo K, Maggi C, et al. . Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer (Oxf Engl: 1990) (2015) 51:587–94. doi: 10.1016/j.ejca.2015.01.054
    1. Grothey A, Sugrue MM, Purdie DM, Dong W, Sargent D, Hedrick E, et al. . Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: Results from a Large observational cohort study (BRiTE). J Clin Oncol (2008) 26:5326–34. doi: 10.1200/jco.2008.16.3212
    1. Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, et al. . Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol (2013) 14:29–37. doi: 10.1016/s1470-2045(12)70477-1
    1. Sperling J, Schäfer T, Ziemann C, Benz-Weiber A, Kollmar O, Schilling MK, et al. . Hepatic arterial infusion of bevacizumab in combination with oxaliplatin reduces tumor growth in a rat model of colorectal liver metastases. Clin Exp Metastasis (2012) 29:91–9. doi: 10.1007/s10585-011-9432-6
    1. Sperling J, Brandhorst D, Schäfer T, Ziemann C, Benz-Weißer A, Scheuer C, et al. . Liver-directed chemotherapy of cetuximab and bevacizumab in combination with oxaliplatin is more effective to inhibit tumor growth of CC531 colorectal rat liver metastases than systemic chemotherapy. Clin Exp Metastasis (2013) 30:447–55. doi: 10.1007/s10585-012-9550-9
    1. Boilève A, De Cuyper A, Larive A, Mahjoubi L, Najdawi M, Tazdait M, et al. . Hepatic arterial infusion of oxaliplatin plus systemic chemotherapy and targeted therapy for unresectable colorectal liver metastases. Eur J Cancer (Oxf Engl: 1990) (2020) 138:89–98. doi: 10.1016/j.ejca.2020.07.022

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