In the era of effective modern systemic chemotherapy (CT), the role of hepatic arterial infusion of fluoxuridine (HAI-FUDR) in the treatment of isolated unresectable colorectal liver metastasis (IU-CRCLM) remains controversial. This study aimed to compare the overall survival (OS) of HAI-FUDR in combination with modern systemic CT versus modern systemic CT alone in patients with IU-CRCLM.
This was a case–control study of IU-CRCLM patients who underwent HAI + modern systemic CT or modern systemic CT alone. Modern systemic CT was defined as the use of multidrug regimens containing oxaliplatin and/or irinotecan ± biologics.
Overall, 86 patients met the inclusion criteria (n = 40 for the HAI + CT group, and n = 46 for the CT-alone group). Both groups were similar in demographics, primary and stage IV tumor characteristics, and treatment-related variables (carcinoembryonic antigen, use of biologic agents, total number of lines of systemic CT administered) (all p > 0.05). Additionally, both groups were comparable with respect to liver tumor burden [median number of lesions (13.5 vs. 15), percentage of liver tumor replacement (37.5 vs. 40 %), and size of largest lesion] (all p > 0.05). Median OS in the HAI + CT group was 32.8 months compared with 15.3 months in the CT-alone group (p < 0.0001). Multivariate analysis revealed HAI + CT (hazard ratio 0.4, 95 % confidence interval 0.21–0.72; p = 0.003), Eastern Cooperative Oncology Group status, and receipt of increasing number of lines of systemic CT to be independent predictors of survival.
In this case–control study of patients with IU-CRCLM, HAI in combination with CT was associated with improved OS when compared with modern systemic CT alone.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.
Manfredi S, Lepage C, Hatem C, et al. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244(2):254–9.
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):104–17.
Masi G, Loupakis F, Pollina L, et al. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg. 2009;249(3):420–5.
Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27(11):1829–35.
Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11(1):38–47.
Wong R, Cunningham D, Barbachano Y, et al. A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann Oncol. 2011;22(9):2042–8.
Uetake H, Yasuno M, Ishiguro M, et al. A multicenter phase II trial of mFOLFOX6 plus bevacizumab to treat liver-only metastases of colorectal cancer that are unsuitable for upfront resection (TRICC0808). Ann Surg Oncol. 2015;22(3):908–15.
Folprecht G, Gruenberger T, Bechstein W, et al. Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study). Ann Oncol. 2014;25(5):1018–25.
Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol. 2005;23(36):9243–9.
Van Cutsem E, Bajetta E, Valle J, et al. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011;29(15):2004–2010.
Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506.
Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12.
Bendell JC, Nemunaitis J, Vukelja SJ, et al. Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2011;29(33):4394–400.
Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706–13.
Leal JN, Kingham TP. Hepatic artery infusion chemotherapy for liver malignancy. Surg Oncol Clin N Am. 2015;24(1):121–48.
Kemeny N, Jarnagin W, Paty P, et al. Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol. 2005;23(22):4888–96.
Kemeny NE, Melendez FDH, Capanu M, 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. 2009;27(21):3465–71.
D’Angelica MI, Correa-Gallego C, Paty PB, 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(2):353–60.
Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065–75.
Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32(21):2240–7.
Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011–9.
Venook AP, Niedzwiecki D, Lenz H-J, 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). ASCO Meeting Abstracts 2014;32(18 Suppl):LBA3.
Tarantino I, Warschkow R, Worni M, et al. Prognostic relevance of palliative primary tumor removal in 37,793 metastatic colorectal cancer patients: a population-based, propensity score-adjusted trend analysis. Ann Surg. 2015;262(1):112–20.
Gresham G, Renouf DJ, Chan M, et al. Association between palliative resection of the primary tumor and overall survival in a population-based cohort of metastatic colorectal cancer patients. Ann Surg Oncol. 2014;21(12):3917–23.
Rahbari NN, Lordick F, Fink C, et al. Resection of the primary tumour versus no resection prior to systemic therapy in patients with colon cancer and synchronous unresectable metastases (UICC stage IV): SYNCHRONOUS - a randomised controlled multicentre trial (ISRCTN30964555). BMC Cancer. 2012;12(1):1–11.
Lam-Boer J, Mol L, Verhoef C, et al. The CAIRO4 study: the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer: a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG). BMC Cancer. 2014;14:741.
Anwar S, Peter MB, Dent J, et al. Palliative excisional surgery for primary colorectal cancer in patients with incurable metastatic disease. Is there a survival benefit? A systematic review. Colorectal Dis. 2012;14(8):920-30.
D’Angelica M, Kornprat P, Gonen M, et al. Effect on outcome of recurrence patterns after hepatectomy for colorectal metastases. Ann Surg Oncol. 2011;18(4):1096-103.
Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240(4):644–57; discussion 657-8.
Ardito F, Vellone M, Cassano A, et al. Chance of cure following liver resection for initially unresectable colorectal metastases: analysis of actual 5-year survival. J Gastrointest Surg. 2013;17(2):352–9.
Barone C, Nuzzo G, Cassano A, et al. Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver metastases. Br J Cancer. 2007;97(8):1035–1039.
Skof E, Rebersek M, Hlebanja Z, et al. Capecitabine plus irinotecan (XELIRI regimen) compared to 5-FU/LV plus irinotecan (FOLFIRI regimen) as neoadjuvant treatment for patients with unresectable liver-only metastases of metastatic colorectal cancer: a randomised prospective phase II trial. BMC Cancer. 2009;9:120.
Conflict of Interest
Mashaal Dhir, Heather L. Jones, Yongli Shuai, Amber K. Clifford, Samantha Perkins, Jennifer Steve, Melissa E. Hogg, M. Haroon A. Choudry, James F. Pingpank, Matthew P. Holtzman, Herbert J. Zeh III, Nathan Bahary, David L. Bartlett, and Amer H. Zureikat have no conflicts of interest involving this work.
About this article
Cite this article
Dhir, M., Jones, H.L., Shuai, Y. et al. Hepatic Arterial Infusion in Combination with Modern Systemic Chemotherapy is Associated with Improved Survival Compared with Modern Systemic Chemotherapy Alone in Patients with Isolated Unresectable Colorectal Liver Metastases: A Case–Control Study. Ann Surg Oncol 24, 150–158 (2017). https://doi.org/10.1245/s10434-016-5418-6
- Overall Survival
- Hepatic Arterial Infusion
- Memorial Sloan Kettering Cancer Center
- Unresectable Colorectal Liver Metastasis