Skip to main content

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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Fig. 1
Fig. 2

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.

    Article  PubMed  Google Scholar 

  2. 2.

    Manfredi S, Lepage C, Hatem C, et al. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244(2):254–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):104–17.

    Article  PubMed  Google Scholar 

  4. 4.

    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.

    Article  PubMed  Google Scholar 

  5. 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.

    Article  PubMed  Google Scholar 

  6. 6.

    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.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    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.

    CAS  Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. 9.

    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.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    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.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    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.

    Article  PubMed  Google Scholar 

  12. 12.

    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.

    Article  PubMed  Google Scholar 

  13. 13.

    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.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    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.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    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.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Leal JN, Kingham TP. Hepatic artery infusion chemotherapy for liver malignancy. Surg Oncol Clin N Am. 2015;24(1):121–48.

    Article  PubMed  Google Scholar 

  17. 17.

    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.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    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.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    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.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    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.

    Article  PubMed  Google Scholar 

  23. 23.

    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.

  24. 24.

    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.

    Article  PubMed  Google Scholar 

  25. 25.

    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.

    Article  PubMed  Google Scholar 

  26. 26.

    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.

    Article  Google Scholar 

  27. 27.

    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.

    Article  Google Scholar 

  28. 28.

    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.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    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.

    Article  PubMed  Google Scholar 

  30. 30.

    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.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    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.

    Article  Google Scholar 

  32. 32.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Amer H. Zureikat MD.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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

Download citation

Keywords

  • Overall Survival
  • Hepatic Arterial Infusion
  • FUDR
  • Memorial Sloan Kettering Cancer Center
  • Unresectable Colorectal Liver Metastasis