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Floxuridine Hepatic Arterial Infusion Associated Biliary Toxicity Is Increased by Concurrent Administration of Systemic Bevacizumab

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Systemic bevacizumab (Bev) was added to hepatic arterial infusion (HAI) floxuridine (FUDR)-based chemotherapy in three studies in an attempt to improve outcomes. A specific review of biliary toxicity was carried out.

Methods

This analysis included 203 patients from three prospective studies. The first (study A) was an adjuvant study after liver resection of colorectal metastases in which patients received HAI and systemic chemotherapy (Sys) with or without Bev. Study B comprised unresectable colorectal patients who received HAI and Sys plus Bev. Study C included patients with unresectable cholangiocarcinoma or hepatocellular carcinoma who received HAI plus systematic Bev. The outcome and toxicity of patients in studies B and C were compared with historical controls.

Results

In all three studies, the incidence of hyperbilirubinemia and biliary stent placement within 1 year of treatment was increased with the addition of Bev. In the no-Bev versus Bev groups, the placement of biliary stents was as follows: study A, 0 of 38 versus 4 of 35 patients (p = 0.05); study B, 0 of 49 versus 3 of 24 (p = 0.06); and study C, 0 of 34 versus 3 of 22 (p = 0.15). Elevation in bilirubin was noted in the no-Bev versus Bev groups: study A, 0 of 38 versus 5 of 35 patients (p = 0.02); study B, 1 of 49 versus 7 of 24 (p = 0.005); and study C, 2 of 34 versus 5 of 22 (p = 0.10). The addition of Bev did not seem to be associated with improved progression-free or overall survival.

Conclusions

The addition of Bev to HAI FUDR resulted in increased biliary toxicity in three separate studies. Although the sample sizes were small, there was no evidence of improved PFS or OS with the addition of Bev. Bev should not be combined with HAI FUDR.

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References

  1. Kemeny N, Capanu M, D’Angelica M, et al. 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. Ann Oncol. 2009; 20: 1236–1241.

    Article  CAS  PubMed  Google Scholar 

  2. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999;341:2039–2048.

    Article  CAS  PubMed  Google Scholar 

  3. Kemeny N, Jarnagin W, Gonen M, et al. Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer. J Clin Oncol. 2003;21:3303–3309.

    Article  CAS  PubMed  Google Scholar 

  4. 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;23:4888–4896.

    Article  CAS  PubMed  Google Scholar 

  5. Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy—an intergroup study. J Clin Oncol. 2002;20:1499–1505.

    Article  PubMed  Google Scholar 

  6. Ensminger WD, Gyves JW. Clinical pharmacology of hepatic arterial chemotherapy. Semin Oncol. 1983;10:176–182.

    CAS  PubMed  Google Scholar 

  7. Ensminger WD, Rosowsky A, Raso V, et al. A clinical-pharmacological evaluation of hepatic arterial infusions of 5-fluoro-2′-deoxyuridine and 5-fluorouracil. Cancer Res. 1978;38:3784–3792.

    CAS  PubMed  Google Scholar 

  8. De Jong FA, Mathijssen RH, Verweij J. Limited potential of hepatic arterial infusion of irinotecan. J Chemother. 2004; 16(Suppl 5):48–50.

    PubMed  Google Scholar 

  9. Kemeny NE, Schwartz L, Gonen M, et al. Treating primary liver cancer with hepatic arterial infusion of floxuridine and dexamethasone: does the addition of systemic bevacizumab improve results? Oncology. 2011;80:153–159.

    Article  CAS  PubMed  Google Scholar 

  10. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann Oncol. 2009; 20:1589–1595.

    Article  CAS  PubMed  Google Scholar 

  11. Ito K, Ito H, Kemeny NE, et al. Biliary sclerosis after hepatic arterial infusion pump chemotherapy for patients with colorectal cancer liver metastasis: incidence, clinical features, and risk factors. Ann Surg Oncol. 2012;19:1609–1617.

    Article  PubMed  Google Scholar 

  12. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–2019.

    Article  CAS  PubMed  Google Scholar 

  13. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342.

    Article  CAS  PubMed  Google Scholar 

  14. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.

    Article  CAS  PubMed  Google Scholar 

  15. Kemeny NE, Jarnagin WR, Capanu M, 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. 2011;29:884–889.

    Article  CAS  PubMed  Google Scholar 

  16. Kemeny NE, Melendez FD, 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;27:3465–3471.

    Article  PubMed  Google Scholar 

  17. Cercek A, Kemeny N. Hepatic arterial infusion pumps, Chapter 11. In: Goodman MD, Cercek A, Kemeny N, editors. Regional therapeutics for advanced malignancies. 2012. p. 121–131.

  18. Skitzki JJ, Chang AE. Hepatic artery chemotherapy for colorectal liver metastases: technical considerations and review of clinical trials. Surg Oncol. 2002;11:123–135.

    Article  PubMed  Google Scholar 

  19. Northover JM, Terblanche J. A new look at the arterial supply of the bile duct in man and its surgical implications. Br J Surg. 1979;66:379–384.

    Article  CAS  PubMed  Google Scholar 

  20. Zeng ZS, Zhang ZF, Sigurdson ER. Toxicity study of hepatic artery infusion chemotherapy with massive dose FUDR in rats. Surg Oncol. 1995;4:147–155.

    Article  CAS  PubMed  Google Scholar 

  21. Kemeny N, Seiter K, Niedzwiecki D, et al. A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone versus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer. Cancer. 1992;69:327–334.

    Article  CAS  PubMed  Google Scholar 

  22. Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29:11–16.

    Article  CAS  PubMed  Google Scholar 

  23. De Gramont A, Van Cutsem E, Tabernero J, Moore MJ, et al. AVANT: results from a randomized, three-arm multinational phase II study to investigate bevacizumab with either XELOX or FOLFOX4 versus FOLFOX4 alone as adjuvant treatment for colon cancer. J Clin Oncol. 2011;29(suppl 4):abstr 362.

  24. Gordon MS, Cunningham D. Managing patients treated with bevacizumab combination therapy. Oncology. 2005;69(Suppl 3):25–33.

    Article  CAS  PubMed  Google Scholar 

  25. Hurwitz H, Saini S. Bevacizumab in the treatment of metastatic colorectal cancer: safety profile and management of adverse events. Semin Oncol. 2006;33(5 Suppl 10):S26–34.

    Article  CAS  PubMed  Google Scholar 

  26. Horowitz JR, Rivard A, van der Zee R, et al. Vascular endothelial growth factor/vascular permeability factor produces nitric oxide–dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium. Arterioscler Thromb Vasc Biol. 1997;17:2793–2800.

    Article  CAS  PubMed  Google Scholar 

  27. Eremina V, Sood M, Haigh J, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003;111:707–716.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. DeLeve LD, Wang X, Hu L, et al. Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation. Am J Physiol Gastrointest Liver Physiol. 2004;287:G757–763.

    Article  CAS  PubMed  Google Scholar 

  29. Kamba T, Tam BY, Hashizume H, et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006;290:H560–576.

    Article  CAS  PubMed  Google Scholar 

  30. Lambrechts D, Carmeliet P. VEGF at the neurovascular interface: therapeutic implications for motor neuron disease. Biochim Biophys Acta. 2006;1762:1109–1121.

    Article  CAS  PubMed  Google Scholar 

  31. Rosmorduc O, Wendum D, Corpechot C, et al. Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am J Pathol. 1999;155:1065–1073.

    Article  CAS  PubMed  Google Scholar 

  32. Mourad JJ, des Guetz G, Debbabi H, et al. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol. 2008;19:927–934.

    Article  PubMed  Google Scholar 

  33. Bates DO, Jones RO. The role of vascular endothelial growth factor in wound healing. Int J Low Extrem Wounds. 2003;2:107–120.

    Article  PubMed  Google Scholar 

  34. Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol. 2005;91:173–180.

    Article  CAS  PubMed  Google Scholar 

  35. Wicherts DA, de Haas RJ, Sebagh M, et al. Impact of bevacizumab on functional recovery and histology of the liver after resection of colorectal metastases. Br J Surg. 2011;98:399–407.

    Article  CAS  PubMed  Google Scholar 

  36. Goere D, Deshaies I, de Baere T, et al. Prolonged surviacl of initially unresectable hepatic colorectal cancer patients treated with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases. Ann Surg. 2010;251:686–691.

    Article  PubMed  Google Scholar 

  37. Feng WM, Tang CW, Huang SX, et al. Prophylactic adjuvant hepatic arterial infusion chemotherapy reduced hepatic metastases from stage III colorectal cancer after curative resection. Hepatogastrenterology. 2012;59:1087–1090.

    CAS  Google Scholar 

  38. Kern W, Beckert B, Lang N, et al. 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. 2001;12:599–603.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Andrea Cercek MD, Derek Power MD, Alexandra Gewirtz BA, Dina Patel BA & Nancy E. Kemeny MD

  2. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Michael D’Angelica MD, Peter Allen MD, Yuman Fong MD, Ronald P. DeMatteo MD & William R. Jarnagin MD

  3. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Marinela Capanu PhD

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  1. Andrea Cercek MD
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Correspondence to Andrea Cercek MD.

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Cercek, A., D’Angelica, M., Power, D. et al. Floxuridine Hepatic Arterial Infusion Associated Biliary Toxicity Is Increased by Concurrent Administration of Systemic Bevacizumab. Ann Surg Oncol 21, 479–486 (2014). https://doi.org/10.1245/s10434-013-3275-0

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  • DOI: https://doi.org/10.1245/s10434-013-3275-0

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