World Journal of Surgery

, Volume 37, Issue 8, pp 1919–1926 | Cite as

Unresectable Colorectal Liver Metastases: The Safety and Efficacy of Conversion Therapy Using Hepatic Arterial Infusion Immunochemotherapy with 5-Fluorouracil and Polyethylene Glycol-Interferon α-2a

  • Takuya Nakai
  • Kiyotaka Okuno
  • Hiroshi Kitaguchi
  • Hajime Ishikawa
  • Mitsuo Yamasaki
Article

Abstract

Background

Hepatic arterial infusion (HAI) or systemic chemotherapy has been used to treat unresectable colorectal liver metastases. The prognosis of the disease in recent years has been improved because chemotherapy is performed before hepatectomy to reduce tumor size (conversion therapy). The purpose of this study was to investigate the safety and efficacy of conversion therapy following HAI immunochemotherapy.

Methods

Hepatic arterial infusion of 5-fluorouracil (5-FU)/polyethylene glycol (PEG)-IFNα-2a was performed in 21 patients. The primary endpoint was the safety of HAI and hepatectomy. The secondary endpoints were response rate, rate of conversion to hepatectomy, survival rate, and prognostic factors.

Results

With regard to side effects, drugs were discontinued temporarily in one patient because of a decrease in white blood cell count; however, other patients continued chemotherapy. The response rate with HAI was 61.9 %, and the conversion rate was 38.1 %. Hepatectomy was completed successfully without mortality. Median progression-free survival (PFS) was 11.5 months (with and without conversion, 16.7 and 4.8 months, respectively; p = 0.021). Median overall survival was 34.6 months (with and without conversion, 48.4 and 26.6 months, respectively; p = 0.003). Prognosis was poor when the number of metastatic tumors was ≥10 [PFS: hazard ratio (HR) 32.21, p = 0.003; overall survival (OS): HR 9.13, p = 0.07], but prognosis improved after hepatectomy (OS: HR 0.08, p = 0.09).

Conclusions

Hepatic arterial infusion immunochemotherapy with 5-FU/PEG-IFNα-2a was performed safely without major side effects. Prognosis is expected to improve after successful conversion to hepatectomy.

References

  1. 1.
    Abdalla EK, Adam R, Bilchik AJ, Jack D, Vauthey JN, Mahvi D (2006) Improving respectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 13:1271–1280PubMedCrossRefGoogle Scholar
  2. 2.
    Adam R, Delvart V, Pascal G et al (2004) Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 240:644–658PubMedCrossRefGoogle Scholar
  3. 3.
    Ensminger WD, Gyves JW (1983) Clinical pharmacology of hepatic arterial chemotherapy. Semin Oncol 10:176–182PubMedGoogle Scholar
  4. 4.
    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 24:1395–1403PubMedCrossRefGoogle Scholar
  5. 5.
    Okuno K, Yasutomi M, Kon M et al (1999) Intrahepatic interleukin-2 with chemotherapy for unresectable liver metastases: a randomized multicenter trial. Hepato-Gastroenterol 46:1116–1121Google Scholar
  6. 6.
    Wadler S, Schwarts EL, Goldman M et al (1989) Fluorouracil and recombinant alfa-2a-interferon: active regimen against advanced colorectal carcinoma. J Clin Oncol 7:1769–1775PubMedGoogle Scholar
  7. 7.
    Pohlen U, Rieger H, Mansmann U et al (2006) Hepatic arterial infusion. Comparison of 5-fluorouracil, folinic acid, Interferon alpha-2b and degradable starch microspheres versus 5-fluorouracil and folinic acid in patients with non-resectable colorectal liver metastases. Anticancer Res 26:3957–3964PubMedGoogle Scholar
  8. 8.
    Tanaka T, Arai Y, Inaba Y et al (2003) Radiologic placement of side-Foley catheter with tip fixation for hepatic arterial infusion chemotherapy. J Vasc Interv Radiol 14:64–68CrossRefGoogle Scholar
  9. 9.
    Arai Y, Takeuchi Y, Inaba Y et al (2007) Percutaneous catheter placement for hepatic arterial infusion chemotherapy. Tech Vasc Interv Radiol 10:30–37PubMedCrossRefGoogle Scholar
  10. 10.
    Trotti A, Colevas AD, Setser A et al (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176–181PubMedCrossRefGoogle Scholar
  11. 11.
    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 92:205–216PubMedCrossRefGoogle Scholar
  12. 12.
    Power DG, Healey-Bird BR, Kemeny NE (2008) Regional chemotherapy for liver-limited metastatic colorectal cancer. Clin Colorectal Cancer 7:247–259PubMedCrossRefGoogle Scholar
  13. 13.
    Kingham TP, D’Angelica M, Kemeny NE (2010) Role of intra-arterial hepatic chemotherapy in the treatment of colorectal cancer metastases. J Surg Oncol 102:988–995PubMedCrossRefGoogle Scholar
  14. 14.
    Chu E, Zinn S, Boarman D et al (1990) Interaction of γ interferon and 5-fluorouracil in the H630 human colon carcinoma cell line. Cancer Res 50:5834–5840PubMedGoogle Scholar
  15. 15.
    van der Wilt CL, Smid K, Aherne GW et al (1997) Biochemical mechanisms of interferon modulation of 5-fluorouracil activity in colon cancer cells. Eur J Cancer 33:471–478PubMedCrossRefGoogle Scholar
  16. 16.
    Luxon BA, Grace M, Brassard D (2002) Pegylated interferon for the treatment of chronic hepatitis C infection. Clin Ther 24:1363–1383PubMedCrossRefGoogle Scholar
  17. 17.
    Martin NE, Sy S, Modi M (2000) The enhanced efficacy of PEG(40K)-IFN-2a(PEGASYS) in interferon by a branched methoxy 40 kDa polyethylene glycol(PEG) moiety. 9th international congress on infection diseases, Buenos Aires, 10–13 Apr 2000Google Scholar
  18. 18.
    Curley SA, Chase JL, Roh MS et al (1993) Technical considerations and complications associated with the placement of 180 implantable hepatic arterial infusion devices. Surgery 114:928–935PubMedGoogle Scholar
  19. 19.
    Heinrich S, Petrowsky H, Schwinnen I et al (2003) Technical complications of continuous intra-arterial chemotherapy with 5-fluorodeoxyuridine and 5-fluorouracil for colorectal liver metastases. Surgery 133:40–48PubMedCrossRefGoogle Scholar
  20. 20.
    Allen PJ, Nissan A, Picon AI et al (2005) Technical complications and durability of hepatic artery infusion pumps for unresectable colorectal liver metastases: an institutional experience of 544 consecutive cases. J Am Coll Surg 201:57–65PubMedCrossRefGoogle Scholar
  21. 21.
    Kemeny NE, Melendes FDH, Capaun M et al (2009) Conversion to Resectability using hepatic arterial infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol 27:3465–3471PubMedCrossRefGoogle Scholar
  22. 22.
    Bismuth H, Adam R, Levi F et al (1996) Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 224:509–522PubMedCrossRefGoogle Scholar
  23. 23.
    Tanaka K, Adam R, Shimada H et al (2003) Role of neoadjuvant chemotherapy in the treatment of multiple colorectal metastases to the liver. Br J Surg 90:963–969PubMedCrossRefGoogle Scholar
  24. 24.
    Pawlik TM, Olino K, Gleisner AL et al (2007) Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg 11:860–868PubMedCrossRefGoogle Scholar
  25. 25.
    de Gramont A, Figer A, Seymour M et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947PubMedGoogle Scholar
  26. 26.
    Adam R, Pascal G, Castaing D et al (2004) Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg 240:1052–1064PubMedCrossRefGoogle Scholar
  27. 27.
    Folprecht G, Gruenberger T, Bechstein WO et al (2009) Tumor response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomized phase 2 trial. Lancet Oncol 24:38–47Google Scholar
  28. 28.
    Rubbia-Brandt L, Audard V, Sartoretti P et al (2004) Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 15:460–466PubMedCrossRefGoogle Scholar
  29. 29.
    Nakano H, Oussoultzoglou E, Rosso E et al (2008) Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg 247:118–124PubMedCrossRefGoogle Scholar
  30. 30.
    Fong Y, Bentrem DJ (2006) Chemotherapy-associated steatohepatitis costs. Ann Surg 243:8–9PubMedCrossRefGoogle Scholar
  31. 31.
    Vauthey JN, Pawlik TM, Ribero D et al (2006) Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 24:2065–2072PubMedCrossRefGoogle Scholar
  32. 32.
    Lorenz M, Muller HH (2000) Randomized multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion versus fluorodeoxyuridine administered via hepatic arterial infusion in patients with nonresectable liver metastases from colorectal carcinoma. J Clin Oncol 18:243–254PubMedGoogle Scholar
  33. 33.
    Kerr DJ, McArdle CS, Ledermann J et al (2003) Intrahepatic arterial versus intervenous fluorouracil and folic acid for colorectal cancer liver metastases: a multicentre randomized trial. Lancet 361:368–373PubMedCrossRefGoogle Scholar
  34. 34.
    Grothey A, Sargent D (2005) Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 23:9441–9442PubMedCrossRefGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2013

Authors and Affiliations

  • Takuya Nakai
    • 1
  • Kiyotaka Okuno
    • 1
  • Hiroshi Kitaguchi
    • 1
  • Hajime Ishikawa
    • 1
  • Mitsuo Yamasaki
    • 1
  1. 1.Department of Surgery, Faculty of MedicineKinki UniversityOsaka-SayamaJapan

Personalised recommendations