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01-07-2011 | Hepatobiliary Tumors

Selective Intra-arterial Chemotherapy with Floxuridine as Second- or Third-Line Approach in Patients with Unresectable Colorectal Liver Metastases

Authors: Panagiotis Samaras, MD, S. Breitenstein, MD, S. R. Haile, MD, F. Stenner-Liewen, MD, S. Heinrich, MD, J. Feilchenfeldt, MD, C. Renner, MD, A. Knuth, MD, B. C. Pestalozzi, MD, P. A. Clavien, MD, PhD

Published in: Annals of Surgical Oncology | Issue 7/2011

Abstract

Background

An outcome assessment was performed of patients with unresectable colorectal liver metastases (CRLM) treated in second or third line with floxuridine (FUDR)-based hepatic artery infusion (HAI).

Methods

Twenty-three patients who were pretreated with systemic (immuno)chemotherapy received FUDR-HAI alone or combined with systemic chemotherapy. We reviewed patient charts and our prospective patient database for survival and associated risk factors.

Results

Patients received FUDR-HAI for unresectable CRLM from January 2000 to September 2010. Twelve patients (52%) received concurrent systemic chemotherapy. Median overall survival (OS), progression-free survival (PFS), and hepatic PFS were 15.6 months (range, 2.5–55.7 months), 3.9 months (range, 0.7–55.7 months), and 5.5 months (range, 1.6–55.7 months), respectively. The liver resection rate after HAI was 35%. PFS was better in patients undergoing secondary resection than in patients without resection (hazard ratio [HR] 0.21; 95% confidence interval [95% CI] 0.07–0.66; P = 0.0034), while OS showed a trend toward improvement (HR 0.4; 95% CI 0.13–1.2; P = 0.09). No differences were observed in OS (P = 0.69) or PFS (P = 0.086) in patients who received FUDR-HAI alone compared with patients treated with combined regional and systemic chemotherapy. No statistically significant differences were seen in patients previously treated with one chemotherapy line compared with patients treated with two lines. Presence of extrahepatic disease was a negative risk factor for PFS (liver-only disease: HR 0.03; 95% CI 0.0032–0.28; P < 0.0001). Toxicities were manageable with dose modifications and supportive measures.

Conclusions

FUDR-HAI improves PFS and results in a trend toward improved OS in selected patients able to undergo liver resection after tumor is downsized.

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRef

Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol. 1997;15:938–46.PubMed

Clarkson B, Young C, Dierick W, et al. Effects of continuous hepatic artery infusion of antimetabolites on primary and metastatic cancer of the liver. Cancer. 1962;15:472–88.PubMedCrossRef

Sullivan RD, Norcross JW, Watkins E Jr. Chemotherapy of metastatic liver cancer by prolonged hepatic-artery infusion. N Engl J Med. 1964;270:321–7.PubMedCrossRef

Ensminger WD. Intrahepatic arterial infusion of chemotherapy: pharmacologic principles. Semin Oncol. 2002;29:119–25.PubMedCrossRef

Kemeny N, Daly J, Reichman B, et al. Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized trial. Ann Intern Med. 1987;107:459–65.

Kemeny NE, Niedzwiecki D, Hollis DR, 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.PubMedCrossRef

Rougier P, Laplanche A, Huguier M, et al. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol. 1992;10:1112–8.PubMed

Clavien PA, Selzner N, Morse M, Selzner M, Paulson E. Downstaging of hepatocellular carcinoma and liver metastases from colorectal cancer by selective intra-arterial chemotherapy. Surgery. 2002;131:433–42.PubMedCrossRef

10.

Tang ZY, Zhou XD, Ma ZC, et al. Downstaging followed by resection plays a role in improving prognosis of unresectable hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2004;3:495–8.PubMed

11.

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;341:2039–48.PubMedCrossRef

12.

Lorenz M, Muller HH, Schramm H, et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg. 1998;228:756–62.PubMedCrossRef

13.

Tono T, Hasuike Y, Ohzato H, Takatsuka Y, Kikkawa N. Limited but definite efficacy of prophylactic hepatic arterial infusion chemotherapy after curative resection of colorectal liver metastases: a randomized study. Cancer. 2000;88:1549–56.PubMedCrossRef

14.

Lygidakis NJ, Sgourakis G, Vlachos L, et al. Metastatic liver disease of colorectal origin: the value of locoregional immunochemotherapy combined with systemic chemotherapy following liver resection. Results of a prospective randomized study. Hepatogastroenterology. 2001;48:1685–91.

15.

Pilati P, Mammano E, Mocellin S, et al. Hepatic arterial infusion for unresectable colorectal liver metastases combined or not with systemic chemotherapy. Anticancer Res. 2009;29:4139–44.PubMed

16.

Selzner N, Pestalozzi BC, Kadry Z, et al. Downstaging colorectal liver metastases by concomitant unilateral portal vein ligation and selective intra-arterial chemotherapy. Br J Surg. 2006;93:587–92.PubMedCrossRef

17.

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;11:38–47.PubMedCrossRef

18.

Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25:1670–6.PubMedCrossRef

19.

Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.PubMedCrossRef

20.

Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.PubMedCrossRef

21.

Mocellin S, Pilati P, Lise M, Nitti D. Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J Clin Oncol. 2007;25:5649–54.PubMedCrossRef

22.

Pestalozzi BC, Gruttadauria S, Clavien PA. Hepatic arterial infusion: the beginning of the combination era. J Clin Oncol. 2008;26:2231–2.PubMedCrossRef

23.

Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–13.PubMedCrossRef

24.

Khatri VP, Petrelli NJ, Belghiti J. Extending the frontiers of surgical therapy for hepatic colorectal metastases: is there a limit? J Clin Oncol. 2005;23:8490–9.PubMedCrossRef

25.

Clavien PA, Petrowsky H, DeOliveira ML, Graf R. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med. 2007;356:1545–59.PubMedCrossRef

26.

Watkins E Jr, Khazei AM, Nahra KS. Surgical basis for arterial infusion chemotherapy of disseminated carcinoma of the liver. Surg Gynecol Obstet. 1970;130:581–605.PubMed

27.

Rayner AA, Kerlan RK, Stagg RJ, Price DC, Hohn DC. Total hepatic arterial perfusion after occlusion of variant lobar vessels: implications for hepatic arterial chemotherapy. Surgery. 1986;99:708–15.PubMed

28.

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;21:3303–9.PubMedCrossRef

29.

Kaplan E, Meier, P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

30.

Cox D. Regression models and life tables. J R Stat Soc Ser B. 1972:197–220.

31.

Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.PubMedCrossRef

32.

Rothenberg ML, Cox JV, Butts C, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008;19:1720–6.PubMedCrossRef

33.

Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–44.PubMedCrossRef

34.

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;69:327–34.PubMedCrossRef

35.

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.PubMedCrossRef

36.

Chang AE, Schneider PD, Sugarbaker PH, et al. A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg. 1987;206:685–93.PubMedCrossRef

37.

Hohn DC, Stagg RJ, Friedman MA, 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. 1989;7:1646–54.PubMed

38.

Kemeny N, Gonen M, Sullivan D, et al. Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer. J Clin Oncol. 2001;19:2687–95.PubMed

39.

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;23:4888–96.PubMedCrossRef

40.

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;27:3465–71.PubMedCrossRef

41.

Allen PJ, Nissan A, Picon AI, et al. 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. 2005;201:57–65.PubMedCrossRef

42.

Heinrich S, Petrowsky H, Schwinnen I, et al. Technical complications of continuous intra-arterial chemotherapy with 5-fluorodeoxyuridine and 5-fluorouracil for colorectal liver metastases. Surgery. 2003;133:40–8.PubMedCrossRef

Title: Selective Intra-arterial Chemotherapy with Floxuridine as Second- or Third-Line Approach in Patients with Unresectable Colorectal Liver Metastases
Authors: Panagiotis Samaras, MD
S. Breitenstein, MD
S. R. Haile, MD
F. Stenner-Liewen, MD
S. Heinrich, MD
J. Feilchenfeldt, MD
C. Renner, MD
A. Knuth, MD
B. C. Pestalozzi, MD
P. A. Clavien, MD, PhD
Publication date: 01-07-2011
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 7/2011
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-010-1505-2

At a glance: The STEP trials

Springer Medicine

Selective Intra-arterial Chemotherapy with Floxuridine as Second- or Third-Line Approach in Patients with Unresectable Colorectal Liver Metastases

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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