In Defense of Hepatic Arterial Infusion for Hepatic Metastases of Colorectal Cancer

Author: Nancy Kemeny MD
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The recently published NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of colorectal carcinoma1 are excellent and comprehensive, but I believe that one area deserves more comprehensive review: the use of hepatic arterial infusion (HAI) for the treatment of liver only metastases. I believe 3 circumstances exist in which HAI therapy may be considered. The first is after liver resection. Four randomized controlled trials address the use of HAI therapy after hepatic resection, and 3 of the 4 showed a significant increase in hepatic and overall disease-free survival (Table 1).2–6 The Memorial Sloan-Kettering Cancer Center (MSKCC)2 study randomized 156 patients after hepatic resection to continuous HAI of floxuridine (FUDR) and dexamethasone (Dex) combined with systemic infusion of fluorouracil (5FU) and leucovorin (LV) versus systemic infusion of 5FU/LV alone for 6 months. Updated results after a median follow-up of 10 years reported survival rates of 41% and 27% at 10 years and progression-free survivals of 31.3 and 17.2 months for the HAI + systemic infusion and systemic infusion alone groups, respectively (P = .02).3 An ECOG study4 randomized 100 patients to HAI FUDR + systemic 5FU infusion versus no further therapy after liver resection and showed an increase in progression-free survival. A randomized study of 122 patients from Greece5 reported a significant improvement in disease-free survival for HAI plus chemo-immunotherapy versus systemic infusion alone, although this was not seen in a German study6 that compared 5FU HAI administered through a port instead of a pump. House et...

The recently published NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of colorectal carcinoma1 are excellent and comprehensive, but I believe that one area deserves more comprehensive review: the use of hepatic arterial infusion (HAI) for the treatment of liver only metastases. I believe 3 circumstances exist in which HAI therapy may be considered. The first is after liver resection. Four randomized controlled trials address the use of HAI therapy after hepatic resection, and 3 of the 4 showed a significant increase in hepatic and overall disease-free survival (Table 1).26 The Memorial Sloan-Kettering Cancer Center (MSKCC)2 study randomized 156 patients after hepatic resection to continuous HAI of floxuridine (FUDR) and dexamethasone (Dex) combined with systemic infusion of fluorouracil (5FU) and leucovorin (LV) versus systemic infusion of 5FU/LV alone for 6 months. Updated results after a median follow-up of 10 years reported survival rates of 41% and 27% at 10 years and progression-free survivals of 31.3 and 17.2 months for the HAI + systemic infusion and systemic infusion alone groups, respectively (P = .02).3

An ECOG study4 randomized 100 patients to HAI FUDR + systemic 5FU infusion versus no further therapy after liver resection and showed an increase in progression-free survival. A randomized study of 122 patients from Greece5 reported a significant improvement in disease-free survival for HAI plus chemo-immunotherapy versus systemic infusion alone, although this was not seen in a German study6 that compared 5FU HAI administered through a port instead of a pump. House et al.7 evaluated patients who underwent liver resection between 2001 and 2005 and compared patients treated with HAI plus modern systemic chemotherapy versus systemic therapy alone. They reported improved survival (Figure 1) for those who received HAI.

HAI may also be considered as second-line therapy; studies show significant response rates and survival with this approach. In one study using HAI FUDR/Dex plus systemic oxaliplatin and irinotecan, the response rate in second-line therapy was 88% with a 35-month median survival.8 When compared with second-line systemic therapy, which has a low response rate and survival, HAI therapy seems to be superior and should be part of the treatment plan for patients with liver-only disease (Table 2).915

A third circumstance in which HAI should be considered is in the neoadjuvant (preoperative) setting to shrink hepatic metastases and make liver resection possible. In several systemic therapy–alone chemotherapy trials for patients with liver metastases that cannot be resected, the rate of conversion to resection is 15% to 30% in chemotherapy-naïve patients and less than 20% in previously treated patients. After concurrent neoadjuvant HAI and systemic therapy in a study of 49 patients, 57% of chemotherapy-naïve patients and 38% of previously treated patients were able to undergo resection.8

Table 1

Randomized Studies After Liver Resection: HAI + Systemic Infusion Versus Systemic Infusion Along or Control

Table 1
Figure 1
Figure 1

Between 2001 and 2005, 25 patients underwent resection of liver metastases followed by HAI FUDR + systemic infusion. Results were compared with those of 125 consecutive patients who received adjuvant folfox or folfiri after resection with a median follow-up of 43 months.

Abbreviations: FUDR, floxuridine; HAI, hepatic arterial infusion; RFS, relapse-free survival.

From House MG, Kemeny N, Jarnagin WR, et al. Comparison of adjuvant systemic chemotherapy with or without hepatic arterial infusional chemotherapy after hepatic resection for metastatic colorectal cancer [abstract]. Presented at the 2009 Gastrointestinal Cancer Symposium; January 15–17, 2009; San Francisco, California. Abstract 383.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 5; 10.6004/jnccn.2010.0039

Table 2

Second-Line Therapy for Metastatic Colorectal Cancer

Table 2

These data show the effectiveness of HAI therapy in patients with liver metatases, warranting broader consideration of this treatment option among certain patients with advanced colorectal cancer.

The ideas and viewpoints expressed in this commentary are those of the author and do not necessarily represent any policy, position, or program of the NCCN.

References

  • 1.

    Engstrom PF, Arnoletti JP, Benson AB III. NCCN clinical practice guidelines in oncology: colon cancer. J Natl Compr Canc Netw 2009;7:778831.

  • 2.

    Kemeny N, Huang Y, Cohen AM. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341:20392048.

    • Search Google Scholar
    • Export Citation
  • 3.

    Kemeny N, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med 2005;352:734735.

  • 4.

    Kemeny MM, Adak S, Gray B. 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;20:14991505.

    • Search Google Scholar
    • Export Citation
  • 5.

    Lygidakis NJ, Sgourakis G, Vlachos L. 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;48:16851691.

    • Search Google Scholar
    • Export Citation
  • 6.

    Lorenz M, Muller HH, Schramm H. 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;228:756762.

    • Search Google Scholar
    • Export Citation
  • 7.

    House MG, Kemeny N, Jarnagin WR. Comparison of adjuvant systemic chemotherapy with or without hepatic arterial infusional chemotherapy after hepatic resection for metastatic colorectal cancer [abstract]. Presented at the 2009 Gastrointestinal Cancer Symposium; January 15–17, 2009; San Francisco, California. Abstract 383.

    • Search Google Scholar
    • Export Citation
  • 8.

    Kemeny NE, Melendez FD, Capanu M. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2009;27:34653471.

    • Search Google Scholar
    • Export Citation
  • 9.

    Cunningham D, Humblet Y, Siena S. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337345.

    • Search Google Scholar
    • Export Citation
  • 10.

    Rothenberg M, Oza A, Bigelow R. Superiority of oxaliplatin and fluorouracil-leucovorin comapred with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003;21:20592069.

    • Search Google Scholar
    • Export Citation
  • 11.

    Giantonio BJ, Catalano PJ, Meropol NJ. 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;25:15391544.

    • Search Google Scholar
    • Export Citation
  • 12.

    Saltz LB, Lenz HJ, Hochster H. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. J Clin Oncol 2005;23:248S.

    • Search Google Scholar
    • Export Citation
  • 13.

    Ducreux M, Ychou M, Laplanche A. Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 2005;23:48814887.

    • Search Google Scholar
    • Export Citation
  • 14.

    Kemeny N, Eid A, Stockman J. Hepatic arterial infusion of floxuridine and dexamethasone plus high-dose mitomycin C for patients with unresectable hepatic metastases from colorectal carcinoma. J Surg Oncol 2005;91:97101.

    • Search Google Scholar
    • Export Citation
  • 15.

    Kemeny N, Gonen M, Sullivan D. 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;19:26872695.

    • Search Google Scholar
    • Export Citation

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Dr. Nancy Kemeny is a medical oncologist with a special expertise in treating colorectal cancer. During 35 years at Memorial Sloan-Kettering Cancer Center (MSKCC), she has conducted some of the first studies using drugs such as irinotecan and oxaliplatin, which are now widely used in patients with colorectal cancer, and has investigated many other drugs as well. Her main research has been on regional therapy, involving administering drugs directly into the liver through a pump. With investigators at MSKCC, she has used regional therapy in patients with liver metastases to downstage disease so that liver resection may become possible in unresectable patients and used regional therapy to decrease recurrence after liver resection. In addition to her clinical and research responsibilities at MSKCC, she is a Professor of Medicine at the Weill Medical College of Cornell University. She served as a member of the Oncology Drug Advisory Committee, and held various positions at ASCO, including Director, and Chairperson of the Membership Committee. In addition, she was Principal Investigator of a National CALGB protocol evaluating regional liver therapy versus systemic therapy in patients whose disease spread from the colon to the liver. She is also a scientific reviewer for many journals and on the editorial board of 3 journals.

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    Between 2001 and 2005, 25 patients underwent resection of liver metastases followed by HAI FUDR + systemic infusion. Results were compared with those of 125 consecutive patients who received adjuvant folfox or folfiri after resection with a median follow-up of 43 months.

    Abbreviations: FUDR, floxuridine; HAI, hepatic arterial infusion; RFS, relapse-free survival.

    From House MG, Kemeny N, Jarnagin WR, et al. Comparison of adjuvant systemic chemotherapy with or without hepatic arterial infusional chemotherapy after hepatic resection for metastatic colorectal cancer [abstract]. Presented at the 2009 Gastrointestinal Cancer Symposium; January 15–17, 2009; San Francisco, California. Abstract 383.

  • 1.

    Engstrom PF, Arnoletti JP, Benson AB III. NCCN clinical practice guidelines in oncology: colon cancer. J Natl Compr Canc Netw 2009;7:778831.

  • 2.

    Kemeny N, Huang Y, Cohen AM. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341:20392048.

    • Search Google Scholar
    • Export Citation
  • 3.

    Kemeny N, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med 2005;352:734735.

  • 4.

    Kemeny MM, Adak S, Gray B. 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;20:14991505.

    • Search Google Scholar
    • Export Citation
  • 5.

    Lygidakis NJ, Sgourakis G, Vlachos L. 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;48:16851691.

    • Search Google Scholar
    • Export Citation
  • 6.

    Lorenz M, Muller HH, Schramm H. 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;228:756762.

    • Search Google Scholar
    • Export Citation
  • 7.

    House MG, Kemeny N, Jarnagin WR. Comparison of adjuvant systemic chemotherapy with or without hepatic arterial infusional chemotherapy after hepatic resection for metastatic colorectal cancer [abstract]. Presented at the 2009 Gastrointestinal Cancer Symposium; January 15–17, 2009; San Francisco, California. Abstract 383.

    • Search Google Scholar
    • Export Citation
  • 8.

    Kemeny NE, Melendez FD, Capanu M. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2009;27:34653471.

    • Search Google Scholar
    • Export Citation
  • 9.

    Cunningham D, Humblet Y, Siena S. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337345.

    • Search Google Scholar
    • Export Citation
  • 10.

    Rothenberg M, Oza A, Bigelow R. Superiority of oxaliplatin and fluorouracil-leucovorin comapred with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003;21:20592069.

    • Search Google Scholar
    • Export Citation
  • 11.

    Giantonio BJ, Catalano PJ, Meropol NJ. 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;25:15391544.

    • Search Google Scholar
    • Export Citation
  • 12.

    Saltz LB, Lenz HJ, Hochster H. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. J Clin Oncol 2005;23:248S.

    • Search Google Scholar
    • Export Citation
  • 13.

    Ducreux M, Ychou M, Laplanche A. Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 2005;23:48814887.

    • Search Google Scholar
    • Export Citation
  • 14.

    Kemeny N, Eid A, Stockman J. Hepatic arterial infusion of floxuridine and dexamethasone plus high-dose mitomycin C for patients with unresectable hepatic metastases from colorectal carcinoma. J Surg Oncol 2005;91:97101.

    • Search Google Scholar
    • Export Citation
  • 15.

    Kemeny N, Gonen M, Sullivan D. 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;19:26872695.

    • Search Google Scholar
    • Export Citation
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