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Hepatic Arterial Infusion: A Treatment at the "End of an Era"?

Derek G. Power, Gregory D. Leonard

Department of Medical Oncology, Waterford Regional Hospital, Waterford, Ireland

To the Editor:

We read with great interest the article by Mocellin et al¹ reporting their meta-analysis of hepatic arterial infusion (HAI) for unresectable liver confined metastases from colorectal cancer and concluding that this treatment has now reached the "end of an era." The authors acknowledge that the 10 randomized trials consistently show a superior response rate compared with era-standard systemic fluoropyrimidine-based chemotherapy (42.9% v 18.4%), but state that this treatment is of "no clinical value" compared with response rates seen with modern systemic treatments. In patients with liver-only, but unresectable, metastatic disease, maximizing response rate in an attempt to render patients resectable is the holy grail for oncologists.² Modern systemic therapy using triplet combination chemotherapy and the addition of biologics has improved response rates, but these response rates are still inferior to those demonstrated using HAI in combination with modern systemic chemotherapy.³ HAI in combination with systemic chemotherapy has been shown to be safe, response rates of up to 89% are reported,⁴ and there are increased pathologic response rates.^5,6 These responses have significant "clinical value" considering that resection rates of 45% in clearly unresectable pretreated patients were seen.^7-9 HAI using oxaliplatin in combination with systemic fluoropyrimidines has also resulted in high response rates and resection in previously unresectable patients.^10,11

Most neoadjuvant data for HAI are in patients who have been heavily pretreated, yet response rates appear to exceed those that would be seen using systemic therapy in the second- or third-line setting.^4,12 This apparent tumor resensitization to previously inactive chemotherapy may be analogous to the combination of cetuximab and irinotecan in patients who had previous disease progression while taking irinotecan,¹³ and requires further investigation.

Similarly in the adjuvant setting, fluoropyrimidine-based HAI has an evolving role. A 10-year survival rate of 41% for patients treated with HAI floxuridine/dexamethasone combined with systemic fluorouracil/leucovorin versus 27.2% for those treated with adjuvant systemic fluorouracil/leucovorin alone has been demonstrated.^14,15 HAI floxuridine in combination with systemic irinotecan postresection has shown a 2-year survival rate of 89%.¹⁶ Oxaliplatin administered via HAI has been reported to decrease rates of liver recurrence to 38% at 3 years postresection.⁵

The authors of this meta-analysis state that HAI alone has no role for the treatment of unresectable liver metastases. This may be the case, but the overwhelming impression of their analysis is that HAI is a treatment modality at "the end of an era." In contrast, we feel that recent literature supports HAI therapy as an evolving tool in combination with systemic chemotherapy, particularly with the aim of cure in patients with liver-only metastatic disease, either through increased response rates in the neoadjuvant setting or post-hepatic resection as adjuvant therapy.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

NOTES

published online ahead of print at www.jco.org on April 28, 2008

REFERENCES

1. Mocellin S, Pilati P, Lise M, et al: Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: The end of an era? J Clin Oncol 25:5649-5654, 2007[Abstract/Free Full Text]

2. Folprecht G, Grothey A, Alberts S, et al: Neoadjuvant treatment of unresectable colorectal liver metastases: Correlation between tumour response and resection rates. Ann Oncol 16:1311-1319, 2005[Abstract/Free Full Text]

3. Mandalà M, Mosconi S, Quadri A, et al: Neoadjuvant chemotherapy for patients with liver metastases from colorectal cancer. Expert Rev Anticancer Ther 7:887-897, 2007[CrossRef][Medline]

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 23:4888-4896, 2005[Abstract/Free Full Text]

5. Elias D, Goere D, Boige V, et al: Outcome of posthepatectomy: Missing colorectal liver metastases after complete response to chemotherapy—Impact of adjuvant intra-arterial hepatic oxaliplatin. Ann Surg Oncol 14:3188-3194, 2007[CrossRef][Medline]

6. Taylor RA, White RR, Kemeny N, et al: Predictors of a true complete response in colorectal liver metastases that disappear radiographically following chemotherapy. J Clin Oncol 25:178s 2007 (suppl; abstr 4058)

7. Gallagher DJ, Capanu M, Raggio G, et al: 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 18:1995-1999, 2007[Abstract/Free Full Text]

8. Huitzil FD, Capanu M, Paty P, et al: Predictive factors for resection of unresectable metastases from colorectal cancer in patients treated with hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (DEX) plus IV oxaliplatin (Oxali) and irinotecan (CPT). Presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 25-27, 2008, Orlando, FL (abstr 361)

9. Shitara K, Munakata M, Kudo T, et al: Combination chemotherapy with hepatic arterial infusion of 5-fluorouracil (5-FU) and systemic irinotecan (CPT-11) in patients with unresectable liver metastases from colorectal cancer [Japanese]. Gan To Kagaku Ryoho 33:2033-2037, 2006[Medline]

10. Boige V, Malka D, Elias D, et al: Hepatic arterial infusion of oxaliplatin and intravenous LV5FU2 in unresectable liver metastases from colorectal cancer after systemic chemotherapy failure. Ann Surg Oncol 15:219-226, 2007[CrossRef][Medline]

11. Ducreux M, Ychou M, Laplanche A, et al: 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 23:4881-4887, 2005[Abstract/Free Full Text]

12. 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 19:2687-2695, 2001[Abstract/Free Full Text]

13. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004[Abstract/Free Full Text]

14. 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 341:2039-2048, 1999[Abstract/Free Full Text]

15. Kemeny NE, Gonen M: Hepatic arterial infusion after liver resection. N Engl J Med 352:734-735, 2005[Free Full Text]

16. 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 21:3303-3309, 2003[Abstract/Free Full Text]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Power, D. G. Articles by Leonard, G. D. Search for Related Content PubMed Articles by Power, D. G. Articles by Leonard, G. D. Social Bookmarking                            What's this?