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In Reply

Surgery Branch, Department of Oncological and Surgical Sciences, University of Padova, Padova, Italy

We welcome the correspondence by D'Angelica et al from Memorial Sloan-Kettering Cancer Center, one of the first institutions that promulgated the use of hepatic arterial infusion (HAI) worldwide, which led our institution to adopt this locoregional treatment for more than 20 years. We are glad to hear that "the era of HAI-based fluoropyrimidine therapy alone may have ended," and we like the idea that our meta-analysis may have contributed to make this point clear.

Nevertheless, we regret to notice that D'Angelica et al have been attracted (and ultimately distracted) more by the title ("Meta-Analysis of Hepatic Arterial Infusion for Unresectable Liver Metastases From Colorectal Cancer: The End of an Era?") than by the findings of our article. In fact, instead of focusing on the conclusion ("Currently available evidence does not support the clinical or investigational use of fluoropyrimidine-based HAI alone for the treatment of patients with unresectable CRC liver metastases, at least as a first-line therapy"), D'Angelica et al discuss HAI plus systemic chemotherapy (SCT), although our work was dedicated exclusively to fluoropyrimidine-based HAI alone.

We would like to point out some apparent contradictions and inconsistencies in the authors’ correspondence. First, regarding the statement, "the era of HAI-based fluoropyrimidine therapy alone may have ended," we are wondering what further evidence D'Angelica et al are seeking before they remove the word "may" from their statements on HAI alone.

The second point relates to the following statement: "We are not aware of any current debate regarding whether HAI chemotherapy should be used alone for unresectable metastases." Although HAI alone has been proposed as a potentially valuable therapeutic option,^1-9 this may have been supported by two meta-analyses, which concluded that HAI alone does improve survival compared with contemporary SCT.^10,11 After those meta-analyses, three other randomized controlled trials were published, prompting us to quantitatively summarize the evidence regarding the therapeutic efficacy of HAI alone by performing the meta-analysis that came to opposite findings.

Third, the authors’ statement that HAI chemotherapy alone is "a strategy long since abandoned at our institution" is not completely consistent with articles published by this group, in which HAI alone is proposed as a potentially valuable therapeutic option for patients with unresectable colorectal liver metastases or is still considered a suitable control arm for future trials.^1-5 Although the Memorial Sloan-Kettering Cancer Center may have changed their practice, as a result of these reports, investigators still propose HAI alone.^12-16

Fourth, the authors state, "It must also be acknowledged that meta-analyses of this type have inherent limitations, making firm conclusions difficult." We are unsure what other types of meta-analysis can be performed on randomized controlled trials. In our work, all reasonable subgroup/sensitivity analyses were performed, and we also addressed the cross-over issue mentioned by D'Angelica et al, but no significant result was observed.

Finally, the authors state, "Perhaps most importantly, all of the trials used HAI chemotherapy alone without systemic chemotherapy." Our meta-analysis was not about HAI plus SCT, so therefore, we did not address this issue. In the article, we did comment that the future of HAI relies on drugs other than floxuridine as well as on the combination with modern SCT.

Overall, we believe that one significant result has been achieved out of this debate, and that is to provide the scientific/oncology community with the evidence that we must move forward from HAI alone to give patients the best therapeutic option available.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

REFERENCES

1. White RR, Jarnagin WR: The role of aggressive regional therapy for colorectal liver metastases. Cancer Invest 25:458-463, 2007[CrossRef][Medline]

2. 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 24:1395-1403, 2006[Abstract/Free Full Text]

3. Leonard GD, Brenner B, Kemeny NE: Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 23:2038-2048, 2005[Abstract/Free Full Text]

4. Cohen AD, Kemeny NE: An update on hepatic arterial infusion chemotherapy for colorectal cancer. Oncologist 8:553-566, 2003[Abstract/Free Full Text]

5. Kemeny N, Fata F: Hepatic-arterial chemotherapy. Lancet Oncol 2:418-428, 2001[CrossRef][Medline]

6. Biasco G, Derenzini E, Grazi G, et al: Treatment of hepatic metastases from colorectal cancer: Many doubts, some certainties. Cancer Treat Rev 32:214-228, 2006[CrossRef][Medline]

7. Homsi J, Garrett CR: Hepatic arterial infusion of chemotherapy for hepatic metastases from colorectal cancer. Cancer Control 13:42-47, 2006[Medline]

8. Whisenant J, Venook A: Defining the role of hepatic arterial infusion chemotherapy in metastatic colorectal cancer. Oncology (Williston Park) 18:762-768, 2004[Medline]

9. Skitzki JJ, Chang AE: Hepatic artery chemotherapy for colorectal liver metastases: Technical considerations and review of clinical trials. Surg Oncol 11:123-135, 2002[CrossRef][Medline]

10. Harmantas A, Rotstein LE, Langer B: Regional versus systemic chemotherapy in the treatment of colorectal carcinoma metastatic to the liver: Is there a survival difference? Meta-analysis of the published literature. Cancer 78:1639-1645, 1996[CrossRef][Medline]

11. Meta-Analysis Group in Cancer: Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. J Natl Cancer Inst 88:252-258, 1996[Abstract/Free Full Text]

12. Iguchi T, Arai Y, Inaba Y, et al: Hepatic arterial infusion chemotherapy through a port-catheter system as preoperative initial therapy in patients with advanced liver dysfunction due to synchronous and unresectable liver metastases from colorectal cancer. Cardiovasc Intervent Radiol 31:86-90, 2008[CrossRef][Medline]

13. Hildebrandt B, Pech M, Nicolaou A, et al: Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with colorectal liver metastases: A phase II study and historical comparison with the surgical approach. BMC Cancer 7:69, 2007[CrossRef][Medline]

14. Sameshima S, Horikoshi H, Motegi K, et al: Outcomes of hepatic artery infusion therapy for hepatic metastases from colorectal carcinoma after radiological placement of infusion catheters. Eur J Surg Oncol 33:741-745, 2007[Medline]

15. Pohlen U, Rieger H, Mansmann U, et al: Hepatic arterial infusion (HAI): 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 26:3957-3964, 2006[Abstract/Free Full Text]

16. Matsuoka H, Nagaya M, Tsukikawa S, et al: Repeated hepatic intra-arterial chemotherapy based on results of anticancer drug sensitivity test in patients with synchronous hepatic metastases from colorectal cancer. Surgery 140:387-395, 2006[CrossRef][Medline]

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Related Correspondence

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