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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2231-2232 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.5399
Hepatic Arterial Infusion: The Beginning of the Combination EraDepartment of Oncology, University Hospital Zurich, Switzerland
Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, ISMETT–University of Pittsburgh Medical Center in Italy, Palermo Italy
Visceral and Transplant Surgery, University Hospital Zurich, Switzerland To the Editor: The December 10, 2007, issue the Journal of Clinical Oncology included a meta-analysis of hepatic arterial infusion (HAI) for unresectable liver metastases from colorectal cancer.1 The authors added the provocative question to the title: "The end of an era?" They analyzed 10 randomized trials involving 1,277 patients comparing HAI with systemic chemotherapy (SCT). In nine trials, floxuridine (FUDR) was used for HAI and one study used fluorouracil (FU) plus leucovorin. This was compared with SCT involving FUDR (seven studies) or and leucovorin (four studies). Combining the 10 studies in forest plots, the authors show a clear advantage for HAI in terms of response rate (relative risk, 2.26; 95% CI, 1.80 to 2.84), but no significant survival benefit (hazard ratio for overall survival is significantly in favor of HAI; hazard ratio, 0.90; 95% CI, 0.76 to 1.07). Based on their analysis, the authors conclude, "our work strongly underscores the lack of evidence supporting the use of fluoropyrimidine-based HAI for the treatment of patients with unresectable CRC liver metastases." We strongly disagree with this statement because fluoropyrimidine-based HAI can be readily combined with SCT in adapted doses, and because these "combined regimens" have not been adequately tested against the many currently-available systemic options involving oxaliplatin, irinotecan, as well as bevacizumab, cetuximab, and other drugs. It is entirely possible that a combination of regional and systemic drug treatment will be more effective than systemic treatment alone for downstaging initially unresectable CRC liver metastases.2 When FU, leucovorin, and oxaliplatin (FOLFOX) combinations were shown to be active for neoadjuvant treatment of unresectable liver metastases, rendering them resectable in some patients,3 we initiated a randomized phase II trial comparing FOLFOX-7 (SCT) versus a combination of HAI (FUDR) with adapted-dose FOLFOX (combined chemotherapy). This trial was approved by the local and state human investigations committees. When feasible, portal vein ligation (usually of the right portal vein) was added to the treatment plan.4 Nine patients have been randomly assigned so far: five to the standard (SCT) arm, and four to the experimental (combined chemotherapy) arm. The primary end point of the study is whether the liver is disease-free 1 year after random assignment, results for which are summarized in Table 1.
We estimated that a total of 64 patients would be needed (32 in each arm) to find a meaningful difference at a power of 0.9 (set at 25% freedom from hepatic disease in the standard arm, compared with 40% in the experimental arm). When the trial began, several other centers expressed interest to participate. Unfortunately, only two centers have assigned patients, and a third center has activated and closed it without contributing. The main reason stated by investigators for their dwindling interest was the new availability of targeted and marketed substances such as bevacizumab and cetuximab. Based on this experience, we would like to comment that HAI with FUDR may be unfashionable as a monotherapy, but the combination of HAI with SCT has not been adequately tested and remains a worthwhile investigational approach.2 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Bernhard C. Pestalozzi, Sanofi-aventis Research Funding: Bernhard C. Pestalozzi, Sanofi-aventis Expert Testimony: None Other Remuneration: None
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 2. 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 3. Adam R, Avisar E, Ariche A, et al: Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 8:347-353, 2001[Medline] 4. 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 93:587-592, 2006[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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