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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2232-2233 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.5738
In ReplySurgery Branch, Department of Oncological and Surgical Sciences, University of Padova, Padova, Italy In reply to the commentary by Pestalozzi et al regarding our meta-analysis on the role of fluoropyrimidine-based hepatic arterial infusion (HAI) in the management of unresectable liver metastases from colorectal cancer,1 we would like to point out a few considerations. First, it is noteworthy that our conclusion (ie, HAI alone cannot be recommended as a therapeutic option for patients with unresectable liver metastatic disease from colorectal cancer) is based on the meta-analysis of the 10 phase III randomized controlled trials (RCT) so far performed, which have enrolled more than 1,200 patients allocated to HAI alone or systemic chemotherapy (SCT). In contrast, Pestalozzi et al support their opinion (ie, HAI is "a worthwhile investigational approach") by describing their experience on an ongoing phase II RCT (SCT v SCT with fluoropyrimidine-based HAI), in which nine patients have been thus far enrolled. We can add that some phase I-II noncomparative trials have been completed and published on the combination of HAI with SCT,2-4 whereas no phase III RCT has ever tested the hypothesis that HAI adds any clinical benefit to modern SCT regimens (ie, including oxaliplatin, irinotecan with or without monoclonal antibodies); moreover, to the best of our knowledge, no such RCT are ongoing. In addition to underscoring the strikingly different level of evidence on which the two opinions are based, we would like also to remind readers that phase III RCTs are designed to test the efficacy of an experimental treatment to increase patients’ survival (ie, the ultimate goal of anticancer therapy) as compared with a standard treatment, whereas phase II trials are intended to assess the activity of a given regimen in terms of tumor response to treatment. Therefore, Pestalozzi et al should clarify why they mix apples and oranges when they "strongly disagree" with us on the lack of evidence of any impact of HAI alone on survival by sustaining a role of HAI (combined with SCT) in disease downstaging. In other words, it looks like Pestalozzi et al miss the point of our meta-analysis, in which we demonstrated that the available evidence is against a role of HAI alone (we did not consider HAI with SCT, as Pestalozzi et al do) in prolonging patients’ survival. Furthermore, in the Discussion section we commented on the fact that although HAI is associated with a higher tumor response rate as compared with SCT (42.9% and 18.4%, respectively1), the SCT regimens compared in the meta-analyzed RCT are clearly less active than modern SCT combinations: in particular, the tumor response rates observed with HAI are quite comparable (if not lower) than those observed with modern SCT regimens, which questions the use of fluoropyrimidine-based HAI even as a means to downstage metastatic liver disease. In conclusion, we believe that it is difficult (if not unethical) to sustain the usefulness of fluoropyrimidine-based HAI alone (which was the only focus of our meta-analysis and thus of our conclusions) as a therapeutic option in these patients. Second, as we have clearly stated in the Discussion section of the meta-analysis, we definitely agree with Pestalozzi et al that the only possible future of HAI is based on the use of this locoregional drug delivery system for the administration of drug regimens including drugs other than fluoropyrimidines (eg, oxaliplatin4,5), and/or on the combination of HAI with modern SCT regimens.2-4 In this regard, we congratulate Pestalozzi et al for conducting a randomized trial that might provide clinicians with important insights into the management of these patients. We only hope that the trial being carried out by Pestalozzi et al is designed to enable the investigators to draw meaningful conclusions. In particular, we wonder how the sample size of this phase II randomized trial was calculated. According to a classical randomized trial design for a comparison of proportions (ie, tumor response rates in the two study arms), the number of patients to be recruited is much higher than that stated by Pestalozzi et al (n = 64), as demonstrated in Figure 1. As a consequence, the statistical power of this study is likely to be much lower than that declared by Pestalozzi et al (90%), with the risk that the tumor response difference hypothesized by the investigators could not be proven due to an inadequate sample size. Quite remarkably, even a noncomparative phase II trial planned according to an optimal two-stage design would require a larger sample size (n = 99).
Overall, we are glad to see that our article—also thanks to a provocative question in its title—is fueling a debate on the use of HAI for patients with liver metastasis from colorectal cancer. We also hope that the findings of our meta-analysis will be interpreted correctly (fluoropyrimidine-based HAI alone does not improve patients’ survival) and will prompt investigators to explore novel, more effective therapeutic options that could raise the hopes of cure for patients affected with such a deadly disease. However, we are not as sure as Pestalozzi et al that a new era has already begun for HAI combined with SCT, given that the available evidence is far from adequate to draw any such conclusion. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
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. 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 3. 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 4. 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 5. Neyns B, Van Nieuwenhove Y, Aerts M, et al: Hepatic arterial infusion of oxaliplatin and L-folinic acid-modulated 5-fluorouracil for colorectal cancer liver metastases. Anticancer Res 26:611-619, 2006
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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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error < 5%, power = 90%, probability-0 = 25%, probability-1 = 40%, randomization ratio = 1:1), the required case sample size sample is 216. Any smaller sample size would be associated with a lower statistical power: in particular, a sample size of 64 (as indicated by Pestalozzi et al) is associated with power = 18%.
