Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1149-1151
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.09.9440
In Reply
Wendy R. Cornett,
Linda M. McCall,
Rebecca P. Petersen,
James E. Herndon, II,
Douglas S. Tyler
Duke University Medical Center, Durham, NC
We appreciate the opportunity to respond to the questions raised by Drs Garrido, Ponz, and Espinos regarding our reporting of the results from the American College of Surgeons Oncology Group trial Z0020 in the Journal of Clinical Oncology.1 These authors suggest that the way the data from this trial was analyzed and presented in the original article may have obscured a potential benefit for patients undergoing regional treatment with melphalan plus tumor necrosis factor (TNF). We tend to agree that usually an intent-to-treat analysis is the best way to begin evaluating data from a trial such as Z0020. However, several patients did drop out of the analysis before the 3- and 6-month review as summarized in Table 1. Because roughly equal numbers of patients were excluded from both arms, we felt that presenting data based on who actually did receive the treatment and were available for follow-up would, in this study, provide a better picture of the actual effectiveness of each treatment arm. To address this question, however, we did reprocess the study's data using an intent-to-treat analysis. As shown in Tables 2 and 3, an intent-to-treat analysis, at 3 and 6 months, respectively, demonstrated no difference in treatment arms at either time point. It is important to remember that in an intent-to-treat analysis, patients who are not available for follow-up are treated as nonresponders. Therefore, this methodology frequently lowers the true response rates that one might expect to see with a given treatment.
Although there is still no difference in response between the two treatment arms, even when an intent-to-treat analysis is carried out there does appear to be a trend toward improved response durability in the TNF arm similar to that which we originally reported. We have provided the confidence intervals (Table 4) on the 3- and 6-month response data as originally reported in the article1 as well as for the intent-to-treat analysis, which is summarized in Tables 2 and 3.
As can be seen from the reanalysis of the Z0020 data, there is no difference in our conclusion from the initial article that the addition of TNF does not improve the response rate to a melphalan-based regional perfusion in a statistically significant fashion. What was statistically significant, and clearly reported in the original article, was the three-fold increase in grade 4 adverse events in patients in the TNF arm of the study, including two amputations. While certain centers maintain their enthusiasm for TNF utilized in a regional setting, it is our opinion that this enthusiasm should be tapered by the increased morbidity associated with its use. Based on the original data and the data provided in our reanalysis, we continue to stand by our conclusions in the initial article where it is stated that "the role that TNF should have in limb perfusion, if any, remains unclear. Given the trend toward more complete responders and more durable complete responses as seen in the melphalan plus TNF arm at the 6-month follow-up time point, it is reasonable to consider exploring in future studies the addition of TNF to melphalan in the reperfusion of those patients who respond poorly or incompletely to an initial perfusion with melphalan alone."1
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The authors indicated no potential conflicts of interest.
REFERENCE
1. Cornett WR, Fraker DL, Petersen RP, et al: Prospective randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone versus melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol 24:4196-4201, 2006[Abstract/Free Full Text]
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