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Interleukin-2 and Histamine Dihydrochloride in Metastatic Melanoma

Melanoma Center, University of Pittsburgh, Pittsburgh, PA
University of Göteborg, Göteborg, Sweden
University of Umeå, Umeå, Sweden

To the Editor:Walter J. Urba and W. Gregory Alvord raise important questions in their editorial¹ with regard to our phase III melanoma trial, in which 305 patients with stage IV melanoma were randomized to treatment with interleukin-2 (IL-2) + histamine dihydrochloride (HDC) or monotherapy with IL-2.²

First, Urba and Alvord speculate that the subset of patients with liver metastases (LM), for which the treatment with IL-2 + HDC showed a significant survival benefit, may have been identified post hoc rather than prospectively. We wish to emphasize that the LM group was highlighted in two separate sections in the approved trial protocol. The decision to analyze these patients as an intent-to-treat (ITT) population was based on the favorable survival outcome for LM patients after treatment with IL-2/interferon alfa/HDC observed in phase II trials in Sweden during 1990 to 1996. A prestratification of the LM group would have been the preferred phase III trial design, but we never wavered in our conviction that LM patients should be analyzed separately, with survival as the primary end point.

Second, Urba and Alvord suggest that an imbalance among patients enrolled onto our trial with regard to the number of disease sites may explain the favorable outcome for those treated with IL-2 + HDC. They note that in the LM group, more patients randomized to treatment with IL-2 + HDC had metastases only in the liver than those receiving only IL-2. If this imbalance accounted for the survival benefit for patients receiving IL-2 + HDC, then it remains to be clarified whether treatment with IL-2 + HDC significantly impacted on survival for this group of patients. It is, therefore, encouraging that the results obtained in patients with the liver as the singular site of metastasis were, according to calculations performed by the Food and Drug Administration, the most favorable of the entire trial: patients with only LM treated with IL-2 + HDC lived for a median of 16.4 months, whereas corresponding control patients lived for a median of 3.8 months (P = .0006, log-rank test).

Third, the authors conclude that the survival gain induced by IL-2/HDC "does not represent a significant clinical advantage for patients with metastatic melanoma, even those with liver melanoma." We do not agree; an improvement of median survival of more than 80%, along with a more than five-fold increase in the 2-year survival rate, for patients for whom no other therapeutic options are available is of significant value. As presented at the European Cancer Conference meeting in 2001, the trial results at 2 years after the end of treatment show that 18% of LM patients receiving IL-2 + HDC remain alive as opposed to 3% in the control group (P = .004, Fisher’s exact test). The 2-year results also demonstrate that the survival of all 305 patients randomized is now significantly superior in the IL-2/HDC group (P = .046, log-rank test, ITT analysis), and the survival benefit for IL-2/HDC-treated patients in the ITT-LM group remains significant (P = .0028). These post hoc analyses should be regarded with caution, but they encourage us to further investigate whether the IL-2 + HDC regimen may positively impact on the survival of melanoma patients.

Urba and Alvord finally claim that the positive outcome of our trial may have been false "even if all hypotheses were generated prospectively, the study patients appropriately stratified and appropriate statistical analysis performed," a statement that may be a landmark in scientific pessimism. We instead forward the following view: IL-2/HDC is an acceptably nontoxic treatment that may prolong the survival of stage IV melanoma patients, in particular those with liver involvement. Additional trials are ongoing in Europe and the United States to further evaluate the potential patient benefit of this novel therapeutic strategy.

REFERENCES

1. Urba WJ, Alvord WG: Are all hypotheses generated before data analysis prospective? J Clin Oncol 20: 1431-1433, 2002[Free Full Text]

2. Agarwala SS, Glaspy J, O’Day SJ, et al: Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J Clin Oncol 20: 125-133, 2002[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 Similar articles in PubMed 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 Agarwala, S. S. Articles by Naredi, P. Search for Related Content PubMed PubMed Citation Articles by Agarwala, S. S. Articles by Naredi, P. Social Bookmarking                            What's this?