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High-Dose Interleukin-2 May Not Be Superior to Low-Dose Interleukin-2 Plus Interferon

Divisions of Hematology/Oncology, Department of Medicine, and Division of Biometry, University of Arkansas for Medical Sciences, Little Rock, AR

To the Editor:

We read with interest the results reported by McDermott et al¹ comparing high-dose interleukin-2 (IL-2) with combination low-dose IL-2/interferon in metastatic renal cell carcinoma patients. The results failed to demonstrate 3-year progression-free superiority, the primary study end point, for high-dose IL-2 over the combination. We commend the authors' effort to address an important question, but find that the study seems to be substantially underpowered to achieve the primary goal. As stated by the authors, the study was designed with a 90% power to detect 8% difference in 3-year progression-free survival. To achieve this, a proposal was made to randomly assign equally 174 patients to each treatment arm. Unfortunately, the authors do not provide enough information to reproduce their calculations, but some educated guesses can be made. It is assumed that the authors intended to analyze 3-year progression-free survival as a binary end point and to use a two-sided Fisher's exact test to compare treatments using an level of .05 to determine statistical significance. If these assumptions are correct, the study has less than 65% power to satisfy the primary study goal. To achieve 90% power, an accrual of 320 patients would need to be randomized to each treatment arm (160 each). This sample size calculation also affects the subset analysis reported by the authors and the conclusions thereof. The authors conclude achieving statistically significant superiority of high-dose IL-2 treatments in patients with unresected primary tumor and with liver/bone metastasis. These conclusions are at best exploratory and are based on an underpowered data set. Furthermore, previous reports in metastatic renal cell cancer patients receiving interferon therapy indicate longer survival among patients who have also undergone nephrectomy.² Therefore, we feel that the authors' conclusions limited to the subgroup analysis should be treated only as hypothesis-generating. We do agree with the authors that better criteria to select patients for specific biotherapy regimens are needed. In this regard, we encourage strong participation in a recently launched Cancer and Leukemia Group B trial with a projected accrual of more than 700 patients, which may identify predictive factors in patients who benefit from specific biotherapy combinations with or without nephrectomy.³

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. McDermott DF, Regan MM, Clark JI, et al: Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 23:133-141, 2005[Abstract/Free Full Text]

2. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alpha-2b compared with interferon alfa-2b alone for metastatic renal cell cancer. N Engl J Med 345,1655-1659, 2001[Abstract/Free Full Text]

3. Rini BI, Halabi S, Taylor J, et al: Cancer and Leukemia Group B 90206: A randomized phase III trial of interferon-alpha or interferon-alpha plus anti-vascular endothelial growth factor antibody (bevacizumab) in metastatic renal cell carcinoma. Clin Cancer Res 10:2584-2586, 2004[Abstract/Free Full Text]

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• In Reply:
  David F. McDermott and Meredith M. Regan
  JCO 2005 23: 6268-6269 [Full Text]

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