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In Reply:

Vanderbilt-Ingram Cancer Center, Division of Hematology/Oncology, Nashville, TN

As pointed out by Dr Stadler et al, there is clearly a place for the randomized phase II trial design in the modern conduct of clinical trials. Previous comments were meant neither to impugn the trial design per se or the intent of the authors of such trials, but to point out the frequent misinterpretation of the results and the corresponding widespread misperceptions regarding comparative efficacy vis-à-vis results obtained in phase III trials. Stadler et al correctly conclude that while a randomized phase II design may be an appropriate and cost-effective means to obtain preliminary data on an investigational drug/regimen, there was little additional information to be obtained with the use of this design in the trial by Oudard et al,¹ in which three regimens already widely in use were compared.

The issue of prostate-specific antigen (PSA) response as a surrogate for survival in randomized trials is much more problematic. The fact that PSA is the best we have in terms of biomarkers in prostate cancer does not necessarily mean that it is practical or useful. While there would appear to be a generally positive correlation between PSA response and improved clinical outcome, is the sensitivity/specificity of PSA response in predicting survival benefit sufficient to warrant its use as a screening tool to select which novel compounds and regimens warrant additional study? The results with TAX 327 would suggest that the relationship is not as strong as many advocates would have us believe. In this trial, the two docetaxel containing arms had virtually identical PSA response rates (48% for weekly therapy and 45% for every-3-week therapy), yet the every-3-week regimen demonstrated survival benefit compared to mitoxantrone, while the weekly regimen did not.² Wouldn't we have missed this critical finding by utilizing only PSA-response, and isn't it possible that novel therapeutics might be inappropriately discarded in a randomized phase II trial because of a failure to improve on the PSA response rate of conventional therapy? The authors of the TAX 327 study conducted a subsequent analysis³ of the data and concluded that no more than half of the observed survival benefit could be correlated with PSA response, and concluded, "Therefore, PSA response cannot replace overall survival as the primary end point in phase III trials in metastatic HRPC to confirm overall clinical benefit."³ This 50% correlation shows the limitations of the use of this criteria as a screen, and firmly places PSA response as a surrogate end point in the realm of mediocrity. While all response criteria have their limitations, and PSA-response may be no worse than Response Evaluation Criteria in Solid Tumors, the ability to measure serum PSA to 1/100 of a nanogram/mL does not necessarily imply improved sensitivity or specificity when compared to other response criteria. In the short term, utilization of PSA response as an adjunct to other criteria is likely a necessary evil until better biomarkers are developed, but to ignore its limitations would be foolhardy.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Oudard S, Banu E, Beuzeboc P, et al: Multicenter randomized phase II study of two schedules of docetaxel, estramustine, and prednisone versus mitoxantrone plus prednisone in patients with metastatic hormone-refractory prostate cancer. J Clin Oncol 23:3343-3351, 2005[Abstract/Free Full Text]

2. Tannock IF, deWit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004[Abstract/Free Full Text]

3. Roessner M, deWit R, Tannock IF, et al: Prostate-specific antigen response as a surrogate endpoint for overall survival: Analysis of the TAX 327 study comparing docetaxel plus prednisone with mitoxantrone plus prednisone in advanced prostate cancer. J Clin Oncol 23:391s 2005 (abstr 4554)

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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 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 Roth, B. J. Search for Related Content PubMed Articles by Roth, B. J. Social Bookmarking                            What's this?