CORRESPONDENCE

RESPONSE: Re: A Model to Select Chemotherapy Regimens for Phase III Trials for Extensive-Stage Small-Cell Lung Cancer

T. Timothy Chen, John P. Chute, Ellen Feigal, Bruce E. Johnson, Richard Simon

Affiliations of authors: T. T. Chen, Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, and University of Maryland Greenebaum Cancer Center, Baltimore; E. Feigal (Division of Cancer Treatment and Diagnosis), R. Simon (Biometric Research Branch, Division of Cancer Treatment and Diagnosis), National Cancer Institute; J. P. Chute, Division of Hematology/Oncology and the Naval Medical Research Center, National Naval Medical Center, Bethesda; B. E. Johnson, Department of Adult Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Correspondence to: T. Timothy Chen, Ph.D., Biostatistics Section, University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201 (e-mail: tchen001{at}umaryland.edu ).

Most current phase III clinical trials are justified based on an informal review of phase II response rates for the same experimental regimen. This approach, while acceptable in an era when few biologically based candidate cancer treatments existed, has led to a plethora of negative phase III trials for patients with extensive-stage small-cell lung cancer. Prompted by the negative results, our goal (1,2) was to identify a strategy that would improve the ability to introduce new agents into treatment regimens. With the discovery of numerous molecular targets and chemical entities, it will become increasingly important to better use more of the information from exploratory phase II trials to determine if investigators should continue the development of a particular regimen.

The model we introduced provided a framework for computing the expected power for a phase III trial based on the observed phase II survival result (2). This model is in contrast with current practice, which calculates power based on the hypothetic "wished for" treatment effects. The retrospective data from our analyses showed that several of the phase II trials were themselves too small or the median survival too short to take the same regimen onto a phase III trial. Consequently, we believe that the use of this type of model may be useful when applied prospectively.

By contrast with the assertion by Buyse et al., there is no difficulty in obtaining relevant survival data for standard treatment arms for use with our approach. Such data are available from phase III trials of cooperative oncology groups, and the variability in the survival outcome of different phase III trials of the standard regimens can be incorporated in our model to reflect the uncertainty in predicting the outcome for the standard treatment. We also cannot agree with the apparent preference of Buyse et al. for using no data rather than nonrandomized data in planning phase III trials.

Buyse et al. suggests that similar results could have been obtained by modeling phase III expected power using phase II response rates. However, many cytostatic drugs yet to be developed may not produce tumor shrinkage. We also believe that response rates are generally more subjective and more variable endpoints. In addition, response rates are more influenced by patient factors. Perhaps more important, we are not proposing that response rates should not be used in selecting regimens for phase III trials, but that survival endpoints should also be used. Survival information from phase II trials is typically available when phase III trials are planned.

The current database that we have been able to put together for extensive-stage small-cell lung cancer is inadequate to definitively compare the relative usefulness of the two endpoints in models, such as the one we have proposed. As we stated (2), prospective evaluations of our model are needed. We believe that the type of model we introduced is an additional tool for deciding whether to use a regimen tested in a phase II study in a candidate phase III trial. Our model is potentially of great value, and the initial results, although limited, are sufficiently promising to warrant further evaluation of the approach using phase II trial survival data.

NOTES

Editor's note: Dr. Pazdur declined to respond to the correspondence of Buyse et al.

The views and opinions expressed herein are those of the authors and are not to be construed as the official opinion of the United States Navy or the Department of Defense.

REFERENCES

1 Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 1999;17:1794–801.[Abstract/Free Full Text]

2 Chen TT, Chute JP, Feigal H, Johnson BE, Simon R. A model to select chemotherapy regimens for phase III trials for extensive-stage small-cell lung cancer. J Natl Cancer Inst 2000;92:1601–7.[Abstract/Free Full Text]



             
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