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© The Author 2006. Published by Oxford University Press.
CORRESPONDENCE |
Re: Tamoxifen for the Prevention of Breast Cancer: Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study
Affiliations of authors: Wolfson Institute of Preventive Medicine, University of London, London, United Kingdom (JC); Mater Hospital, University of Newcastle, Newcastle, Australia (JFF); Christie Hospital, Manchester, United Kingdom (AH)
Correspondence to: Jack Cuzick, PhD, Wolfson Institute of Preventive Medicine, University of London, Charterhouse Square, London, EC1M 6BQ, UK (e-mail: jack.cuzick{at}cancer.org.uk).
We read with great interest the recent report of Fisher et al. (1) on the longer-term follow up of the P-1 trial. This article underlines the importance of determining the effect of tamoxifen prophylaxis in the 5-year period following treatment. Unfortunately, interpretation of the data for P-1 is very difficult because the reduced difference in the breast cancer rates after treatment cessation appears to be due to a lower incidence of breast cancer in the control group in years 6 and 7 of follow-up [Fig. 3 of (1)]. An important question is whether this reduced incidence in control subjects is a result of tamoxifen use in the control subjects after unblinding or whether some other mechanism is involved, possibly related to increased dropout in the control subjects.
The Fisher et al. article raises the issue of the conditions under which prevention trials should be stopped prematurely. The authors make several references to the International Breast Cancer Intervention Study (IBIS) studies, particularly in relation to the early stopping of prevention trials. A more complete representation of our views on this issue has recently been published (2). We would like to emphasize that the reporting of statistically significant early results, which is an obligation to the patients in the trial, should not always entail enforced unblinding and early termination of the trial. In the IBIS-I trial, which was very similar to P-1, patients were informed of our early published results (3) and those of P-1 (4), but neither the Independent Data Monitoring Committee nor the Steering Committee felt that the results were sufficient to change clinical practice. Accordingly, the women were told these results, and blinded continuation was recommended by the Steering Committee after written re-consent. Because of the level of communication we maintained with the participants, all but a handful of women agreed to continue in their original trial arm, and the trial remains blinded at this stage, with excellent compliance. We plan an updated analysis of IBIS I next year, with an 8-year median follow-up, and at that time we will review again whether blinded continuation is recommended.
It has been suggested that such an open policy is not possible in the United States. However, the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial also continued blinded despite positive initial results (5), and again unblinding has been rare even in the United States, where more than 2000 patients were entered in this trial.
The starting point for tamoxifen prevention trials was the Royal Marsden study, which commenced in 1986 under the direction of Trevor Powles (6), following a proposal of Cuzick et al. (7). We have yet to reach a definitive conclusion on its use for prevention.
In summary, we feel that early stopping for a successful outcome requires a clear indication of clinical benefit and that important information has been lost from P-1 because of its early termination. A new approach to early termination is needed in which data monitoring committees exercise judgment about clinical impact.
REFERENCES
(1) Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al. Tamoxifen for the prevention of breast cancer: Current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 2005;97:1652–62.
(2) Cuzick J, Howell A, Forbes J. Early stopping of clinical trials. Breast Cancer Res 2005;7:181–3.[Medline]
(3) Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 2002;360:817–24.[CrossRef][Web of Science][Medline]
(4) Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for the prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371–88.
(5) Baum M, Budzar AU, Cuzick J, Foster J, Houghton JH, Klijn JG, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 2002;359:2131–9.[CrossRef][Web of Science][Medline]
(6) Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomized chemoprevention trial. Lancet 1998;352:98–101.[Web of Science][Medline]
(7) Cuzick J, Wang DY, Bulbrook RD. The prevention of breast cancer. Lancet 1986;1:83–6.[Web of Science][Medline]
Response to this Correspondence
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J Natl Cancer Inst 2006 98: 643-644.
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