Breast Cancer Research and Treatment

, Volume 108, Issue 2, pp 265–269 | Cite as

Decision making in adjuvant trials in breast cancer: the NCIC CTG MA.17 trial as an example

  • Joseph Pater
  • Dongsheng Tu
  • Lois Shepherd
  • James N. Ingle
  • Paul E. Goss
Clinical Trial


Decision-making regarding early closure and reporting of clinical trial results became a topic of intense debate following the reporting of the MA.17 adjuvant endocrine therapy trial. This trial was terminated at the first planned interim analysis when a highly significant improvement in disease free survival (DFS) was found. It has been suggested that the criterion for early stopping be made stricter when DFS is the primary study endpoint by ensuring that the targeted effect size is excluded. Our purpose is to examine this approach and to determine whether applying such a criterion would have affected the decision to terminate MA17. The sample size assumptions and the interim analysis of MA17 were reviewed and an appropriate method employed to convert hazard ratios (HR) to absolute differences. Expressed in relative terms, the effect size of MA17 was an HR of 0.78, and the upper boundary (0.75) of the confidence limits around the observed HR (0.57) excluded this value. In absolute terms, the lower confidence limit (3.1%) of best estimate of the 4 year difference in DFS (5.4%) excludes the difference (2.5%) used in the calculation of the targeted HR. We conclude that although the decision to release the results of the interim analysis of MA17 and allow patients on placebo to take letrozole was justified, methods for analyzing and interpreting interim results can be improved.


Breast cancer Adjuvant hormone therapy Clinical trials Data safety monitoring Disease free survival 


  1. 1.
    Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ et al (2003) A randomized trial of letrozole in postmenopausal women after 5 years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793–1802PubMedCrossRefGoogle Scholar
  2. 2.
    Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ et al (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262–1271PubMedCrossRefGoogle Scholar
  3. 3.
    Bryant J, Wolmark N (2003) Letrozole after tamoxifen for breast cancer—what is the price of success? N Engl J Med 349:1855–1857PubMedCrossRefGoogle Scholar
  4. 4.
    Cannistra SA (2004) The ethics of early stopping rules: who is protecting whom? J Clin Oncol 22:1542–1545PubMedCrossRefGoogle Scholar
  5. 5.
    Cuzick J, Howell A, Forbes J (2005) Early stopping of clinical trials. Breast Cancer Res7:181–183Google Scholar
  6. 6.
    Buchanan D, Miller FG (2005) Principles of early stopping of randomized trials for efficacy: a critique of equipoise and an alternative nonexploitation ethical framework. Kennedy Inst Ethics J 15:161–178PubMedCrossRefGoogle Scholar
  7. 7.
    Partridge AH, Slutsman J, Hunsberger SA, Sledge G, Mayer M, Schilsky RL (2005) Ethical and clinical dilemmas resulting from the early closure of recent clinical trials in breast cancer. Am Soc Clin Oncol Educational Book 230–241Google Scholar
  8. 8.
    Goss PE, Ingle JN, Pater JL (2004) Correspondence. N Engl J Med 350:728–729Google Scholar
  9. 9.
    Pater JL, Goss P, Ingle J, Shelley W, Shepherd L (2005) The ethics of early stopping rules (Letters/correspondence). J Clin Oncol 23:2862PubMedCrossRefGoogle Scholar
  10. 10.
    Girling D, Parmar M, Stenning S, Stephens R, Stewart L (2003) Clinical trials in cancer. Principles and practice. Oxford University Press, New York (NY), 245pGoogle Scholar
  11. 11.
    Fisher B, Dignam J, Wieand S, Wolmark N, Wickerham DL (1996) Duration of tamoxifen (TAM) therapy for primary breast cancer: 5 versus 10 years (NSABP-14). Proc Am Soc Clin Oncol 15:113Google Scholar
  12. 12.
    Early Breast Cancer Trialists’ Collaborative Group (1992) Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339:1–15Google Scholar
  13. 13.
    Early Breast Cancer Trialists’ Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of randomized trials. Lancet 351:1451–1467CrossRefGoogle Scholar
  14. 14.
    Girling D, Parmar M, Stenning S, Stephens R, Stewart L (2003) Clinical trials in cancer. Principles and practice. Oxford University Press, New York (NY), 229pGoogle Scholar
  15. 15.
    Wieand S (2003) Is relative risk reduction a useful measure for patients or families who must choose a method of treatment? J Clin Oncol 21:4263–4264PubMedCrossRefGoogle Scholar
  16. 16.
    McAlister FA, Strauss SA, Guyatt GH, Haynes RB (2000) Users’ guide to the medical literature. XX. Integrating research evidence with the care of the individual patient. JAMA 283:2829–2836PubMedCrossRefGoogle Scholar
  17. 17.
    Girling D, Parmar M, Stenning S, Stephens R, Stewart L (2003) Clinical trials in cancer. Principles and practice. Oxford University Press, New York (NY), 105pGoogle Scholar
  18. 18.
    Goss PE, Ingle JN, Palmer MJ, Shepherd LE, Tu D (2005) Updated analysis of NCIC CTG MA.17 (letrozole vs placebo to letrozole vs placebo) post unblinding. Breast Cancer Res Treat 94(Supp1):S10–S11Google Scholar
  19. 19.
    Ingle JN, Tu D, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ et al (2006) Duration of letrozole treatment and outcomes in the placebo-controlled NCIC CTG MA.17 extended adjuvant therapy trial. Breast Cancer Res Treat 99:295–300PubMedCrossRefGoogle Scholar
  20. 20.
    Harris SR (2004) Correspondence. N Engl J Med 350:728Google Scholar
  21. 21.
    Johnson JR, Williams G, Pazdur R (2003) End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 21:1404–1411PubMedCrossRefGoogle Scholar
  22. 22.
    Chlebowski RT, Blackburn GL, Thomson CA, Nixon DW, Shapiro AM, Hoy K et al (2006) Dietary fat reduction and breast cancer outcome: interim efficacy results from the women’s intervention nutrition study. J Nat Cancer Inst 98:1767–1776PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Joseph Pater
    • 1
  • Dongsheng Tu
    • 1
  • Lois Shepherd
    • 1
  • James N. Ingle
    • 2
  • Paul E. Goss
    • 3
  1. 1.Cancer Research InstituteQueen’s UniversityKingstonCanada
  2. 2.Mayo ClinicRochesterUSA
  3. 3.Harvard Medical SchoolBostonUSA

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