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Computer Modeling Is No Substitute for Randomized Clinical Trials for Decision Making in Early Breast Cancer Hormonal Therapy

University Hospital Ghent, Gent, VL, Belgium

To the Editor:

We read with great interest the timely article by Punglia et al¹ concerning the sequence and timing of tamoxifen and an aromatase inhibitor (AI). Although the methodology of a Markov chain model is appropriate in these circumstances the results rely critically on the model parameters used. We repeated the Markov modelling experiment, using the same model and software and came up with different conclusions due to a number of errors in the parameters as presented in the article.

In Figure 1B sequential models are represented as if patients got 2.5 years of tamoxifen followed by 5 years of an AI. As interesting as this option may be, none of the cited trials^2-4 has actually used this treatment scheme, so using their hazard ratios to model a 7-year hormonal treatment cannot be based on available clinical evidence.

In the Markov decision model used by Punglia et al, they model only locoregional recurrence or new primaries and distant recurrences and NOT survival, but in Table 2 and Figure 2 of the article, the term disease-free survival (DFS) is used. In the cited studies,^2-4 DFS includes deaths without breast cancer recurrence. Adding to this confusion is the use (in Fig 1C and Table 1) of hazard ratios (HRs) that—in the corresponding original article—refer to DFS events (as in ATAC²: DFS HR = 0.82 and IES³: DFS HR = 0.67) or local or distant recurrences (as in MA-17⁴: local or distant recurrence HR = 0.57). In a similar recurrence modelling experiment, presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Cuzick et al⁵ used as HRs for 5 years AI (based on ATAC²) 0.74; 2 years of tamoxifen followed by an AI (based on IES³) 0.65 and after 5 years of tamoxifen (based on MA-17⁴) 0.58. Unsurprisingly, Cuzick arrives at different conclusions.

All cited clinical trials^2-4 give different HR for node-positive and node-negative patients. We wondered why these more precise HRs were not used in the modelling by Punglia.

The sensitivity analysis parameters based on ITA data as given in Table 1 and concerning cross-over to an AI after 5 years are purely speculative and should be presented as such in Table 2 and Figure 2.

It is my conviction that the modelling result is undecided and thus—taking into account the uncertainties—inconclusive. Using a correct (based on local and distant recurrences) set of HR parameters changes its conclusions. Clinical decisions can only be guided by large randomized clinical trials. BIG 1-98 is the first trial that will provide us answers concerning the optimal sequence and timing of tamoxifen and an AI.

Author’s Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Punglia RS, Kuntz KM, Winer EP, et al: Optimizing adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer: A decision analysis. J Clin Oncol 23:5178-5187, 2005[Abstract/Free Full Text]

2. Baum M, Buzdar AU, Cuzick J, 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 randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline]

3. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two or three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1090, 2004[Abstract/Free Full Text]

4. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003[Abstract/Free Full Text]

5. Cuzick J, Howell A: Optimal timing of the use of an aromatase inhibitor in the adjuvant treatment of postmenopausal hormone receptor-positive breast cancer. J Clin Oncol 23:43s, 2005 (suppl, abstr 658)

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• In Reply:
  Rinaa S. Punglia and Harold J. Burstein
  JCO 2005 23: 8546-8547 [Full Text]

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 Similar articles in PubMed 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 Vakaet, L. A.M.L. Search for Related Content PubMed PubMed Citation Articles by Vakaet, L. A.M.L. Related Articles Related Reply Social Bookmarking                            What's this?