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In Reply

Institut Claudius Regaud, Toulouse, France

Bernard Asselain

Institut Curie, Paris, France

Anne-Laure Martin

Fédération Nationale des Centres de Lutte Contre le Cancer, Paris, France

We appreciate the opportunity to reply to the correspondence from Drs Demonty and Bogaerts. They raise three questions concerning the methodology and statistical analysis of the PACS01 adjuvant trial, leading to suspicion of the final conclusions.¹

The first question is about the presence of imbalances in the patients' baseline characteristics and their consequences on the primary end point. To some degree, imbalances are inherent in clinical trials. The randomization process is mainly applied to allow a statistical test on treatment efficacy and not to obtain an equal distribution of the prognostic factors between the two arms. Here, only the hormone receptor status repartition was statistically different. We have chosen to stratify on center, age, and nodal status. As the trial was performed in 85 centers, blocks of randomization within strata may explain the small excess of one to three positive nodes patients in the fluorouracil, epirubicin, and cyclophosphamide plus docetaxel arm. The reverse would have been possible.

Consequences on disease-free survival can be analyzed using three different statistical expressions of results: nonadjusted analysis (P = .011; hazard ratio [HR], 0.793; 95% CI, 0.663 to 0.949), stratification factor adjusted analysis (P = .012; HR, 0.798; 95% CI, 0.667 to 0.955), and the Cox model analysis adjusted with the prognostic factors (P = .037; HR, 0.825; 95% CI, 0.689 to 0.989). All of these estimates are consistent with a treatment superiority of the sequential arm despite the observed imbalances.

The second point relates to the nonadjusted analysis of disease-free survival. In fact, Figure 1 plots the efficacy adjusted with the Cox model to better integrate imbalances and prognostic factors. Misunderstanding is due to confusion with the nonadjusted HR, and this explains the apparent discordance in the P value. Moreover, values are rounded to the second digit. Indeed, we have rounded the 0.825 exact HR down to 0.82 in the text and up to 0.83 in the Forrest plot, but the CIs still remain within the ranges of statistical significance. This explains why Demonty and Bogaerts obtained a reanalyzed P value of .043 instead of .037.

Finally, the third question refers to a lower adjusted rather than nonadjusted HR P value. The 0.83 value reported in the text is the adjusted one. Validation of the consistency of all data comes from the different HR reported above: it rises from 0.793 to 0.796 after adjustment for stratifications criteria and to 0.825 after integration of major prognostic factors.

We have to admit that a better definition of the Forrest plot HR derived from the Cox model and more extensive reports of HR values together with their CIs would have prevented such debate. In any case, these explanations strongly reinforce the conclusion: docetaxel after fluorouracil, epirubicin 100 mg/m², and cyclophosphamide improves the clinical outcome for node-positive breast cancer patients.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Henri Roché, Sanofi-aventis Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A

REFERENCE

1. Roche H, Fumoleau P, Spielmann M, et al: Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 01 trial. J Clin Oncol 24: 5664-5671, 2006[Abstract/Free Full Text]

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Related Correspondence

• PACS 01 Trial: Questions About Patients' Characteristics and Reported Results
  Gaston Demonty and Jan Bogaerts
  JCO 2007 25: 2143 [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 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 Roché, H. Articles by Martin, A.-L. Search for Related Content PubMed Articles by Roché, H. Articles by Martin, A.-L. Related Articles Related Correspondence Social Bookmarking                            What's this?