Journal of the National Cancer Institute Advance Access published online on April 8, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn085
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Neoadjuvant Vinorelbine–Capecitabine Versus Docetaxel–Doxorubicin–Cyclophosphamide in Early Nonresponsive Breast Cancer: Phase III Randomized GeparTrio Trial
On behalf of the German Breast Group
Affiliations of authors: German Breast Group, Frankfurt, Germany (GvM, SL, KM); Universitäts-Frauenklinik, Essen, Germany (SK); Frauenklinik, Horst Schmidt Kliniken, Wiesbaden, Germany (PV); Frauenklinik vom Roten Kreuz, Munich, Germany (CH); Universitäts-Frauenklinik, Kiel, Germany (HE); Frauenklinik Henriettenstiftung, Hannover, Germany (J. Hilfrich); Universitäts-Frauenklinik, Rostock, Germany (BG); Universitäts-Frauenklinik, Tübingen, Germany (J. Huober); Universitäts-Frauenklinik, Magdeburg, Germany (SDC); Städtisches Klinikum Offenbach, Germany (CJ); Universitäts-Frauenklinik, Frankfurt, Germany (GvM, SL, MK)
Correspondence to: Gunter von Minckwitz, MD, Universitäts-Frauenklinik Frankfurt & German Breast Group, c/o GBG Forschungs GmbH, Schleussner Strasse 42, 63263 Neu-Isenburg, Germany (e-mail: minckwitz{at}germanbreastgroup.de).
Background: Among breast cancer patients, nonresponse to initial neoadjuvant chemotherapy is associated with unfavorable outcome. We compared the response of nonresponding patients who continued the same treatment with that of patients who switched to a well-tolerated non–cross-resistant regimen.
Methods: Previously untreated breast cancer patients received two 3-week cycles of docetaxel at 75 mg/m2, doxorubicin at 50 mg/m2, and cyclophosphamide at 500 mg/m2 per day (TAC). Patients whose tumors did not decrease in size by at least 50% were randomly assigned to four additional cycles of TAC or to four cycles of vinorelbine at 25 mg/m2 and capecitabine at 2000 mg/m2 (NX). The outcome was sonographic response, defined as a reduction in the product of the two largest perpendicular diameters by at least 50%. A difference of 10% or less in the sonographic response qualified as noninferiority of the NX treatment. Pathological complete response was defined as no invasive or in situ residual tumor masses in the breast and lymph nodes. Toxic effects were assessed. All statistical tests were two-sided.
Results: Of 2090 patients enrolled in the GeparTrio study, 622 (29.8%) who did not respond to two initial cycles of TAC were randomly assigned to an additional four cycles of TAC (n = 321) or to four cycles of NX (n = 301). Sonographic response rate was 50.5% for the TAC arm and 51.2% for the NX arm. The difference of 0.7% (95% confidence interval = –7.1% to 8.5%) demonstrated noninferiority of NX (P = .008). Similar numbers of patients in both arms received breast-conserving surgery (184 [57.3%] in the TAC arm vs 180 [59.8%] in the NX arm) and had a pathological complete response (5.3% vs 6.0%). Fewer patients in the NX arm than in the TAC arm had hematologic toxic effects, mucositis, infections, and nail changes, but more had hand–foot syndrome and sensory neuropathy.
Conclusion: Pathological complete responses to both regimens were marginal. Among patients who did not respond to the initial neoadjuvant TAC treatment, similar efficacy but better tolerability was observed by switching to NX than continuing with TAC.
| CONTEXT AND CAVEATS Prior knowledge Breast cancer that is not responsive to initial neoadjuvant chemotherapy is associated with unfavorable outcome. Study design Phase III randomized trial among previously untreated breast cancer patients who did not respond to two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) that evaluated four additional TAC cycles or four cycles of vinorelbine and capecitabine (NX) for the noninferiority of NX. The outcome was sonographic response, defined as a reduction in tumor area by 50%. A pathological complete response was no invasive or in situ tumor mass in the breast and lymph nodes. Contribution The noninferiority of NX, compared with TAC, was demonstrated. However, pathological complete responses to both regimens were marginal. Similar efficacy but better tolerability was observed by switching to NX than continuing with TAC. Implications New neoadjuvant treatment options are urgently required for patients who do not respond to current neoadjuvant therapies. Limitations This noninferiority trial was not designed to determine whether TAC and NX had equal activity, and so the results may not apply to the general population.
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Dr von Minckwitz is conducting research sponsored by Sanofi-Aventis and Roche. Dr Huober is in the speaker's bureaus for Sanofi-Aventis, GlaxoSmithKline, and Roche. Dr Jackisch has received honoraria from Roche-Pharma, Germany. Dr Kaufmann has received honoraria for lectures from Pfizer, Astra-Zeneca, Novartis, Sanofi-Aventis, Roche, and Amgen.
Dr Erika Graf provided independent external statistical review of the manuscript.
The authors had full responsibility in the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.
Manuscript received October 24, 2007; revised February 11, 2008; accepted February 28, 2008.
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J Natl Cancer Inst 2008 100: 521-523.
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