Journal of the National Cancer Institute Advance Access originally published online on April 8, 2008
JNCI Journal of the National Cancer Institute 2008 100(8):552-562; doi:10.1093/jnci/djn089
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© The Author 2008. Published by Oxford University Press.
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Intensified Neoadjuvant Chemotherapy in Early-Responding Breast Cancer: Phase III Randomized GeparTrio Study
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, 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: Patients with an early response to neoadjuvant chemotherapy have chemosensitive tumors and a high probability for a pathological complete response at surgery. The relationship between extended chemotherapy and pathological complete response at surgery was investigated in a clinical trial.
Methods: 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 (TAC). Those whose tumor size decreased by 50% or more by sonographic measurement (ie, reduction in the product of the two largest perpendicular diameters by at least 50%) were classified as responders and randomly assigned to receive four or six more cycles of TAC, for a total of six or eight TAC cycles. The primary aim was to increase the rate of a pathological complete response (defined as no invasive or in situ residual tumor masses in the breast and lymph nodes) from 20% to 26%. Sonographic response rates and rates of breast-conserving surgery and adverse effects were also assessed. All statistical tests were two-sided.
Results: Of the 2090 patients in the GeparTrio trial, 1390 (66.5%) were randomly assigned as responders after two initial TAC cycles to receive an additional four (n = 704) or six (n = 686) TAC cycles. Rates of pathological complete response were not statistically significantly different between the arms (21.0% with six TAC cycles and 23.5% with eight TAC cycles; difference = 2.5%, 95% confidence interval [CI] = –1.8% to 6.8%; P = .27). More clinical (48.2% vs 52.9%, difference = 4.7%; 95% CI = –0.55% to 9.95%; P = .08) and sonographic (22.6% vs 27.6%, difference = 5%; 95% CI = 0.45% to 9.55%; P = .033) complete responses at surgery were observed with eight TAC cycles than with six TAC cycles. The rate of breast-conserving surgery was similar in both arms (67.5% vs 68.5%, respectively, P = .68). Grade 3 or 4 leukopenia and edema and various grade 1 or 2 adverse events were more frequent in patients receiving eight TAC cycles than in those receiving six cycles.
Conclusion: Patients receiving eight TAC cycles had statistically significantly higher sonographic response rates but not pathological complete response rates than those receiving six TAC cycles. However, they also had more toxic effects. So far, eight cycles of TAC cannot be recommended for the whole group of patients responding to two initial cycles of TAC.
| CONTEXT AND CAVEATS Prior knowledge Patients with an early response to neoadjuvant chemotherapy have chemosensitive tumors and a high probability for a pathological complete response at surgery. Study design Phase III randomized trial among previously untreated breast cancer patients who responded to two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) that evaluated four or six more cycles of TAC, for a total of six or eight TAC cycles. Sonographic response rates and rates of breast-conserving surgery and adverse effects were also assessed. Contribution Patients who received eight TAC cycles had statistically significantly higher sonographic response rates and more toxic effects but not pathological complete response rates than those who received six TAC cycles. Implications Eight cycles of TAC cannot be recommended for the whole group of patients who respond to two initial cycles of TAC. Limitations The power of the study to detect a statistically significant difference between arms was reduced because of the small sample size. More patients in the eight-cycle arm than in the six-cycle arm discontinued treatment. High interobserver variability in the assessment of sonographic and clinical responses exists.
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Manuscript received October 24, 2007; revised February 11, 2008; accepted February 28, 2008.
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