Charles E Geyer1,2, Hanna Bandos3,4, Priya Rastogi3,5,6, Samuel A Jacobs3, André Robidoux3,7, Louis Fehrenbacher3,8, Patrick J Ward3,9, Jonathan Polikoff3,10, Adam M Brufsky3,6, Louise Provencher3,11, Alexander H G Paterson3,12, John T Hamm3,13, Robert L Carolla3,14, Luis Baez-Diaz3,15, Thomas B Julian3,16, Sandra M Swain3,17, Eleftherios P Mamounas3,18, Norman Wolmark3,5. 1. NRG Oncology, Nova Tower 2, Two Allegheny Center, Suite 1245, Pittsburgh, PA, 15212, USA. charles.geyer@nsabp.org. 2. UPMC Hillman Cancer Center, Pittsburgh, PA, USA. charles.geyer@nsabp.org. 3. NRG Oncology, Nova Tower 2, Two Allegheny Center, Suite 1245, Pittsburgh, PA, 15212, USA. 4. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA. 5. UPMC Hillman Cancer Center, Pittsburgh, PA, USA. 6. Department of Oncology, Magee Womens Hospital, Pittsburgh, PA, USA. 7. Department of Surgery, Breast Cancer Research Group (GRCS), Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada. 8. Kaiser Permenente Northern California, Vallejo, CA, USA. 9. Department of Medical Oncology, Onoclogy/Hematology Care Clinical Trials, Cincinnati, OH, USA. 10. Department of Research and Evaluation - Clinical Trials -Oncology, Kaiser Permanente Southern California, San Diego, CA, USA. 11. Centre des Maladies du Sein du CHU de Québec - Université Laval, Québec, QC, Canada. 12. Department of Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada. 13. Norton Cancer Institute, Louisville, KY, USA. 14. Department of Medical Oncology, CCOP, Ozark Health Ventures LLC-Cancer Research for the Ozarks, Springfield, MO, USA. 15. Cancer Medicine Department of Hematology/Oncology, Puerto Rico NCORP/UPR Comprehensive Cancer Center, San Juan, PR, USA. 16. Department of Surgery, Allegheny Health Network/Allegheny General Hospital, Pittsburgh, PA, USA. 17. Department of Research Development, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, MedStar Health, Washington, DC, USA. 18. Department of Surgery, Orlando Health UF Health Cancer Center, Orlando, FL, USA.
Abstract
PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHOD: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS). RESULTS: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group. CONCLUSION: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00087178.
PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHOD: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS). RESULTS: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group. CONCLUSION: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00087178.
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