Ten-Year Results of Intense Dose-Dense Chemotherapy Show
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Annals of Oncology 29: 178–185, 2018 doi:10.1093/annonc/mdx690 Published online 24 October 2017 ORIGINAL ARTICLE Ten-year results of intense dose-dense chemotherapy show superior survival compared with a conventional schedule in high-risk primary breast cancer: final results of AGO phase III iddEPC trial V. Mo¨bus1*, C. Jackisch2,H.J.Lu¨ck3, A. du Bois4, C. Thomssen5, W. Kuhn6, U. Nitz7, A. Schneeweiss8, J. Huober9, N. Harbeck10, G. von Minckwitz11, I. B. Runnebaum12, A. Hinke13, G. E. Konecny14, M. Untch15 & C. Kurbacher16, on behalf of the AGO Breast Study Group (AGO-B)† 1Department of Gynecology and Obstetrics, Klinikum Frankfurt Ho¨chst, Frankfurt; 2Department of Gynecology and Obstetrics, Sana Klinikum Offenbach GmbH, Offenbach am Main; 3Gynecologic Oncology Practice, Hannover; 4Department of Gynecology & Gynecologic Oncology, Klinikum Essen-Mitte, Essen; 5Department of Gynecology, Martin-Luther University Halle-Wittenberg, Halle (Saale); 6Department of Gynecology and Obstetrics, University of Bonn, Bonn; 7Breast Center Niederrhein, Evangelic Hospital Bethesda, Mo¨nchengladbach; 8National Centre of Tumor Diseases, University of Heidelberg, Heidelberg; 9Department of Gynecology and Obstetrics, University of Ulm, Ulm; 10Department of Gynecology and Obstetrics, University of Munich, Munich; 11German Breast Group, Neu- Isenburg; 12Department of Gynecology, University of Jena, Jena; 13WiSP Research Institute, Langenfeld, Germany; 14David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA; 15Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin; 16Medical Center, Bonn-Friedensplatz, Bonn, Germany *Correspondence to: Prof. Dr Volker J. Mo¨bus, Department of Gynecology and Obstetrics, Klinikum Frankfurt Ho¨chst, Academic Hospital of the Goethe University Frankfurt, Gotenstrasse 6-8, D-65929 Frankfurt, Germany. Tel: þ49-69-300-599-45; Fax: þ49-69-300-599-46; E-mail: [email protected] †The investigators (physicians and staff) at the participating institutions (3 recruited patients) on behalf of the AGO Breast Study Group are given in the Appendix. Note: This study was previously presented in part at the 35th Annual San Antonio Breast Cancer Symposium (SABCS), 4–8 December 2012. Background: Primary breast cancer (BC) patients with extensive axillary lymph-node involvement have a limited prognosis. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) trial compared intense dose-dense (idd) adjuvant chemotherapy with conventionally scheduled chemotherapy in high-risk BC patients. Here we report the final, 10-year follow- up analysis. Patients and methods: Enrolment took place between December 1998 and April 2003. A total of 1284 patients with 4 or more involved axillary lymph nodes were randomly assigned to receive 3 courses each of idd sequential epirubicin, paclitaxel and cyclophosphamide (iddEPC) q2w or standard epirubicin/cyclophosphamide followed by paclitaxel (EC ! P) q3w. Event- free survival (EFS) was the primary end point. Results: A total of 658 patients were assigned to receive iddEPC and 626 patients were assigned to receive EC ! P. The median duration of follow-up was 122 months. EFS was 47% (95% CI 43% to 52%) in the standard group and 56% (95% CI 52% to 60%) in the iddEPC group [hazard ratio (HR) 0.74, 95% CI 0.63–0.87; log-rank P ¼ 0.00014, one-sided]. This benefit was independent of menopausal, hormone receptor or HER2 status. Ten-year overall survival (OS) was 59% (95% CI 55% to 63%) for patients in the standard group and 69% (95% CI 65% to 73%) for patients in the iddEPC group (HR ¼ 0.72, 95% CI 0.60–0.87; log-rank P ¼ 0.0007, two-sided). Nine versus two cases of secondary myeloid leukemia/myelodysplastic syndrome were observed in the iddEPC and the EC ! P arm, respectively. Conclusion: The previously reported OS benefit of iddEPC in comparison to conventionally dosed EC ! P has been further increased and achieved an absolute difference of 10% after 10 years of follow-up. Key words: high-risk early breast cancer, dose-dense, intense dose-dense VC The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: [email protected]. Annals of Oncology Original article Introduction Totally, 1154 assessable patients had to be recruited and followed for a median period of 5 years in order to achieve 80% power to identify an im- For adjuvant treatment of primary breast cancer (BC), anthracy- provement from 60% to 67% in EFS after 5 years with 5% type I error cline and taxane-based chemotherapy regimens are considered (one-sided). Some over-recruitment was allowed to increase the statis- standard of care [1]. In addition, dose-dense (dd) [2–4], intense tical validity of the prospectively planned subgroup comparisons in the dd (idd) regimens [5] or tailored dd regimens [6] have shown su- strata with 4–9 and 10 positive ALN (558 and 598 patients were perior clinical outcomes when compared with conventionally required to have 80% power for an anticipated improvement from 60% to 70% and 45% to 55%, respectively). dosed chemotherapy, however, clinical follow-up has been rela- Time to event distributions were estimated using the Kaplan–Meier tively short in these studies [median 5 (range 3–7) years] and method [8], and compared between treatment and prognostic groups long-term clinical outcome data are missing [2, 4, 5, 6]. using the log-rank test [9]. For multivariable analysis, a Cox proportional Hematological toxicity is more pronounced with dd regimens, hazard model was applied. Either Fisher’s exact test or an exact version of but grade 3/4 neutropenia and febrile neutropenia can safely be the Cochran–Armitage trend test was used to compare toxicity scores. All prevented by primary prophylaxis with granulocyte-colony stim- tests except for the primary hypothesis were two-sided and of explorative ulating factors (G-CSF). Primary prophylaxis even leads to less nature. This includes all subgroup analyses and multivariable models. treatment-related deaths in comparison to conventionally dosed chemotherapy [2, 7]. Here, we report the 10-year follow-up results for idd versus Results conventionally dosed chemotherapy. Patient characteristics Patients and methods A total of 1284 patients were recruited between November 1998 and April 2003 in 165 centers in Germany (iddEPC N ¼ 658, Patients EC ! P N ¼ 626). Six hundred forty-one (97%) and 611 (98%) patients were assessable for the primary end point (supplemen Main inclusion criteria were: women with histologically confirmed pri- tary Figure S1, available at Annals of Oncology online). Three pa- mary BC stage II and IIIA with 4positive axillary lymph nodes (ALN); tients in the iddEPC arm were considered non-eligible (cardiac age between 18 and 65 years, M0 status, and R0 resection of the primary arrhythmia, liver metastasis present before randomization, severe tumor and axilla with a minimum of 10 ALN removed. Additional eligi- bility criteria have been previously published [5]. wound healing complication). All three patients were excluded The ethics committees of all participating institutions approved the from the analysis of the primary end point. study. All patients provided written informed consent. The treatment arms were well balanced with respect to demo- graphic and prognostic factors (Table 1). In both study arms, the Randomization and masking median number of positive ALN was eight and 42% of the pa- tients had 10 involved ALN. Randomization was stratified according to institution, number of posi- tive ALN (4–9 versus 10) and menopausal status. Computer-generated randomization lists were used for each stratum and were balanced by Treatment block randomization with randomly varying block sizes of 2, 4 and 6. After central review of eligibility, random assignment was done by fax. All planned cycles of chemotherapy were administered to 91% of Patients and treating physicians could not be masked to allocation be- patients in the conventional arm, and to 84% in the idd arm. The cause of the nature of the interventions, and investigators were not predominant causes for treatment discontinuation in the iddEPC masked since the outcomes (relapse, death) were objectives. arm were toxicity (65% of withdrawals) and patients’ preference (20%). Differences in dose reduction and treatment delays have Treatment been reported [5]. Relapse during treatment occurred more fre- Idd treatment consisted of sequential administration of epirubicin (E) quently under conventional dosing (11 versus 3 patients). (150 mg/m2 i.v. as bolus infusion) q2w for three cycles, followed by pacli- taxel (P) (225 mg/m2 i.v.) q2w for three cycles, followed by cyclophos- phamide (C) (2500 mg/m2 i.v.) q2w for three cycles. By definition, the Hematological toxicity iddEPC regimen was dd and used a higher total dose per cycle. Patients Hematological toxicity was more pronounced in the idd arm and received filgrastim subcutaneously days 3–10 of each cycle. Women in the incidence was highest during treatment with cyclophospha- the iddEPC arm were additionally randomized to receive or not epoetin alfa during the entire chemotherapy period. The standard treatment con- mide and modest under paclitaxel. The difference between arms sisted of 4 cycles of EC (90/600 mg/m2 iv.) q3w followed by 4 cycles of was significant (P < 0.0001) with respect to all three peripheral paclitaxel (175 mg/m2) q3w (EC!P), without primary growth factor blood cell lines. Overall, at least one episode of febrile neutro- support (Figure 1). Post-study treatment recommendations were exten- penia was recorded in 5% of the patients (iddEPC arm 7% versus sively published [5]. EC ! P 2%, P < 0.0001). Only 6 patients (1%) in the EC ! P arm compared with 127 patients (20%) in the iddEPC arm Statistical aspects received red blood cell transfusions (P < 0.0001, Fisher’s exact test). The sub-randomization plus/minus Epoetin-alpha had no The primary end point was event-free survival (EFS) defined as locore- gional or distant relapse, contralateral invasive BC, second primary can- effect on EFS or OS in the iddEPC arm [10].