T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study

original article

Annals of Oncology 18: 52–57, 2007 doi:10.1093/annonc/mdl355 Published online 17 October 2006

Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/ cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study 1 Hoˆpital Henri-Mondor, Cre´teil; 2Institut Sainte-Catherine, Avignon; 3Hoˆpital de´partemental, La Roche-sur-Yon; 4Clinique Saint-Come et Saint-Damien, Blois; 5Clinique Sainte-Clotilde, Saint-Louis de la Re´union; 6Hoˆpital Fontenoy, Chartres; 7Clinique Plein Ciel, Mougins; 8Clinique de l’Espe´rance, Hye`res; 9CRLCC Val d’Aurelle, Montpellier; 10Centre Hospitalier, Draguignan, France, for the European Association for Research in Oncology; 11Soisy-sous-Montmorency and 12International Drug Development Institute, Brussels, Belgium

Received 28 August 2006; accepted 29 August 2006

original article

Background: Adding a taxane to anthracycline-based adjuvant chemotherapy prolongs survival in node-positive patients but optimal dose and schedule remain undetermined. This study aimed to select a dose-dense regimen for further assessment in phase III studies. Patients and methods: Ninety-nine patients with node-positive invasive breast adenocarcinoma were randomly assigned to docetaxel (Taxotere) (T) 75 mg/m2, epirubicin (E) 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 (TEC) · 6, every 3 weeks; E 100 mg/m2, C 600 mg/m2 · 4, then T 100 mg/m2 · 4 (EC/T) or the reverse sequence (T/EC), every 2 weeks, with pegfilgrastim support. The primary end point was the incidence of grade 4 toxicity. Results: Dose intensity was almost doubled with dose-dense regimens, compared with TEC. Twenty-seven patients experienced grade 4 toxicity: 26%, 40% and 18% with TEC, EC/T and T/EC, respectively, mainly neutropenia, but febrile neutropenia occurred only in 11%, 10% and 3%. Grade 3–4 nail disorders, hand–foot syndrome and peripheral neuropathy occurred in 46%, 73% and 68% of patients with TEC, EC/T and T/EC, respectively. Conclusions: Dose-dense regimens yield more frequent and severe nonhematological toxic effects than standard dose TEC regimen. Though grade 4 toxicity rates appear acceptable with the T/EC regimen, the incidence of grade 3–4 events makes it difficult to recommend either dose-dense regimen for further investigation. Key words: cyclophosphamide, docetaxel, dose-dense chemotherapy, epirubicin, node-positive breast cancer, randomized phase II study

introduction Axillary lymph node involvement is the strongest prognostic factor for patients with early-stage breast cancer, though its relative weight has been recently minimized in patients with one to three involved nodes [1]. Despite growing evidence [2–10] that adding a taxane to conventional anthracycline-based regimens is one of the best therapeutic options for patients with node-positive disease [11] and taxanes are already approved in this indication, the optimal dose and schedule of taxane remain undetermined. Two studies *Correspondence to: Dr P. Piedbois, Department of Medical Oncology, Hoˆpital Henri-Mondor, Assistance Publique Hoˆpitaux de Paris, 94000 Cre´teil, France. Tel: +33 1 49 81 25 82; Fax: +33 149 81 25 79; E-mail: [email protected]

ª 2006 European Society for Medical Oncology

have indicated that sequential anthracycline followed by docetaxel (Taxotere, Sanofi-Aventis) was more effective than concomitant anthracycline and docetaxel in the neo-adjuvant setting [12, 13]. The role of sequence (docetaxel first or following anthracycline) is unknown, but one study carried out in metastatic disease indicated that docetaxel followed by adriamycin plus cyclophosphamide (AC) was more toxic in terms of febrile neutropenia [14] than the reverse sequence. Hryniuk et al. [15] first suggested that dose intensity of adjuvant chemotherapy was correlated to disease-free survival (DFS) in breast cancer. This concept was on the basis of potentially biased statistical analyses [16] and has never been confirmed in prospective clinical trials. However, optimal antitumor activity seems to be achieved only above a dose-intensity threshold and

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P. Piedbois1*, D. Serin2, F. Priou3, P. Laplaige4, S. Greget5, E. Angellier6, E. Teissier7, J.-F. Berdah8, M. Fabbro9, B. Valenza10, P. Herait11, V. Jehl12 & M. Buyse12

original article

Annals of Oncology

patients and methods study objectives The primary objective was to select a dose-dense regimen for further assessment in phase III studies. The secondary objective was a preliminary assessment of efficacy.

patient selection This study enrolled female patients aged >18 years, Eastern Cooperative Oncology Group performance status 0–1, with histologically proven invasive breast adenocarcinoma, R0 resection of their primary tumor within 60 days before randomization and at least one histologically positive axillary lymph node among at least six resected nodes, adequate biological functions [hemoglobin >10 g/dl; absolute neutrophil count >1.5 · 109/l; platelets >100 · 109/l; serum creatinine clearance >60 ml/min; bilirubin 50%]. Noneligibility criteria were: T4, N2-3 or M1 stage, bilateral, second or inflammatory breast cancer, lymph node involvement determined by immunohistochemistry alone, ductal carcinoma in situ (DCIS), aminotransferases >1.5 · UNL concomitant with ALP >2.5 · UNL, sensory neuropathy of grade >2, prior history of cancer within 10 years (except basal skin carcinoma or cervical CIS, lobular CIS or ipsilateral DCIS of the breast), previous or concomitant anticancer therapy including radiation and hormone therapy, participation to another clinical trial, pregnant or breast-feeding patient or inadequate contraception.

study design and treatment The Ethics Committee of the Henri-Mondor Hospital gave nationwide approval for the conduct of this study. Having given a written informed consent, patients were stratified according to center and number of involved lymph nodes (1–3, 4–9, >9) and randomly assigned to one of three treatment arms: ‘standard’ TEC regimen [docetaxel (T) 75 mg/m2, epirubicin (E) 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 every 3 weeks for six cycles; arm A], one of two dose-dense regimens: EC/T (E 100 mg/m2 and C 600 mg/m2 every 2 weeks for four cycles, followed by T 100 mg/m2 every 2 weeks for four cycles; arm B) or the reverse sequence T/EC (arm C). Premedication with antiemetics and oral dexamethasone was systematic. A unique dose of pegfilgrastim 6 mg (Neulasta
; Amgen, Paris, France) was recommended in all patients on day 2 after each chemotherapy cycle. Treatment could be resumed only when biological parameters returned to values required for inclusion. After a 2-week delay, patients

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without adequate recovery were to be withdrawn from the study. No dose reduction was planned after a first episode of febrile neutropenia. A 20% dose reduction of each drug was planned in case of second occurrence of febrile neutropenia or platelet nadir <75 · 109/l. Drug-specific (T and/or E) 20% dose reductions were planned in case of grade 3–4 diarrhea or stomatitis or grade 2 peripheral neuropathy or liver function tests elevation. Patients were to go off study in case of grade 3 peripheral neuropathy or toxicity recurrence with the same intensity after dose reduction. After completion of chemotherapy, locoregional radiation therapy in all patients and hormone therapy for 5 years in hormone receptor-positive patients were recommended and carried out according to local standards of care.

assessment Toxicity was graded according to National Cancer Institute of Canada Common Toxicity Criteria version 3. Safety was assessed by an Independent Data Monitoring Committee including representatives of Institut Curie, France, and National Surgical Adjuvant Breast and Bowel Project (NSABP).

statistical considerations The primary end point was the incidence (r) of grade 4 toxicity. The study was designed as a one-stage three-outcome phase II study [19], in which H0 was: r > 50% and HA: r < 25%. Under these assumptions and with a and b errors rate of 5% each, 33 patients per arm were necessary to correctly reject a toxic treatment (with >50% grade 4) and correctly accept a nontoxic treatment (with <25% grade 4) with a probability >90%. If <11 grade 4 toxic events occurred, the treatment was to be considered tolerable. If >13 grade 4 toxic events occurred, the treatment was to be considered intolerable. If 12 grade 4 toxic events occurred, the study was not conclusive. This trial was not powered to detect differences between treatment arms. Nevertheless descriptive comparisons were carried out using a two-sided Fisher’s exact test, without adjustment for multiple comparisons. Efficacy end points (DFS and OS) were only exploratory. Results are not mature and are not presented in this paper.

results patients One hundred patients (arm A: 35, arm B: 31 and arm C: 34) were enrolled into the study from 12 December 2003 to 30 September 2004. Patient characteristics are summarized in Table 1. The median number of examined lymph nodes was 12 (range: 4–24) and the median number of pathologically involved nodes was 2 (range: 1–20). Seven patients were considered ineligible because they did not meet the predefined criteria: T4 (n = 1), N2–3 (n = 3) tumors, prior hormone therapy (n = 1), prior radiation therapy (n = 1) and R1 resection (n = 1). In addition, three patients had only five and one only four axillary lymph nodes analyzed with one or two positive nodes and were considered as minor protocol violations. There were no evident imbalances in baseline characteristics. exposure to treatment One patient in arm B did not receive study treatment. In the TEC treatment arm, two patients (6%) did not receive the six planned cycles. In the dose-dense arms, five (17%) and three (9%) patients in arm B and C, respectively, did not receive the eight planned cycles. Two patients in arm B never received docetaxel and two in arm C never received EC (Figure 1). Four patients (11%) in the TEC arm had at least one cycle delayed by >7 days, compared with 16 (53%) in the EC/T arm

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high-risk patients to benefit most of dose intensification [17]. One method for increasing dose intensity is to reduce the interval between conventional drug doses (dose-dense regimens). The Cancer and Leukemia Group B Trial 9741 compared different sequential schedules of AC and paclitaxel (Taxol, Bristol-Myers Squibb) given either every 3 weeks (conventional) or every 2 weeks (dose dense) with systematic granulocyte colony-stimulating factor (G-CSF) support in the dose-dense arms [18]. The dosedense regimens significantly prolonged both DFS and overall survival (OS) without increasing toxicity. We have undertaken this randomized phase II study to test the feasibility and safety of two sequential, dose-dense regimens [epirubicin and cyclophosphamide (EC) followed by docetaxel or the reverse sequence], in order to select one of them as the experimental arm of further phase III studies. On the basis of results of the Breast Cancer International Research Group (BCIRG) trial 001, we used as control a three-drug regimen given with conventional dose intervals.

original article

Annals of Oncology

Table 1. Baseline characteristics of randomized patients

Age (years) Postmenopausal T stage

N stage

Pathological T size

No. of nodes analyzed No. of nodes involved

Histology Hormone receptor HER-2b

1 2 3 4 X 0 1 2 3 X Tumorectomy Mastectomy <2 cm 2–5 cm >5 cm Median Range Median Range 1–3a 4–9a >9a Ductal Lobular ER positive PR positive Positive

Arm B (EC/T), n = 31

Arm C (T/EC), n = 34

53.7 31–75 19 (54%) 11 (31%) 15 (43%) 4 (11%) 0 (–) 5 (14%) 21 (60%) 7 (20%) 2 (6%) 0 (–) 5 (14%) 24 (69%) 11 (31%) 16 (46%) 18 (51%) 1 (3%) 12 5–22 1 1–12 26 (74%) 7 (20%) 2 (6%) 31 (89%) 4 (11%) 24 (69%) 20 (57%) 6 (24%)

55.4 32–72 20 (65%) 10 (32%) 15 (48%) 3 (10%) 1 (3%) 2 (6%) 22 (71%) 6 (19%) 0 (–) 1 (3%) 2 (6%) 19 (61%) 12 (39%) 17 (55%) 12 (39%) 2 (6%) 11 4–24 2 1–20 25 (81%) 4 (13%) 2 (6%) 27 (87%) 4 (13%) 22 (71%) 14 (45%) 2 (10%)

53.9 31–69 19 (56%) 17 (50%) 14 (41%) 1 (3%) 0 (–) 2 (6%) 24 (71%) 8 (24%) 0 (–) 0 (–) 2 (6%) 25 (74%) 9 (26%) 18 (53%) 15 (44%) 1 (3%) 12 6–24 2 1–11 27 (79%) 6 (18%) 1 (3%) 28 (82%) 6 (18%) 23 (68%) 19 (56%) 6 (29%)

a

Stratification categories. Percentage among 67 tested patients. ER, estrogen receptor; PR, progesterone receptor; TEC, docetaxel, epirubicin and cyclophosphamide.

b

and 13 (38%) in the T/EC arm. Six patients (17%) in the TEC arm had at least one dose reduction, compared with 11 (37%) in the EC/T arm and 11 (32%) in the T/EC arm. The absolute dose intensity was almost doubled with dosedense regimens, compared with TEC, while the cumulative dose of all three compounds were slightly higher with TEC (Table 2). Only three patients (all in the TEC arm) did not receive any GCSF. G-CSF was given in 88% of cycles in the TEC arm, 94% in the EC/T arm and 90% in the T/EC arm. G-CSF was given as primary prophylaxis in the vast majority of patients (80% with TEC and EC/T and 94% with T/EC).

safety Five patients prematurely discontinued study treatment due to toxicity (Figure 1). In arm A, one patient went off study after the fourth TEC cycle due to febrile neutropenia concomitant with grade 4 asthenia and vomiting. In arm B, one patient experienced a congestive heart failure after her fourth EC cycle and did not further received docetaxel. Two patients withdrew after docetaxel cycle 1 and three due to grade 3 peripheral

54 | Piedbois et al.

neuropathy and nail disorder, respectively. In arm C, one patient withdrew due to grade 3 hand–foot syndrome (HFS) associated with nail and ocular toxicity after her third docetaxel cycle. In addition, four patients (one in arm A, two in arm B and one in arm C) refused to complete their treatment. In at least one of them in arm B, this refusal was related to accumulation of grade 3 toxic effects over cycles (Figure 1). No toxic death occurred. As shown in Table 3, 27 patients experienced grade 4 toxicity: 12 patients (40%) in arm B (EC/T), nine (26%) in arm A (TEC) and six (18%) in arm C (T/EC). Twenty-six out of the 27 patients with grade 4 toxicity had grade 4 neutropenia. Febrile neutropenia occurred in four, three and one patients in arm A, B and C, respectively, despite G-CSF prophylaxis in seven of these eight patients. Other grade 4 toxic events were fatigue in two patients, thrombocytopenia and nausea in one patient each. More patients given dose-dense regimens reported nail disorders, HFS, peripheral neuropathy and fluid retention of any grade and more grade 3 or 4 events (73% and 68% for arm B and arm C, respectively), compared with the TEC regimen

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Type of surgery

Median Range

Arm A (TEC), n = 35

Annals of Oncology

original article

(46%). There was no clear difference in the overall incidence and in grade 3–4 incidence between the two dose-dense regimens, except for neutropenia and mucositis, which occurred more frequently with EC/T than with T/EC. One patient in arm B experienced grade 3 congestive heart failure with LVEF of 35%.

discussion Both dose-dense regimens actually doubled the dose intensity of all three drugs, compared with conventional TEC, without increasing the cumulative dose, which allows for a proper assessment of these regimens. Indeed, concomitant increase of dose intensity and cumulative dose has been a confounding factor in many trials assessing dose intensification [17]. As expected, more patients had cycle delay or dose reduction with the dose-dense regimens, compared with TEC every 3 weeks. The most frequent toxicity was neutropenia. Since blood cell counts were carried out before each chemotherapy cycle or in case of clinical symptoms, but not systematically between cycles, the exact incidence of hematological toxicity might have been underestimated and the duration of grade 4 neutropenia could

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not be assessed. Nevertheless, the incidence of febrile neutropenia was relatively low (<10%) and similar to that observed with conventional TEC. It is likely that this low incidence was due to systematic G-CSF support, as reported by others [18]. The actual dose-limiting toxic effects of dose-dense regimens were docetaxel specific toxic effects, such as skin and nail disorders and peripheral neuropathy that occurred more frequently with the dose-dense schedules and a specific toxicity of dose-dense docetaxel, i.e. HFS, as previously described [20]. Of note, in a phase III study using a similar dose-dense regimen, with AC followed by paclitaxel, the incidence of neuropathy and skin toxicity was much lower [18]. These toxic effects, albeit manageable, notably impaired patients’ quality of life and the benefit/risk ratio of dose-dense regimens in the adjuvant setting should be cautiously evaluated. The primary end point was the incidence of grade 4 toxic events. According to the statistical design of the trial, both TEC and T/EC regimens had acceptable toxicity with nine patients (26%) and six patients (18%), respectively, experiencing grade 4 toxicity. By contrast, 12 patients (40%) experienced grade 4 toxicity with EC/T. The study therefore cannot conclude that this regimen has an acceptable safety profile. Furthermore, more

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Figure 1. Exposure to study treatment and reasons for treatment discontinuation. TEC, docetaxel, epirubicin, cyclophosphamide every 3 weeks; EC, epirubicin, cyclophosphamide every 2 weeks; T, docetaxel every 2 weeks; Cy, cycle number; CHF, congestive heart failure; HFS, hand–foot syndrome. *Scar infection and cycle delay. **Grade 3 nausea, vomiting after EC cy2, then grade 3 asthenia, mucous dryness and taste alteration after T cy1.

original article

Annals of Oncology

Table 2. Cumulative dose and dose intensity in treated patients (n = 99)

Cumulative dose (mg/m2)

Epirubicin Cyclophosphamide Docetaxel

Absolute dose intensityc (mg/m2/week)

Epirubicin Cyclophosphamide Docetaxel Epirubicin Cyclophosphamide Docetaxel

Arm B (EC/T), n = 30

Arm C (T/EC), n = 34

447.5 286–497 2994 1908–3345 445.0 255–497 24.5 15–26 165.0 97–173 24.5 13–26 0.98 0.58–1.04 0.99 0.58–1.04 0.98 0.52–1.04

398.7 298–410 2392 1658–2458 377.7b 0–409 48.3 33–51 289.5 184–305 40.7b 0–51 0.97 0.66–1.02 0.97 0.61–1.02 0.81b 0–1.02

393.3a 0–411 2360a 0–2458 392.4 98–409 47.9a 0–51 286.0a 0–306 47.7 12–52 0.96a 0–1.02 0.95a 0–1.02 0.96 0.25–1.04

a

Includes two patients who never received EC. Includes two patients who never received T. c Total actual dose received by patient, divided by number of weeks of treatment (plus theoretical time of missing cycles in case of early discontinuation). d Absolute dose intensity, divided by planned-dose intensity. TEC, docetaxel, epirubicin and cyclophosphamide. b

Table 3. Incidence of adverse events in treated patients

Alopecia Nausea Vomiting Skin and nail disorders Hand–foot syndrome Peripheral neuropathy Mucositis Infection Fluid retention Cardiac toxicity Anemia Neutropenia Febrile neutropenia Thrombocytopenia Events leading to treatment discontinuation Any grade 3–4 event Any grade 4 event 95% confidence interval

Arm A (TEC), n = 35 All Grade 3–4

Arm B (EC/T), n = 30 All Grade 3–4

Arm C (T/EC), n = 34 All Grade 3–4

35 29 21 9 3 6 8 12 6 3 30 12 4 11 1 16

28 26 19 23 17 16 15 8 9 4 27 19 3 9 3 22

33 24 14 26 20 16 8 12 14 2 32 18 1 9 1 23

(100%) NA (83%) 2 (6%) (60%) 3 (9%) (26%) 0 (9%) 0 (17%) 0 (23%) 0 (34%) 1 (3%) (17%) 0 (9%) 0 (86%) 0 (34%) 10 (29%) (11%) 4 (11%) (31%) 1 (3%) (3%) (46%) 9 (26%) 12%–43%

(93%) NA (87%) 5 (17%) (63%) 3 (10%) (77%) 5 (17%)a (57%) 6 (20%)c (53%) 3 (10%)e (50%) 0 (27%) 1 (3%) (30%) 1 (3%) (13%) 1 (3%) (90%) 1 (3%) (63%) 14 (47%) (10%) 3 (10%) (30%) 0 (10%) (73%)g 12 (40%)i 23%–59%

(97%) NA (71%) 1 (3%) (41%) 2 (6%) (76%) 7 (21%)b (59%) 6 (18%)d (47%) 3 (9%)f (24%) 0 (35%) 2 (6%) (41%) 0 (6%) 0 (94%) 1 (3%) (53%) 10 (29%) (3%) 1 (3%) (26%) 1 (3%) (3%) (68%)h 6 (18%)j 7%–35%

P values versus TEC: a0.017; b0.005; c0.007; d0.011; e0.093; f0.11; g0.043; h0.09; i0.29; j0.56. NA, not applicable; TEC, docetaxel, epirubicin and cyclophosphamide.

grade 3–4 hematological toxicity and mucositis were also observed in this arm and more related adverse events led to treatment discontinuation, leading to assume that this sequence is not feasible. This intriguing difference between the two sequences of dose-dense chemotherapy should be interpreted

56 | Piedbois et al.

cautiously because the study was not powered for adequate comparison. In addition, this result is not in agreement with another study using conventional dose density, which indicated that the reverse sequence (T/AC) was more toxic [14].

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Relative dose intensityd

Median Range Median Range Median Range Median Range Median Range Median Range Median Range Median Range Median Range

Arm A (TEC), n = 35

Annals of Oncology

In conclusion, our results indicate that the dose-dense regimen T/EC might be selected for further assessment in phase III trials, according to the protocol hypothesis. Nevertheless, because of the high incidence of grade 3–4 toxicity (68%) recorded with this schedule compared with more conventional TEC (46%), a favorable benefit/risk ratio is unlikely unless very promising mature efficacy results are further observed in this phase II study.

acknowledgements

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5. Martin M, Pienkowski T, Mackey J et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005; 352: 2302–2313. 6. Roche´ H, Fumoleau P, Spielmann M et al. Five years analysis of the PACS01 trial: 6 cycles of FEC 100 versus 3 cycles of FEC 100 followed by 3 cycles of docetaxel for the adjuvant treatment of node positive breast cancer. Breast Cancer Res Treat 2004; 88 (Suppl 1): S16 (Abstr 27). 7. Henderson IC, Berry DA, Demetri GD et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003; 21: 976–983. 8. Piedbois P, Serin D for the AERO. Phase III trial comparing 6 FEC100 to 4 FEC100 followed by 4 paclitaxel in the adjuvant treatment of node positive breast cancer: preliminary safety analysis of the AERO-B2000 study. Ann Oncol 2002; 13 (Suppl 5): 38 (Abstr. 136P). 9. Mamounas EP, Bryant J, Lembersky B et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 2005; 23: 3686–3696. 10. Rodriguez-Lescure A, Martin M, Ruiz A et al. Multicenter, randomized phase III study of adjuvant chemotherapy for axillary positive breast cancer (APBC) comparing 6 cycles (cy) of FEC vs 4 cy of FEC followed by 8 weekly paclitaxel (T) administrations: Safety analysis of GEICAM 9906 trial. J Clin Oncol 2004; 22 (Suppl 14S): 27s (Abstr 596). 11. Trudeau M, Charbonneau F, Gelmon K et al. Selection of adjuvant chemotherapy for treatment of node-positive breast cancer. Lancet Oncol 2005; 6: 886–898. 12. von Minckwitz G, Raab G, Caputo A et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol 2005; 23: 2676–2685. 13. Miller KD, McCaskill-Stevens W, Sisk J et al. Combination versus sequential doxorubicin and docetaxel as primary chemotherapy for breast cancer: a randomized pilot trial of the Hoosier Oncology Group. J Clin Oncol 1999; 17: 3033–3037. 14. Perez EA, Geeraerts L, Suman VJ et al. A randomized phase II study of sequential docetaxel and doxorubicin/cyclophosphamide in patients with metastatic breast cancer. Ann Oncol 2002; 13: 1225–1235. 15. Hryniuk W, Levine MN. Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 1986; 4: 1162–1170. 16. Buyse M, Piedbois P. On the relationship between response to treatment and survival. Stat Med 1996; 15: 2797–2812. 17. Hryniuk W. Dosage parameters in chemotherapy of breast cancer. Breast Dis 2001; 14: 21–30. 18. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/ Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21: 1431–1439. 19. Sargent DJ, Chan V, Goldberg RM. A three-outcome design for phase II clinical trials. Control Clin Trials 2001; 22: 117–125. 20. Schwartz J, Domchek SM, Hwang WT, Fox K. Evaluation of anemia, neutropenia and skin toxicities in standard or dose-dense doxorubicin/cyclophosphamide (AC)-paclitaxel or docetaxel adjuvant chemotherapy in breast cancer. Ann Oncol 2005; 16: 247–252.

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We thank Drs Yvelyse Goubely-Brewer, Peter Hilgers, Sylvie Kircher (Clinique Sainte-Catherine, Avignon); Laurent Zelek, Elizabeth Fabre-Guillevin, Anne-Catherine Piketty, Frank Feuilhade (Hoˆpital Henri-Mondor, Cre´teil); Gilles Baumont, Re´gis Soleilhac, Jean-Luc Ratoanina (Clinique Sainte-Clotilde, Saint-Louis de la Re´union); Miche`le Mangold, David Solub, Isabelle de Harting (Hoˆpital Fontenoy, Chartres); Sabine Rieul-Dides (Clinique Plein-Ciel, Mougins); Gilles Romieu (Centre Val d’Aurelle, Montpellier); Bernard Leduc, Isabelle Sillet-Bach (Centre Hospitalier Ge´ne´ral, Brives); Jacques Salvat (Centre Hospitalier le Morillon, Thonon-les-Bains); David Khelif and Lam Kang Sang Lam (Groupe Hospitalier Sud Re´union; Saint-Pierre de la Re´union) for their participation as investigators. We thank Drs Ve´ronique Die´ras (Institut Curie, Paris, France) and Norman Wolmark (NSABP, Pittsburgh, PA, USA) for their appreciated participation in the Independent Data Monitoring Committee and Annie Jouhaud for her precious administrative assistance and monitoring coordination. The research was supported by European Association for Research in Oncology and by grants of Sanofi-Aventis and Amgen, Paris, France.

original article