Annals of Oncology Advance Access originally published online on October 17, 2006
Annals of Oncology 2007 18(1):52-57; doi:10.1093/annonc/mdl355
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© 2006 European Society for Medical Oncology
breast cancer |
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 Hôpital Henri-Mondor, Créteil
2 Institut Sainte-Catherine, Avignon
3 Hôpital départemental, La Roche-sur-Yon
4 Clinique Saint-Come et Saint-Damien, Blois
5 Clinique Sainte-Clotilde, Saint-Louis de la Réunion
6 Hôpital Fontenoy, Chartres
7 Clinique Plein Ciel, Mougins
8 Clinique de l'Espérance, Hyères
9 CRLCC Val d'Aurelle, Montpellier
10 Centre Hospitalier, Draguignan, France, for the European Association for Research in Oncology
11 Soisy-sous-Montmorency
12 International Drug Development Institute, Brussels, Belgium
* Correspondence to: Dr P. Piedbois, Department of Medical Oncology, Hôpital Henri-Mondor, Assistance Publique Hôpitaux de Paris, 94000 Créteil, France. Tel: +33 1 49 81 25 82; Fax: +33 149 81 25 79; E-mail: pascal.piedbois{at}hmn.aphp.fr
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Abstract |
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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) x 6, every 3 weeks; E 100 mg/m2, C 600 mg/m2 x 4, then T 100 mg/m2 x 4 (EC
T) or the reverse sequence (TEC), 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, ECT and TEC, 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, ECT and TEC, 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 TEC 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
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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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 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 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 dose-dense 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.
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patients and methods |
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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 x 109/l; platelets >100 x 109/l; serum creatinine clearance >60 ml/min; bilirubin <upper normal limit (UNL), alkaline phosphatase (ALP) <5 x UNL and aminotransferases <2.5 x UNL] and adequate cardiac function [left ventricular ejection fraction (LVEF) >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 x UNL concomitant with ALP >2.5 x 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: ECT (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 TEC (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 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 x 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 
and ß 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.
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results |
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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.
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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).
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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 and 13 (38%) in the TEC arm. Six patients (17%) in the TEC arm had at least one dose reduction, compared with 11 (37%) in the ECT arm and 11 (32%) in the TEC arm.
The absolute dose intensity was almost doubled with dose-dense 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 G-CSF. G-CSF was given in 88% of cycles in the TEC arm, 94% in the ECT arm and 90% in the TEC arm. G-CSF was given as primary prophylaxis in the vast majority of patients (80% with TEC and ECT and 94% with TEC).
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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 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 (ECT), nine (26%) in arm A (TEC) and six (18%) in arm C (TEC). 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.
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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 (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 TEC. One patient in arm B experienced grade 3 congestive heart failure with LVEF of 35%. |
discussion |
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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 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 TEC 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 ECT. The study therefore cannot conclude that this regimen has an acceptable safety profile. Furthermore, more 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 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 (TAC) was more toxic [14].
In conclusion, our results indicate that the dose-dense regimen TEC 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.
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Acknowledgements |
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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 (Hôpital Henri-Mondor, Créteil); Gilles Baumont, Régis Soleilhac, Jean-Luc Ratoanina (Clinique Sainte-Clotilde, Saint-Louis de la Réunion); Michèle Mangold, David Solub, Isabelle de Harting (Hôpital Fontenoy, Chartres); Sabine Rieul-Dides (Clinique Plein-Ciel, Mougins); Gilles Romieu (Centre Val d'Aurelle, Montpellier); Bernard Leduc, Isabelle Sillet-Bach (Centre Hospitalier Général, Brives); Jacques Salvat (Centre Hospitalier le Morillon, Thonon-les-Bains); David Khelif and Lam Kang Sang Lam (Groupe Hospitalier Sud Réunion; Saint-Pierre de la Réunion) for their participation as investigators. We thank Drs Véronique Diéras (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.
Received for publication August 28, 2006. Accepted for publication August 29, 2006.
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References |
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