Phase II trial combining docetaxel and doxorubicin as neoadjuvant chemotherapy in patients with operable breast cancer

G. Ganem1,+, M. Tubiana-Hulin2, P. Fumoleau3, M. Combe4, J.-L. Misset5, J.-M. Vannetzel6, T. Bachelot7, L. R. De Ybarlucea4, V. Lotz8, B. Bendahmane8 and V. Dieras9

1 Centre Jean Bernard, Le Mans; 2 Centre R. Huguenin, St Cloud; 3 Centre R. Gauducheau, IRCNA, Nantes, St Herblain; 4 C. H., Le Mans; 5 Hôpital Paul Brousse, Villejuif; 6 Clinique Hartmann, Neuillys/Seine; 7 Centre L. Bérard-Lyon; 8 Laboratoire Aventis, Paris; 9 Institut Curie, Paris, France

Received 20 February 2003 ; revised 22 May 2003; accepted 28 July 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

This study was conducted to assess the antitumour activity of docetaxel in combination with doxorubicin for neoadjuvant therapy of patients with breast cancer.

Patients and methods:

Forty-eight women were treated with intravenous doxorubicin 50 mg/m2 over 15 min followed by a 1-h infusion of docetaxel 75 mg/m2 every 3 weeks for six cycles. Dexamethasone or prednisolone premedication was allowed. Granulocyte colony-stimulating factor was not allowed as primary prophylaxis. The primary end point was the pathologically documented complete response rate (pathological response).

Results:

The mean relative dose intensity calculated for four or more cycles was 0.99 for doxorubicin and 0.99 for docetaxel. Overall, the pathological response rate was 13%. There were 11 complete and 29 partial clinical responses for an overall response rate of 85% [95% confidence interval (CI) 75% to 95%] in the evaluable population (n = 47). Disease-free and overall survival rates were 85% (95% CI 71% to 94%) and 96% (95% CI 85% to 99%), respectively, after a median follow-up of 36.6 months. Grade 3/4 neutropenia was observed in 65% of patients and 17% reported grade 4 febrile neutropenia.

Conclusions:

Docetaxel and doxorubicin is an effective and well-tolerated combination in the neoadjuvant therapy of breast cancer. Future controlled trials are warranted to investigate the best schedules and to correlate response with biological factors.

Key words: breast cancer, docetaxel, doxorubicin, neoadjuvant chemotherapy


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Chemotherapy is now indicated for the majority of patients with early breast cancer [1, 2]. The timing of chemotherapy in relation to surgery has recently been the subject of several clinical studies [35]. The use of neoadjuvant chemotherapy (also called primary, preoperative or induction chemotherapy) is supported by animal models [6]. Theoretically, the advantages of neoadjuvant chemotherapy include the provision of earlier treatment, an individual in vivo chemosensitivity test of the tumour, improved survival {correlation has been established with pathologically documented complete response [pathological complete response (pCR)]} and an increase in the rate of breast-conserving surgery. Moreover, the efficacy of new agents can be more rapidly assessed. The current trend is to extend the use of neoadjuvant treatment to T1 tumours. Potential disadvantages of neoadjuvant therapy are the risk of delaying surgery. In contrast, in a mathematical model based on the size of primary tumour, Thames et al. [7] formulated a disadvantage or no benefit from neoadjuvant treatment for T1 patients.

At the initial diagnosis of breast cancer, the indication for chemotherapy in addition to locoregional treatment can frequently be based upon clinical factors (e.g. size of the tumour, age, axillary nodal status, hormone receptor status, bone marrow micrometastasis). Based on the results of these trials, this study was initiated to evaluate the efficacy of combination docetaxel (Taxotere®; Aventis, Dagenham, UK) and doxorubicin (Adriblastine®; Pharmacia Upjon, Saint-Quentin en Yvelines, France) as neoadjuvant chemotherapy in locally advanced operable breast cancer, particularly in cases where breast-conserving surgery is desired by the patient.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient population
Patients with newly diagnosed breast cancer, who met the following criteria, were eligible: histologically proven unilateral breast carcinoma; aged 18–65 years; tumour diameter >=2 cm measurable at least clinically or ultrasonographically, any clinical node status (T2 or T3 with N0–N2 tumours); World Health Organisation (WHO) performance status <=1; adequate haematological, renal and hepatic function [neutrophils >=2 x 109/l, platelets >=100 x 109/l, haemoglobin >=10 g/dl, total bilirubin <=1 x upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase <=2.5 x ULN, alkaline phosphatases <=2.5 x ULN, creatinine <=1.5 x ULN], normal cardiac function [electrocardiogram and left ventricular ejection fraction (LVEF)]; negative pregnancy test; and written informed consent. Non-eligibility criteria were: inflammatory or T4 tumours; multifocal tumours or presenting with diffuse microcalcifications (not allowing a breast conservative approach); and presence of metastasis.

Initial staging included clinical examination, mammography, ultrasonography of the breast and axillary lymph nodes, chest radiography, bone scan and liver ultrasonography or tomodensitometry and haematological blood tests. All patients gave their written informed consent and the study was reviewed by a local ethics committee.

Treatment
Chemotherapy consisted of intravenous doxorubicin (50 mg/m2 over 15 min) immediately followed by docetaxel (75 mg/m2 over 1 h) every 3 weeks for six cycles. Granulocyte colony-stimulating factor (G-CSF) was not allowed as primary prophylaxis. Dexamethasone (8 mg), prednisolone (50 mg) or methylprednisolone (40 mg) was administered twice daily for six doses, starting 1 day before each cycle as premedication. Antinausea prophylaxis with ondansetron (Zophren®; GlaxoWellcome, Marly-le-Roi, France) or metoclopramide (Primperan®; Sanofi-Synthelabo, France) was administered from cycle 1. Dose modifications were based on nadir blood counts and interval toxicity. A 20% dose reduction of each drug was mandated after a second episode of febrile neutropenia or grade 4 neutropenia lasting at least 7 days, in spite of G-CSF administered as secondary prophylaxis (lenograstim 0.263 mg/day beginning at day 6 until haematological recovery). If grade 4 thrombocytopenia occurred, the dose of doxorubicin was reduced from 50 to 40 mg/m2. If a second episode occurred, the docetaxel dose was reduced from 75 to 60 mg/m2 and doxorubicin was administered at a dose of 40 mg/m2. Chemotherapy was withdrawn for any subsequent episodes of grade 4 thrombocytopenia. Specific dose reductions were also required in cases of grade 3/4 mucositis or diarrhoea. Cardiac toxicity was assessed every two cycles (electrocardiogram and LVEF). National Cancer Institute Common Toxicity Criteria grading was recorded for each cycle. In cases of unacceptable toxicity or if clinical and radiologically documented (radiological) tumour regression was <25% after four cycles, the chemotherapy could be stopped. Surgery (mastectomy, lumpectomy or quadrantectomy) with classic axillary lymph node dissection was followed by radiotherapy, post-operative chemotherapy and/or hormone therapy according to the investigator’s discretion. In the case of complete clinical response after neoadjuvant chemotherapy, wide local excision or, at least surgical biopsies, were warranted.

Clinical response criteria
Patients were evaluable for efficacy and toxicity if they received one or more cycles of chemotherapy. The response to chemotherapy was assessed physically, radiographically and sonographically. Pathological response rate was evaluated on the intention-to-treat population (those receiving one or more cycles of chemotherapy) and on the evaluable population (those receiving one or more cycles of chemotherapy with surgery after the last cycle). Response was considered complete if there was no evidence of the primary breast tumour by the assessment method. Response was considered complete according to WHO criteria if there was a total disappearance of the tumour. Pathological response was considered complete (i.e. pCR) if there was no evidence of primary breast tumour or carcinoma in situ, and nodes were negative. Response was considered partial if there was a reduction of >=50% in the product of the two largest perpendicular diameters of the tumour. If the tumour area showed a reduction of <50% or an increase of <25%, no change was considered to have occurred. Progression was defined by an increase of >25% in the products of the largest diameters.

Laboratory investigations
Assessments of biological markers were undertaken before neoadjuvant chemotherapy and on post-chemotherapy surgical specimens. Expression of p185 protein (encoded by c-erbB-2 oncogene), p170 (encoded by multidrug resistance type-1 gene), protein associated with the mutated tumour suppressor gene p53, and protein encoded by Bcl2 were detected by classic immunohistochemical techniques [8]. All laboratory investigations were undertaken in the same department of pathology (General Hospital of Le Mans). Expressions of results of these data are derived from the review of Hamilton and Piccart [9]. Isotypes of tubuline beta were studied in another laboratory (Central Hospital in Lyon) for their possible relationship with resistance to docetaxel. Hormonal receptor status was determined in a two-step process using pressure-cooker antigen retrieval with antiestrogen and antiprogesterone receptors.

End points
The primary end point was pCR, according to Chevallier et al. [10] and Sataloff et al. [11] classifications. All pathological specimens were reviewed by two pathologists in a blinded fashion with respect to clinical characteristics and treatment results. Secondary end points were clinical and radiological response rates, rate of breast-conserving surgery, safety profile, relapse-free survival and local failure rate.

Statistical methods
The required number of patients for this phase II study was initially determined according to a two-stage Simon design [12]. The design parameters assessed the treatment to be insufficiently active if the pathological response rate was <5% and sufficiently active if the pathological response rate was >=20%. A maximum of 45 evaluable patients needed to be included in the study, assuming an {alpha} error rate of 0.05 and a ß error rate of 0.10. The efficacy analysis was carried out on all patients and on evaluable patients. The 95% confidence intervals (CIs) are provided for pathological and response rates.

A univariate analysis was used to describe factors having a predictive influence on the likelihood of response. A multivariate analysis was planned.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
From February 1999 to June 1999, 48 patients were enrolled in the study. Initial patient characteristics are summarised in Table 1. The median age was 48 years (range 31–63 years). Median pretreatment tumour size was 5 cm (range 2.5–11.0). Clinically positive lymph nodes were noted in 20 patients (42%) (19 N1 and one N2) and estrogen receptors were positive in 25 patients (52%). Ductal invasive carcinoma was present in 38 patients (79%). Five patients (10%) received adjuvant chemotherapy and 29 patients (60%) received adjuvant hormone therapy. In the absence of neoadjuvant chemotherapy, mastectomy was recommended in 43 patients (90%). All patients were assessible for toxicity and 46 for efficacy (one patient stopped chemotherapy after one cycle because of hypersensitivity reaction and one patient was lost to follow-up after four cycles).


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Table 1. Patient characteristics
 
Toxicity and compliance to chemotherapy
Forty-two (88%) of the 48 patients received the planned six cycles. Two patients stopped chemotherapy because of toxicity (one patient had a hypersensitivity reaction after the first cycle, and one had a non-symptomatic LVEF decrease of 20% after four cycles, but the LVEF (left ventricular ejection fraction) value remained within normal range). One patient was lost to follow up after four cycles. Two patients progressed during chemotherapy and clinical response was considered insufficient in one patient after four cycles. Mean relative dose intensity of chemotherapy (calculated for at least the first four cycles) was 0.99 for doxorubicin (range 0.89–1.03) and 0.99 for docetaxel (range 0.89–1.04).

Haematological toxicity is summarised in Table 2. Febrile neutropenia occurred in 17% of the patients (n = 8) and in 4% of cycles (10 of 273). Introduction of G-CSF as secondary prophylaxis allowed maintaining the dose intensity in the three patients among the eight who experienced febrile neutropenia after the first cycle. No grade 3/4 anaemia was observed. Grade 2 ungueal toxicity (pain and ungueal loss) occurred in one patient. No clinical cardiac toxicity was observed. LVEF decreases >=10% occurred in two patients and a decrease >=20% in one patient, but the values remained within normal range. Reversible alopecia was observed in all patients.


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Table 2. Haematological toxicity
 
Efficacy
Pathological response was assessable in 46 patients. According to the pathologists’ centre, a complete disappearance of the primary tumour with negative axillary nodes was observed in five patients (11%) and one patient (2%) presented in situ lesion alone with negative axillary nodes; pCR = 13% (Table 3).


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Table 3. Pathologically documented complete response rate (pCR) (according to the pathologists’ centre)
 
All responses were reviewed by an independent blinded review according to Chevallier et al. and Sataloff et al. classifications [10, 11]. According to Chevallier’s classification [10], the grade 1 and 2 pathological response was 15% (95% CI 5% to 25%) among the entire population. Complete disappearance of the primary tumour with negative axillary node was observed in four patients (9%). Three patients (6%) presented a pCR with persistence of in situ lesions alone with negative axillary nodes (Table 4). However, one patient presented a pathological response rate in the primary tumour with three positive axillary nodes and three patients presented in situ lesions alone with positive axillary nodes. Using Sataloff’s classification [11], type A responses were observed in seven patients (15%), but two patients presented a pCR rate with positive axillary nodes (Table 5).


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Table 4. Independent review of pathologically documented complete response rates (pCRs) (according to Chevallier classification [10])
 

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Table 5. Independent review of pathologically documented complete response rate (pCRs) (according to Sataloff classification [11])
 
The overall response rate as assessed by physical examination was 85% (40 patients) in the evaluable population (95% CI 75% to 95%) and 83% in the entire population (95% CI 73% to 94%). Eleven patients had no palpable tumour at the time of surgery (clinical complete remission) (Table 6). Response was assessed according to WHO criteria.


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Table 6. Clinical response rates
 
Radiological (mammography) response rate was 52% (21 patients) in the evaluable population (95% CI 37% to 68%) (Table 7). Overall, one patient had clinically defined disease progression and three patients had radiological progression. Two patients withdrew because of disease progression during chemotherapy.


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Table 7. Radiologically documented response rates (mammography)
 
Surgical treatment
In the absence of preoperative chemotherapy, 43 patients (89%) were expected to undergo radical mastectomy. After neoadjuvant treatment, a conservative approach was possible in 32 of 46 assessable patients (69%): lumpectomy has been carried out in 31 patients and multiple biopsies alone were carried out in one patient in complete clinical response after neoadjuvant chemotherapy.

Biological studies
No correlation was observed between assessments of biological factors before and after chemotherapy and response (data not shown). Moreover, among the 14 patients with overexpression of p53, five showed a complete pathological response in the primary tumour.

We have been disappointed by the results of biological tests, even if carried out in the same laboratory.

Disease control
As of 15 June 2002, the median follow-up period was 36.6 months (range 10.7–39.9 years). Eight patients have relapsed and two of them have died from metastatic progressive disease. The tumour size for patients who relapsed ranged from 25 x 25 mm to 100 x 80 mm, positive estrogen receptors were present in three patients and two patients had N1 status. Six patients have had metastatic relapse (bone and/or liver and/or lung and/or nodes and/or pleura) between 17.4 and 37.9 months after initial diagnosis. One patient experienced local failure and another patient had both local failure and metastatic relapse (lung). Of the patients who relapsed, one had achieved a pCR with positive axillary nodes. Two patients were lost to follow up [one after 6 months (death) and another after 11 months]. Among the 46 evaluable patients, disease-free and overall survival were 85% (95% CI 71% to 94%) and 96% (95% CI 85% to 99%), respectively.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Given the results of the meta-analysis conducted by the Early Breast Cancer Trialist’s Collaborative Group [1] and those of prospective randomised studies [35], neoadjuvant chemotherapy can be applied to most cases of primary breast cancer [7]. Our study was conducted to assess the efficacy and toxicity of the docetaxel and doxorubicin combination as preoperative chemotherapy in staged T2 or T3, N0–N2 breast carcinoma. The choice of our regimen was based on: (i) the high activity of docetaxel in metastatic breast cancer [1315]; (ii) the results of phase I/II studies that evaluated the combination of docetaxel and doxorubicin [1618] in metastatic breast cancer; and (iii) the lack of increased cardiac toxicity by addition of docetaxel to doxorubicin [19].

Our study confirms the good toxicity profile of the combination of doxorubicin and docetaxel administered at these dose levels, and our results indicate that this combination is active in the neoadjuvant setting. Only one patient was unable to receive the planned treatment due to a severe hypersensitivity reaction during the first cycle. Compliance was excellent with an average relative dose intensity of each agent of 0.99. The main toxicity was haematological, but it was easily managed. The absence of modifications of pharmacokinetics of doxorubicin by docetaxel probably explains the good observance of this regimen.

Early efficacy of the combination appeared high with a clinical response rate of 85% and a pCR of 15% in the evaluable population. The radiological response rate was 52%. The complete pathological response (Chevallier classification grade 1 and 2) was 14.6% (95% CI 5% to 25%). Total disappearance of the invasive component of the primary tumour or persistence of ductal carcinoma in situ alone with negative axillary nodes was observed in seven patients (15%). However, one patient presented a pathological response rate in the primary tumour in the presence of three positive axillary nodes, and three patients presented a pathological response rate in situ alone with positive axillary nodes. The persistence of positive nodes after neoadjuvant chemotherapy is probably the main adverse prognostic factor [1921]. These results appear more favourable than those observed with a combination of cyclophosphamide and anthracyclines used at conventional dosages [3, 17] or anthracyclines alone [22, 23].

We expected to see greater efficacy with docetaxel and doxorubicin in this setting, even though comparisons with other studies are difficult, primarily because of the different pathological classifications used [3, 10, 11, 24] and the differences in patient characteristics at the start of neoadjuvant chemotherapy. The rate of pCR in our series may have been adversely affected particularly by the large tumour size (median 5 cm; range 2.5–11.0 cm). However, our results, in terms of response, appear similar to those reported in previous studies [2428] combining docetaxel and either doxorubicin or epirubicin. The study published by Miller et al. [26] indicates that sequential treatment schedules (monochemotherapy with doxorubicin followed by docetaxel) may result in more substantial axillary lymph node clearance than concomitant combinations.

In the absence of a control arm, the 69% rate of breast-conserving surgery after neoadjuvant chemotherapy cannot be compared with the planned 89% rate of mastectomy without neoadjuvant chemotherapy. This rate is similar to the 67% observed in the large prospective randomised National Surgical Adjuvant Breast and Bowel B-18 study [29], which included 26% T1 tumours (60% in the primary surgery arm). Although an increased rate of breast-conserving surgery has been observed with neoadjuvant chemotherapy, a recent European Organisation for Research and Treatment of Cancer study showed no significant advantage with a doxorubicin/cyclophosphamide/5-fluorouracil combination [30]. However, the follow-up is currently too short to analyse survival. Probably because of the small size of our population, neither prognostic nor biological factors could be identified as having an influence on pathological response.

Our trial confirms the excellent toxicity profile of the combination of docetaxel and doxorubicin, and contributes to the body of knowledge on the use of neoadjuvant chemotherapy in breast cancer. Future trials are warranted to investigate the best schedules (concomitant or sequential) and exploit the potential correlation of response with biological factors.


    Acknowledgements
 
In addition to the authors, the following also contributed to the study: A. de Roquancourt (St Louis, Paris), B. Fabiani (Centre Hospitalier, Le Mans) (anatomopathologist reviewers) and J.-C. Pouget (statistician), who validated the statistical analyses and contributed to this paper.


    Footnotes
 
+ Correspondence to: Dr G. Ganem, Centre Jean Bernard, 9 rue Beauverger, 72000 Le Mans, France. Tel: +33-02-43-39-13-00; Fax: +33-02-43-28-85-34; E-mail: gganem{at}noos.fr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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