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Clinical Cancer Research Vol. 9, 686-692, February 2003
© 2003 American Association for Cancer Research

Clinical Trials

Weekly Docetaxel as Neoadjuvant Chemotherapy for Stage II and III Breast Cancer

Efficacy and Correlation with Biological Markers in a Phase II, Multicenter Study1

Laura G. Estévez2, José Miguel Cuevas, Antonio Antón, Jesús Florián, José Manuel López-Vega, Amalia Velasco, Francisco Lobo, Ana Herrero and José Fortes

Fundación Jiménez Díaz, 28040 Madrid [L. G. E., F. L., J. Fo.]; Hospital de la Ribera, Valencia [J. M. C.]; Hospital Universitario Miguel Servet, Zaragoza [A. A., A. H.]; Hospital de Barbastro, Huesca [J. Fl.]; Hospital Marqués de Valdecilla, Santander [J. M. L-V.]; and Hospital de la Princesa, Madrid [A. V.], Spain


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: This is one of the first reports of weekly docetaxel (Taxotere) in the neoadjuvant treatment of stage II and III breast cancer. We evaluated docetaxel’s efficacy and safety and analyzed correlations between response and the expression of c-erbB2, ER status, and Ki-67 labeling index.

Experimental Design: Patients with previously untreated, stage II and III breast cancer were entered into the study. Docetaxel (40 mg/m2) was given i.v. once weekly for the first 6 weeks of an 8-week cycle for 2 cycles.

Results: A total of 56 patients were evaluated by intention-to-treat analysis for efficacy and safety. The overall clinical response rate was 68% (complete and partial response, 29 and 39%, respectively). Nine patients (16%) achieved a pathological complete response. There was no correlation between response to docetaxel and the expression of molecular markers, however, the majority of the pathological complete responses were observed in patients with c-erbB2-negative tumors. Nonhematological toxicity was more common than hematological toxicity, with alopecia and asthenia the most frequently reported adverse events (89 and 77% of patients, respectively). Severe hematological toxicity was rare.

Conclusions: Weekly docetaxel appears to be very effective in the neoadjuvant setting. A high pathological response rate was achieved with tolerable toxicity.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Neoadjuvant chemotherapy, also termed primary, induction, or preoperative chemotherapy, is defined as chemotherapy administered before locoregional treatment. It was first used in locally advanced breast cancer 30 years ago. Classically, these tumors were treated with radical surgery and/or radiotherapy. However, despite this aggressive local therapy, most patients relapsed with distant metastases and eventually died (1 , 2) . The aim of neoadjuvant therapy is to reduce the tumor volume in patients before surgical resection, thus increasing the likelihood of breast conservation. More recently, neoadjuvant therapy has been studied as a way of testing the relevance of biological markers in predicting disease outcome. The expression of the proto-oncogenes c-erbB2 (her2/neu), bcl-2 and p53 have been evaluated as predictive markers in several trials without clearly defined results (3, 4, 5, 6) .

At least six randomized trials have compared survival in patients managed with either the neoadjuvant or adjuvant approaches (7, 8, 9, 10, 11, 12, 13) . Two of the smaller trials suggested a survival advantage for patients treated with neoadjuvant chemotherapy (9 , 11) . Other studies, including the largest trial (1523 patients) run by the NSABP3 , found no differences in disease-free and overall survival (8 , 10 , 13) .

Induction of a pCR should be one of the primary goals of neoadjuvant therapy because patients with no evidence of tumor cells in breast and lymph nodes after treatment may have a longer disease-free and overall survival (14) .

Weekly regimens may enhance dose intensity by minimizing regrowth of cells between cycles of treatment and can also be combined with other new drugs such as biological agents directed against the tyrosine kinase I receptor c-erbB2 (15) . The first published report with weekly taxane therapy in metastatic breast cancer showed it to be an active and well tolerated regimen (16) . Docetaxel is one of the most active agents in breast cancer. Efficacy has been shown in metastatic disease and in anthracycline-refractory tumors (17 , 18) . One trial has reported the use of weekly, single-agent docetaxel in patients with metastatic breast cancer, with favorable response rates and minimal toxicity (19) . Experience with docetaxel as neoadjuvant chemotherapy has mainly been in combination with an anthracycline (Table 1)Citation . The rates of pCR reported in these trials are similar to those obtained with standard regimens, although the best regimen with docetaxel as neoadjuvant chemotherapy has not yet been defined.


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  		Table 1 Docetaxel neoadjuvant studies

 
We report here the results of a multicenter, Phase II trial of single-agent docetaxel given on a weekly schedule as neoadjuvant treatment for patients with breast cancer. Our primary aim was to measure the overall objective clinical response rate to weekly docetaxel. Secondary objectives included assessing the safety of the regimen, measuring the pathological response rate to docetaxel, and evaluating the role of the c-erbB2 receptor, ER and Ki-67 labeling index as potential predictive factors of response to single-agent docetaxel.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population.
Patients with previously untreated, histologically or cytologically confirmed, stage II or III breast cancer were included in the study. Infiltrating disease was confirmed before chemotherapy for all patients, regardless of the diagnostic method used. Patients were required to have disease measurable by physical examination and diagnostic breast imaging (mammogram or ultrasound) with a primary tumor >= 2 cm. All patients were ages >= 18 years. Patients had to have Eastern Cooperative Oncology Group performance status < 2, hemoglobin >= 10 g/dl, neutrophils >= 2 x 109/liter, and platelets >= 100 x 109/liter, with adequate hepatic and renal function (including calculated creatinine clearance >= 60 ml/min). Cardiac function was evaluated by cardiac ultrasound or multiple-gated acquisition scan and a left ventricular ejection fraction of >=50% was required. Patients were excluded if they had bilateral tumor or metastatic disease as confirmed by chest radiography, liver ultrasound or computer tomography imaging and bone scintigraphy, or if they had any other severe or uncontrolled systemic disease. Fertile women had to have a negative pregnancy test and had to be using adequate, nonhormonal contraception. All patients gave written informed consent before entering the study. Ethics committee approval was obtained at every center.

Treatment.
Docetaxel was given as a 30-min i.v. infusion at a dose of 40 mg/m2 weekly for 6 weeks, followed by 2 weeks rest. Patients received two 8-week cycles of treatment. Patients achieving a CR or partial response or who had stable disease at the end of treatment proceeded directly to surgery. After surgery, adjuvant chemotherapy was delivered according to the standard regimen at each participating center.

Docetaxel administration was delayed for up to 1 week in the event of a neutrophil count < 1 x 109/liter, platelet count <100 x 109/liter, or mucositis >= grade 2. If the toxicity had not recovered during this period, the patient was withdrawn from the study and treated at the investigator’s discretion. The dose was reduced to 36 mg/m2/week in the event of febrile neutropenia, mucositis >= grade 3, cutaneous toxicity (mainly acral erythema) >= grade 2, and all other grade 3 toxicities. Patients were withdrawn from the study in the event of an additional episode of febrile neutropenia or mucositis >= grade 3 or in the event of any grade 4 toxicity apart from neutropenia. Growth factors were not allowed.

Dexamethasone (8 mg) was given oral as premedication the night before chemotherapy and 1 h before docetaxel infusion. A third dose was also given on the night of chemotherapy. Antiemetic treatment was administered at the discretion of the investigators.

Assessments.
Clinical response was assessed by physical examination after two cycles of docetaxel treatment and classified according to World Health Organization criteria (20) . CR was defined as the complete disappearance of all known disease. Partial response was defined as a >=50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions. Stable disease was defined as a reduction of <50% or an increase of <25% in the size of the measurable lesions and progressive disease as an increase of >=25% in the size of one or more measurable lesions or the appearance of a new lesion. A mammogram or ultrasound were also performed at the end of treatment, before definitive surgery. The surgical procedure was carried out at the discretion of the surgeons (mastectomy or conservative surgery with full axillary dissection). Sentinel lymph node procedure was not considered. All patients who underwent breast-conserving surgery received standard radiotherapy in the remaining breast. pCR was defined as no evidence of invasive malignancy in the breast and lymph nodes at the time of definitive surgery. The presence of carcinoma in situ was included in this description.

Safety of treatment was monitored by assessment of all adverse events and weekly measurement of hematological and biochemical parameters. Adverse events were graded according to National Cancer Institute common toxicity criteria (21) where possible or recorded as mild, moderate, or severe in the absence of an appropriate National Cancer Institute classification.

Laboratory Methods.
A fine needle aspirate or tumor biopsy was performed in all eligible patients before treatment. Histological samples were preferred to facilitate assessment of molecular markers. Paraffin-embedded tumor specimens were sent to a central laboratory for analysis of the c-erbB2 receptor, ER, and Ki-67 labeling index. Tissue sections (5-µm thick) from the paraffin blocks were mounted on slides and the paraffin extracted. Endogenous peroxidase activity was blocked by immersing the sections in an aqueous solution of 3% hydrogen peroxide for 5 min. Sections were then incubated with the primary antibody for 30 min. Estrogen receptors were measured using a mononuclear antibody (1:30 dilution; Novocastra Laboratories Ltd). Tumors were classified as ER negative if <5% of tumor cell nuclei stained positive. Ki-67 labeling index was evaluated with the antibody MIB-1 (1:30 dilution; Dako Corp.). Tumors were considered to have high rates of proliferation if >20% of cell nuclei stained positive for Ki-67. Expression levels of the c-erbB2 receptor were analyzed by immunochemistry using the HercepTest (Dako/Roche). Samples were scored as follows: score 0, membrane staining in <=10% of tumor cells; score 1+, partial and/or faint membrane staining in >10% of tumor cells; score 2+, weak to moderate, complete membrane staining in >10% tumor cells; and score 3+, strong, complete membrane staining in >10% of tumor cells. Scores 0 and 1+ were considered negative, and scores 2+ and 3+ were considered positive for c-erbB2 overexpression.

Statistical Analysis.
The primary end point of this study was the overall clinical response to the docetaxel regimen. An overall clinical response in the range 60–80% was anticipated on the basis of similar studies reported in the literature. The sample size was calculated using the Simon method, with a type I error of 5% and a study power of 80%. The target enrollment was estimated to be 43 evaluable patients. All patients who fulfilled the inclusion criteria and received at least one infusion were evaluated for efficacy and safety on an intention-to-treat analysis. The statistical analysis was performed by SPSS version 10 statistical package. All variables were analyzed by descriptive methods. Mann-Whitney test was used to correlate the clinical and pathological response with molecular factors.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients.
Fifty-six patients from six Spanish hospitals were included in the trial. Characteristics of the patients are summarized in Table 2Citation . All patients were evaluated for efficacy and safety on an intention-to-treat basis. Twelve patients were withdrawn from the study: 2 patients with progressive disease during treatment, 5 following adverse events with docetaxel, 3 withdrew their consent, and 2 following a protocol violation.


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  		Table 2 Baseline characteristics of patients

 
Efficacy.
The overall clinical response rate in 56 patients was 68% (95% confidence interval, 56–80%; Table 3Citation ). Clinical CR was obtained in 16 patients (29%) and a partial response in 22 patients (39%). Stable disease was achieved in 15 patients (27%) and the disease progressed in 3 patients (5%), one after completing study treatment. Surgery was performed in 52 patients, with breast conservation in 16 of these patients (29%). Before treatment, only 11 (20%) patients were eligible for lumpectomy, and no patient initially scheduled for lumpectomy subsequently required mastectomy. The precise surgical procedure carried out was decided upon by the surgeon on a case-by-case basis, with consent from the patient. A pCR, with no evidence of invasive tumor in breast and lymph nodes, was confirmed in 9 of 56 patients (16%), including 2 patients with residual carcinoma in situ only.


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  		Table 3 Response rate to docetaxel on intention-to-treat basis

 
Immunohistochemistry.
Tumor paraffin blocks were obtained from 46 patients before treatment, although the analysis of the biological markers was not possible in all cases (Table 4)Citation . No correlation was seen between clinical or pathological response with the expression of any of the biological markers assessed, however, the majority of the pCRs were observed in patients with c-erbB2-negative tumors.


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  		Table 4 Correlation between biological markers and response

 
Safety.
A total of 649 infusions were administered with a median of 12/patient (range, 3–18). Two patients received 18 infusions based on the investigator criteria and were considered as protocol violations. Forty-four patients completed two cycles (12 infusions) of treatment. The dose was reduced in 14 patients (25%) for the following reasons: cutaneous toxicity manifest as acral erythema (4 patients); stomatitis (3 patients); conjunctivitis (2 patients); increase in serum bilirubin (1 patient); asthenia (1 patient); diarrhea with nail disorder (1 patient); diarrhea with stomatitis (1 patient); and for reasons unrelated to the treatment (1 patient). Dosing was delayed in 15 patients (27%) because of hematological toxicity in 4 patients, and nonhematological toxicity in an additional 4 patients (1 case each of cutaneous toxicity, anxiety, and grade 2 diarrhea; 1 case for which details were not specified). The reason for delay was unspecified in 2 patients, and in the remaining 5 patients, the reason was not treatment related. The median docetaxel dose intensity administered was 30.0 mg/m2/week, corresponding to 100% (range, 0.8–1.3) of the dose foreseen in the protocol.

Toxicity was assessed in 56 patients (Table 5)Citation . The most common grade 3 or 4 nonhematological toxicities included asthenia (9 patients, 16%), nail disorders (9 patients, 16%), and cutaneous toxicity (8 patients, 14%). The schedule was not associated with significant hematological toxicity. Only 1 patient developed grade 3–4 anemia, and 2 patients presented with grade 3–4 neutropenia, however, no febrile neutropenia was observed. Twenty-seven patients (48%) experienced grade 1 or 2 leukopenia.


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  		Table 5 Hematological and nonhematological adverse events (n = 56)

 
Five patients were withdrawn following adverse events, which involved hypersensitivity reaction to docetaxel, cutaneous toxicity with malaise and paresthesias, severe conjunctivitis, cutaneous toxicity with stomatitis, and conjunctivitis and stomatitis.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is one of the first reported studies of single-agent docetaxel in a weekly schedule as neoadjuvant chemotherapy for stage II and III breast cancer. Although the overall response rate was slightly low (68%) compared with other recent studies (22, 23, 24, 25, 26, 27, 28, 29, 30) , the pCR rate was very high with 9 patients (16%) showing no evidence of invasive tumor at definitive surgery.

Most of the neoadjuvant trials reported to date with docetaxel are Phase II studies in combination with an anthracycline (see Table 1Citation ; Refs. 22, 23, 24, 25, 26, 27, 28, 29, 30 ). The number of patients studied has generally been small, and no particular combination or regimen appears to be outstanding in terms of pathological and clinical response rates. Recently, the NSABP group presented the preliminary results of the NSABP-B27 Phase III trial (31) . This study examined the role of docetaxel in a neoadjuvant setting in operable breast carcinoma. Patients were randomized to three arms. All three groups received an initial four cycles of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2); group II also received four cycles of neoadjuvant docetaxel (100 mg/m2) after the AC regimen; and in group III, docetaxel was delivered as a coadjuvant treatment. Preliminary results show that the addition of docetaxel as neoadjuvant treatment provides a benefit in terms of pCR and overall response rate (25 and 91%, respectively) when compared with the standard AC regimen.

Futhermore, the Aberdeen Breast Group have recently published results of an interesting study, which examined the role of neoadjuvant docetaxel in patients who responded to an initial four cycles of CVAP and in those who did not (30) . A total of 162 patients was recruited, and 102 (66%) achieved a CR or partial response to CVAP. These patients were then randomized to four additional cycles of CVAP (n = 50) or to four cycles of docetaxel (n = 47) before final clinical assessment and surgery. The objective tumor response rate was significantly higher in the docetaxel group (94%) than in the group receiving additional CVAP (66%). Of even greater interest was the difference in pCR, with 34% achieved in patients receiving docetaxel, as opposed to 16% in those treated with only CVAP. At a median follow-up of 104 weeks, survival also appeared better in responders who switched to docetaxel (32) . These data suggest that the current widespread practice of continuing to give anthracyclines to patients showing an initial response to these agents can be improved upon.

In our study, using single-agent docetaxel in a weekly schedule, resulted in a high number of pathological responses and a favorable toxicity profile. The fact that the proportion of stage II patients included was high (87%), with a relatively small median tumor size (4.6 cm), may have favorably affected this pCR.

Docetaxel was generally well tolerated. Apart from alopecia, asthenia was the most frequent side effect but did not result in patient withdrawal from the study. Nail disorders and acral erythema were frequent, although the number of patients with grade 3–4 events was low, and the symptoms were reversible. Twenty-seven patients (48%) reported increased lacrimation, and 16 of these patients also reported conjunctivitis that may have been a complication of the tearing. Chronic dacryocystitis was the reason for prolonged tearing in 2 patients at one center in the study. Tearing has been previously reported in studies using weekly docetaxel (18) . Grade 3–4 myelosuppression was rare in our study, with only 2 cases of neutropenia and none of thrombocytopenia.

Neoadjuvant chemotherapy offers the ability to evaluate tumor specimens before and after treatment. In one of the first studies evaluating predictive factors for response to neoadjuvant chemotherapy, tumor samples were taken from 90 patients before treatment with mitoxantrone, methotrexate (± mitomycin C), and tamoxifen (14) . Of all of the markers tested, only c-erbB2 was associated with a statistically significant difference in response rate to treatment. Tumors negative for c-erbB2 had a higher response rate than those that were c-erbB2-positive.

Other studies, many of them retrospective, have also looked at the role of c-erbB2 in predicting response to chemotherapy given in a variety of settings (33, 34, 35) . Interpretation of the results is complicated by the wide variety of reagents and technologies used to detect c-erbB2 gene amplification or overexpression (36) . None of the previously published studies have yet evaluated the relevance of c-erbB2 in predicting response to docetaxel. In our study, we found no association between overexpression of c-erbB2 and the clinical and pathological response to neoadjuvant docetaxel. However, the majority of the pCRs were observed in patients with c-erbB2-negative tumors. The number of the patients in our study was low, and this trend should be studied in a larger trial. In addition, these data suggest that blocking c-erbB2 overexpression using a monoclonal antibody such as trastuzumab (Herceptin) could enhance the response to docetaxel (37 , 38) .

Although there seems to be a correlation between highly proliferative tumors and response to chemotherapy, our results showed no relationship between Ki-67 labeling index and pathological response to chemotherapy (4) . In addition, no difference in pCR was found for ER-positive or -negative tumors.

This Phase II trial highlights the need to identify the best schedule for neoadjuvant docetaxel. In our study, single-agent docetaxel given on a weekly schedule appeared to be very effective and well tolerated as neoadjuvant chemotherapy, with a high documented pCR. As a result of these positive findings, and together with data from the NSABP-B27 (31) and Aberdeen (30) studies, the Spanish Breast Cancer Research Group (GEICAM) is planning a Phase II pilot trial testing weekly docetaxel after an AC standard regimen as neoadjuvant treatment in operable breast carcinoma.


   ACKNOWLEDGMENTS
 
We thank Biométrica for the statistical analysis, Aventis Pharma SA for supporting the study, and Dr. Andrew Seidman for his assistance with the preparation of the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This study was supported by Aventis Pharma SA and is presented on behalf of the Spanish Breast Cancer Research Group (GEICAM). Back

2 To whom requests for reprints should be addressed, at Medical Oncology Service, Fundación Jiménez Díaz, Avenida Reyes Católicos no. 2, 28040 Madrid, Spain. Phone: 34-91-5494908; Fax: 34-91-5498860; E-mail: lestevez{at}fjd.es Back

3 The abbreviations used are: NSABP, National Surgical Adjuvant Breast and Bowel Project; AC, doxorubicin-cyclophosphamide; CR, complete response; CVAP, cyclophosphamide-vincristine-doxorubicin-prednisilone; ER, estrogen receptor; NCI, National Cancer Institute; pCR, pathological complete response. Back

Received 5/16/02; revised 7/29/02; accepted 8/ 5/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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