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Annals of Oncology Advance Access originally published online on March 17, 2007
Annals of Oncology 2007 18(6):1015-1020; doi:10.1093/annonc/mdm076
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© 2007 European Society for Medical Oncology

breast cancer

A phase II study of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine and pegfilgrastim support as preoperative therapy for patients with stage II, IIIA breast cancer

C Natoli1, E Cianchetti2, N Tinari1, D Angelucci1, A Grassadonia1, M Zilli1, C Ficorella3, E Ricevuto3, S Grossi2, M De Tursi1, C Carella1, AI Rispoli3 and S Iacobelli1,*

1 Department of Oncology and Neurosciences and Foundation, University "G. D'Annunzio", Chieti-Pescara
2 Department of Surgery, University "G. D'Annunzio", Chieti-Pescara
3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy

* Correspondence to: Dr S. Iacobelli, Department of Oncology and Neurosciences, Foundation University "G. D'Annunzio", Via dei Vestini, 5-66100 Chieti, Italy. Phone: +39 08713556732; Fax: +39 08713556707; E-mail: iacobell{at}unich.it


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
Background: This phase II study was conducted to evaluate tumor response rate and safety profile of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine given preoperatively to patients with stage II or IIIA breast cancer.

Patients and methods: Patients underwent four cycles of dose-dense cyclophosphamide 600 mg/m2 and epirubicin 90 mg/m2 every 2 weeks followed by two cycles of docetaxel 36 mg/m2 on days 1, 8, and 15 plus capecitabine 1250 mg/m2 on days 5–18 every 4 weeks, with prophylactic pegfilgrastim. The primary objective of the study was to determine the incidence of pathologic complete response defined as the absence of invasive or in situ cancer in the breast and the axillary nodes at definitive surgery.

Results: Forty-four patients were enrolled in the study and 41 (93%) were assessable for response to chemotherapy. An objective clinical response was observed in 38 (93%) patients. Seven patients (17.1%) exhibited a pathologic complete response. Breast-conserving surgery was carried out in 36 (88%) patients. Grade 3/4 neutropenia occurred in 4.3% of 252 administered chemotherapy cycles. No febrile neutropenia, cardiac toxicity, thrombocytopenia or other serious adverse event was registered.

Conclusion: The sequential combination of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine is an effective and well-tolerated neo-adjuvant chemotherapy for stage II, IIIA breast cancer.

Key words: breast cancer, dose-dense chemotherapy, pathologic complete response, preoperative chemotherapy


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Acknowledgements
 References
 
Preoperative systemic chemotherapy, also known as neo-adjuvant chemotherapy, is the standard of care in patients with inoperable locally advanced or inflammatory breast cancer, and is increasingly being considered for patients with operable disease [1–3]. Randomized trials have demonstrated that preoperative systemic therapy is as effective as adjuvant chemotherapy with respect to disease-free and overall survival and increases the rate of breast-conserving surgery [3–6]. Patients with pathologic complete response (pCR), however, have a better outcome than those with a partial response, stable disease, or progressive disease [4, 7, 8]. This has led to the hypothesis that local tumor response is associated with response of distant micrometastases and can therefore be used as a surrogate marker for clinical outcome.

The optimal regimen of preoperative systemic chemotherapy remains undefined. Combination chemotherapy regimens containing anthracyclines are superior to nonanthracycline-containing combinations. The majority of patients receiving anthracyclines, however, achieve only a suboptimal response to this treatment [9, 10]. Several studies have shown that the sequential administration of anthracyclines and docetaxel result in a significantly greater pCR rate as compared with continuing treatment with anthracyclines [11, 12]. Moreover, the combination of docetaxel with capecitabine, an oral fluoropyrimidine prodrug, resulted in superior tumor response, time to progression, and overall survival over the single-agent docetaxel in advanced breast cancer [13]. Capecitabine is converted to 5-fluorouracil through the action of thymidine phosphorylase [14]. Docetaxel has been found to up-regulate thymidine phosphorylase in tumor tissue, indicating a potential mechanism for synergy between docetaxel and capecitabine [15, 16]. Thus, for an optimal combination effect, taxane administration should precede that of capecitabine [17]. To date, few studies have used capecitabine plus docetaxel in neo-adjuvant setting [18], and none in sequence after anthracyclines.

Likely, further advances in the neo-adjuvant treatment of breast cancer may come from the optimization of treatment schedules. For example, the administration of doxorubicin–cyclophosphamide combinations with a shortened treatment interval, referred to as ‘dose dense’, has been proven to be more effective than conventional schedules [19]. The biological basis of this approach are provided by the Norton–Simon model, which indicate that increasing the dose density of chemotherapy will increase its efficacy by minimizing the opportunity for regrowth of tumor cells between the cycles of chemotherapy [20–22].

On the basis of the above considerations, we developed a preoperative treatment program consisting of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine with pegfilgrastim support, for women with stage II or IIIA breast cancer. The primary end point of the study was the rate of pCR obtained in the breast and the axillary nodes.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Acknowledgements
 References
 
eligibility
Patients with histologically confirmed invasive breast carcinoma, clinical stage II or IIIA, primary tumors >2 cm on physical examination or mammography, not candidate to breast-conserving surgery, were eligible for this study.

Patients were required to be >18 and <65 years of age, with a World Health Organization performance status of zero to one, and to be neither pregnant nor nursing. Eligible patients had baseline neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l, hamoglobin ≥10 g/dl, bilirubin, and aspartate aminotransferase within institutional limits of normality, and creatinine <1.5 mg/dl. Baseline evaluation also included an electrocardiogram (ECG) to exclude ischemic changes or ventricular hypertrophy and chest radiogram to exclude active cardiac or pulmonary disease. Patients were required to have baseline left ventricular ejection fraction ≥50%.

Patients were excluded from participation if there was evidence of inflammatory, bilateral or multifocal breast cancer; presence of metastases; prior history of malignancy other than in situ cancer of the cervix or squamous cell carcinoma of the skin; pregnancy or lactation at the time of diagnosis; preexisting active cardiac disease; uncontrolled diabetes; severe hematologic, renal, or hepatic abnormalities; or active infection or other significant illness that might influence the tolerability of the treatment.

The study was conducted in accordance with the Declaration of Helsinki and the study protocol was approved by the Ethics Committee of the University "G. D'Annunzio" of Chieti-Pescara, Italy. Patients provided written informed consent before entering the study.

treatment plan
Patients were scheduled to receive four cycles of preoperative epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 (EC) administered i.v. every 2 weeks, followed by two cycles of docetaxel (Taxotere, Sanofi-Aventis, Milan, Italy) 36 mg/m2 (1-h infusion) on days 1, 8, 15 in combination with capecitabine (Xeloda, Roche, Milan, Italy) 625 mg/m2 per os twice daily on days 5–18 (DXe) every 4 weeks. Before docetaxel infusion, all patients received a premedication consisting of prednisone 50 mg (given orally at 12 and 1 h before docetaxel, and 12 h after docetaxel) and diphenhydramine 50 mg intramuscularly (1 h before docetaxel). Pegfilgrastim (6 mg) was administered s.c. on day 2 during treatment with EC dose dense. Additionally, it was administered on day 19 during DXe to avoid treatment delay. Use of erythropoietin was permitted at investigator's discretion.

Chemotherapy was postponed for a maximum of 2 weeks if the absolute neutrophil count was <1.5 x 109/l, if the platelet count was <100 x 109/l or if the hemoglobin was <10 g/dl on the day of the planned chemotherapy administration. In case of anemia, thrombocytopenia or non-hematologic National Cancer Institute—Common Toxicity Criteria (NCI-CTC) grade 3 toxicity, subsequent chemotherapy was administered with a 25% dose reduction, within a maximum of 2 weeks. If grade 3 toxicity did not resolve in this period, and in case of any toxicity of grade 4, patients were taken off study.

Definitive breast surgery was carried out within 4 weeks after the completion of chemotherapy. Patients underwent either modified radical mastectomy or lumpectomy, both with complete axillary lymph node dissection. Sentinel lymph node procedure was not allowed. Postoperative therapy (radiotherapy, chemotherapy, and/or hormone therapy) was at the investigator's discretion.

study assessments
Initial assessment of patients was carried out within 4 weeks before study entry and included medical history, physical examination, routine blood chemistry, pregnancy test, bilateral mammography, optional ultrasonography of the breast and axillary lymph nodes, chest radiography, bone scan, liver ultrasonography, ECG, and echocardiogram. ECG was repeated before each treatment cycle and echocardiogram was repeated after EC and after the completion of the chemotherapy.

All patients had to undergo tru-cut or Mammotome® (Ethicon Endo-Surgery, Hamburg, Germany) biopsy. The diagnosis of invasive breast carcinoma was confirmed and the nuclear grade was assessed according to the Nottingham grading system [23]. Estrogen (ER)/progesterone receptors (PgR) and human epidermal growth factor type 2 receptor (HER2) were determined on pretreatment biopsy by immunohistochemistry. Hormone receptor (HR) status was considered positive if ≥10% of tumor cells stained for ER and/or PgR. HER2 status was assessed by HercepTest (Dako Italia, Milan, Italy). 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. FISH was carried out on all tumors with HercepTest 2+. Tumors with a score of 3+ by immunohistochemistry (IHC) or gene amplification by FISH were considered as HER2 positive.

For the assessment of clinical tumor response, tumor diameters were measured with a caliper before each treatment cycle and on mammograms taken after completion of chemotherapy. Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used for response evaluation [24]. Patients were assessable for tumor response if they received the planned six cycles of chemotherapy. pCR was defined as no evidence of viable tumor cells, invasive or in situ, in the surgical breast specimen and the axillary nodes.

Safety of treatment was monitored by assessment of all adverse events, weekly measurement of hematological parameters, and biochemical parameters at each treatment cycle. Adverse events were graded according to the NCI-CTC criteria.

statistical analysis
The sample size was calculated according to the Simon's [25] two-step optimal design. The null response rate (P0) below which there would be no further interest in the proposed regimen was set at 5%, and the rate beyond which further studies would be of interest (P1) was set at 20%. Assuming an {alpha} error rate of 0.05 and a ß error rate of 0.10, 21 patients were to be accrued in the first step. If two or more pCRs were observed, 20 more patients were to be entered. The regimen was considered of clinical interest if ≥5 pCRs were observed among 41 treated patients.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 Acknowledgements
 References
 
From June 2004 to February 2006, a total 44 patients were enrolled in the study. Baseline patient characteristics are summarized in Table 1. The median age was 46 years (range 27–63). Median pretreatment tumor size was 4.5 cm (range 2.2–10 cm). Seventeen women (39%) showed clinical axillary involvement. Twenty-six (59%) patients had ER- and/or PgR-positive tumors. Breast-conserving surgery was carried out in 36 (88%) patients.


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  		Table 1. Patient characteristics at study entry (N = 44)

 
tumor response: clinical, radiological, and pathological
Forty-one patients were assessable for clinical and radiological response. Clinical complete response was observed in 16 (39%) and clinical partial response in 22 (56%) patients, for an overall objective response rate of 93%. Objective response rate by mammography was 80.5%. No patient had clinical or radiological progression. No relevant concordance was observed between clinical and mammographic responses (Table 2).


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  		Table 2. Clinical and mammographic response

 
Pathologic response rate was based on the information obtained from 41 patients who had surgery after chemotherapy and is shown in Table 3. A pCR was observed in seven (17.1%) patients. Notably, two patients with no residual tumor in the breast but nodal involvement and two patients with residual in situ carcinoma in the breast were not considered to have a pCR. In agreement with other studies [9, 26–28], patients with HR-negative tumors had a higher pCR rate compared with those with HR-positive tumors (38.8% versus 0%, P < 0.002, by Fischer's exact test). Premenopausal women were more likely to have pCR compared with those in postmenopause (41.7% versus 6.9%, P < 0.016). No relationship between pCR rate and HER2 status, tumor size, tumor grade was seen. Twenty-three (56%) patients were without pathological nodal involvement at the time of definitive surgery.


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  		Table 3. pCR according to HR status, HER2 status, tumor grade, and menopause

 
toxicity
In all, 41 of 44 enrolled patients received the planned six cycles of chemotherapy. Three patients went off study: one for G4 neutropenia, and two for patients’ choice to have immediate surgery. Toxicity of chemotherapy was recorded as the number of toxic events per cycle and is shown in Table 4. Grade 3/4 neutropenia was observed in 4.3% of cycles (11 of 252). No febrile neutropenia, grade 3/4 anemia or thrombocytopenia was observed. Non-hematological grade 3/4 toxic effects, including mucositis, palmar-plantar erythrodysesthesia, nail disorders, and diarrhea, were uncommon. Five patients required a 25% dose reduction of capecitabine: two patients because of mucositis and three patients because of palmar-plantar erythrodysesthesia. One patient developed grade 3 diarrhea and discontinued the treatment with capecitabine. No clinical cardiac toxicity was observed.


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  		Table 4. Toxic reactions

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Acknowledgements
 References
 
Given the results of the meta-analysis conducted by the Early Breast Cancer Trialist's Collaborative Group [26] and those of prospective randomized studies [4, 9], neo-adjuvant chemotherapy can be considered as a valid treatment option even for operable primary breast cancer [29]. The timing of systemic therapy, pre- or postsurgery, seems to have no impact on survival [4]. Nevertheless, preoperative administration of chemotherapy can significantly improve the rate of breast-conserving surgery [5, 30] and allows a rapid evaluation of the activity of new regimens.

The present study was conducted in order to assess the antitumor activity and safety of a novel regimen consisting of dose-dense EC followed by DXe given preoperatively to women with stage II or IIIA breast cancer, not candidate to breast-conserving surgery. The choice of this regimen was based on the following considerations: (i) the increase of pCR rate when docetaxel is used sequentially after anthracyclines [11, 12]; (ii) the synergism between docetaxel and capecitabine observed in preclinical studies [15], and the survival advantage of this drug combination in metastatic breast cancer [13]; and (iii) the survival benefit of a dose-dense anthracycline–taxane regimen in the adjuvant setting [19].

The rate of pCR (17.1%) observed in the present study is higher than those obtained with a combination of cyclophosphamide and anthracyclines [31], anthracyclines alone [32] or concomitant anthracycline–docetaxel regimens [33–37], and it appears comparable to those of previous studies using sequential taxanes after anthracyclines [11, 12, 38–40]. We are aware that a comparison of the results of our study with those of others cannot be done because of differences in patient characteristics, treatment schedules, and definition of pCR [8, 31, 41–43]. It should be mentioned that two important neo-adjuvant trials, the National Surgical Adjuvant Breast and Bowel Project B-27 (NSABP B-27) and the Aberdeen trial, however, have adopted a relaxed definition of pCR which includes the presence of in situ carcinoma in the breast, regardless of the axillary node status. In the NSABP B-27 [12], which compares Adryamicin-Cyclophosphamide (AC) followed by docetaxel to AC alone in stage I–III breast cancer, the sequential combination significantly improved overall response and pCR rate in the breast (14 versus 26.1%; P < 0.001). Using the same definition of pCR, i.e. absence of invasive tumor cells in the breast, the pCR rate observed in the present study (27%) is similar to that observed in the sequential arm of the NSABP B-27 study, despite the shorter duration of our regimen (16 weeks versus 24 weeks in the sequential preoperative arm of NSABP B-27 trial), and the administration of six, rather than eight cycles of chemotherapy. In the Aberdeen trial [8], patients with tumors >3 cm or T3–4, N2, received four cycles of cyclophosphamide, vincristine, doxorubicin, and prednisone (CVAP), and responding patients were randomized to four additional cycles of CVAP or to four cycles of docetaxel, whereas nonresponding patients received docetaxel in a nonrandomized arm. In patients achieving a clinical response to CVAP, switching to docetaxel resulted in a higher pCR rate (31% versus 15%), a better survival, and a higher breast-conserving surgery rate [11]. For patients not responding to CVAP, pCR rate was 2% after switching to docetaxel. In all patients receiving CVAP–docetaxel, pCR rate was 19% lower than that observed in the present study (27%, if in situ tumor residues in the breast, regardless of the axillary node status, are included in pCR definition). Another important neo-adjuvant trial, the German Preoperative Adriamycin Docetaxel Study Group (GEPARDUO) trial [39], used the same pCR we adopted. In this study AC followed by docetaxel resulted in a pCR rate of 14.3%, similar to that obtained in the present study, but higher than that obtained with the concurrent combination of dose-dense doxorubicin and docetaxel. The lower activity of the dose-dense regimen in the GEPARDUO trial can be explained by the use of the combined anthracyclines and docetaxel rather than their sequential administration.

A recent randomized phase II study by Budzar et al. [44] focused on the addition of trastuzumab to neo-adjuvant chemotherapy for patients with HER2-positive breast cancer. Forty-two patients were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. The trial was stopped because of the superiority of trastuzumab plus chemotherapy. pCR rates, defined as no evidence of residual invasive cancer both in breast and axilla, were 26% and 66.7% for chemotherapy and trastuzumab plus chemotherapy, respectively. When the present study was planned, trastuzumab was not approved for the adjuvant (neo-adjuvant) treatment of breast cancer. Although the results of the two studies are not directly comparable, the pCR rate obtained by our regimen in patients with HER2-positive tumors (29.4%) appears comparable to that of control arm in the Budzar's trial (26%), despite the shorter duration of our chemotherapy regimen (16 versus 24 weeks) and the exclusion of in situ residual disease in our pCR definition.

A merit of neo-adjuvant chemotherapy is its ability to increase the rate of breast-conserving surgery by downsizing the primary tumor. None of the patients enrolled in our study was candidate to breast-conservative surgery. Nevertheless, at the end of our chemotherapy program, breast-sparing procedures were carried out in 36 patients (88%), which compares favorably with the rate observed in previous studies [11, 12, 38, 39].

The chemotherapy regimen used in the present study was well tolerated. With the use of pegfilgrastim given prophylactically and erythropoietin support when needed, grade 3/4 hematological toxicity was rare. The most frequent adverse effect was neutropenia, but no case of febrile neutropenia was observed. Only one patient withdrew from the study for grade 4 neutropenia, likely as a consequence of poor storage conditions of pegfilgrastim (kept by mistake at room temperature instead than at 4°C). A 25% dose reduction of capecitabine was required in five patients because of mucositis (in two patients) and palmar-plantar erythrodysesthesia (in three patients). There was only one case of grade 3 diarrhea. This patient, who discontinued capecitabine, was later shown to suffer from a partial deficiency of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-fluorouracil catabolism. Only two patients refused to receive the planned treatment, one after the first and one after the fourth EC cycle. The high adherence to the treatment may have been due to the relatively short duration of the therapy program (16 weeks) and due to the high rate of clinical response. In fact, most of the patients experienced the change of the breast lump, with the tumor becoming softer and smaller soon after the beginning of the therapy.

The combination of epirubicin, cyclophosphamide, docetaxel, and capecitabine with pegfilgrastim support, as given in this study, proved to be feasible, effective, and endowed with mild toxicity in the neo-adjuvant setting of stage II and IIIA breast cancer patients.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
References
 
Partially supported by a grant PRIN 2004 from Ministero dell'Università e della Ricerca to CN and CF.

Received for publication November 6, 2006. Revision received February 1, 2007. Accepted for publication February 2, 2007.


   References
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 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
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