Abstract and Introduction
Background and objectives: The modern management of locally advanced breast cancer includes a multimodal approach consisting of neoadjuvant chemotherapy (usually given as initial treatment), surgery, radiotherapy and adjuvant hormone therapy. This therapeutic approach converts many patients with initially unresectable disease to reasonable surgical candidates, with acceptable rates of loco-regional disease control. Induction of a pathological complete response (pCR) with modern chemotherapy agents or combined with immunotherapy, when applicable, should be one of the primary goals of neoadjuvant therapy in order to achieve better disease-free and overall survival in this subset of patients. Neoadjuvant chemotherapy is now standard for patients with locally advanced breast cancer, and this method of treatment has been extended to patients with earlier disease without affecting the treatment outcome. The objectives of this study were: (1) to conduct a phase II study to assess the efficacy and availability of epirubicin and paclitaxel in the neoadjuvant setting in women with locally advanced or high tumour-to-breast ratio breast cancer (no patient in either of these subgroups was a candidate for breast-conserving surgery prior to chemotherapy); (2) to evaluate the incidence of clinically relevant toxicity and, in particular, cardiac toxicity after treatment with an epirubicin + paclitaxel regimen in this group of patients.
Methods: In this open-label, phase II, single-centre trial carried out in a university-affiliated tertiary-care municipal hospital, the rate of objective response, evaluated by clinical and pathological examinations, was the primary endpoint of the study. Other endpoints were the rates of breast-conserving surgery, local recurrence, disease-free survival and overall survival. Sixty patients were enrolled from September 1998 to September 2003 with a median follow-up of 56 months (range 16-96). All 60 women met the criteria for inclusion and agreed to participate in the study. They were diagnosed as having locally advanced or high tumour-to-breast ratio breast cancer that did not initially permit breast-conserving surgery. Epirubicin 75 mg/m2 and paclitaxel 175 or 200 mg/m2 were administered for five courses. Rates of adverse events were also analysed.
Results: Eight patients experienced a pCR, five had a pathological partial response with an almost complete pathological response, and 39 were able to undergo breast-conserving surgery. Adverse effects were mostly of grade 1 or 2 severity. The most common adverse reactions were fatigue and neutropenic fever. One patient developed local recurrence during the median 56-month follow-up. Among examined biological markers, only estrogen receptor negativity was a strong predictor of a pCR. The rates of disease-free and overall survival following the neoadjuvant combination were similar for those who had tumours positive for the estrogen receptor and those who were negative for this.
Conclusion: Treatment with a combination of epirubicin and paclitaxel enabled lumpectomy in a substantial proportion of women who were previously deemed to not be suitable candidates for breast-conserving surgery. Clinical responses were not influenced by the initial tumour volume, and the only statistically significant predictor of pCR was the estrogen receptor status of the tumour.
The management of locally advanced breast cancer has evolved over the past few decades to the currently popular multimodal approach with neoadjuvant chemotherapy, surgery, radiotherapy and adjuvant hormone therapy. Neoadjuvant chemotherapy, also termed primary, induction or preoperative chemotherapy, is defined as chemotherapy administered before locoregional treatment. It was first used in the treatment of locally advanced breast cancer approximately 30 years ago. Traditionally, these tumours were treated with radical surgery and/or radiotherapy, but most patients relapsed with distant metastases and eventually died. At present, there is no standard of care regarding the use of preoperative chemotherapy; however, neoadjuvant chemotherapy has potential advantages in increasing the rate of breast-conserving surgery and predicting the outcome of a particular chemotherapy regimen. The data emerging from clinical trials have shown that: (1) a clinical partial or complete response of the primary tumour was documented in 70--80% of the patients; (2) a pathological complete response (pCR) was observed in 15--28% of the patients and may be a predictor of prolonged overall survival; (3) disease progression during chemotherapy is very rare (2--3%); (4) treatment does not increase surgical morbidity; and (5) axillary node status retains its prognostic value. This treatment approach converts many patients with initially unresectable disease to possible surgical candidates, with acceptable rates of loco-regional disease control.
The safety of induction chemotherapy for patients with initially resectable breast cancer was confirmed by the National Surgical Adjuvant Breast Project (NSABP) B-18 study, which demonstrated outcomes that were similar overall for patients randomised to preoperative versus postoperative doxorubicin (adriamycin)-based combination therapy and that patient prognosis was not adversely affected by delaying resection. In addition, patients who achieved a pCR had longer recurrence-free survival. Thus, while the goals of a preoperative chemotherapeutic approach are to monitor the tumour response invivo and to improve rates of breast-conserving surgery, induction of a pCR with the new drugs should be one of the primary goals, affording longer disease-free and overall survival.
The inclusion of anthracyclines in therapy for breast cancer in general increased the response rates, remission duration and survival of patients with locally advanced breast cancer, with approximately 20% of patients who achieve a complete response remaining disease-free 10 years later. Unfortunately, the clinical value of anthracyclines is limited by the occurrence of ventricular dysfunction. A regimen consisting of doxorubicin 60 mg/m2 and paclitaxel 175--200 mg/m2 every 3 weeks had been reported to be associated with an unacceptable rate of congestive heart failure (18%) when given for eight cycles.
Epirubicin (4'-epidoxorubicin) has been shown to be less cardiotoxic and less myelotoxic than the parent compound, at equimolar doses. The combination of epirubicin and paclitaxel showed promise as first-line chemotherapy for advanced breast cancer, yielding a high level of activity with an overall clinical response rate of 84% and a low incidence of cardiotoxicity: only 6% of patients developed mild congestive heart failure. The reduced cardiotoxicity of this combination, as opposed to treatment with doxorubicin and paclitaxel, can be explained by the lesser cardiotoxic effects of epirubicin compared with doxorubicin, as well as by the limited pharmacokinetic interaction of paclitaxel with epi-rubicin. Although epirubicin has a lower cardio-toxic potential than doxorubicin, at cumulative doses of >1000 mg/m2 it induces cardiac failure in 16--35% of patients, with an incidence of death related to this that ranges from 20% to 38%.
The usual proposed risk factors for anthracycline cardiotoxicity include higher cumulative doses, prior chest wall radiotherapy, childhood or advanced age, female sex, pre-existing heart disease, hypertension and diabetes. In particular, previous cardiac irradiation, especially following anthracycline-based chemotherapy, and higher cumulative doses of an anthracycline, have been shown to be independent risk factors for histologically documented cardiac damage.
Prevention of cardiotoxicity during therapy with anthracyclines is therefore an important goal, and one possible way to achieve this is to use a less cardiotoxic anthracycline analogue, such as epirubicin.
We conducted a phase II study to assess the efficacy of combined epirubicin and paclitaxel as neoadjuvant therapy in women with locally advanced or high tumour-to-breast ratio breast cancer to determine the parameters associated with a positive response to the regimen, and to evaluate the clinically relevant toxicity of this treatment.
Clin Drug Invest. 2006;26(12):691-701. © 2006 Adis Data Information BV
Cite this: Neoadjuvant Treatment with Paclitaxel and Epirubicin in Invasive Breast Cancer - Medscape - Dec 01, 2006.