Docetaxel as Neoadjuvant Chemotherapy in Patients With Stage III Breast Cancer

August 1, 1997

Optimal management of locally advanced breast cancer (stage III) generally includes a combination of primary chemotherapy followed by surgery (if feasible), and local radiotherapy and adjuvant chemotherapy with or

ABSTRACT: Optimal management of locallyadvanced breast cancer (stage III) generally includes a combination ofprimary chemotherapy followed by surgery (if feasible), and local radiotherapyand adjuvant chemotherapy with or without hormonal therapy. An ongoingphase II study is being performed to evaluate the use of 4 cycles of 100mg/m² of docetaxel (Taxotere) administered as a 1-hour intravenousinfusion once every 3 weeks followed by surgery, 4 cycles of standard-dosedoxorubicin/cyclophosphamide (Cytoxan, Neosar) chemotherapy, and radiation,with and without tamoxifen (Nolvadex) in patients with locally advancedbreast cancer. Preliminary results from 33 patients included in this phaseII study are reported here. A partial response was achieved in 22 patients(67%), with 6 patients (18%) experiencing a complete response with thisregimen. One patient with a complete response was confirmed to have a completepathologic response at the time of surgery. Febrile neutropenia was notedin 8 patients (24%) and in 8 of the 120 treatment cycles (7%) administered.Future trials aimed at increasing the number of pathologic complete responsesin patients with stage III breast cancer may require the use of docetaxelin combination with other active agents or the use of dose-dense schedulingschemes. [ONCOLOGY 11(Suppl 8):15-18, 1997]

Introduction

The substantial antitumor activity of docetaxel (Taxotere) in first-and second-line chemotherapy for patients with metastatic breast cancerprovides the rationale for further investigation of this agent in otherbreast cancer treatment settings.[1-11] One area is the incorporation ofdocetaxel into multimodality regimens in which chemotherapy and/or endocrinetherapy is combined with surgery and radiation.

Earlier studies have shown that induction chemotherapy may result insignificant reductions in the size of the primary tumor, thereby increasingthe number of candidates for breast conservation by a combination of surgeryand radiation.[12-16] One benefit of using neoadjuvant therapy in thissetting is that it allows clinical and pathological assessment of tumorresponse to the chemotherapy regimen.[17,18]

In a randomized study by Powles and colleagues,[17] use of neoadjuvantchemoendocrine therapy and postsurgery chemotherapy in 212 women with primaryoperable breast cancer was evaluated. Of these 212 patients, 105 were randomizedto receive neoadjuvant treatment and received 4 cycles of chemotherapyfor 3 months before surgery, followed by another 4 cycles after surgery.For comparison, 107 patients were randomized to adjuvant therapy and received8 cycles of chemotherapy over 6 months after surgery.

The findings from this trial showed that neoadjuvant therapy resultsin an overall response rate of 85% and a complete response in 10% of patients.In addition, there was a significant reduction in the requirement for mastectomyin patients who received neoadjuvant treatment (13%) compared with thosewho received adjuvant therapy (28%) (P < .005).

We conducted a phase II study to determine the clinical response rateto primary therapy with docetaxel followed by surgery, cyclophosphamide(Cytoxan, Neosar), and doxorubicin, and radiation with or without adjuvanttamoxifen (Nolvadex) in patients with stage III breast cancer. This preliminaryanalysis addresses the response rate, side effects, and toxicity profileof this therapeutic approach.

Methods

Patients

Women aged 18 to 75 years with stage III breast cancer were accruedinto this open-label, phase II multicenter study. Patients with locallyadvanced adenocarcinoma of the breast and measurable and/or evaluable diseasewere eligible for entry into the study provided they had a performancestatus of at least 60% (Karnofsky index) and had not received previouschemotherapy.

Laboratory entry criteria included the following values: absolute neutrophilcount ³ 2.0 × 109/L; a platelet count ³ 100.0 × 109/L; total bilirubin £ 1.25 × uppernormal limit (UNL); aspartate aminotransferase (ASAT) or alanine aminotransferase(ALAT) £ 3 × UNL; alkaline phosphatase £ 6 × UNL;ASAT or ALAT or both £ 1.5 × UNL associated with alkaline phosphatase £2.5 × UNL; serum creatinine £ 1.5 × UNL; a restingleft ventricular ejection fraction above the lower normal limit of theinstitution, as measured by echocardiography or radionuclide angiocardiography.

Treatment Plan

Patients with locally advanced stage III breast cancer were initiallytreated with 4 cycles of 100 mg/m² of docetaxel administered as a1-hour intravenous infusion once every 3 weeks. Following the 4 cyclesof docetaxel, patients underwent either breast-conserving surgery or mastectomy.Standard-dose doxorubicin/cyclophosphamide chemotherapy--4 cycles of 60mg/m² of Adriamycin and 600 mg/m² of cyclophosphamide--was initiatedfollowing surgery. Radiation therapy was then delivered, which varied accordingto the type of surgery performed.

For patients who had undergone breast-conserving surgery, radiationconsisted of conventional fractionation at a dose of 5,000 or greater cGy(180 to 200 cGy/day) and a boost to a total tumor dose of 6,040 cGy. Forpatients who had undergone modified radical mastectomy, radiation therapyto the chest wall and supraclavicular region was employed to a total doseof 5,000 or greater cGy. Tamoxifen therapy (20 mg/day for 5 years) wasprovided to all patients who were hormone-receptor positive or who wereover the age of 50 years.

All patients received premedication with 8 mg of oral dexamethasonetwice daily for 5 days, starting 1 day prior to docetaxel administration.Growth factor support with granulocyte colony-stimulating factor (G-CSF)(filgrastim [Neupogen]) was provided to patients who developed febrileneutropenia (and was initiated prophylactically to these patients on subsequentcycles).

Study Assessment

Tumor measurements were performed before initiation of therapy and everytwo cycles thereafter, according to the World Health Organization criteria.

The primary efficacy variable was clinical response rate, defined asthe percentage of patients who achieved a complete or partial response.In patients who received at least 2 cycles of therapy, response to treatmentwas classified as follows: complete response, partial response, stabledisease, or progressive disease. A complete response was defined as thecomplete resolution of all known lesions on 2 separate measurements atleast 4 weeks apart. A partial response was defined as reduction of tumorvolume by at least 50%. Stable disease was defined as a decrease of < 50% or an increase of < 25%. Progressive disease was definedas a > 25% increase in an existing tumor or the appearance ofnew lesions.

The secondary efficacy variable was time to progression, calculatedfrom the date of the administration of the first cycle of chemotherapyto the first sign of disease progression.

Results

Patient Demographics

This preliminary analysis is based on data from 33 patients. The demographicsare listed in Table 1. The mean age ofpatients was 50 years (range, 27 to 68 years). Thirty-two of the 33 patientshad a Karnofsky performance status of 90%. A total of 12 patients (36%)had stage IIIA disease and 16 (49%) had stage IIIB disease. The remaining5 patients (15%) were unspecified stage III, but appeared to have largeprimary tumors > 5 cm, with no clear indication of the nodal statuson clinical examination. A total of 120 cycles were administered duringthe study.

Response Rate

Partial and complete responses were achieved in 22 (67%) and 6 (18%)patients, respectively, for an overall response rate of 85% (Table2). Disease was stable in 4 patients (12%) and progressed in 1(3%).Of the 6 patients with complete clinical responses, 1 patient was actuallyconfirmed to have achieved a complete pathologic response at the time ofsurgery.

Data on the time-to-progression and disease-free survival after 1 and2 years of treatment are not yet available.

Toxicity

The primary toxicity observed during the docetaxel administration portionof this trial was myelosuppression (Table3). Febrile neutropenia was noted in 8 patients (24%) and in 8 of the120 treatment cycles (7%) administered. Grade 4 neutropenia was experiencedby 31 patients (94%) during at least 1 cycle. The majority of patients(88%) experienced grade 4 neutropenia during the first cycle, with a medianduration of 7 days or less. Thrombocytopenia did not occur. Although anemiadid occur, no patient required a blood transfusion.

Nonhematologic toxicities are shown in Table4. The most common National Cancer Institute (NCI) gradeable toxicitiesincluded alopecia (97%), nausea (51%), diarrhea (46%), and stomatitis (35%).Grade 3 nonhematologic toxicities were uncommon and included diarrhea (6%),stomatitis (6%), allergy (3%), and nausea (3%). Grade 3 to 4 or severeneurotoxicity was not observed in any patient. Other toxicities not gradedusing the NCI criteria included asthenia, which was noted in 70% of patients,but was severe in only 9%. Peripheral edema and nail disorders were mildto moderate in severity, with no reports of severe cases.

Conclusion

The preliminary results from this phase II study suggest that single-agentdocetaxel has significant antitumor activity as neoadjuvant therapy inpatients with stage III breast cancer. The overall response rate was 85%,with 18% complete responses. The most common toxicity was neutropenia;however, only a small fraction of cases were associated with febrile neutropenia.Future trials aimed at increasing the number of pathologic complete responsesin patients with stage III breast cancer may require the use of docetaxelin combination with other active agents or the use of dose-dense schedulingschemes.

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