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© 1999 American Society for Clinical Oncology Maximized Reduction of Primary Breast Tumor Size Using Preoperative Chemotherapy With Doxorubicin and DocetaxelFrom the Klinik für Gynäkologie und Geburtshilfe, Goethe-Universität Frankfurt, Frankfurt am Main; Frauenklinik vom Bayerischen Roten Kreuz, Munich; Frauenklinik der Charité, Humboldt-Universität zu Berlin, Berlin; Frauenklinik, Klinikum Bayreuth, Bayreuth; and Universitäts-Frauenklinik Münster, Münster, Germany. Address reprint requests to Gunter von Minckwitz, MD, Klinik der Frauenheilkunde und Geburtshilfe, Goethe-Universität Frankfurt, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany; email minckwitz{at}em.uni-frankfurt.de
PURPOSE: To assess the toxicity and efficacy of preoperative chemotherapy with doxorubicin and docetaxel in patients with primary operable breast cancer. PATIENTS AND METHODS: Forty-two patients with histologically confirmed primary breast cancer tumors of at least 2 cm in diameter received doxorubicin (50 mg/m2 intravenously [IV] over 15 minutes) and docetaxel (75 mg/m2 IV over 1 hour) every 14 (24 patients) or 21 (18 patients) days for four cycles. RESULTS: The median size of the primary tumor decreased significantly, from 4 cm (range, 2 to 10 cm) to 2 cm (range, 0 to 5 cm) on physical examination and from 3.4 cm (range, 1 to 8 cm) to 1.8 cm (range, 0 to 4 cm) on sonography (P < .001). The overall response rate as assessed by physical examination was 93%, and complete remission of the primary tumor occurred in 33% of patients. The remission rate as assessed by sonographic measurement was 67%. Two patients (5%) had histologically confirmed complete responses. Sonography was more reliable than palpation in predicting histologically determined response. No grade 4 toxicity was noted, and grade 3 toxicity was reported with alopecia (95%), lethargy (17%), loss of appetite (10%), stomatitis (7%), leukopenia (5%), skin desquamation (5%), infection (5%), motor neuropathy (2%), and nausea (2%). The 3-week schedule was associated with less toxicity than the 2-week schedule. CONCLUSION: Preoperative combination chemotherapy with doxorubicin and docetaxel is highly effective and feasible in primary operable breast cancer.
THE TIMING OF CHEMOTHERAPY in relation to surgery has recently been the subject of intensive investigations. Preoperative chemotherapy leads to a significant reduction in tumor size (downstaging) and improves both the rate and the cosmetic results of breast-conserving surgery. The response of the primary tumor is a reliable prognostic factor and can in addition be regarded as an "in vivo" chemosensitivity test. This is in contrast to postoperative therapy, in which no effect on the primary tumor can be achieved and tumor response can be assessed only through long-term follow-up studies.1 In a study conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) that included 1,523 patients, Fisher et al2 recently demonstrated that there is no difference in prognosis between patients who are treated preoperatively and those treated postoperatively with doxorubicin and cyclophosphamide. Another randomized trial, which included 414 premenopausal patients with T2 or T3 tumors, was reported on by Scholl et al.3 Preoperative treatment with four cycles of cyclophosphamide, doxorubicin, and fluorouracil was found to be superior, at 54-month follow-up, to postoperative treatment using the same schedule. However, this survival advantage could be partially explained by the study design; in the postoperative arm, only node-positive patients received chemotherapy, whereas in the preoperative chemotherapy arm, all patients were given chemotherapy. The rates of response of the primary tumor to preoperative chemotherapy can reach 90%,4,5 and the numbers of patients with positive lymph nodes can be reduced significantly.2 This can result in a rate of breast-conserving surgery of up to 85% among patients with tumors larger than 3 cm in diameter.1 Although complete remissions can be detected clinically in about one fourth of patients, remission can be confirmed histologically in only 4% to 8%.2,6,7 Docetaxel has proved to be highly active in the treatment of metastatic breast cancer.8 The overall response rate for a 3-week schedule of docetaxel 100 mg/m2 administered intravenously (IV) was 41%, even in patients resistant to anthracycline therapy. In a phase III trial comparing docetaxel therapy and doxorubicin therapy in patients in whom previous alkylating chemotherapy had failed, overall response rates were 47.8% for the docetaxel arm and 33.3% for the doxorubicin arm (P = .008).9 These two drugs are therefore among the most active substances for the treatment of breast cancer. They do not seem to be cross-resistant and they have different nonhematologic toxicity profiles, making treatment with a combination of the two drugs a reasonable approach. A French group combined the two drugs in a phase I/II study.10 Forty-two patients with metastatic breast cancer received the combination as a first-line therapy, and a 3-week schedule of doxorubicin 50 mg/m2 plus docetaxel 75 mg/m2 was recommended. Leukopenia with subsequent infection was dose limiting (grade 4 neutropenia occurred in 93% of the patients not receiving granulocyte colony-stimulating factor [G-CSF]). The overall response rate was 71.5%. Because response to preoperative chemotherapy is predictive of prognosis, a major aim of further clinical investigations should be to improve the rates of response to preoperative chemotherapy. The aim of the present study was to determine the efficacy and toxicity of preoperative combination chemotherapy with doxorubicin and docetaxel in patients with primary operable breast cancer.
Patient Population Patients with newly diagnosed breast cancer who met all of the following eligibility criteria were included in the study: histologically confirmed diagnosis by a core-cut or incisional biopsy; unilateral breast cancer, with a maximum tumor diameter of at least 2 cm; two-dimensional measurable tumor on ultrasonogram; no history or electrocardiographic evidence of abnormal cardiac function; normal cardiac function, with a left ventricular ejection fraction of at least 60%, measured by echocardiography; age 18 to 75 years; Karnofsky performance status of at least 70; life expectancy of at least 12 months; adequate hematologic, renal, and hepatic function (WBC count > 4.0 x 109/L, platelets > 1 x 1011/L; bilirubin, serum creatinine, and transaminase levels within normal range); negative pregnancy test and appropriate nonhormonal contraception in fertile women; and written informed consent and presumed compliance of the patient. Specific criteria for exclusion were as follows: previous treatment for breast cancer, including surgery, radiation, and cytotoxic and endocrine treatments (except surgical diagnostic procedures); previous malignancy other than breast cancer; noninvasive breast lesions, if the disease-free interval was less than 10 years; metastatic, locally inoperable, bilateral, or inflammatory breast cancer; previous cytotoxic treatment for any condition; pre-existing neurotoxicity greater than grade 2 (National Cancer Institute of Canada [NCIC] grading); active infection or other significant illness that could affect toleration of treatment; current treatment with sex hormones (treatment had to have been discontinued before the start of systemic therapy); and psychiatric illness or drug addiction that would preclude obtaining informed consent. Patients were recruited from six centers in Germany. In a protocol amendment, the schedule was changed from a 2-week interval to a 3-week interval. Ethics committee approvals were obtained before the start of the study. Eligible patients received doxorubicin 50 mg/m2 IV over 15 minutes, followed by docetaxel 75 mg/m2 IV over 1 hour. Administration of the drug was repeated in the first cohort as a dose-intensified treatment every 2 weeks, and in a second cohort every 3 weeks, for four cycles. Premedication for hypersensitivity reactions, fluid retention, and nausea consisted of oral dexamethasone 8 mg bid the day before the treatment, dexamethasone 8 mg IV immediately before the start of doxorubicin infusion, and oral dexamethasone 8 mg bid on days 2 to 4. Further antiemetic premedication consisted of ondansetrone 8 mg IV. The G-CSF lenograstim was given prophylactically at a dosage of 150 µg/m2 from day 3 to day 12. Treatment was postponed for a week if grade 4 (NCIC grading) hematologic toxicity, grades 2 to 4 neurotoxicity, or other nonhematologic forms of toxicity (except alopecia), grades 3 or 4, occurred. Chemotherapy was stopped if the adverse event did not then improve. No dose reduction was planned. Patients were scheduled to undergo surgery 2 to 4 weeks after the fourth cycle. Surgery was to be performed earlier in cases of obvious progression or prolonged toxicity. The aim of surgery was to obtain tumor-free margins of at least 1 cm, with the whole previously involved area being excised if cosmetically acceptable. A biopsy specimen of adequate size was to be taken from a representative area if there was complete tumor regression. A standard axillary lymph node dissection, with excision of at least 10 lymph nodes, was to be performed. A physical and sonographic assessment (Sonotron Synergy; Diasonic Sonotron, Munich, Germany; or Logic 500; General Electric-Kranzbühler, Solingen, Germany) of the primary tumor in the breast and of the axillary nodes had to be carried out within 3 weeks before the start of chemotherapy. Both measurements had to be repeated every cycle and before surgery. Distant metastases had to be excluded by liver ultrasound, chest radiography, and bone scintigraphy. Electrocardiography and cardiac ultrasound examinations were performed to exclude pre-existing cardiomyopathy on entry onto the study and were repeated before surgery. Additional ultrasound examinations were carried out immediately before surgery and 6 weeks after the operation. Blood counts were conducted weekly, and blood chemistry was measured before every cycle. Toxicity data were recorded for every cycle; NCIC grading was used. The response to chemotherapy was assessed physically, sonographically, and histologically. Response was considered complete if there was no evidence of the primary breast tumor by the assessment method concerned. Response was considered partial if there was a reduction of 50% or more in the product of the two largest perpendicular diameters of the tumor. If the tumor area showed a reduction of less than 50% or an increase of less than 25%, no change was considered to have occurred. In multifocal or multicentric disease, only the largest lesion was evaluated.
Statistics
Forty-two patients were recruited onto this phase II study. Twenty-four patients received chemotherapy every 2 weeks and 18 patients received it every 3 weeks (Table 1). One patient withdrew consent after the first cycle, and one patient refused surgery after undergoing four cycles of chemotherapy. All patients were evaluated for drug tolerance and efficacy based on intent-to-treat analysis. Data from the two patients who withdrew were excluded only from the histologic response evaluation.
The median age of the patients was 50 years (range, 21 to 70 years). Half of the patients had clinical stage II disease, and a quarter of them had stage IIIA disease. Patients with stage IIIB disease (seven patients) were eligible for the study because the primary tumor was considered completely resectable with modified radical mastectomy. The median tumor size on physical examination was 4.0 cm (range, 2 to 10 cm) for the largest diameter and 16 cm2 (range, 3 to 100 cm2) by two-dimensional measurements. Sonographic measurements yielded a median diameter of 3.4 cm (range, 1 to 8 cm) and an area of 9 cm2 (range, 1 to 64 cm2). Axillary lymph nodes were palpable in 71% of patients (Table 2).
Toxicity The schedule was associated with only slight hematologic toxicity. More severe leukopenia was avoided by prophylactic use of G-CSF. Only one patient, who did not receive G-CSF, developed grade 4 leukopenia (WBC, 0.8 x 109/L) and neutropenia (neutrophil count, 0.24 x 109/L) during the first cycle. No neutropenia occurred in the following cycles with adjunctive G-CSF. One additional patient developed grade 3 leukopenia in the second cycle. Grade 1 or 2 leukopenia on day 8 was noted in 5% to 17% of patients, with the incidence increasing from cycle to cycle. Grade 1 anemia (RBC count, > 10 g/L) and grade 2 anemia (RBC count, 80 to 99 g/L) was documented in five and seven patients, respectively, in the fourth cycle. No grade 3 or 4 anemia occurred. None of the patients developed thrombocytopenia of any grade (Table 3).
Nearly all of the patients (95%) developed complete alopecia (grade 3) after two or three cycles. Apart from alopecia, the most common form of toxicity was lethargy, which was grade 3 in seven patients (17%) and grade 2 in 16 patients (38%). Other manifestations of grade 3 toxicity were loss of appetite (n = 4, 10%), stomatitis (n = 3, 7%), skin desquamation (n = 2, 5%), infection (n = 2, 5%), nausea (n = 1, 2.5%), and weakness (n = 1, 2.5%). No fluid retention or cardiac events were observed (Fig 1). Cardiac ultrasound performed before surgery showed an asymptomatic reduction of left ventricular ejection fraction of 10% in three patients and 20% in three patients, but ejection fraction remained greater than 50% in all patients. Redness of the skin was observed in 19 patients, predominantly on the hands and feet. In more severe cases, dry (n = 7) or moist (n = 2) skin desquamation occurred. All cutaneous symptoms disappeared by 4 weeks after the final administration of doxorubicin and docetaxel. The number of grade 3 events (apart from alopecia) increased from two and one in the first two cycles to 10 and 14 in cycles three and four. This trend was mainly due to anemia, leukopenia, lethargy, stomatitis, skin desquamation, and infections, which are therefore considered cumulative toxicities. Whereas 20 grade 3 and 112 grade 2 hematologic and nonhematologic events (apart from alopecia) were observed with the 2-week schedule, only five and 42 patients developed grade 3 and grade 2 toxicities, respectively, with the 3-week schedule.
Efficacy
A similar effect was found sonographically. The response rate was 67%, with complete disappearance of the tumor in 13% of patients. No difference between the two time schedules was detectable. The median tumor diameter decreased from 3.4 cm (range, 1 to 8 cm) to 1.8 cm (range, 0 to 4 cm) (P < .001). One of the five patients with complete disappearance of the tumor had a complete histologic remission. The other four patients had histologic tumor residues of 0.5 to 0.8 cm in diameter. The median maximal tumor size on histologic evaluation was 1.8 cm (range, 0-5.1 cm) in diameter, with an area of 3.24 cm2 (range, 0-26 cm2). On histologic evaluation, tumor size was found to have decreased by 50% or more in 71% of patients, compared with initial physical measurements, or 50% of patients, compared with initial sonographic measurements. Clinical measurement of tumor diameter and area after chemotherapy yielded significantly larger values than did histologic evaluation (P = .05). The sonographic estimate did not differ significantly from the histologic estimate (P = .6) (Table 2). A significant downstaging effect occurred with preoperative chemotherapy. Tumor stage was significantly decreased after chemotherapy (P < .001). Whereas all patients had disease of at least stage II at the start of treatment, 45% were found to have stage 0 or I disease on histologic evaluation. Before administration of chemotherapy, breast-conserving therapy had been intended in 15 patients (36%). However, after chemotherapy, breast-conservation surgery was possible in 59%. At the beginning of the study, 12 patients (28.6%) had clinically noninvolved axillar nodes. Before surgery, the number increased to 22 patients (52%). Eighteen patients were node-negative by histologic examination.
The meta-analysis conducted by the Early Breast Cancer Trialists' Collaborative Group demonstrated that adjuvant systemic chemotherapy and/or endocrine therapy can improve survival in patients with node-positive or node-negative breast disease.11,12 A significant benefit was found for all patients treated with chemotherapy, irrespective of nodal or receptor status. Given the equivalent results of preoperative and postoperative chemotherapy,2 preoperative chemotherapy can be applied in most cases of primary breast cancer. New systemic forms of therapy can be evaluated more precisely and rapidly, and with a limited number of patients, in the preoperative setting than in the adjuvant or advanced disease setting.
Doxorubicin and docetaxel belong to the two most active groups of cytotoxic drugs for the treatment of breast cancer. In the present phase II study, we evaluated a combination of the two drugs. In this intent-to-treat analysis, an overall clinical response rate of 93% was obtained. In the small subset of patients on the 2-week schedule, the response rate was 96%. This response rate is better than those reported in the literature, even though the patient characteristics were unfavorable. In the NSABP B-18 trial,2 before the start of chemotherapy, the median tumor size was approximately 3 cm, 29% of the tumors were Only one report has been published concerning preoperative use of a combination of anthracyclines and taxanes (paclitaxel). In a pilot study involving 73 patients, a clinical response was observed in 88%.5 The complete response rate as assessed by physical measurement was 15%, and in 7% no histologic tumor residues were found. The patient characteristics were quite comparable to those in the present study because patients with stage II, III, and IV disease were included in the trial. Dieras et al13 presented preliminary results of a preoperative chemotherapy trial comparing the combination of doxorubicin and cyclophosphamide with the combination of doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2). The clinical response rate for the latter combination was 85%, which included a complete-remission rate of 14%. However, grade 3 cardiotoxicity was reported in 18% of subjects. The present study was initiated with the 2-week schedule. At the first interim analysis, there was an impression that more than 8 weeks were required for tumor remission. The protocol was therefore amended to include a 3-week schedule. However, because of the small number of patients, no final conclusion can be drawn regarding superiority of one schedule over another. Palpation seems to be an imprecise method for determining tumor response. The overall response rate was overestimated, although clinical measurements indicated larger tumors than did sonography or histology. Only two of 14 patients with clinically assessed complete disappearance of the tumor were found to have no residual tumor in the resected specimen. The correlation between sonographic assessment and histology was better, but only one of five patients with sonographically undetectable tumor was found to have a complete remission histologically. The use of sonography to predict histologic tumor size needs to be evaluated in further studies. Because mammography also does not seem to detect minimal residual tumor,14 further imaging methods such as magnetic resonance imaging or positron emission tomography must be evaluated as well. Although the toxicity was lower with the 3-week schedule, the 2-week schedule was well tolerated, and dose-limiting toxicity was not reported. No chronic toxicity was observed. The use of more than four cycles to increase the activity of the schedule further does not seem to be feasible, because significantly more toxic events took place in cycles 3 and 4. In addition, the time interval of 8 weeks between diagnosis and surgery was well-accepted by the patients. The low incidence of febrile neutropenia and infection raises the question of whether G-CSF should be delivered as a prophylaxis. However, one patient who did not receive G-CSF developed grade 4 neutropenia. Therefore, we have decided to evaluate, in a future study, primary prophylaxis with G-CSF, given on days 5 to 10 only, rather than as an intervention. Because of the trend identified here toward more efficacy with toxicity below clinically relevant levels, the German Adjuvant Breast Cancer Group has started a phase III trial for further evaluation of the dose-intensified 2-week schedule. In this randomized study, the addition of tamoxifen to preoperative chemotherapy with doxorubicin and docetaxel is being investigated.
Supported by Rhône-Poulenc Rorer, Cologne, Germany.
1. Bonadonna G, Valagussa P, Brambilla C, et al: Primary chemotherapy in operable breast cancer: Eight-year experience at the Milan Cancer Institute. J Clin Oncol 16:93-100, 1998
2.
Fisher B, Brown A, Mamounas E, et al: Effect of pre-operative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15:2483-2493, 1997 3. Scholl SM, Fouquet A, Asselain B, et al: Primary versus adjuvant chemotherapy in premenopausal patients with tumors considered too large for breast conserving surgery: Preliminary results of a randomised trial. Eur J Cancer 30A:645-652, 1994
4.
Smith IE, Walsh G, Jones A, et al: High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer. J Clin Oncol 13:424-429, 1995 5. Moliterni A, Tarenzi E, Capri G, et al: Pilot study of primary chemotherapy with doxorubicin plus paclitaxel in women with locally advanced or operable breast cancer. Semin Oncol 24:10-14, 1997 (suppl 17)
6.
Feldmann L, Hortobagyi G, Buzdar A, et al: Pathological assessment of response to induction chemotherapy in breast cancer. Cancer Res 46:2578-2581, 1986 7. Hortobagyi GN, Ames FC, Buzdar AU, et al: Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62:2507-2516, 1988[Medline] 8. von Minckwitz G, Costa SD: Docetaxel (Taxotere) zur Therapie des Mammakarzinoms: Höchste Wirksamkeit bei moderaten Nebenwirkungen. Med Klin 9:24-29, 1997 (suppl 4) 9. Chan S, Friedrichs K, Noel D, et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol (in press) 10. Bourgeois H, Gruia G, Dieras V, et al: Docetaxel in combination with doxorubicin as 1st-line CT of metastatic breast cancer (MBC): A phase I dose-finding study. Proc Am Soc Clin Oncol 15:148, 1996 (abstr 259) 11. Early Breast Cancer Trialists' Collaborative Group: Effects of adjuvant tamoxifen and cytotoxic therapy on mortality in early breastcancer: An overview of 61 randomized trials among 28,896 women. N Engl J Med 319:1681-1692, 1988[Abstract] 12. Kaufmann M, von Minckwitz G: Das primäre Mammakarzinom:Vorschläge und aktuelle Aspekte zur adjuvanten systemischen Therapie. Dtsch Ärzteblatt 93:755-758, 1996 13. Dieras V, Fumoleau P, Romieu G, et al: A randomized, parallel study of doxorubicin/Taxol (paclitaxel) (AT) and doxorubicin/cyclophosphamide (AC) as neoadjuvant treatment of breast cancer. Breast Cancer Res Treat 50:233, 1998 (abstr 25)
14.
Winnicombe SJ, MacVicar AD, Guy RL, et al: Primary breast cancer: Mammographic changes after neoadjuvant chemotherapy, with pathological correlation. Radiology 198:333-340, 1996 Submitted October 5, 1998; accepted February 22, 1999. This article has been cited by other articles:
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 cm in diameter, and the percentage of node-positive patients was 26%; in our study, before chemotherapy was initiated, the median tumor size was 4 cm and 71% of patients had positive nodes. No patients with stage IIIB disease were included in the NSABP trial. Such exclusions actually influence response rates, because small tumor size has been identified as an independent predictor of response to preoperative chemotherapy.
