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Feasibility and Tolerability of Sequential Doxorubicin/Paclitaxel Followed by Cyclophosphamide, Methotrexate, and Fluorouracil and Its Effects on Tumor Response as Preoperative Therapy

Authors' Affiliations: ¹ Istituto Nazionale Tumori, Milan, Italy; ² Hospital Vall d'Hebron and ³ Hospital de San Pau, Barcelona, Spain; ⁴ Frauenklinik vom Roten Kreuz, Munich, Germany; ⁵ Istituto Valenciano de Oncologia and ⁶ Hospital Clinico Universitario de Valencia, Valencia, Spain; ⁷ N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia; ⁸ Central Clinical Hospital named after N.A. Semashko, Moscow, Russia; and ⁹ Azienda Ospedaliera Santa Maria della Misericordia, Udine, Italy

Requests for reprints: Luca Gianni, CTO Coordinating Center, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milan, Italy. Phone: 39-02-2390-2789; Fax: 39-02-2390-2678; E-mail: gianni{at}istitutotumori.mi.it.

	Abstract

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Purpose: The European Cooperative Trial in Operable breast cancer (ECTO) randomly tested whether efficacy of adjuvant doxorubicin followed by i.v. cyclophosphamide, methotrexate, and fluorouracil (CMF; doxorubicin CMF, arm A) could be improved by adding paclitaxel (doxorubicin/paclitaxel CMF) as adjuvant (arm B) or primary systemic therapy (PST, arm C). We report here feasibility, tolerability, locoregional antitumor activity, and breast conservation rate.

Methods: A total of 1,355 women entered the study. Feasibility and safety were compared in arm A versus arms B plus C. Surgical findings were compared in arms A plus B versus arm C.

Results: Grade 3 or 4 National Cancer Institute toxicities were low (<5%) in all arms. Neuropathy was more frequent in the paclitaxel-containing arms (grade 2, 20.5% versus 5.0%; grade 3, 1.3% versus 0.2%). At 31 months of follow-up, asymptomatic drop of left ventricular ejection fraction was similar in all arms, whereas symptomatic cardiotoxicity was recorded in three patients (0.5%) in A and in three patients (0.3%) in B plus C. PST induced clinical complete plus partial remission in 78%, with an in-breast pathologic complete response rate of 23% and an in-breast plus axilla pathologic complete response rate of 20%. In the multivariate analysis, only estrogen receptor (ER) status was significantly associated with pathologic complete response (odds ratio for ER negative, 5.77; 95% confidence interval, 3.49-9.52; P < 0.0001). PTS induced a significant axillary downstaging (P < 0.001), and breast sparing surgery was feasible in 65% versus 34% (P < 0.001).

Conclusions: Doxorubicin/paclitaxel CMF is feasible, safe, and well tolerated. Given as PST, it is markedly active, allowing for breast-sparing surgery in a large fraction of patients.

Based on the activity of the above regimens, in 1996, we designed a trial [known as European Cooperative Trial in Operable breast cancer (ECTO); Fig. 1] addressing the potential role of introducing paclitaxel within a sequential regimen of non–cross-resistant chemotherapies. The ECTO study randomized patients with breast cancer > 2 cm to adjuvant doxorubicin CMF or doxorubicin/paclitaxel CMF (Fig. 1, arms A and B, respectively). In the ECTO study, the planned delivery of maximum of four cycles of doxorubicin/paclitaxel (240 mg/m² of total doxorubicin) before CMF seemed therefore consistent with the goal of exploiting the potential benefits of doxorubicin/paclitaxel without exposing the patients to excessive cardiac risk.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. ECTO study design. Women with breast tumor > 2 cm at diagnosis were randomized to either arm A, B, or C. A, doxorubicin; AT, doxorubicin and paclitaxel; T, Taxol; CMF, cyclophosphamide, methotrexate, and fluorouracil; S, surgery.

	Patients and Methods

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Patient eligibility and study procedures. Women at participating ECTO centers who had primary operable breast tumor > 2.0 cm at diagnosis (T₂-T₃, N₀-N₁, M₀) were eligible for this study. Patients with locally advanced or bilateral breast carcinoma, prior anticancer treatment, inadequate bone marrow reserve, abnormal renal and liver function tests, and history of relevant cardiac disease were not eligible for the study. Also excluded were patients pregnant or lactating or with active infection or with a history of other invasive malignancy.

The study and the informed consent form had to be approved by each local ethic committee. Patients were to undersign the written informed consent to enter the study.

Between November 6, 1996 and May 29, 2002, a total of 1,355 patients were enrolled. Breast cancers were diagnosed by core biopsy (82%) or fine-needle aspiration cytology (18%). Either method of diagnosis was evenly distributed among the three treatment arm. Approximately 50% of the tumor diagnosed by fine-needle aspiration had clinical involvement of axillary nodes, and after major surgical intervention, all tumors were classified as invasive carcinomas. Assessment of hormonal receptor status and tumor grade was required.

Treatment allocation was done centrally at the ECTO Operations Office using a minimization algorithm (19) to balance assignments according to primary tumor size (<4.0 versus >4.0 cm), tumor grade (low versus intermediate versus high), and hormonal receptor status (estrogen and/or progesterone positive versus both negative). Geographic area of the participating center was also taken into account before randomization.

Treatment. Patients in arm A first received surgery followed by sequential single-agent doxorubicin and CMF; patients in arm B first underwent surgery followed by sequential doxorubicin/paclitaxel and CMF; patients in arm C received sequential doxorubicin/paclitaxel and CMF followed by surgery.

Breast irradiation (50 Gy through two opposing tangential fields to be started after completion of chemotherapy or within 4 weeks from surgery in arm C) was required after breast sparing surgery. In the presence of pT₄ lesion after mastectomy, chest wall irradiation was recommended.

In arm A (Fig. 1), doxorubicin was given at the dose of 75 mg/m² by i.v. bolus every 3 weeks. In arms B and C, doxorubicin was given as a 60 mg/m² i.v. bolus followed by paclitaxel at 200 mg/m² infused over 3 hours, and each course was repeated every 3 weeks. CMF consisted in i.v. cyclophosphamide (600 mg/m²), methotrexate (40 mg/m²), and fluorouracil (600 mg/m²) on days 1 and 8 every 4 weeks. No dose reduction was allowed except following febrile neutropenia (as defined by absolute neutrophil count < 500/µL and fever > 38°C), grade >2 neuropathy due to paclitaxel, and grade >2 gastrointestinal toxicity on doxorubicin/paclitaxel regimen, when a 25% temporary reduction was required. In the presence of hematologic toxicity on the planned day of treatment, drug administration was delayed until marrow recovery. Before paclitaxel, premedication consisted of prednisone (25 mg orally the evening before therapy), hydrocortisone (250 mg i.v.) plus chlorphenamine (10 mg i.v. or i.m.), and cimetidine (300 mg i.v.), all given 30 minutes before the taxane. Antiemetic therapy was administered according to the policy of the participating center.

At the end of the surgery-chemotherapy approach, all patients, regardless of age and receptor status, were originally offered tamoxifen (20 mg/d) for five consecutive years. The protocol was amended, and after June 30, 2000, tamoxifen was offered only to women whose tumors were either estrogen or progesterone positive.

Primary tumor size determination and evaluation of primary systemic therapy response. Clinical size of primary breast cancers was determined at diagnosis and before administration of each cycle of chemotherapy. Mammogram or breast ultrasound were planned at the end of each chemotherapy regimen. In the absence of clinical evidence of tumor in the breast and in the absence of any new lesions, treatment response was categorized as clinically complete. When the reduction in size of the breast tumor was >50% in the product of the two greatest perpendicular diameters, the response was judged to be partial; when the reduction was <50% but >25%, the response was categorized as minor. When there was an increase of >50% compared with a previous measurement or when a new lesion appeared, the patient was considered to have progressive disease. Patients whose tumor response did not meet any of the above definitions were considered nonresponders.

Surgical breast and axillary node resection specimens were carefully evaluated for pathologic tumor response according to the guidelines provided by an ad hoc committee before starting the trial. Patients who had no residual invasive cancer in the breast were considered to have had a pathologic complete response. Because this definition did not take histologic nodal status into account, patients with noninvasive or no residual cancer could have had positive axillary lymph nodes.

Side effects from chemotherapy. Side effects were assessed at each treatment cycle and graded according to the National Cancer Institute Common Toxicity Criteria (20). Electrocardiogram, physical examination, and measurement of left ventricular ejection fraction (LVEF) were required at diagnosis, at the end of each chemotherapy regimen and every 6 months during at least the first 2 years of follow-up.

Statistical methods. The primary objective of the ECTO study was to assess the freedom from breast cancer progression or relapse as measured from the date of randomization. Based on the prior experience of the doxorubicin CMF regimen at the Milan Cancer Institute, it was planned to accrue 450 patients in each study arm, with an 80% power of the log-rank test to detect a 30% between-group relative difference in the hazard of occurrence of end point events, at the 5% significance level (two-sided test).

The second objective of the study, which is the aim of this report, was to compare the rate of breast-saving procedures and of pathologic nodal status after primary chemotherapy (arm C) versus primary surgery (arms A and B grouped together). Simple proportions were examined by use of the ² test. A second aim was attempting to identify pretreatment variables likely to predict clinical and pathologic response to primary chemotherapy with doxorubicin/paclitaxel CMF. Assessment was done by analyzing both simple proportions on univariate analyses and by performing logistic regression analyses using a backward procedure (21). All analyses are based on data received as of July 31, 2003.

	Results

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Patient population and tumor characteristics. A total of 1,355 patients were enrolled into study (Table 1). Eight patients (0.6%) failed to meet the eligibility criteria because of locally advanced disease (n = 2), distant metastases (n = 2), no invasive breast cancer on biopsy (n = 2), bilateral breast cancer (n = 1), and chronic hepatitis (n = 1). In addition, 23 women (1.7%) refused to be treated according to their allocated program. Main patient characteristics at randomization (Table 1) remained evenly distributed in the study arms. Approximately 20% of patients had tumors > 4.0 cm, and more than half were ages 50 years. Approximately one third of tumors were both estrogen receptor (ER) and progesterone receptor negative, and more than half were categorized as intermediate grade.

In view of the even distribution of main patient characteristics and treatment delivery in the three arms of the study (Table 1), further analysis of toxicity can be presented pooling together observations and events in arms B and C, in which patients received the same regimen consisting of doxorubicin/paclitaxel CMF. Data in Table 2 show that almost all major toxic events were similar whether or not paclitaxel was part of the chemotherapy regimen. As expected, reversible peripheral neuropathy was significantly more frequent with the paclitaxel-containing regimen (Table 2). Signs and symptoms of peripheral neuropathy were documented after the second cycle of doxorubicin/paclitaxel, lasted in median 3 months, and completely recovered before the end of CMF. In only one woman did neuropathy last 8 months before complete recovery.

Comparison of surgical procedures and pathologic findings after primary surgery or primary systemic therapy. A total of 296 women (34%) in the primary surgery arms underwent breast conservative surgery, with no differences between arm A and B. After primary chemotherapy, the rate of breast conservative surgery increased to 65% (284 of 438), showing a statistically significant reduction (P < 0.001) in the requirement for mastectomy. Figure 2 shows the effects of primary systemic therapy on locoregional disease. Breast-sparing surgical procedures were significantly more frequent after primary systemic therapy in all categories of initial tumor size. This is especially marked for tumors > 4 cm at diagnosis (Fig. 2A). The low rate of breast conservative surgery in patients presenting with tumors measuring up to 3.0 cm in arms A and B can in part be explained by the fact that many centers in Europe still perform mastectomy in women with tumors > 2.5 cm, especially if axillary nodes are clinically palpable.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Effects of primary systemic chemotherapy on locoregional disease. A, rate of breast conserving surgery and initial tumor size. Black columns are for patients randomized to surgery as first treatment modality; light gray columns are for patients randomized to primary systemic therapy before surgery. Difference between groups is statistically significant (P < 0.001, 2 test). B, rate of patients with indicated axillary nodes involved by tumor at histology. Black columns are for patients randomized to surgery as first treatment modality; light gray columns are for patients randomized to primary systemic therapy before surgery. Difference between groups is statistically significant (P < 0.001, 2 test).

The administration of primary chemotherapy also contributed to a significant downstaging of pathologic nodal status: 263 (60%) patients were pathologically node negative compared with 39% in the primary surgery group (P < 0.001). Of note, fewer positive nodes were found in patients who received primary chemotherapy, as shown in Fig. 2B.

Clinical response after primary systemic therapy. Major shrinkage of the primary tumor was measured in 78% of the patients (clinically complete response, 49%; partial response, 29%) after primary doxorubicin/paclitaxel CMF. An analysis of the degree of response after doxorubicin/paclitaxel and after CMF was feasible in 373 patients and is reported in Table 3. Overall, 100 patients (27%) achieved a clinically complete response after the first four cycles of doxorubicin/paclitaxel. Of note, 151 of 273 patients (55%) having a residual clinically palpable tumor mass after doxorubicin/paclitaxel had an improvement of the response with CMF. Three women (1%) had progressive disease while on therapy.

Univariate and multivariate analysis of clinical and pathologic response. The likelihood of achieving a response to primary doxorubicin/paclitaxel CMF was assessed as a function of main pretreatment variables (age, clinical tumor size, clinical nodal status, ER and progesterone receptor status, and tumor grade). Table 4 shows the univariate analysis for clinical and pathologic complete response, respectively. ER and progesterone receptor status and tumor grade were all significantly associated with the likelihood of achieving clinical and pathologic response. The logistic regression analysis revealed that ER status was the only significant variable independently capable of influencing treatment outcome, with an odds ratio for negative versus positive ER of 2.1 (95% CI, 1.36-3.23; P = 0.0008) for clinically complete response, and of 5.77 (95% CI, 3.49-9.52; P < 0.0001) for the achievement of pathologic response.

	Discussion

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In the ECTO trial, the most careful monitoring was applied to the cardiac function because of the higher-than-expected cardiac toxicity reported in early studies of doxorubicin/paclitaxel (7, 8). LVEF was similarly affected in patients receiving single-agent doxorubicin in arm A for a total dose of 300 mg/m² and in those treated with doxorubicin/paclitaxel in arms B and C for a total dose of 240 mg/m² of doxorubicin. The decrease was almost always non symptomatic and was reversible in the vast majority of patients after delivery of chemotherapy. Symptomatic cardiac events (grade 3) were rare, had similar incidence with both regimens (0.5% in arm A versus 0.3% in arms B and C), were responsive to cardiac medications, and were all observed during or soon after chemotherapy. At median 31 months after randomization, the incidence of grade 3 events is lower than the one reported with other anthracycline-containing regimens for early breast cancer (5, 25, 26). Although longer follow-up only will rule out that the regimen does not entail increased cardiac risk at later times, the early findings reported here are reassuring.

The proportion of women achieving eradication of invasive carcinoma in the breast after four cycles of chemotherapy has been in the low range of 3% to 14% in spite of the much higher proportion of them having major clinical response (15–18). Many trials of primary chemotherapy in the 1990s attempted at improving the rate of pathologic complete response by designing new regimens that included taxanes and/or new modalities of drug administration (23, 24, 27), while also prolonging the total duration of treatment. This report shows that doxorubicin/paclitaxel CMF leads to major clinical response in 78% (complete in 49%), an in-breast pathologic complete response rate of 23% and an in-breast plus axilla pathologic complete response rate of 20%. These results are of the same order of magnitude of those reported by other studies that included preoperative taxanes (23, 24, 28) and raise the question whether the improved rate of pathologic complete response should be attributed to the introduction of the taxanes, the duration of preoperative treatment, or the sequencing of non–cross-resistant regimens. Two adjuvant studies showed that adding four cycles of thrice-weekly paclitaxel after standard doxorubicin and cyclophosphamide led to improved efficacy (29, 30). Because of the study design, neither trial allows for discriminating whether the advantage depended on the merits of the taxane or on the more prolonged duration of the chemotherapy in the experimental arm. Such a question is addressed in the ECTO study that compares two regimens of identical duration and similar feasibility, one with and one without paclitaxel, but efficacy outcomes of the ECTO trial will be analyzed after follow-up longer than now available. In a French study (31), doxorubicin and paclitaxel were given preoperatively for either four or six cycles. The longer administration led to an improved rate of clinical and histologic response (31). The finding would be in keeping with the interpretation that treatment duration is factoring into the antitumor activity of the doxorubicin/paclitaxel regimen and is in line with the results of the first report of the activity of doxorubicin/paclitaxel in women with metastatic breast cancer (7). In that trial, patients received up to eight cycles of doxorubicin/paclitaxel, and continuous delivery of single-agent paclitaxel contributed to increasing complete responses from 26% to the remarkable rate of 42% (7, 32). However, the ECTO trial also suggests a role of the sequential application of non–cross-resistant regimens. Indeed, clinical response to CMF contributed to improving the overall response in 151 women and obtained almost doubling of the rate of clinical complete response (27% after doxorubicin/paclitaxel versus 49% after CMF), including patients who only had minor or no response to doxorubicin/paclitaxel. Another preoperative trial has addressed the question of duration or sequencing with an elegant design whereby, after receiving four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone, responding patients were randomly assigned to continuing with additional four cycles of the same cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen or four cycles of docetaxel (27). Switching to docetaxel led to significant increase of clinical and pathologic complete response rate (27) and to significantly improved disease-free and overall survival at three and at 5 years of follow-up (33, 34), documenting that sequential administration of non–cross-resistant regimens is prevailing over duration of a nontaxane regimen in driving to improved response and efficacy (33, 34).

The ECTO study also provides a relevant qualification of the tumor response after doxorubicin/paclitaxel CMF. Of note, 42% of patients with ER negative tumors had pathologic complete response versus 12% in the ER-positive group and in multivariate analysis ER status emerged as the only independent variable significantly associated with likelihood of achieving a clinically complete response (odds ratio, 2.1), and most importantly a pathologic complete response (odds ratio, 5.77; P < 0.0001). The association between ER status and likelihood of pathologic complete response is in agreement with other reports, indicating that ER-negative tumors are more sensitive to chemotherapy than ER-positive ones (23, 24). In the ECTO trial, this different sensitivity according to ER status was remarkably high, but it should be pointed out that pathologic complete response rate in ER-positive tumors should not be discounted as negligible. On the contrary, the different pathologic complete response rate in the two subsets of patients justifies the design of different drug approaches according to hormonal receptor status.

The present report points out to an immediate advantage of the preoperative regimen when comparing surgical findings after doxorubicin/paclitaxel CMF to those in patients undergoing surgery first (arms A and B). Tumor size was decreased enough to allow for breast sparing procedures in 65% of patients versus 34% in the adjuvant arms. Importantly, at a median follow-up in excess of 24 months from surgery, such an improvement in breast conservation was not at the cost of an increased risk of local relapses (35).

	Appendix 1: List of Active ECTO Participating Centers

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Coordinating Center, Istituto Nazionale Tumori, Milan, Italy (G. Bonadonna, L. Gianni, M. Zambetti, M. Greco, S. Pilotti, L. Mariani, C. Dipace, and P. Valagussa); Hospital Vall D'Hebron, Barcelona, Spain (J. Baselga, B. Queralt, and D. Sabadell); Frauenklinik vom Roten Kreuz, Munich, Germany (W. Eiermann and G. Raab); Istituto Valenciano de Oncologia, Valencia, Spain (V. Guillem Porta, A. Llombart Cussac, and C. Vazquez); N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia (V. Semiglazov and A. Bozhok); Hospital Clinico Universitario de Valencia, Valencia, Spain (J. Garcia-Conde, A. Lluch, and A. Martinez-Agulló); Central Clinical Hospital named after N.A. Semashko, Moscow, Russia (M. Byakhov); Azienda Ospedaliera S. Maria della Misericordia, Udine, Italy (M. Mansutti and G. Gentile); Hospital de San Pau, Barcelona, Spain (J. Lopez-Lopez and C. Alonso); Policlinico Monteluce, Perugia, Italy (M.A. Colozza); Oncology Clinical Dispenser, Moscow, Russia (V. Borisov); Hospital Universitario 12 de Octubre, Madrid, Spain (H. Cortés-Funes); Klinika Nowotworow Sutka, Warsaw, Poland (T. Pienkowski); Ospedale S. Bortolo, Vicenza, Italy (V. Fosser); Latvian Cancer Center, Riga, Latvia (J. Berzins); Klinika Chemioterapii/Instytut Onkologii, Krakow, Poland (M. Pawlicki); Istituto San Raffaele, Milano, Italy (E. Villa); Regional Oncology Clinic, Murmansk, Russia (V. Zinykevich); Hospital of Oncology-Clinicum of the University of Tartu, Tartu, Estonia (P. Padrik); Ospedale S. Chiara, Trento, Italy (E. Galligioni); Semmelweis Medical School, Budapest, Hungary (M. Dank); LBI for Applied Cancer Research-Kaiser Franz Josef Spital, Wien, Austria (C. Dittrich); Uzsoki Hospital, Budapest, Hungary (T. Nagykálnai); Oddzial Chemioterapii-Regionalne Centrum Onkologii, Bydgoszcz, Poland (J. Tujakowski); Faculty Hospital, Ostrava-Poruba, Czech Republic (P. Vodvarka); Krakowski Szpital Specjalistyczny im. Ludwiga Rydgiera, Krakow, Poland (P. Koralewski); Katedra Onkologii-Szpital Kliniczny nr 1, Poznan, Poland (K. Roznowski); St. Elisabeth Oncology Institute, Bratislava, Slovakia (S. Spanik); Cancer Research RAMS-Dept. of Clinical Pharmacology, Moscow, Russia (A. Garin); and Cancer Research RAMS/Department of Cancer Chemotherapy, Moscow, Russia (V. Gorbounova).

	Acknowledgments

 
We thank all the patients who have participated in our clinical trial; the many associates, in particular medical oncologists, surgeons, radiation therapists, pathologists, research nurses and data managers for their cooperation during the study; and the members of the International Advisory Board: Drs. John Bryant, Gabriel Hortobagyi, Larry Norton, Abraham Recht, and William Wood.

	Footnotes

 
Grant support: Bristol Meyers Squibb.

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.

Note: Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18 to 21, 2002, Orlando, Florida.

Received 3/10/05; revised 9/15/05; accepted 9/27/05.

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