Cancer Therapy: Clinical Feasibility and Tolerability of Sequential Doxorubicin/Paclitaxel Followed by Cyclophosphamide, Methotrexate, andFluorouracilandItsEffectsonTumor Response as Preoperative Therapy Luca Gianni,1Jose¤Baselga,2 Wolfgang Eiermann,4 Vicente Guillem Porta,5 Vladimir Semiglazov,7 An‹ aLluch,6 Milvia Zambetti,1Dolores Sabadell,2 Gu«nther Raab,4 Antonio Llombart Cussac,5 Alla Bozhok,7 Angel Martinez-Agullo¤,6 Marco Greco,1Mikhail Byakhov,8 JuanJose' Lopez Lopez,3 Mauro Mansutti,9 Pinuccia Valagussa,1and Gianni Bonadonna1 for the European Cooperative Trial in Operable Breast Cancer Study Group Abstract Purpose: The European CooperativeTrial 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%)inallarms.Neuropathy was more frequent in the paclitaxel-containing arms (grade 2, 20.5% versus 5.0%; grade 3, 1.3% versus 0.2%). At 31months 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 remissionin 78%,withanin-breastpathologiccompleteresponse rate of 23%andanin-breastplus axillapathologiccompleteresponse rateof 20%.Inthemultivariateanalysis,onlyestrogenreceptor (ER)statuswas significantlyassociatedwithpathologiccompleteresponse(oddsratioforERneg- ative, 5.77; 95% confidence interval, 3.49-9.52; P < 0.0001). PTS induced a significant axillary downstaging (P < 0.001),andbreast sparing surgery was feasiblein 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. The superior efficacy of the sequential approach with non– by Norton and Simon (1) and was clinically proven in a piv- cross-resistant drugs/regimens was postulated in the early 1980s otal study of the Istituto Nazionale Tumori with the regimen of doxorubicin and cyclophosphamide, methotrexate, and fluorouracil (doxorubicin ! CMF; refs. 2, 3). An independent study has confirmed that sequential epirubicin ! CMF is sig- Authors’ Affiliations: 1Istituto Nazionale Tumori, Milan, Italy; 2Hospital Vall d’Hebron and 3Hospital de San Pau, Barcelona, Spain; 4Frauenklinik vom Roten nificantly superior to CMF (4). In the mid-1990s, clinical Kreuz, Munich, Germany; 5Istituto Valenciano de Oncologia and 6Hospital Clinico studies indicated that paclitaxel had marked antitumor activity Universitario de Valencia, Valencia, Spain; 7N.N. Petrov Research Institute of in women with metastatic breast cancer while lacking complete 8 Oncology, St. Petersburg, Russia; Central Clinical Hospital named after N.A. clinical cross-resistance with anthracyclines (5, 6). Subse- Semashko, Moscow, Russia; and 9Azienda Ospedaliera Santa Maria della Misericordia, Udine, Italy quently, the combination of doxorubicin and paclitaxel Received 3/10/05; revised 9/15/05; accepted 9/27/05. resulted in a marked antitumor activity in women with Grant support: Bristol Meyers Squibb. metastatic breast cancer who had received minimal or no prior The costs of publication of this article were defrayed in part by the payment of page chemotherapy, although associated with higher than expected charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cardiac toxicity (7, 8) that could later be in part attributed to Note: Presented in part at the 38th Annual Meeting of the American Society of pharmacokinetic and biochemical interactions between pacli- Clinical Oncology, May 18 to 21, 2002, Orlando, Florida. taxel and doxorubicin (9, 10). The cardiotoxic enhancement Requests for reprints: Luca Gianni, CTO Coordinating Center, Istituto Nazionale was not clinically apparent when doxorubicin was given for a Tumori,Via Venezian, 1, 20133 Milan, Italy. Phone: 39-02-2390-2789; Fax: 39-02- 2 2390-2678; E-mail: [email protected]. maximum total dose of 360 mg/m with paclitaxel (11). F 2005 American Association for Cancer Research. Based on the activity of the above regimens, in 1996, we doi:10.1158/1078-0432.CCR-05-0539 designed a trial [known as European Cooperative Trial in www.aacrjournals.org 8715 Clin Cancer Res 2005;11(24) December 15, 2005 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2005 American Association for Cancer Research. Cancer Therapy: Clinical Operable breast cancer (ECTO); Fig. 1] addressing the potential Between November 6, 1996 and May 29, 2002, a total of 1,355 role of introducing paclitaxel within a sequential regimen of patients were enrolled. Breast cancers were diagnosed by core biopsy non–cross-resistant chemotherapies. The ECTO study random- (82%) or fine-needle aspiration cytology (18%). Either method of ized patients with breast cancer > 2 cm to adjuvant doxorubicin diagnosis was evenly distributed among the three treatment arm. Approximately 50% of the tumor diagnosed by fine-needle aspiration ! CMF or doxorubicin/paclitaxel ! CMF (Fig. 1, arms A and B, had clinical involvement of axillary nodes, and after major surgical respectively). In the ECTO study, the planned delivery of 2 intervention, all tumors were classified as invasive carcinomas. maximum of four cycles of doxorubicin/paclitaxel (240 mg/m Assessment of hormonal receptor status and tumor grade was required. of total doxorubicin) before CMF seemed therefore consis- Treatment allocation was done centrally at the ECTO Operations tent with the goal of exploiting the potential benefits of Office using a minimization algorithm (19) to balance assignments doxorubicin/paclitaxel without exposing the patients to exces- according to primary tumor size (<4.0 versus >4.0 cm), tumor grade sive cardiac risk. (low versus intermediate versus high), and hormonal receptor status Based on kinetic considerations (12) and on animal experi- (estrogen and/or progesterone positive versus both negative). Geo- ments indicating that systemic therapy before surgery inhibited graphic area of the participating center was also taken into account the tumor growth stimulatory response triggered by surgery before randomization. Treatment. Patients in arm A first received surgery followed by (13, 14), the ECTO study is also addressing the effectiveness sequential single-agent doxorubicin and CMF; patients in arm B first of doxorubicin/paclitaxel ! CMF before surgery (Fig. 1, arm B underwent surgery followed by sequential doxorubicin/paclitaxel and versus C). The pivotal NSABP-B18 study showed that the CMF; patients in arm C received sequential doxorubicin/paclitaxel doxorubicin and cyclophosphamide combination afforded and CMF followed by surgery. equivalent efficacy when given either as primary or adjuvant Breast irradiation (50 Gy through two opposing tangential fields to systemic therapy (15, 16). The same investigation and other be started after completion of chemotherapy or within 4 weeks from studies also showed that eradication of the invasive tumor in surgery in arm C) was required after breast sparing surgery. In the the breast assessed at surgery (pathologic complete response) is presence of pT4 lesion after mastectomy, chest wall irradiation was an independent predictor of long term outcome (15–18). In recommended. 2 the ECTO trial, we reasoned that a prolonged administration of In arm A (Fig. 1), doxorubicin was given at the dose of 75 mg/m by a sequential non–cross-resistant chemotherapy containing 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 paclitaxel could yield a large increment of the rate of pathologic 3 hours, and each course was repeated every 3 weeks. CMF consisted complete response that may increase the likelihood of in i.v. cyclophosphamide (600 mg/m2), methotrexate (40 mg/m2), and observing a difference of benefit. Analysis of the main efficacy fluorouracil (600 mg/m2) on days 1 and 8 every 4 weeks. No dose outcomes of the ECTO study awaits for the appropriate period reduction was allowed except following febrile neutropenia (as defined of observation. However, at median 31 months of follow-up, by absolute neutrophil count < 500/AL and fever > 38jC), grade >2 data on toxicity of the delivered regimens and on locoregional neuropathy due to paclitaxel, and grade >2 gastrointestinal toxicity on antitumor activity of primary systemic therapy, a secondary aim doxorubicin/paclitaxel regimen, when a 25% temporary reduction was of the ECTO trial, are available and reported here. 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 Patients and Methods the evening before therapy), hydrocortisone (250 mg i.v.)