Purpose: To compare the efficacy of a standard anthracycline-based regimen to a dose-intensified anthracycline regimen in locally advanced breast cancer. Patients and Methods: Locally advanced breast cancer patients were randomly assigned onto a study comparing cyclophosphamide (C; 75 mg/m2 orally days 1 to 14), epirubicin (E; 60 mg/m2 intravenously [IV] days 1, 8), and fluorouracil (F; 500 mg/m2 IV days 1, 8) six cycles every 28 days versus E (120 mg/m2 IV day 1), C (830 mg/m2 IV day 1), and granulocyte colony-stimulating factor (filgrastim; 5 g/kg/d subcutaneously days 2 to 13) six cycles every 14 days. The study was designed to detect a 15% improvement; that is, from 50% to 65% in median progression-free survival (PFS) in favor of the dose-intensified regimen. Results: A total of 448 patients were enrolled over a period of 3 years. The median dose intensity delivered for C and E reached, respectively, 85% and 87% of that planned in the CEF arm and 96% and 95% of that planned in the EC arm. The dose-intensified arm was slightly more emetogenic and generated more grade 3 to 4 anemia but less febrile neutropenia episodes. After a median follow-up of 5.5 years, 277 events have been reported. The median PFS was 34 and 33.7 months for CEF and EC, respectively (P .68), and the 5-year survival rate was 53% and 51% for CEF and EC, respectively (P .94). Conclusion: Dose-intensified EC does not provide a measurable therapeutic benefit over CEF as neoadjuvant chemotherapy for unselected locally advanced breast cancer patients. J Clin Oncol 21:843-850. © 2003 by American Society of Clinical Oncology.

PURPOSE:To compare the efficacy of a standard anthracycline-based regimen to a dose-intensified anthracycline regimen in locally advanced breast cancer.PATIENTS AND METHODS:Locally advanced breast cancer patients were randomly assigned onto a study comparing cyclophosphamide (C; 75 mg/m(2) orally days 1 to 14), epirubicin (E; 60 mg/m(2) intravenously [IV] days 1, 8), and fluorouracil (F; 500 mg/m(2) IV days 1, 8) six cycles every 28 days versus E (120 mg/m(2) IV day 1), C (830 mg/m(2) IV day 1), and granulocyte colony-stimulating factor (filgrastim; 5 micro g/kg/d subcutaneously days 2 to 13) six cycles every 14 days. The study was designed to detect a 15% improvement; that is, from 50% to 65% in median progression-free survival (PFS) in favor of the dose-intensified regimen.RESULTS:A total of 448 patients were enrolled over a period of 3 years. The median dose intensity delivered for C and E reached, respectively, 85% and 87% of that planned in the CEF arm and 96% and 95% of that planned in the EC arm. The dose-intensified arm was slightly more emetogenic and generated more grade 3 to 4 anemia but less febrile neutropenia episodes. After a median follow-up of 5.5 years, 277 events have been reported. The median PFS was 34 and 33.7 months for CEF and EC, respectively (P =.68), and the 5-year survival rate was 53% and 51% for CEF and EC, respectively (P =.94).CONCLUSION:Dose-intensified EC does not provide a measurable therapeutic benefit over CEF as neoadjuvant chemotherapy for unselected locally advanced breast cancer patients.

PURPOSE: To compare the efficacy and tolerability of the combination of doxorubicin and paclitaxel (AT) with a standard doxorubicin and cyclophosphamide (AC) regimen as first-line chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Eligible patients were anthracycline-naive and had bidimensionally measurable metastatic breast cancer. Two hundred seventy-five patients were randomly assigned to be treated with AT (doxorubicin 60 mg/m2 as an intravenous bolus plus paclitaxel 175 mg/m2 as a 3-hour infusion) or AC (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2) every 3 weeks for a maximum of six cycles. A paclitaxel (200 mg/m2) and cyclophosphamide (750 mg/m2) dose escalation was planned at cycle 2 if no grade ≥ 3 neutropenia occurred in cycle 1. The primary efficacy end point was progression-free survival (PFS). Secondary end points were response rate (RR), safety, overall survival (OS), and quality of life. RESULTS: A median number of six cycles were delivered in the two treatment arms. The relative dose-intensity and delivered cumulative dose of doxorubicin were lower in the AT arm. Dose escalation was only possible in 17% and 20% of the AT and AC patients, respectively. Median PFS was 6 months in the two treatments arms. RR was 58% versus 54%, and median OS was 20.6 versus 20.5 months in the AT and AC arms, respectively. The AT regimen was characterized by a higher incidence of febrile neutropenia, 32% versus 9% in the AC arm. CONCLUSION: No differences in the efficacy study end points were observed between the two treatment arms. Treatment-related toxicity compromised doxorubicin-delivered dose-intensity in the paclitaxel-based regimen

BACKGROUND:The potential cardiotoxicity of the doxorubicin-paclitaxel regimen, when paclitaxel is given shortly after the end of the anthracycline infusion, is an issue of concern, as suggested by small single institution Phase II studies.METHODS:In a large multicenter Phase III trial, 275 anthracycline naive metastatic breast carcinoma patients were randomized to receive either doxorubicin (60 mg/m(2)) followed 30 minutes later by paclitaxel (175 mg/m(2) 3-hour infusion; AT) or a standard doxorubicin-cyclophosphamide regimen (AC; 60/600 mg/m(2)). Both treatments were given once every 3 weeks for a maximum of six cycles. Close cardiac monitoring was implemented in the study design.RESULTS:Congestive heart failure (CHF) occurred in three patients in the AT arm and in one patient in the AC arm (P = 0.62). Decreases in left ventricular ejection fraction to below the limit of normal were documented in 33% AT and 19% AC patients and were not predictive of CHF development.CONCLUSIONS:AT is devoid of excessive cardiac risk among metastatic breast carcinoma patients, when the maximum planned cumulative dose of doxorubicin does not exceed 360 mg/m(2).

Background: We performed a phase I study of polyethylene glycol (pegylated, Stealth(R)) liposomal doxorubicin (Caelyx(R), Doxil(R)) using a prolonged (6-week) dose interval to reduce the incidence of skin toxicity that was dose-limiting at more conventional dose intervals, and which appeared to be schedule dependent.Patients and methods: Eligible for the study were metastatic breast cancer patients who had received a maximum of one prior therapy for metastatic disease. The defined dose levels were 60, 70, 80 and 90 mg/m(2).Results: Twenty patients were assessed at starting doses of 60 mg/m(2) (n = 9) or 70 mg/m(2) 2 (n = 11). The dose-limiting toxicity was mucositis. Severe skin toxicity was not observed at the 60 mg/m2 dose level, and occurred n only one patient treated at 70 mg/m(2). Significant neutropenia, alopecia, and nausea and vomiting were rare events. No clinical cardiac events occurred, despite a median cumulative doxorubicin dose of 323 mg/m(2) (range 5-630 mg/m(2)). Partial responses were documented in five patients, Pharmacokinetics were assessed in 15 patients, and confirmed the long terminal half-life of the agent (median 77 h) demonstrated in earlier studies.Conclusions: The recommended dose of Caelyx(R)/Doxil(R) using this schedule is 60 mg/m(2) every 6 weeks, This is a safe and effective regimen that permits prolonged administration of anthracycline to patients with metastatic breast cancer.

The aim of the project was to identify clinical and quality of life (QL) factors that together predict survival and response to chemotherapy in advanced breast cancer. Potential prognostic factors were studied in 187 women with baseline QL data from a trial of paclitaxel versus doxorubicin as first-line chemotherapy. Demographic and clinical factors studied were age, performance status, dominant site of disease and preceding disease-free interval (DFI). Factors from the EORTC QLQ-C30 were all function scales, fatigue, nausea/vomiting, pain, dyspnoea, insomnia, loss of appetite and global QL. The proportional hazards regression model with stratification for treatment, and the logistic regression model adjusting for treatment arm were used for univariate and multivariate analyses of survival and response to treatment, respectively. For survival, multiple sites of visceral disease, pain, global QL and fatigue were significant prognostic factors in the univariate analysis. The final multivariate model predicted poor survival with multiple sites of visceral disease (P=0.003), DFI ⩽2 years (P=0.026) and pain (P=0.003). For response, age, dyspnoea, fatigue and global QL were significant predictive factors in the univariate analysis. The final multivariate model for response selected DFI (P=0.009), multiple sites of visceral disease (P=0.037) and dyspnoea (P=<0.001) using forward selection, but model instability was indicated by the inclusion of fatigue and emotional function in the final model when backward selection was used. In addition to known clinical factors, patient-assessed QL variables appear to be prognostic for survival and response to chemotherapy in women with advanced breast cancer. However, identification of prognostic factors from responses to questionnaires may be unstable, and their reliability and clinical utility should be tested prospectively.

PURPOSE To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival ¿PFS) and to explore the degree of cross-resistance between the two agents. PATIENTS AND METHODS Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m(2), 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m(2), intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. RESULTS Objective response in first-line therapy was significantly better (P =.003) for doxorubicin (response rate ¿RR, 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P <.001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P =.38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. CONCLUSION At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting.

This study assesses the potential value of the tumor markers p53, HER2, and Bcl-2 in predicting the clinical response to doxorubicin and paclitaxel as single agents in the treatment of metastatic breast cancer. The primary tumors of 114 patients in the European Organization for Research and Treatment of Cancer 10923 trial were assessed by immunohistochemistry using monoclonal antibodies; the results were correlated with clinical response to therapy. HER2 was positive in 24% of patients, p53 was positive in 25% of patients, and Bcl-2 was positive in 49% of patients. There was no correlation between the expression of any of the markers and the clinical response to either agent. Although methodologically limited, this study does not support the use of p53, HER2, or Bcl-2 to assist the selection of anthracycline versus taxane in metastatic breast cancer.

The activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in advanced breast cancer patients who have failed doxorubicin treatment is well established, but the optimal sequence between these two important agents remains to be determined. The European Organization for Research and Treatment of Cancer therefore designed a prospective randomized clinical trial in which patients not exposed to anthracyclines in the adjuvant setting received either first-line paclitaxel, given as a 3-hour infusion at a dose of 200 mg/m2 followed at the time of disease progression by second-line doxorubicin, given as a bolus injection at a dose of 75 mg/m2 or the reverse sequence. The target accrual is 330 patients. Interim results on 207 evaluable patients of 289 randomized are presented.

Tabled 1 Taxol(n = 51) Doxorubicin(n = 55) Neutropenia gr 4 35% 78% Febrile Neutropenia 4% 13% Vomiting gr 3–4 4% 18% Stomatitis gr 3–4 0% 13% Sensory Neurotoxicity gr 2–3 22% 0% Delays in Drug Administration (% of cycles) 5% 19% Open table in a new tab Possible hypersensitivity reactions (Weiss R.B. JCO Vol. 8: 1263–68) were seen in 2 of 236 Taxol cycles. This analysis shows that Taxol 200 mg/m2 over 3-hours is well tolerated in comparison to Doxorubicin 75 mg/m2 for the same population of patients. Accrual is planned to be completed by May 1995 (total of 240 pts). At the time of the meeting, further toxicity data will be presented. Possible hypersensitivity reactions (Weiss R.B. JCO Vol. 8: 1263–68) were seen in 2 of 236 Taxol cycles. This analysis shows that Taxol 200 mg/m2 over 3-hours is well tolerated in comparison to Doxorubicin 75 mg/m2 for the same population of patients. Accrual is planned to be completed by May 1995 (total of 240 pts). At the time of the meeting, further toxicity data will be presented.

BACKGROUND:In an attempt to increase chemotherapy dose intensity by step-wise reduction of the time interval between treatment cycles, filgrastim was administered to breast cancer patients receiving a three-month combination chemotherapy with epirubicin (E) and cyclophosphamide (C).PATIENTS AND METHODS:Chemotherapy-naïve patients with locally advanced or metastatic breast cancer received fixed doses of E (120 mg/m2) and C 9830 mg/m2) by 15-min i.v. infusion on day 1 of each cycle and filgrastim at a dose of 4 micrograms/kg once daily by SC injection starting 24 hours after chemotherapy. Cohorts of patients were treated in successive schedules, each schedule corresponding to a specified time interval between chemotherapy cycles. The toxicity observed in each schedule was evaluated before patients were accrued to the next schedule, which corresponded to a shorter time interval between chemotherapy cycles.RESULTS:The maximum tolerated schedule was E (120 mg/m2) plus C 9830 mg/m2) given every 14 days with filgrastim support from day 2 until day 13. On this schedule, 5 of 12 patients experienced dose-intensity-limiting toxicities (DLT) during the 3-month study period. Non-hematological DLT occurred in 2/12 patients (mucositis, skin toxicity) while /312 experienced febrile neutropenia requiring i.v. antibiotics. All patients achieved recovery of ANC to >1.5 x 10(9)/l by the time of scheduled retreatment. The combination of filgrastim with this regimen did not seem to add major toxicities. The efficacy was high, with 87% of patients achieving an objective response and a median response duration of 18 months (range: 4-52 months).CONCLUSIONS:Filgrastim permits at 33% increase in 'EC' dose intensification over that of the conventional every-3-week administration. Randomized studies should now be initiated to evaluate the merit, if any, of 'accelerated' chemotherapy in advanced breast cancer.