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Final Results of a Randomized Phase III Trial Comparing Cyclophosphamide, Epirubicin, and Fluorouracil With a Dose-Intensified Epirubicin and Cyclophosphamide + Filgrastim as Neoadjuvant Treatment in Locally Advanced Breast Cancer: An EORTC-NCIC-SAKK Multicenter Study

From the European Organization for Research and Treatment of Cancer (EORTC) Data Center, Brussels, Belgium; Institut Bergonie, Bordeaux, France; Medical Academy, Gdansk, Poland; Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands; Institute of Oncology, Ljubljana, Slovenia; Hopitaux Universitaires de Genève, Geneva, Switzerland; Ottawa Regional Cancer Center, Ottawa; Toronto-Sunnybrook Regional Cancer Center, Toronto, Canada; Institut J. Bordet, Brussels, Belgium.

Address reprint requests to P. Therasse, MD, EORTC Data Center, Ave E. Mounier, 83/11, 1200 Brussels, Belgium; email: pth{at}eortc.be.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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 µg/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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
LOCALLY ADVANCED breast cancer is a subgroup of cancer that encompasses a wide spectrum of malignant breast tumors and represents between 10% and 30% of newly diagnosed breast cancers depending on the geographic area. Patients with these tumors may be classified as stage IIB, IIIA, or IIIB according to the tumor, node, metastasis classification.¹

The poor long-term outcome after locoregional treatment only² triggered the introduction of chemotherapy and hormonotherapy in the primary management of this disease at the end of the 1970s. Induction chemotherapy followed by irradiation and/or surgery has been studied by several groups in small studies that indicated a better outcome for time to progression and duration of survival.³ The benefit of chemotherapy and hormonotherapy was later confirmed in a large, randomized study.^4,5

The concept of a chemotherapy "dose-response" relationship in breast cancer was demonstrated during the 1980s,⁶ and the role of high-dose chemotherapy was the subject of several phase III trials conducted through the 1990s.⁷ The present study was designed to investigate the possible benefit offered by a dose-intensified anthracycline-containing regimen over a standard delivery schedule. The investigational regimen was previously piloted within the European Organization for Research and Treatment of Cancer (EORTC),⁸ and the selected control was an optimized standard anthracycline-containing regimen developed by the Clinical Trials Group of the National Cancer Institute of Canada that has since been shown to be superior to classical cyclophosphamide, methotrexate, and fluorouracil (CMF regimen).⁹

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Selection
Female patients with locally advanced breast cancer were eligible for this study. Locally advanced breast was defined as belonging to one of the following categories: any T₄, any N, M₀, or any T, N₂/N₃, M₀, or inflammatory breast carcinoma. Inflammatory breast cancer was clinically defined as redness over at least one third of the breast (with or without other clinical signs).

The other eligibility criteria were as follows: World Health Organization (WHO) performance status 0 or 1, adequate bone marrow, liver and kidney function, no evidence of metastasis, no previous treatment for breast cancer, no previous or concomitant malignancy, absence of significant cardiac disease, normal left ventricular function, no hormonal replacement therapy, and adequate nonhormonal contraception therapy. The study protocol was reviewed and approved by the EORTC Protocol Review Committee and by the ethics committees of all participating institutions. The informed consent of each patient was obtained before study participation.

Eligible patients were randomly assigned centrally, and the treatment allocation was performed following the minimization technique, taking into account the following stratification factors: institution, age 50 years versus more than 50 years, and inflammatory versus noninflammatory breast cancer.¹⁰

Chemotherapy
All patients were randomly assigned between the following regimens: cyclophosphamide (C), epirubicin (E), and fluorouracil (FU) (CEF) for six cycles (C, 75 mg/m² orally [PO], day 1 through day 14; E, 60 mg/m² intravenously [IV] days 1 and 8; and FU, 500 mg/m² IV days 1 and 8, cycled every 28 days) and EC plus granulocyte colony-stimulating factor (G-CSF) for six cycles (E, 120 mg/m² IV day 1; C, 830 mg/m² IV day 1; G-CSF, 5 µg/kg/d subcutaneously [SC] day 2 through day 13, cycled every 14 days).

All patients received a continuous prophylactic antibiotherapy with trimethoprim-sulfamethoxazole (two tablets bid) for the duration of the treatment.

Dose modifications were performed according to predefined guidelines based on hematological and nonhematological toxicity. In particular, patients experiencing an absolute drop of 15% or more of the left ventricular ejection fraction (LVEF) stopped their treatment and were switched to a standard CMF (IV, days 1, 8).

Locoregional Therapy
Before entering the first patient into the study, each center (or group) had to select one policy of locoregional management of the tumor after chemotherapy. The possible locoregional treatment strategies were as follows: surgery alone, radiotherapy alone, a combination of surgery and radiotherapy, or a flexible policy to be adapted to the response to neoadjuvant chemotherapy.

Hormonal Therapy
At the end of chemotherapy, all patients received tamoxifen 20 mg/d until progression (or for a maximum of 5 years without progression), regardless of hormonal receptor status.

Patient Assessment
The initial staging included medical history, tumor assessment, complete physical examination, routine hematology and chemistry, bone scan (and skeletal x-rays when relevant), chest x-ray, liver ultrasound, bilateral mammography, measurement of LVEF by echography or multiple-gated acquisition scan and ECG. The same evaluation was performed at the end of chemotherapy. Examinations during treatment were limited to periodic hematology and chemistry analyses, tumor assessment (after three cycles), and cardiac function evaluation (after a cumulative dose of 480 mg/m² of E). After completion of chemotherapy, patients were followed every 3 months the first year, every 4 months the second year, and every 6 months thereafter. Complementary examinations were recommended only in case of suspicion of distant progression. Cardiac function was evaluated by multiple-gated acquisition scan or echography once after 6 months and then if clinically indicated.

Toxicity was graded according to the National Cancer Institute of Canada (NCIC)-Clinical Trials Group expanded common toxicity criteria.

Outcome Measures
The principal outcome measure of the study was progression-free-survival (PFS), defined as the time between assignment and progression (local and/or distant) or death, whichever occurred first. Secondary end points included overall survival (OS), response rate, safety, quality of life, and cost-effectiveness. OS was defined as the time between assignment and the date of death. Response rates were evaluated using the WHO response criteria. However, because inflammatory breast cancer is difficult to measure accurately, partial responses and stable disease were pooled together. Tumor assessments were performed before treatment, after three cycles, and at the end of the chemotherapy.

Quality-of-life (QoL) evaluation used the EORTC QLQ C-30 questionnaire administered before treatment, then once per month for the first 3 months and afterwards at months 6, 12, 20, 28, 36, 42, and 48. Cost-effectiveness evaluation was based on data collected on specific questionnaires (RANDMOS, EUROQUOL, and questions related to the cost of the treatment), following the same timing as the QoL evaluation. Additional information concerning the cost of the treatment was collected directly on site in some countries.

Statistical Analysis
The 3-year PFS in the control group was estimated to be 50% on the basis of the previous EORTC study in the same patient population. The present study was designed to detect a 15% improvement; that is, from 50% to 65% in PFS in favor of the accelerated regimen. To detect such a difference, a total of 166 events (first occurrence of local progression, distant metastases, or death) was required (two-sided tests, alpha = 0.05 and beta = 0.15),¹¹ and therefore, 388 patients should be recruited and followed for an average of 3 years. Accounting for ineligibility and drop out, a total of 440 patients were planned for recruitment.

For the time-to-event analyses (PFS and OS) and for reporting of response to treatment, all patients were taken into account (intent to treat analysis). For safety reporting, all patients who started their assigned treatment were included in the analysis. Patients lost to follow-up were censored at the time of last information for the time-to-event analyses.

Time-to-event curves were calculated using the Kaplan-Meier product limit estimate and compared using the two-sided log-rank test.^12,13 The Cox proportional hazard model was used to detect the effect of underlying prognostic factors on outcome.¹⁴ Dose-intensity ratios were calculated following the recommendations of Hryniuk and Bush.⁶

The EORTC global health status/QoL scale was taken as the primary QoL scale.¹⁵ The analysis focuses on the QoL outcome during the first year after assignment. The area under the curve (AUC) method was used to compare QoL between the two groups, and a sensitivity analysis was performed to investigate the effect of nonlinear change between consecutive time points.¹⁶

The following categories were included in the cost calculation: hospital costs, medication costs, non-hospital-care costs, travel costs, and productivity costs. The average cost was then calculated for each treatment. All statistical analyses were carried out with SAS statistical software (SAS Institute, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Population
The protocol was initiated in 1993 and completed recruitment in 1996. Forty-six centers from 12 countries and three cooperative groups participated in this trial.

In total, 448 women with locally advanced breast cancer were recruited, 224 in the CEF arm and 224 in the EC arm. Eleven patients were ineligible, seven in CEF and four in EC. The reasons for ineligibility were as follows: wrong staging (eight patients), one patient with prior therapy for breast cancer, and two patients with concurrent malignancies. Two patients in CEF never started their treatment, and one patient was treated with EC although randomly assigned to receive CEF; these three patients are not included in the safety analysis for CEF (221 patients instead of 224). The baseline characteristics were well balanced between the two treatment groups (Table 1).

Treatment administration had to be modified (delayed, reduced, or temporarily interrupted) for 70% of the patients in the CEF arm and 39% of the patients in the EC arm.

The best clinical response to chemotherapy is reported in Table 3. The complete clinical response rates were 31% and 27% in the CEF and EC arms, respectively. For the subgroup of patients with measurable disease at entry who did not achieve a complete clinical response, 80% of the patients in CEF and 90% of the patients in EC achieved a measurable partial response. For 19 patients in CEF and 17 in EC, the clinical response could not be assessed because of inadequate tumor assessment at entry (15 patients) or during the treatment (21 patients).

The pathological response could be determined for 133 and 148 patients in CEF and EC arms, respectively. Nineteen patients (14%) in CEF and 15 patients (10%) in EC had a complete pathological response.

Quality of Life
The compliance for completion of QoL questionnaires was 75% during the first year after treatment initiation. Compared with CEF, EC had a significantly lower QoL score during the first 3 months. At month 6, the QoL score returned to pretreatment levels in the intensified arm. On average, QoL scores remained stable during CEF therapy. No statistical difference was observed between the two groups over 1 year after randomization (Fig 1).

View larger version (12K): [in this window] [in a new window]   Fig 1. Global quality of life (QoL) score evaluated monthly after random assignment. Low score indicates worse quality of life. C, cyclophosphamide; E, epirubicin, F, fluorouracil.

The average overall cost of CEF has been estimated at 26,480 euro ($23,830), with a range across countries from 23,288 up to 29,606 euro. Hospital costs contributed to 72% of the overall cost and drug costs contributed for 23%.

The average overall cost of EC has been estimated at 37,411 euro ($33,670), with a range across countries from 36,981 up to 39,261 euro. Drug costs contributed for 51% of the overall cost and hospital costs for 45%. Regarding average overall cost, EC treatment was about 10,000 euro ($9,000) more expensive than CEF per patient.

PFS
After a median follow-up of 5.5 years, a total of 277 events have been reported: 133 and 144 in the CEF and EC arms, respectively. Fifteen (6.8%) patients in the CEF arm and 13 (5.8%) patients in the EC arm were considered lost to follow-up.

The median PFS of the CEF patients was 34 months (95% confidence interval [CI], 21% to 53%), compared with 33.7 months in the EC arm (95% CI, 26% to 46%; log-rank P = .68; Fig 2). No statistically significant difference was detected in the pattern of events between the treatment groups.

View larger version (10K): [in this window] [in a new window]   Fig 2. Progression-free survival. O, observed number of events; N, number of events; C, cyclophosphamide; E, epirubicin, F, fluorouracil.

Survival
A total of 217 deaths have been reported: 108 in the CEF arm and 109 in the EC arm. The 5-year survival rate of the CEF patients was 53% (95% CI, 46% to 59%), compared with 51% in the EC arm (95% CI, 45% to 58%; log-rank P = .94; Fig 3).

View larger version (10K): [in this window] [in a new window]   Fig 3. Survival. O, observed number of events; N, number of events; C, cyclophosphamide; E, epirubicin, F, fluorouracil.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
There are at least five models allowing the delivery of a higher overall anthracycline dose-intensity in the treatment of breast cancer.^17,18 These models are all based on the adaptation of one or more of the following variables: the dose of anthracycline delivered per cycle, the interval between cycles, and the cumulative dose. This study is so far the largest study investigating dose-intensification in breast cancer (and in particular in the neoadjuvant setting) by shortening the interval between cycles with the same number of cycles and the same total cumulative dose. In reality, this study investigates two dose-intensity concepts in parallel. On one hand, a dose-intensity approach by which the same total cumulative dose of an anthracycline is delivered within a shorter period (3 months instead of 6 months), and on the other hand, a dose-dense approach by which a higher dose of an anthracycline is administered all at once (epirubicin 120 mg/m² instead of 60 mg/m²). E was selected (instead of doxorubicin) because this drug has a more favorable cardiotoxicity profile.¹⁹ The total doses of C (both planned and delivered) were not exactly identical but were similar between the treatment arms taking into account that the different routes of administration (PO v IV) could be potentially a confounding factor. An optimal trial design would have required abandoning the FU component in the standard arm. However, without any published literature supporting the use of E and C without FU, this might have prevented many participants from taking part in the study. Therefore, participating groups preferred a head-to-head comparison of the regimens tested in pilot studies by EORTC and NCIC.

The trial was powered to detect a clinically relevant difference in PFS between the treatment arms, and the planned dose-intensity ratio for E and C between the treatment arms was achieved. Therefore, the lack of superiority of the accelerated EC over CEF cannot be attributed to treatment compliance problems or lack of statistical power.

At least four hypotheses can be formulated to explain these negative results: 1) the relation between dose-intensification as it is applied in this model and treatment efficacy is not linear; 2) the absence of FU in the intensified arm is detrimental; 3) the overall duration of chemotherapy in the intensified arm (3 months) is too short to provide optimal efficacy; and 4) the population selected for this study is too heterogeneous and the possible benefit of dose intensification is diluted within the relative "low"-risk subgroup of patients (noninflammatory, estrogen receptor/progesterone receptor–positive).

The efficacy of dose intensification of an anthracycline-based regimen by shortening the interval between courses has been studied already in metastatic disease (Table 5). Two studies^20,21 used as a single variable the interval between the courses, and one study²² investigated both intensification (the dose delivered at once) and acceleration (the interval between the courses) of chemotherapy delivery in the same setting. None of these studies has demonstrated any relevant benefit in time to progression or survival in favor of dose intensification. However, none of these trials was adequately powered to detect a realistic difference in these end points and their contribution to a definitive conclusion in the metastatic setting is limited.

FU, discovered at the end of the 1960s, is an interesting cytotoxic agent that has demonstrated relevant activity against a wide range of tumor types, including breast cancer. The studies mentioned above either included^21,22 or excluded²⁰ FU in both treatment arms. As stated previously, none of these studies identified any advantage from the accelerated approach. Although one cannot conclude from these data that FU is an unnecessary component of the CEF regimen, it does not appear to be critical in the activity of the accelerated approach, and hence, it does not provide a satisfactory explanation for the lack of superiority of the investigational regimen in this study.

Several studies investigating the possible effect of a longer duration of treatment have already been conducted.^24–27 Two of these studies^26,27 demonstrated some benefit in favor of the longer duration of treatment, which may be more significant for estrogen receptor–negative tumors.²⁶ However, critical reviews of the results of these trials^28,29 do not provide a definitive conclusion about the optimal duration of treatment in the adjuvant or neoadjuvant setting (3 or 6 months). The interpretation of these results also suffers from the design of the studies inasmuch as the reduction in treatment duration was not compensated for by an increase of dose intensity to achieve the same total dose of chemotherapy in both arms. For anthracycline-based regimens, the total dose of anthracycline that can be administered to a patient is limited by the risk of cumulative cardiotoxicity. This obviously prohibits the extended delivery of dose-intensified regimens such as the one we have studied. Moreover, in our series, the median time to partial response for partial responders was after three cycles and after five or six cycles for the complete responders, regardless of the treatment schedule.

It is also noteworthy that the number of complete pathological responses was not significantly different in the two arms: 19 patients (14%) in CEF and 15 patients (10%) in EC.

These data therefore do not support the existence of a relationship between the duration of chemotherapy and antitumor effect. On the contrary, they indicate that comparable efficacy is achieved in a shorter time, and this may provide the opportunity to investigate the sequential administration of the accelerated regimen with other agents such as taxanes for a total duration of treatment that does not exceed 6 months. This hypothesis is now being investigated in NCIC trial MA 21, where arm 2 is composed of dose-intensified EC for six cycles followed by paclitaxel for four cycles.

Finally, inflammatory breast cancer is renowned as an aggressive form of locally advanced cancer. The results of the exploratory analyses reported in this article, which compares the PFS and the survival of this subgroup of patients with the locally advanced noninflammatory subgroup, confirm that these two populations have a different outcome. Rapid growth and short doubling times are characteristic of inflammatory breast cancer,³⁰ and one may postulate that rapidly dividing diseases could be more sensitive to a dose-intensified treatment that shortens the interval between treatment administrations. This hypothesis has been explored through a subset analysis of a possible treatment effect within the inflammatory subgroup of patients, and although no direct statistical comparison was computed, the survival and PFS curves of both groups were almost superimposable.

The locoregional management of locally advanced breast cancer after neoadjuvant chemotherapy also remains a controversial issue.^31–33 In this study, 52% of the centers chose for their patients a flexible policy of locoregional management (ie, depending on the outcome of neoadjuvant chemotherapy). This lack of standardization in locoregional therapy has encouraged the EORTC to launch a trial specifically looking at the role of mastectomy versus breast conserving therapy (EORTC 10974).

Both regimens affected the overall QoL negatively for the duration of treatment. The accelerated regimen clearly affected the overall QoL score more strongly as well as the fatigue scale over the period of chemotherapy administration, but the QoL scale and fatigue scale returned to normal more quickly as the therapy was completed earlier. Although the QoL assessments did not reveal any significant difference between the treatment arms over a year after randomization, one may suspect that continuing treatment beyond the first 3 months after the accelerated regimen would significantly affect on QoL. This aspect will be investigated in the ongoing NCIC MA 21 trial.

Without a therapeutic advantage offered by the accelerated regimen, the foreseen cost-effectiveness analysis has not been performed. The data collected revealed that the average difference recorded between the total costs of the two chemotherapy regimens roughly corresponded to the total cost of filgrastim administered concomitantly with EC.

In conclusion, this study shows that dose-intensification through the acceleration of the chemotherapy delivery does not provide a significant therapeutic benefit in the neoadjuvant setting. The results of two large adjuvant trials are awaited before concluding the relevance of such a treatment model in breast cancer.

New strategies of treatment are desperately needed for locally advanced breast cancer. One way forward may be to focus our attention on customizing existing chemotherapy regimens according to specific tumor biologic features. The recently launched EORTC trial 10994 compares a standard anthracycline-based regimen with the sequential administration of taxane and anthracycline, prospectively testing the predictive value of p53 mutations for response to taxanes in this population.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Participating Centers (number of patients recruited): EORTC, Belgium: Institut Jules Bordet (18), Algemeen Ziekenhuis Middelheim (4), Centre Hospitalier Régional de la Citadelle (7), UZ Gasthuisberg (14), Clinique Saint Elisabeth (5); Czech Republic: General Teaching Hospital in Prague (2), Thomayer’s Teaching Hospital (6), Center of Clinical Oncology (2), University Hospital in Plzen (2); France: Centre Henri Becquerel (16), Institut Bergonie (52), Centre Georges-François-Leclerc (11), Centre Alexis Vautrin (8), Centre René Huguenin (10); Poland: Medical University of Gdansk (47), Maria Skoldowska-Curie Cancer Center (1), Medical Academy of Lodz (16), Maria S. Curie Memorial Institute (14); Portugal: Hospitais da Universidade de Coimbra (13); Russia: Petrov Research Institute of Oncology (10), Cancer Research Center (17); Slovenia: The Institute of Oncology (22); South Africa: The Medical Oncology Center of Rosebank (3); the Netherlands: Diakonessenhuis (4), Antoni van Leeuwenhoekhuis (24), AZ Rotterdam-Daniel Den Hoed Kliniek (2), University Medical Center Nijmegen (5), AZ Utrecht (2), Leiden University Medical Center (2), AZ Maastricht (2); United Kingdom: Weston Park Hospital (7), Guy’s Hospital (4); NCIC Clinical Trials Group (68); SAKK: Hopital Cantonal Universitaire de Genève (14), Inselspital (1), Kantonsspital St Gallen (6), Centre Hospitalier Universitaire Vaudois (7).

	ACKNOWLEDGMENTS

 
We would like to acknowledge the essential contribution of all investigators (listed below) and also our data managers, F. Mignolet and I. Van Hoorebeeck. L. Duchateau, and X. Paoletti for their support in the statistical analysis, M. Koopmanschap and F. Rutten from IMTA and E. Suetens, K. Vanschoubroek and B. Standaert from Amgen.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. International Union Against Cancer (UICC): TNM—Classification of Malignant Tumors (ed 5). New York, Wiley-Liss, 1997

2. Zucali R, Uslenghi C, Kenda R, et al: Natural history and survival of inoperable breast cancer treated with radiotherapy and radiotherapy followed by radical mastectomy. Cancer 37:1422–1431, 1976[CrossRef][Medline]

3. Valero V, Buzdar A, Hortobagyi G: Locally advanced breast cancer. Oncologist 1:8–17, 1996[Abstract/Free Full Text]

4. Rubens RD, Bartelink H, Engelsman E, et al: Locally advanced breast cancer: The contribution of cytotoxic and endocrine treatment to radiotherapy. An EORTC Breast Cancer Cooperative Group trial (10792). Eur J Cancer Clin Oncol 25:667–678, 1989[CrossRef][Medline]

5. Bartelink H, Rubens RD, van der Schueren E, et al: Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: A European Organisation for Research and Treatment of Cancer randomised phase III trial. J Clin Oncol 15:207–215, 1997[Abstract/Free Full Text]

6. Hryniuk W, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2:1281–1288, 1984[Medline]

7. Antman K, Corringham R, de Vries E, et al: Dose intensive therapy in breast cancer. Bone Marrow Transplant 10:67–73, 1992 (suppl 1)

8. Piccart M, Bruning P, Wildiers J, et al: An EORTC pilot study of filgrastim (recombinant human granulocyte colony stimulating factor) as support to a high dose-intensive epiadriamycin-cyclophosphamide regimen in chemotherapy-naive patients with locally advanced or metastatic breast cancer. Ann Oncol 6:673–677, 1995[Abstract/Free Full Text]

9. Levine M, Bramwell V, Pritchard K, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 16:2651–2658, 1998[Abstract]

10. Freedman LS, White SJ: On the use of Pocock and Simon’s method for balancing treatment numbers over prognostic factors in the controlled clinical trial. Biometrics 32:691–694, 1976[CrossRef][Medline]

11. Freedman LS: Tables of the number of patients required in clinical trials using the logrank test. Stat Med 1:121–129, 1982[Medline]

12. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomised clinical trials requiring prolonged observation of each patient. Analysis and examples. Br J Cancer 35:1–39, 1977[Medline]

13. Kaplan E, Meier P: Nonparametric estimations from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]

14. Cox DR: Regression models and life-tables. J R Stat Soc 34:187–202, 1972

15. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organisation for Research and Treatment of Cancer QLQ-C30: A Quality-of-life Instrument for Use in International Clinical Trials in Oncology. J Natl Cancer Inst 85:365–376, 1993[Abstract/Free Full Text]

16. Curran D, Aaronson NK, Therasse P, et al: Summary measures and statistics in the analysis of quality of life data: An example from an EORTC-NCIC-SAKK locally advanced breast cancer study. Eur J Cancer 36:834–844, 2000[CrossRef][Medline]

17. Biganzoli L, Piccart M: The bigger the better?. . . or what we know and what we still need to learn about anthracycline dose per course, dose density and cumulative dose in the treatment of breast cancer. Ann Oncol 8:1177–1182, 1997[Free Full Text]

18. Piccart M, Biganzoli L, Di Leo A: The impact of chemotherapy dose density and dose intensity on breast cancer outcome: What have we learned? Eur J Cancer 36:S4–S10, 2000 (suppl 1)

19. Cersosimo RJ, Hong WK: Epirubicin: A review of the pharmacology, clinical activity, and adverse effects of an adriamycin analogue. J Clin Oncol 4:425–439, 1986[Abstract/Free Full Text]

20. Fountzilas G, Athanassiades A, Giannakakis T, et al: A randomised study of epirubicin monotherapy every four or every two weeks in advanced breast cancer. A Hellenic Cooperative Oncology Group study. Ann Oncol 8:1213–1220, 1997[Abstract/Free Full Text]

21. Arridzzoni A, Venturini M, Sertoli MR, et al: Granulocyte-macrophage colony-stimulating factor (GM-CSF) allows acceleration and dose intensity increase of CEF chemotherapy: A randomised study in patients with advanced breast cancer. Br J Cancer 69:385–391, 1994[Medline]

22. Del Mastro L, Venturini M, Lionetto R, et al: Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicenter, randomised phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group. J Clin Oncol 19:2213–2221, 2001[Abstract/Free Full Text]

23. Venturini M, Del Mastro L: More on dose-intensity of anthracyclines in breast cancer. Ann Oncol 9:461, 1998[Free Full Text]

24. Sauerbrei W, Bastert G, Bojar H, et al: Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients: An update based on 10 years’ follow-up. German Breast Cancer Study Group. J Clin Oncol 18:94–101, 2000[Abstract/Free Full Text]

25. Maass H: 3 versus 6 cycles of CMF in breast cancer patients with 1 to 9 positive nodes: Results of the German Adjuvant Breast Cancer (GQBQ) III trial. Proc Am Soc Clin Oncol 19:73a, 2000 (abstr 283)

26. International Breast Cancer Study Group: Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol 14:1885–1894, 1996[Abstract/Free Full Text]

27. Fumoleau P, Bremond A, Kerbral P, et al: Better outcome of premonopausal node-positive (N+) breast cancer patients (pts) treated with 6 cycles vs 3 cycles of adjuvant chemotherapy: Eight-year follow-up results of FASG 01. Proc Am Soc Clin Oncol 18:67a, 1999 (abstr 252)

28. Piccart M, Lohrisch C, Duchateau L, et al: Taxanes in the adjuvant treatment of breast cancer: Why not yet? J Natl Inst Monogr 30:88–95, 2001

29. National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development conference statement: Adjuvant therapy for breast cancer, Nov 1–3, 2000. J Natl Cancer Inst Monogr 30:5–15, 2001

30. Kuske RR: Diagnosis and management of inflammatory breast cancer. Semin Radiat Oncol 4:270–282, 1994[CrossRef][Medline]

31. De Lena M, Varini M, Zucali R, et al: Multimodal treatment for locally advanced breast cancer: Results of chemotherapy-radiotherapy versus chemotherapy-surgery. Cancer Clin Trials 4:229–236, 1981[Medline]

32. Olson JE, Neuberg D, Pandya KJ, et al: The role of radiotherapy in the management of operable locally advanced breast carcinoma: results of a randomised trial by the Eastern Cooperative Oncology Group. Cancer 79:1138–1149, 1997[CrossRef][Medline]

33. Schwartz GF, Birchansky CA, Komarnicky LT, et al: Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast. Cancer 73:362–369, 1994[CrossRef][Medline]

Submitted May 20, 2002; accepted November 8, 2002.

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