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Journal of Clinical Oncology, Vol 19, Issue 8 (April), 2001: 2213-2221
© 2001 American Society for Clinical Oncology

Accelerated-Intensified Cyclophosphamide, Epirubicin, and Fluorouracil (CEF) Compared With Standard CEF in Metastatic Breast Cancer Patients: Results of a Multicenter, Randomized Phase III Study of the Italian Gruppo Oncologico Nord-Ouest–Mammella Inter Gruppo Group

By Lucia Del Mastro, Marco Venturini, Rita Lionetto, Flavio Carnino, Domenico Guarneri, Luigi Gallo, Antonio Contu, Paolo Pronzato, Lorella Vesentini, Marina Bergaglio, Silvia Comis, Riccardo Rosso

From the Department of Medical Oncology, and Unit of Clinical Epidemiology and Trials, National Cancer Research Institute, Genoa; Oncologia Medica, E.O. Ospedali Galliera, Genoa; Divisione Ginecologia C, Ospedale S. Anna, Torino; U.O. Oncologia Medica, Ospedale G. Borea, Sanremo; Oncologia Medica, Azienda Ospedaliera 1, Sassari; U.O. Oncologia Medica, Ospedale S. Andrea, La Spezia; and Aventis Pharma SpA, Origgio, Italy.

Address reprint requests to Lucia Del Mastro, MD, Department of Medical Oncology, Istituto Nazionale per la Ricerca sul Cancro, L.go R. Benzi 10, 16132 Genoa, Italy; email: ldelmast{at}hp380.ist.unige.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate whether an accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) chemotherapy regimen with the support of granulocyte colony-stimulating factor (G-CSF) induces a higher activity and efficacy compared with standard CEF in metastatic breast cancer patients.

PATIENTS AND METHODS: Stage IV breast cancer patients were randomized to receive as first-line chemotherapy either standard CEF (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2) administered every 21 days (CEF21) or accelerated-intensified CEF (cyclophosphamide 1,000 mg/m2, epirubicin 80 mg/m2, and fluorouracil 600 mg/m2) administered every 14 days (HD-CEF14) with the support of G-CSF. Treatment was administered for eight cycles.

RESULTS: A total of 151 patients were randomized (74 patients on the CEF21 arm and 77 on the HD-CEF14 arm). In both arms, the median number of administered cycles was eight. The dose-intensity actually administered was 93% and 86% of that planned, in CEF21- and HD-CEF14–treated patients, respectively. Compared with the CEF21 arm, the dose-intensity increase in the HD-CEF14 arm was 80%. Both nonhematologic and hematologic toxicities were higher in the HD-CEF14 arm than in the CEF21 arm. During chemotherapy, four deaths occurred in the HD-CEF14 arm. No difference in overall response rate (complete plus partial responses) was observed: 49% and 51% in the CEF21 and HD-CEF14 arms, respectively (P = .94). A slightly non–statistically significant higher percentage of complete response was observed in the HD-CEF14 arm (20% v 15%). No difference in efficacy was observed. The median time to progression was 14.3 and 12.8 months in the CEF21 and HD-CEF14 arms, respectively (P = .69). Median overall survival was 32.7 and 27.2 months in the CEF21 and HD-CEF14 arms, respectively (P = .16).

CONCLUSION: In metastatic breast cancer patients, an 80% increase in dose-intensity of the CEF regimen, obtained by both acceleration and dose intensification, does not improve the activity and the efficacy compared with a standard dose-intensity CEF regimen.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
RETROSPECTIVE STUDIES have suggested that chemotherapy dose-intensity (DI) can affect the outcome of breast cancer patients.1 Randomized studies have clearly shown the detrimental effect of using regimens with lower than standard DI both in metastatic and early breast cancer.2-5 However, the benefit of increasing DI above the standard level is still controversial despite the relevance of its definition, because only a real clinical benefit to patients can justify the increased toxicity and cost of treatments with high DI.

DI increase can be reached by different approaches: by increasing doses of antineoplastic drugs (intensification), by reducing the interval between cycles (acceleration), or by both approaches (acceleration-intensification). The rationale for using intensification is preclinical evidence showing that tumor-cell kill is directly proportional to the dose and time of exposure. The rationale for acceleration is the hypothesis that tumor regrowth between cycles can be reduced by shortening intervals.

The majority of randomized trials have evaluated the role of a DI increase obtained by using higher dosages of drugs, whereas few data are available on the role of acceleration6 or acceleration-intensification. The acceleration of chemotherapy became easily feasible with the availability of hematopoietic colony-stimulating factors (CSFs), which are able to reduce the duration of myelosuppression, thus allowing the administration of chemotherapy at shorter intervals than standard ones.

In 1990, we started a program to verify the clinical importance of the DI. In a previous controlled study we demonstrated that by using granulocyte-macrophage CSF (GM-CSF), the cyclophosphamide, epirubicin, and fluorouracil (CEF) regimen can be administered at a median interval of 16 days compared with 20 days in the control group, with a consequent DI increase of approximately 25%.7 In a subsequent dose-finding study, we demonstrated that the use of GM-CSF allows not only the acceleration but also the increase of doses of cyclophosphamide and epirubicin (acceleration-intensification).8 Finally, we found that granulocyte CSF (G-CSF) allows acceleration of CEF chemotherapy with lower toxicity when indirectly compared with GM-CSF.9 Eventually, we designed the present randomized study to evaluate whether accelerated-intensified CEF chemotherapy with the support of G-CSF induces a higher activity and efficacy compared with standard CEF in metastatic breast cancer patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility
Eligible patients were women with stage IV breast cancer, Eastern Cooperative Oncology Group performance status less than or equal to 2, WBC count greater than or equal to 3 x 109/L, platelet count greater than or equal to 100 x 109/L, bilirubin less than 1.5 x upper normal limit (UNL), creatinine less than 1.5 x UNL, and measurable and/or evaluable disease. Previous radiotherapy and endocrine therapy but not chemotherapy for the metastatic disease were allowed. Previous adjuvant chemotherapy was allowed if completed at least 12 months before randomization. Patients who received anthracycline-containing adjuvant chemotherapy were required to have a left-ventricular ejection fraction more than 50%. Exclusion criteria were history of recent myocardial infarction, clinical evidence of heart failure, arrhythmia requiring medication, brain metastases as the only site of disease, and life expectancy less than 3 months. All patients gave their written informed consent before study entry.

Study Design
The study was designed as a multicenter phase III trial. The experimental arm was represented by accelerated-intensified CEF (HD-CEF14 group); the control arm was represented by standard DI CEF (CEF21 group). The study was conducted in 17 Italian centers and was approved by the Protocol Review and the Ethical Committees of the National Cancer Research Institute of Genoa, Italy.

Objective of the Study
The primary objective was to study if the more intensive chemotherapy regimen could increase the overall response rate. The secondary objective was to observe an increase in median time to progression.

Randomization
The randomization lists were generated by computer with the Moses algorithm procedure, and kept in a central office. The only stratification factor was the participant institution. Each list was generated using blocks of different, randomized size to allow for balancing. Randomization was performed through telephone calls to the central office, after checking of the eligibility criteria.

Sample Size
To justify risks and costs of a treatment with high-DI chemotherapy, the gain in response rate had to be high, not less than 25%. The response rate for the control arm was known to be between 35% and 40%. For type I error equal to 5% and power equal to 90%, the foreseen total sample size was 150. With such sample size it is also possible to evaluate an increase in median time to progression from 8.5 months to 13.5 months with type I error equal to 5% and power equal to 80%, under the hypothesis of proportional hazards.

Treatment Regimens
Standard-dose CEF21 consisted of cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2. All drugs were given intravenously (IV) on day 1, every 21 days. The accelerated-intensified regimen, HD-CEF14, consisted of cyclophosphamide 1,000 mg/m2, epirubicin 80 mg/m2, and fluorouracil 600 mg/m2 IV on day 1; cycles were repeated every 14 days. G-CSF (lenograstim, Rhône-Poulenc Rorer, Origgio, Italy) was self-administered by the patient at the dose of 263 µg subcutaneously from day 4 to day 11 after each cycle of HD-CEF14. In both arms, at least eight cycles of chemotherapy were planned in the absence of disease progression. In responding patients, a maximum of 12 cycles was allowed. Treatment was delayed by 1 week in the presence of WBC count less than 3 x 109/L, platelet count less than 100 x 109/L, or other grade 2 or 3 toxicities (except alopecia and anemia) at the time of recycle. A 25% reduction in the dosages of all three drugs was performed if one or more of the following toxicities occurred: WBC count less than 2 x 109/L and/or platelet count less than 50 x 109/L at the time of recycle, grade 4 neutropenia lasting more than 7 days, febrile neutropenia, and a platelet count less than 25 x 109/L. RBC transfusions were performed if hemoglobin value fell below 8 g/dL or if symptomatic anemia (dyspnea, tachycardia) occurred.

DI Calculation
DI of each drug as well as cumulative average relative DI (ARDI) was calculated according to the method described by Hryniuk and Bush.1,10 The increase in the dose per cycle of cyclophosphamide and epirubicin and the acceleration of chemotherapy were planned to lead to a DI increase of 150%, 100%, and 50% for cyclophosphamide, epirubicin, and fluorouracil, respectively. Overall, the ARDI increase expected with HD-CEF14 compared with CEF21 was 95%.

Study Parameters
At baseline, all patients underwent history; tumor assessment; physical examination; and evaluation of performance status, hematology, and blood chemistry. Tumor assessment was made by chest radiographs, bone scan with radiographs of abnormal areas, liver ultrasound or computed tomographic scan, and other radiographs or relevant scan if indicated. Hematology and evaluation of toxicity according to World Health Organization (WHO) criteria11 were performed every cycle. Tumor response was evaluated according to standard WHO criteria. First tumor response was evaluated after at least two cycles but not later than four cycles and then repeated every two cycles.

Statistical Methods
All the analyses were performed according to the principle of "intention to treat." Univariate analysis for response rate is reported with statistical significance calculated by {chi}2. Logistic regression analysis was computed to explain the probability of response (complete response [CR] plus partial response [PR] v stable disease plus other failures) as a function of a set of independent variables (age, performance status, estrogen receptor, prior therapy for metastases, prior adjuvant chemotherapy, site of disease, treatment at random).

Progression-free survival (PFS) was computed as the time from randomization to the first observation of disease progression or death attributable to any cause. For descriptive purposes, overall survival was computed as the time from randomization to death attributable to any cause. Kaplan-Meier estimate and log-rank test allowed comparisons.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
From November 1994 to March 1997, 151 patients were randomized. Two (1.3%) patients were not eligible (one because of prior chemotherapy for the metastatic disease and one because of pleural effusion as the only site of disease, ie, not evaluable disease). The main patient characteristics are listed in Table 1. A slightly higher percentage of patients had a performance status of 2 in the HD-CEF14 arm compared with the CEF21 arm (12% v 7%). More than 40% of patients on both arms were previously treated with adjuvant chemotherapy, and approximately 30% of patients had received at least one line of endocrine therapy for the metastatic disease. More than 50% of patients on both arms had two or more sites of disease.


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  		Table 1. Patient Characteristics
 
Compliance With the Treatment
Four patients (two on the CEF21 arm and two on the HD-CEF14 arm) never received chemotherapy because of treatment refusal (two patients) and choice to be followed by other centers (two patients). Median number of received cycles was eight in patients on the CEF21 arm (range, 0 to 10) and on the HD-CEF14 arm (range, 0 to 12). A delay of treatment was necessary in 18 patients (24%) and 19 patients (25%) on the CEF21 and HD-CEF14 arms, respectively. Reasons for delay in patients on the CEF21 arm were leukopenia (8%), skin toxicity (1%), flu (1%), organizational problems (1%), and patient request (12%). Reasons for delay in patients on the HD-CEF14 arm were anemia (7%), leukopenia (8%), infection (1%), mucositis (1%), fever (1%), organizational problems (1%), and patient request (5%). Only one patient needed dose reduction on the CEF21 arm because of thrombocytopenia compared with 11 patients on the HD-CEF14 arm. Reasons for dose reduction in patients on the HD-CEF14 arm were leukopenia (7%), thrombocytopenia (3%), mucositis (1%), infection (1%), diarrhea (1%), and asthenia (1%).

Dose-Intensity
The main DI results are listed in Table 2. Because of the increase in the dose per cycle of cyclophosphamide and epirubicin, patients on the HD-CEF14 arm received a cumulative dose for both these drugs higher than that received by CEF21-treated patients. On the other hand, because the dose per cycle of fluorouracil was the same in patients on both arms, the cumulative dose of this drug was superimposable. CEF21-treated patients received 93% of the planned DI and HD-CEF14 patients received 86% of the planned DI. The DI increase in patients on the HD-CEF14 arm compared with the CEF21 arm was slightly lower than that expected because of treatment delay or dose reduction. In particular, the DI increases were 120% for cyclophosphamide, 80% for epirubicin, and 40% for fluorouracil, compared with the expected increases of 150%, 100%, and 50%, respectively. The ARDI increase in the HD-CEF14 arm compared with the CEF21 arm was 80%.


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  		Table 2. DI Results
 
Toxicity
We observed four deaths during chemotherapy among patients on the HD-CEF14 arm. Deaths were attributable to early progression (two patients), liver and kidney failure (one patient), and unknown cause (one patient).

The main toxicities are listed in Table 3. Nonhematologic toxicity was higher in the HD-CEF14 arm. The most relevant differences between the two arms were related to a higher incidence of diarrhea, fever, infection, bone pain, and asthenia in the HD-CEF14 arm. Moreover, HD-CEF14 patients more frequently experienced grade 3 mucositis (13% v 3%) and grade 2 and 3 nausea and vomiting (60% v 40%). HD-CEF14 treatment was associated with significantly more myelosuppression compared with CEF21. Twenty-nine percent of HD-CEF14–treated patients experienced thrombocytopenia compared with only 4% of CEF21-treated patients. In the HD-CEF14 arm, grade 3 or 4 anemia occurred in 19% of patients compared with 2.4% of those on the CEF21 arm and, as a consequence, a higher percentage of HD-CEF14–treated patients needed RBC transfusions compared with CEF21-treated patients (13% v 3%).


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  		Table 3. Main Toxicities
 
Activity
Table 4 lists the response rates observed in the two arms. In the CEF21 arm, six patients were not evaluable for response because of ineligibility (one patient), bone lesions evaluated only by bone scan (two patients), evaluation of response with different methods compared with baseline (one patient), and treatment never started (two patients). In the HD-CEF14 arm, eight patients were not evaluable for response because of ineligibility (one patient), death caused by toxicity before response assessment (one patient), refusal of patient to continue treatment before response assessment (four patients), and treatment never started (two patients). No difference in overall response rate was observed: CR plus PR rates were 49% (95% confidence interval [CI], 37% to 60%) and 51% (95% CI, 39% to 62%) in the CEF21 and HD-CEF14 arms, respectively. A slightly higher percentage of CR was observed in patients on the HD-CEF14 arm (20% v 15%).


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  		Table 4. Response Rate by Treatment Arm
 
At univariate analysis, factors significantly associated with the probability of response were performance status and site of disease. At logistic regression analysis, only the site of disease maintained the statistically significant association with probability of response ( Table 5).


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  		Table 5. Objective Responses to Treatment: Univariate and Logistic Regression Analyses
 
Time to Progression and Overall Survival
As of March 1999, 118 patients have progressed (59 on the CEF21 arm and 59 on the HD-CEF14 arm) and 80 patients have died (37 on the CEF21 arm and 43 on the HD-CEF14 arm). Eleven patients (7.2%) were lost to follow-up (five on the CEF21 arm and six on the HD-CEF14 arm): six patients without documented disease progression and five patients after the evidence of progressive disease.

Time to progression (TTP) in the two treatment arm is shown in Fig 1. No difference between the two arms was observed: median TTP was 14.3 and 12.8 months in patients on the CEF21 and HD-CEF14 arms, respectively (P = .69). No difference in overall survival (OS) was observed (Fig 2): median OS was 32.7 and 27.2 months in patients on the CEF21 and HD-CEF14 arms, respectively. Patients surviving at 2 years were 62% and 53% on the CEF21 and HD-CEF14 arms, respectively.



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  		Fig 1. PFS by treatment group.

 


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  		Fig 2. OS by treatment group.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In vitro and animal models show dose–response curves for most chemotherapy regimens, with the degree of tumor-cell kill being directly proportional to both dose and duration of exposure.12 The potential role in humans of these factors (dose and time) was suggested by retrospective studies indicating that DI, which can be considered a measurement taking into account both dose and time, can affect patient outcome. Both preclinical evidence and clinical retrospective findings prompted studies evaluating the role of escalating doses and/or DI beyond the conventional range. Strategies to test the hypothesis are derived either from the use of high-dose chemotherapy requiring bone marrow support13 or from the use of regimens with an increase in dose or DI within ranges not requiring bone marrow support. The increase in DI was achieved by dose intensification, by acceleration, or by both, with or without the support of hematopoietic CSFs.

Intensification of epirubicin dose has been evaluated in various randomized studies in which an adequate dose of the same drug was used in the standard arm ( Table 6).7-18 Overall, all the studies reported no advantage in overall survival, from the strategy of the dose intensification. A difference in TTP was observed in two studies,15,19 and a significant difference in response rate (RR) was observed in four studies.15,17-19


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  		Table 6. Randomized Studies Comparing Standard Versus High-DI Epirubicin-Containing Chemotherapy
 
Acceleration of chemotherapy has been prospectively evaluated by Fountzilas et al.6 They compared epirubicin 110 mg/m2 administered every 4 weeks with the same regimen administered every 2 weeks. No difference in RR, TTP, and OS were observed (Table 6), whereas a significant difference was observed in CR (17% v 5%). In our study, we applied both approaches (ie, dose-intensification and acceleration of chemotherapy with the G-CSF support). Our results are superimposable on those of Fountzilas et al.

To synthesize data reported in Table 6, we conducted a meta-analysis on these eight trials for a total of 1,753 patients. Trials were retrieved from MEDLINE searches and selected according to the following selection criteria: randomized clinical trial, and standard versus intensified chemotherapy regimens. All the studies in which the control arm received a chemotherapy regimen with doses below the standard ones (ie, epirubicin < 50 mg/m2) were excluded. After checking for heterogeneity, a quantification of the size difference observed between the two groups (high dose v standard dose) was performed using the Peto odds ratio estimator: Exp[(observed - expected)/variance (observed - expected)], and the rate difference with the estimate of the 95% CI. Data were pooled by the intention-to-treat principle (patients not eligible and not evaluable were included in the denominator). The study by Bastholt et al18 was analyzed considering as the standard-dose arm the first two dose levels (40 + 60 mg/m2 of epirubicin) and as the high-DI arm the other two levels (90 + 135 mg/m2 of epirubicin). Results of the meta-analysis are reported in Fig 3. The pooled odds of being a responder for patients of the high-DI chemotherapy arm is 1.58 the odds of being a responder for those of the standard arm (95% CI, 1.30 to 1.92). Since the estimator is greater than unity, the experimental arm really raises the probability of being a responder, and this is statistically significant (P = .000). The pooled rate difference is 0.11, and this is also statistically significant. If this is the real difference we can foresee with high-DI chemotherapy, then a trial able to show it should have at least 900 patients. This can explain the lack of statistically significant difference in RR of the majority of the trials, which had a low number of patients. To summarize, the predominance of evidence suggests that dose intensification of one or more drugs of the CEF regimen within the ranges used in our and other studies is unable to substantially ameliorate the outcome of metastatic breast cancer patients, the expected benefit being an 11% increase in RR. On the other hand, all studies, including the present one, showed an increase in the rate of CR obtained with the dose-intensified arm. Further efforts should be aimed to identify patients (eg, those with Her2-neu overexpression tumors) who may benefit from intensified anthracycline DI therapy by obtaining a high rate of CR.



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  		Fig 3. Odds ratio of RR. When the odds ratio is at the right of the vertical line (odds ratio = 1) the difference is in favor of high-DI chemotherapy. The heterogeneity {chi}2 = 10.67 (df = 7), P = .154. Test of odds ratio = 1: z = 4.66, P = .000.

 
An additional finding of our study was the observation of longer than expected PFS and OS in both arms. In a previous study, we performed an analysis on the activity and efficacy of first-line CEF by pooling data from 326 metastatic breast cancer patients entered onto four randomized trials carried out by the GONO group from 1983 to 1994.19 Selection criteria as well as the objective response rate observed (CR plus PR, 49%; CR, 16%) were similar to those reported in the present study, but both PFS (median, 9.8 months) and OS (median, 17.9 months) were shorter than those observed in the current study. Potential factors affecting PFS and OS were similar in the present as compared with our previous studies: the percentages of patients previously treated with adjuvant chemotherapy were 42% and 56%, respectively, and prior hormonal therapy for metastasis was given to 30% and 35% of patients. On the other hand, a difference that may explain the longer PFS and OS in the present study is the duration of chemotherapy: the median number of chemotherapy cycles administered was eight in both arms in the present study as compared with six cycles in our previous studies. The same differences in both PFS and OS as well as in the number of received cycles are observed when our study is compared with other ones evaluating the role of DI (Table 6). The hypothesis that the longer duration of chemotherapy may be one of the reasons of the good outcome observed is supported also by results of numerous randomized studies showing the longer PFS in metastatic breast cancer patients of prolonged chemotherapy compared with a shorter one.20-24

In conclusion, the results obtained in our study as well as reviews of the studies prospectively evaluating the role of DI25,26 suggest that in metastatic breast cancer the increase of DI above an "adequate" dose level, considered standard, is not able to substantially improve outcome and should not be used outside clinical trials. Whether the anthracycline DI increase may improve the CR rate and the OS of a selected subset of patients is a matter for future studies.

APPENDIX
The following investigators and their institutions also participated in the study: Centro Oncologico, Ospedale di Arezzo, Arezzo (P. Ghezzi); Servizio Oncologia, Ospedale Civile Sestri Levante, Levante (A. Lavarello); Servizio Oncologia, Ospedale Santa Corona, Pietra Ligure (U. Folco); Servizio Oncologia, Ospedale S. Elia, Caltanisetta (S. Vitello); Servizio di Oncologia Medica, Ospedale Alba, Alba (G. Porcile); Ospedale S. Spirito, Casale Monferrato (B. Castagneto); U.O. Oncologia Medica, Ospedale S. Chiara, Pisa (P.F. Conte); Divisione Oncologia ed Ematologia, Ospedale Carlo Poma, Mantova (F. Smerieri); Servizio di Oncologia, Ospedale S. Paolo, Savona (F. Brema); Ospedale Sampierdarena, Genoa (E. Paganini); and U.O. Oncologia, Ospedale Civile, Asti, Italy (F. Testore).


   ACKNOWLEDGMENTS
 
Supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro.

We thank Elda Montanaro for data management.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Hryniuk W, Bush H: The importance of dose-intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 4: 1281-1288, 1984[Free Full Text]

2. Carmo-Pereira J, Costa FO, Henriques E, et al: A comparison of two doses of Adriamycin in the primary chemotherapy of disseminated breast carcinoma. Br J Cancer 56: 471-473, 1987[Medline]

3. Habeshaw T, Paul J, Jones R, et al: Epirubicin at two dose levels with prednisolone as treatment for advanced breast cancer: The results of a randomized trial. J Clin Oncol 9: 295-304, 1991[Abstract]

4. Tannock IF, Boyd NF, DeBoer G, et al: A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 6: 1377-1387, 1988[Abstract/Free Full Text]

5. Wood WC, Budman DR, Korzun AH, et al: Dose and dose-intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330: 1253-1259, 1994[Abstract/Free Full Text]

6. Fountzilas G, Athanassiades A, Giannakakis T, et al: A randomized 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]

7. Ardizzoni 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]

8. Venturini M, Del Mastro L, Testore F, et al: Erythropoietin and granulocyte-macrophage colony-stimulating factor allow acceleration and dose escalation of cyclophosphamide/epidoxorubicin/5-fluorouracil chemotherapy: A dose-finding study in patients with advanced breast cancer. Cancer Chemother Pharmacol 38: 487-494, 1996[Medline]

9. Del Mastro L, Garrone O, Sertoli MR, et al: A pilot study of accelerated cyclophosphamide, epirubicin and 5-fluorouracil plus granulocyte colony stimulating factor as adjuvant therapy in early breast cancer. Eur J Cancer 30A: 606-610, 1994

10. Hryniuk WM, Bush H: The importance of dose-intensity in the outcome of chemotherapy. Important Adv Oncol 121-141, 1988

11. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[Medline]

12. Schabel FM Jr, Griswold DP, Corbett TH, et al: Increasing the therapeutic response rate to anticancer drugs by applying the basic principles of pharmacology. Cancer 50: 1160-1167, 1980

13. Stadtmauer EA, O’Neill A, Goldstein LJ, et al: Conventional dose chemotherapy compared with high dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 342: 1069-1076, 2000[Abstract/Free Full Text]

14. Focan C, Andien JM, Closon MT, et al. Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: A prospective randomized trial. J Clin Oncol 11:1253-1263, 1993

15. French Epirubicin Study Group: A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol 9: 305-312, 1991[Abstract]

16. Brufman G, Colajori E, Ghilezan N, et al: Doubling epirubicin dose-intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rate. An international randomised phase III study in metastatic breast cancer. Ann Oncol 8: 155-162, 1997[Abstract/Free Full Text]

17. Marschner N, Krelenberg R, Souchon R, et al: Evaluation of the importance and relevance of dose intensity using epirubicin and cyclophosphamide in metastatic breast cancer: Interim analysis of a prospective randomized trial. Semin Oncol 21: 10-16, 1994 (suppl 1)

18. Bastholt L, Dalmark M, Gjedde B, et al: Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: A randomized study of epirubicin at four different dose levels performed by the Danish breast cancer cooperative group. J Clin Oncol 14: 1146-1155, 1996[Abstract/Free Full Text]

19. Venturini M, Bruzzi P, Del Mastro L, et al: Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line cyclophosphamide, epidoxorubicin, and fluorouracil in patients with metastatic breast cancer. J Clin Oncol 14: 764-773, 1996[Abstract/Free Full Text]

20. Coates A, Gebski V, Bishop JF, et al: Improving the quality of life during chemotherapy for advanced breast cancer: A comparison of intermittent and continuous treatment strategies. N Engl J Med 317: 1490-1495, 1987[Abstract]

21. Muss HB, Case DL, Richards F, et al: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer: The Piedmont Oncology Association. N Engl J Med 325: 1342-1348, 1991[Abstract]

22. Ejlertsen B, Pfeiffer P, Pedersen D, et al: Decreased efficacy of cyclophosphamide, epirubicin and 5-fluorouracil in metastatic breast cancer when reducing treatment duration from 18 to 6 months. Eur J Cancer 29A: 527-531, 1993

23. Gregory RK, Powles TJ, Chang JC, et al: A randomised trial of six versus twelve courses of chemotherapy in metastatic carcinoma of the breast. Eur J Cancer 33: 2194-2197, 1997

24. Falkson G, Gelman RS, Pandya KJ, et al: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol 16: 1669-1676, 1998[Abstract]

25. Savarese DMF, Hsieh C, Stewart MF: Clinical impact of chemotherapy dose escalation in patients with hematologic malignancies and solid tumors. J Clin Oncol 15: 2981-2995, 1997[Abstract]

26. Biganzoli L, Piccart MJ: 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]

Submitted May 25, 2000; accepted January 4, 2001.


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