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© 2000 American Society for Clinical Oncology Epirubicin-Based Chemotherapy in Metastatic Breast Cancer Patients: Role of Dose-Intensity and Duration of TreatmentFrom the French Epirubicin Study Group. Address reprint requests to Philippe Bastit, Département d’Oncologie, Centre Hospitalier de Bretagne Sud, BP 2233, 56322 Lorient Cedex, France.
PURPOSE: To determine whether the duration and the dose of epirubicin modify the long-term outcome of patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Four hundred seventeen anthracycline-naive MBC patients were randomized to receive one of the following regimens: arm A: 11 cycles of fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 (FEC 75) every 21 days; arm B: four cycles of FEC 100 (same regimen but with epirubicin 100 mg/m2) then eight cycles of FEC 50 (epirubicin 50 mg/m2); and arm C: four cycles of FEC 100 then restart the same regimen at disease progression in case of prior response or stabilization. RESULTS: Hematologic toxicity was similar. Nausea/vomiting and stomatitis were significantly less frequent in arm A as was left ventricular ejection fraction decrease in arm C (A = six patients, B = five patients, and C = one patient). Six patients died of infections (A = four patients and C = two patients). After four cycles, the objective response rate (ORR) was better with FEC 100 than with FEC 75 (49.2% v 40%, respectively; P = .07). The ORR was better with the longer regimens (arm A, 56.9%; B, 64%; and C, 47.6%; P = .06) and was 41% after second-line FEC 100. After a median follow-up of 41 months, the response duration and time to progression (TTP) were significantly better with arm B, the longer regimen (P = .012 and P < 10-3, respectively). The median survival times for arms A, B, and C were similar (17.9, 18.9, and 16.3 months, respectively; P = .49). CONCLUSION: In MBC, longer epirubicin-based regimens are better in terms of response duration and TTP. FEC 100 regimens improve the ORR. However, four initial cycles of FEC 100 and identical retreatment at disease progression yielded equivalent overall survival to longer regimens.
BREAST CANCER is the most frequent malignancy in women. Approximately 50% of patients develop metastatic disease, essentially involving the viscera, bones, and soft tissues. The primary treatment aim in metastatic breast cancer (MBC) is to relieve symptoms and, if possible, to prolonge life without excessive toxicity. Anthracycline-containing regimens are frequently used to treat disseminated breast cancer. In a retrospective study examining the natural history of MBC patients after complete responses (CRs),1 multivariate survival analysis identified anthracyclines as significant predictors of good long-term outcome. The French Epirubicin Study Group has conducted several phase III trials involving previously untreated MBC patients. The first compared a combination of cyclophosphamide, fluorouracil, and either doxorubicin (FAC) or epirubicin (FEC) at equimolar doses (50 mg/m2) in terms of efficacy and toxicity.2 The FEC regimen was as effective as FAC in terms of the response rate, time to progression (TTP), and overall survival (OS) and also had fewer hematologic, gastrointestinal, and cardiac adverse effects. We then conducted a second randomized phase III trial comparing epirubicin 75 mg/m2 alone, FEC 50 (epirubicin 50 mg/m2), and FEC 75 (epirubicin 75 mg/m2) as first-line chemotherapy for advanced breast cancer.3 The overall response rates of FEC 50 and FEC 75 were similar and better than with epirubicin alone (P = .04 and P = .0006, respectively). The CR rate was better with FEC 75 than with FEC 50 (P = .025) or epirubicin alone (P = .002). Epirubicin alone had better tolerability than the other two regimens (which had similar toxicity). TTP was not different among the three groups. Survival tended to be better with FEC 75 than with epirubicin alone (P = .06). On the basis of these preliminary results, the French Epirubicin Study Group started a third trial in 1987. In the present study, two questions are addressed. First is the issue of whether to continue chemotherapy in patients with metastatic disease who respond versus stopping then resuming the same treatment at progression after a previous objective response or stabilization. Second is the question of whether a higher versus lower dose of epirubicin (100 or 75 mg/m2) in the FEC regimen is more effective.
Patients Between April 1987 and February 1994, 417 women with MBC were enrolled onto the study. They were recruited from 21 institutions in France on the basis of the following eligibility criteria: (1) at least one measurable lesion; (2) no prior chemotherapy for metastatic disease; (3) adjuvant chemotherapy without anthracyclines was permitted; (4) age between 18 and 70 years; (5) World Health Organization (WHO) performance status (PS)  2; (6) normal hematologic, hepatic, and renal functions; and (7) no cardiac dysfunction (baseline left ventricular ejection fraction [LVEF]  50%). Written or oral informed consent was obtained from each patient in a standard procedure at each participating institution.
Chemotherapy Regimens The cumulative epirubicin dose was similar (800 mg/m2) in the three arms. This dose was considered as optimal and under the cumulative cardiotoxic dose. Preventive use of granulocyte colony-stimulating factors and antibiotics was prohibited. Antiemetic treatment was prescribed routinely before each cycle. A cooling cap could be used, according to usual practices of each institution. An absolute granulocyte count less than 2,000/µL and/or a platelet count less than 100,000/µL on day 21 led to a treatment interruption of at least 1 week. Treatment was stopped if hematologic recovery took more than 3 weeks. The epirubicin dose was reduced by 50% if serum bilirubin levels were 35 to 50 µmol/L, and treatment was stopped if bilirubin levels exceeded 50 µmol/L. Tolerability was evaluated before each cycle with an ECG and a total blood cell count on day 21, and nonhematologic toxicity was evaluated during the period between each cycle, according to WHO criteria. LVEF was assessed at the end of chemotherapy. Tumor extension was measured during the 3 weeks before inclusion, with chest radiography, computed tomography, or ultrasound examination of the liver and a bone scan. Tumor response was evaluated according to WHO criteria every two cycles and 4 weeks after the end of chemotherapy. Treatment was stopped in case of disease progression and/or unacceptable toxicity. Salvage therapies were left to the discretion of investigators. The patients underwent clinical, biochemical, and radiologic assessments every 6 months during follow-up. WHO PS was measured before chemotherapy and after each cycle. Quality of life was not measured in the trial.
Statistical Analysis The response duration was calculated in responders as the interval between the date of the first response and the date of the first relapse. The TTP was calculated for all assessable patients as the interval between the date of randomization and the date of first relapse. The response duration, TTP, and survival rates were computed according to the Kaplan-Meier method, and survival curves were compared with the log-rank test or the stratified log-rank test, as appropriate.6,7
Patient Characteristics Four hundred seventeen patients were enrolled in the study (139 in arm A, 145 in arm B, and 133 in arm C). Twenty-five patients (6%) were not treated (13 were lost to follow-up after randomization, six patients refused treatment, two patients had nonmetastatic disease, two patients had LVEF < 50%, and two patients received another treatment). Therefore, 392 patients (130 in arm A, 136 in arm B, and 126 in arm C) were assessable for compliance, safety, response, and TTP analyses. Patients with nonmetastatic disease (n = 2) and those who were lost to follow-up after randomization (n = 13) were excluded from the survival analysis. As a result, 402 patients (132 in arm A, 141 in arm B, and 129 in arm C) were assessable for survival. At inclusion, major protocol violations were similarly frequent in the three arms. The violations involved age greater than 70 years (n = 3), ECG not performed (n = 30), ECG abnormalities (n = 16), LVEF not performed (n = 66), LVEF less than 50% (n = 7), previous chemotherapy for MBC (n = 1), and no measurable lesions (n = 4). Treatments of the initial disease are listed in Table 1. Only 36 patients (8.6%) received adjuvant chemotherapy, which consisted of the CMF regimen in 83.3% of these cases. All baseline characteristics were well-balanced among the three treatment arms, except that relapses before inclusion were more frequent in arm B and time between first diagnosis of breast cancer and first metastases was longer in arm C (Table 2). At the cutoff date for analysis (October 1998), the median follow-up period was 41 months (range, 1 to 105 months).
Treatment Among the 392 patients receiving first-line chemotherapy, the mean number of cycles administered was 8.3 of an intended 11 cycles, 8.1 of an intended 12 cycles, and 3.7 of an intended four cycles in arms A, B, and C, respectively. In arm C, 61 patients received the second line of treatment, with a mean of 3.7 of an intended four cycles. The median cumulative epirubicin dose was 689 mg/m2 in arm A, 601 mg/m2 in arm B, and 399 mg/m2 and 799 mg/m2 in arm C for patients who received only the first line of treatment and those who received both lines, respectively. The number of patients who received the complete schedule was significantly different in the three treatment arms (58 [44.6%] in arm A, 39 [28.7%] in arm B, and 104 [82.5%] for the first line of arm C (P < 10-3). The mean epirubicin relative dose-intensity actually administered did not differ among the three treatment arms (86.1%, 89.1%, and 88.4% in arms A, B, and C, respectively).
Response Rate and Response Duration
At the end of first-line chemotherapy, the ORR was 56.9% (95% CI, 48.4% to 65.4%), 64.0% (95% CI, 55.9% to 72.1%), and 47.6% (95% CI, 38.9% to 56.3%) in arms A, B, and C, respectively (P = .06) (Table 3). There was no difference in ORR among the three arms according to the tumor sites (Table 3). When patients who received the long regimens (arms A and B) were compared with those who received the short regimen (arm C), the former yielded a significantly better ORR (60.5% v 47.6%, respectively; P = .016). Moreover, the long regimens yielded significantly better CR rates than arm C (18.8% v 7.9%, respectively; P = .005) (Table 3). The median response duration was 8.9 months (95% CI, 7.6 to 10.3), 8.5 months (95% CI, 5.9 to 11), and 6.3 months (95% CI, 4.8 to 7.7) in arms A, B, and C, respectively (P = .012), with no difference between the longer regimens (arms A and B) (P = .40) (Table 4). The response duration was significantly better with the longer regimens (arms A and B) compared with arm C (8.7 v 6.3 months, respectively; P = .004). The response duration was significantly longer in patients with CRs compared with partial responses (PRs) (9.6 v 7.5 months, respectively; P = .02).
Sixty-one patients in arm C received the second line of therapy. After the first four cycles, seven patients had CR, 38 had PR, and 16 had stable disease. After the second line of treatment, the ORR was 41% (95% CI, 28.7% to 53.3%), with 10 CR (16.4%) and 15 PR (24.6%).
TTP and OS
OS was evaluated in 402 patients. There were 360 deaths; 119 (90.2%) of 132 patients in arm A, 126 (89.4%) of 141 in arm B; and 115 (89.1%) of 129 in arm C. The median survival time was 17.9 months (95% CI, 14.6 to 21.2), 18.9 months (95% CI, 14.5 to 23.3), and 16.3 months (95% CI, 13.3 to 19.4) in arms A, B, and C, respectively (P = .49) (Table 4, Fig 2). In terms of survival, there was no difference between the long and short regimens (P = .47). Overall, patients who achieved CR, compared with those who did not, had a significantly longer TTP (11.8 v 8.0 months, respectively; P < 10-3) and OS time (24.8 v 16.6 months, respectively; P = .03).
Safety Toxicity was evaluated in 392 patients. Table 5 lists the adverse events. Hematologic toxicity did not differ among the three arms, with 21.1%, 18.8%, and 15.0% of patients developing grade 3/4 neutropenia in arms A, B, and C, respectively. The incidence of grade 3 infections was higher in arm C. Grade 4 infections occurred in seven patients (A, n = 4; B, n = 1; and C, n = 2) and were fatal in six cases (A, n = 4 and C, n = 2). Grade 3/4 nausea/vomiting was more frequent in patients receiving FEC 100 (arms B and C, P = .097), as was grade 3/4 stomatitis (P = .002).
Among the 392 treated patients, 374 (95.4%) had a pretreatment evaluation of the PS. After each chemotherapy cycle, change in PS was compared with the pretreatment evaluation. After the first four cycles, PS worsening was significantly higher in patients who received FEC 100 (arms B and C) compared with those who received FEC 75 (arm A) (25.4% v 14.4%, respectively; P = .023) (Table 6). In contrast, at the end of first-line chemotherapy, there was no difference in PS change between long (arms A and B) and short (arm C) treatments (Table 6). Finally, when patients who received continuous treatments (arms A and B) were compared with those who received interrupted treatment after response or stabilization (arm C), change in PS was similar (Table 6).
Nineteen cardiac abnormalities were diagnosed during chemotherapy (A, n = 9; B, n = 8; and C, n = 2). There were no cases of congestive heart failure (CHF) or cardiac deaths. Among these 19 patients, 12 had a decrease in LVEF, and one had lower-limb edema requiring digitalo-diuretic treatment. LVEF depression was more frequent with the longer regimens (six cases in arm A, five cases in arm B, and one case in arm C). Two cases of acute myeloblastic leukemia (AML) occurred. One woman in arm A developed AML M4 with inv16 8 months after randomization; this patient had received adjuvant treatment including cyclophosphamide, methotrexate, and fluorouracil (CMF), tamoxifen, and radiation therapy, then a cumulative epirubicin dose of 263 mg/m2. The patient died of bone and liver progression of her breast cancer. One woman in arm C developed AML M5 41 months after randomization; this patient had received adjuvant radiation therapy, then a cumulative epirubicin dose of 801 mg/m2 followed by tamoxifen. She died of AML 1 month after its diagnosis.
After four cycles, the overall response rate favored FEC 100 over FEC 75, although the CR rates were not significantly different. After treatment completion, ORR, median duration of response, and TTP were significantly improved by the longer regimens. However, in the short treatment arm (arm C), identical retreatment with four cycles of FEC 100 yielded an ORR of 41%. The treatment duration and dose-intensity of the FEC regimens studied here did not influence median OS. The concept of anthracycline dose-intensity has been widely studied in MBC. In our previous study, FEC 50 and FEC 75 had an equivalent ORR. FEC 75 gave a significantly higher CR rate compared with FEC 50 (6.6% v 15.4%, respectively; P = .025), but there was no difference in TTP or survival.3 In the present study, the ORR was better after FEC 100 than after FEC 75, but TTP and survival did not differ. These results are consistent with those of other studies of the dose-effect of epirubicin in MBC.8-11 Bastholt et al8 found an increase in the response rate and TTP when they increased the epirubicin monotherapy dose from 40 to 90 mg/m2. Marschner et al,9 in a randomized trial, compared 60 and 120 mg/m2 epirubicin combined with cyclophosphamide 600 mg/m2 and obtained a significantly better ORR with the higher compared with the lower dose (63% v 47%, respectively; P < .01), but no improvement in the TTP. Focan et al10 compared FEC 50 with FEC 100 (FEC 50 days 1 and 8) as first-line chemotherapy for patients with advanced breast cancer and found that FEC 100 gave a significantly higher ORR than FEC 50 (69% v 41%, respectively; P < 10-3), with longer responses (22 v 14 months, respectively; P < .01) and TTP (19 v 8 months, respectively; P < .02), but survival was not improved. Finally, Brufman et al11 compared FEC 100 with FEC 50 and obtained a significantly better ORR with FEC 100 (57% v 41%, respectively; P = .003) and a trend toward a higher CR rate (12% v 7%, respectively; P = .07), whereas TTP and survival were not improved. In contrast, doxorubicin dose increments have given controversial results. Carmo-Pereira et al12 found a correlation between the doxorubicin dose-intensity and ORR, whereas Hortobagyi et al13 compared FAC 50 and FAC 100 and found no difference in terms of ORR (78% v 78%), TTP (10 v 12 months, respectively), or survival (20 v 20 months). Overall, these studies show that dose intensification can improve ORR and, sometimes, TTP but not OS. The main issue is to evaluate properly the impact of subsequent treatments after disease progression. In regard to the other question addressed in this study, the duration of treatment and the cumulative dose, we found an advantage with the longer regimens (arms A and B) compared with the shorter regimen (arm C) in terms of ORR (60.5% v 47.6%, respectively; P = .016), response duration (8.7 v 6.3 months, respectively; P = .004), and TTP (9.6 v 6.2 months, respectively; P < 10-3). Other teams have investigated the impact of short, long, continuous, and intermittent treatments on the outcome of MBC.14-16 Gregory et al14 compared six and 12 courses of chemotherapy and found that the longer regimen did not increase the ORR but did significantly increase the response duration (P = .02) and TTP (P = .01). Muss et al15 randomized patients between observation and CMF maintenance after six cycles of FAC 50 and found that TTP was significantly improved by maintenance therapy (P < 10-3). Finally, Coates et al16 tested continuous versus intermittent FAC and CMF plus prednisone and found a significant better ORR (P = .02) and TTP (P < 10-3) with continuous chemotherapy. Thus, continuous and long regimens consistently improve TTP. In our study, compared with the shorter regimens, the longer regimens increased the ORR by 14.3% (46.2% v 60.5%, respectively) and the CR rate by 10.6% (8.2% v 18.8%, respectively). Patients with CRs had significantly better TTP and survival time. Greenberg et al17 found that 16.6% of patients achieved CRs after standard chemotherapy and that only 3.1% of them remained in complete remission for more than 5 years. Theses investigators concluded that standard chemotherapy regimens necessitate consolidation strategies.17 Falkson et al18 addressed the question of maintenance chemotherapy for patients with CR after induction therapy. Only TTP was improved by maintenance therapy (P < 10-3), survival being unaffected (P = .74). However, the maintenance chemotherapy (CMF-prednisone, tamoxifen, and fluoxymesterone) did not include an anthracycline, allowing the possibility that a well-tolerated anthracycline, such as epirubicin, might be effective in consolidating CR. After four cycles of FEC 100, we found that retreatment with exactly the same regimen yielded an ORR of 41% and a CR rate of 16.4%, which is noteworthy for a second-line treatment. Peters et al19 tested intensification with autologous stem-cell transplantation after CR and obtained a better TTP (P = .008); however, OS was significantly improved when intensification was started only after, compared with before, disease progression (3.2 v 1.9 years, respectively; P = .04). As in our study, none of the above authors found any increase in OS when treatment was prolonged. The only study that showed a survival benefit was that by Ejlertsen et al,20 comparing FEC for 6 and 18 months, but toxicity was excessive with the longer regimen. For patients with MBC, the tolerability of treatment and quality of life must remain uppermost because long-term outcome is hardly modified by the treatment modality. In our study, hematologic toxicity was not significantly influenced by the dose-intensity or treatment duration. Likewise, the incidence of severe infections was not influenced by the treatment duration (the higher incidence of grade 3 infections in arm C was probably a chance occurrence). Toxic deaths caused by grade 4 infections were not related to the dose or duration of treatment. Grade 3/4 nausea/vomiting and stomatitis were not influenced by the duration of treatment but were more frequent in patients receiving the higher dose regimens. In previous trials of epirubicin dose escalation, there was an increase in hematologic toxicity (mainly neutropenia), but the epirubicin dose was doubled; whereas, in our study, it was increased by only one third.9-11 The incidence of nausea/vomiting and infections were not increased in these trials, whereas stomatitis was more frequent, as in our study. Gregory et al14 observed no difference between six and 12 cycles of treatment in terms of the incidence of toxicities, but duration was increased in patients receiving 12 cycles. Muss et al15 observed a higher incidence of nausea/vomiting and stomatitis in the maintenance chemotherapy group; whereas, these effects were influenced not by the duration of treatment but by its intensity in our study. Finally, Coates et al16 found that continuous and intermittent regimens were similarly toxic, but quality of life was improved by continuous treatment. Quality of life was not assessed in our study. The analysis of PS showed similar results for short and long regimens, and PS was more frequently worsened with the higher doses and seemed to be correlated with the occurrence of nausea/vomiting and stomatitis. In regard to cardiac toxicity, decreases in LVEF were less frequent with the shorter regimen. Except in one case, these decreases occurred from the sixth cycle onwards and after a median cumulative epirubicin dose of 600 mg/m2 (range, 451 to 817 mg/m2). There were no cases of CHF and no cardiac deaths. These results are in keeping with those of previous trials. Only Brufman et al11 observed cases of CHF (one in each arm) and LVEF decreases (seven cases with FEC 100 and four cases with FEC 50). It is now well established that the risk of anthracycline-related cardiomyopathy correlates strongly with the cumulative dose.21,22 Moreover, epirubicin was found to be less toxic than doxorubicin, both clinically and histologically (endomyocardial biopsy).23 In our first study comparing the FAC and FEC regimens for metastatic breast cancer, we observed better cardiac tolerability with the latter; no cases of CHF occurred with FEC, whereas 3.2% of patients treated with FAC developed CHF.2 An increased incidence of AML after chemotherapy with alkylating agents and/or topoisomerase II inhibitors has been observed in a number of studies. Secondary AML in patients treated with alkylating agents is generally of the M1-M2 FAB subtypes, as opposed to M4-M5 in patients treated with topoisomerase II inhibitors. In the present study, two patients developed M4 and M5 AML probably because of anthracycline exposure. Although one of these patients died from AML, the risk of secondary leukemia is a secondary issue in patients with MBC. Our results suggest that epirubicin dose escalation improves the response rate, whereas longer treatment improves the duration of responses and the TTP. All three regimens tested here were well-tolerated. Importantly, OS was equivalent whatever the dose or duration of treatment. Moreover, our study was conducted between 1987 and 1994 and is now very mature. The study population is quite different from the current populations with MBC because more than 90% of patients were chemotherapy-naive and only 25% of them had received adjuvant hormone therapy. We conclude that the choice of chemotherapy for MBC should be based on tolerability, quality of life, prior treatments, and the patient’s own informed opinion.
Supported by grants from Pharmacia & Upjohn, Saint-Quentin en Yvelines, France. We are indebted to Jacques Bonneterre and Philippe Huc (Centre Oscar Lambret, Lille, France) for their collaboration.
In order of institutional accrual, the organizations and trialists are as follows: Centre Henri Becquerel, Rouen (P. Bastit, B. Chevallier  ); Institut Claudius Régaud, Toulouse (C. Chevreau, J. Mihura, H. Roché); Centre Antoine Lacassagne, Nice (M. Namer); Centre Eugène Marquis, Rennes (D. Gédouin, P. Kerbrat, T. Lesimple); Centre Georges-François Leclerc, Dijon (B. Coudert, P. Fargeot, C. de Gislain, F. Mayer); Centre Alexis Vautrin, Nancy (E. Luporsi, M. Rios, B. Weber); Centre Léon Bérard, Lyon (A. Brémond, Y. Devaux); Centre Hospitalier Jean Minjoz, Besançon (P. Montcuquet, S. Schraub); Institut Gustave Roussy, Villejuif (M. Hayat, E. Zambon); Centre Hospitalier André Boulloche, Montbéliard (A. Grandgirard, A. Monnier, X. Sun); Centre Hospitalier Universitaire, Dupuytren (P. Clavère, J.P. Ollivier, B. Rhein, B. Roullet); Centre Jean Perrin, Clermont-Ferrand (P. Chollet, I. Van Praagh); Institut Jean Godinot, Reims (A. Cattan, J.C. Eymard, C. Pourny); Centre Hospitalier Notre-Dame de Bon Secours, Metz (T. Facchini, S. Walter); Clinique le Méridien, Cannes (S. Dides, R. Ramos); Hôpitaux Universitaires, Strasbourg (N. Guiochet); Hôpital Nord, Saint-Etienne (P. Seffert, X. Perpoint); Centre Hospitalier Général, Epinal (J.F. Sztermer); Centre Hospitalier Général, Montélimar (J. Cretin); Centre Hospitalier de Bretagne Sud, Lorient (M.J. Goudier, F. Morice); and Centre René Gauducheau, Nantes, France (V. Delecroix, P. Fumoleau).
1. Tomiak E, Piccart M, Mignolet F, et al: Characterisation of complete responders to combination chemotherapy for advanced breast cancer: A retrospective EORTC Breast Group Study. Eur J Cancer 32: 1876-1887, 1996 2. French Epirubicin Study Group: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil and either doxorubicin or epirubicin. J Clin Oncol 6: 679-688, 1988[Abstract] 3. 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] 4. Snedecor GW, Cochran WG: Statistical Methods (ed 7). Ames, IA, Iowa State University Press, 1980 5. Duncan DB: P-tests and intervals for comparison suggested by the data. Biometrics 31: 339-359, 1980 6. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 7. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc A 135: 185-198, 1972
8.
Bastholt L, Dalmark M, Gjedde SB, 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 9. 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
10.
Focan C, Andrien 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
11.
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 rates: An international randomised phase III study in metastatic breast cancer. Ann Oncol 8: 155-162, 1997 12. 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] 13. Hortobagyi GN, Bodey GP, Buzdar AU, et al: Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: A prospective randomized study. J Clin Oncol 5: 354-364, 1987[Abstract] 14. 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 15. Muss HB, Case LD, Richards II F et al: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. N Engl J Med 325: 1342-1348, 1991[Abstract] 16. 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] 17. Greenberg PAC, Hortobagyi GN, Smith TL, et al: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14: 2197-2205, 1996[Abstract] 18. 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] 19. Peters WP, Jones RB, Vredenburgh J, et al: A large, prospective, randomized trial of high-dose combination alkylating agents (CBP) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM). Proc Am Soc Clin Oncol 15: 149a, 1996 (abstr) 20. Ejlertsen B, Pfeiffer P, Pedersen D, et al: Decreased efficacy of cyclophosphamide, epirubicin and 5-fluorouracil in metastatic breast cancer when reducing treatment from 18 to 6 months. J Cancer 29: 527-531, 1993 21. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91: 710-717, 1979 22. Praga C, Beretta G, Vigo PL, et al: Adriamycin cardiotoxicity: A survey of 1273 patients. Cancer Treat Rep 62: 931-934, 1979
23.
Torti FM, Bristow MM, Lum BL, et al: Cardiotoxicity of epirubicin and doxorubicin: Assessment by endomyocardial biopsy. Cancer Res 46: 3722-3727, 1986 Submitted October 4, 1999; accepted April 24, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to compare baseline categorical variables, the incidence of adverse events, and the response rates.
), 8.3 months for group B (•), and 6.2 months for group C (
) (P < 10-3).
