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Docetaxel in Combination with Epirubicin as Neoadjuvant Therapy in Operable Breast Cancer
research in
brief
Docetaxel in Combination with Epirubicin as Neoadjuvant Therapy in Operable Breast Cancer Rationale • Docetaxel and epirubicin are both efficacious in the treatment of metastatic breast cancer (MBC). Their different, nonoverlapping mechanisms of action have led to studies of the combination, which has been shown to be safe and effective in MBC.1-3 • The 5-fluorouracil/epirubicin/cyclophosphamide (FEC) regimen is effective as first-line treatment of advanced breast cancer.4 • The results of a randomized phase III trial to evaluate and compare the efficacy and safety of the docetaxel/epirubicin and FEC 100 regimens in the neoadjuvant setting, presented by Dr. Luporsi and colleagues at the 2000 American Society of Clinical Oncology Meeting held in New Orleans, LA, are discussed below.5
Study Design Eligibility Criteria Patients between 18 and 65 years of age with histologically proven, unilateral, noninflammatory, operable T2, T3 N0, T3 N1 M0, or T4 breast tumors
were eligible for this study. A WHO performance status ≤ 1 and normal hematologic, renal, liver, and cardiac function were required.
Treatment Schema
5-Fluorouracil, 500 mg/m2, I.V.
(n = 112) Maximum of 6 cycles
ED (n = 48)
Age Median
Efficacy FEC 100
Patients with operable T2, T3 N0, T3 N1 M0, or T4 breast tumor
FEC 100 (n = 48)
45 years 48 years One hundred twelve paRange 27-60 years 27-65 years tients were randomized to re0 ceive either 5-fluorouracil WHO PS 45 47 500 mg/m2, epirubicin 100 1 3 1 mg/m2, cyclophosphamide T1 Clinical Tumor 2 – 500 mg/m2, each given intraT Stage T2 34 27 venously (I.V.) every 3 weeks (No. of patients) T3 (FEC 100), or epirubicin 100 10 20 mg/m2 I.V. bolus and doceT4 2 1 taxel 75 mg/ m2 I.V., given Clinical Lymph N0 21 21 every 3 weeks (ED) (Figure Node Status 27 27 (No. of patients) N1 1). Six chemotherapy cycles were administered. A biopsy Abbreviations: ED = epirubicin/docetaxel; FEC = 5-fluorouracil/ was performed after cycle 2, epirubicin/cyclophosphamide; PS = performance status; and response was evaluated WHO = World Health Organization before cycle 4 and after cycle 6. Surgery was performed 3 weeks after chemotherapy was com- FEC 100 regimen was 45 years and for pleted and was followed by radiation those given ED it was 48 years. Most (96%) patients had a WHO performtherapy. ance status of 0. The majority (95%) of tumors were T2 or T3 and patients Results had clinical lymph node status of N0 Patient Characteristics or N1 (Table 1). The median age of patients on the
Figure 1: Treatment Schema
R A N D O M I Z E
Table 1: Patient Characteristics
Epirubicin, 100 mg/m2, I.V. Cyclophosphamide, 500 mg/m2, I.V. q. 3 weeks
Clinical response, evaluated in 38 patients on each regimen, was higher in the ED arm as compared to the FEC 100 arm. The overall response rates
Table 2: Clinical Response FEC 100 ED (n = 38) (n = 38)
(n = 55)
ED Epirubicin, 100 mg/m2, I.V. bolus Docetaxel, 75 mg/m2, I.V., 1 hour q. 3 weeks (n = 57)
Complete Response (CR)
26%
29%
Partial Response (PR)
29%
53%
Overall Response (CR + PR)
55%
82%
Abbreviations: ED = epirubicin/docetaxel; FEC = 5-fluorouracil/ epirubicin/cyclophosphamide
Clinical Breast Cancer July 2000 • 107
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sponse (53%) than those given FEC 100 (29%). Table 2 sumTOXICITY FEC 100 ED marizes the clinical response data. 56 % 72% Neutropenia (Grade 3/4) Forty patients on 1% 9% each regimen were Febrile Neutropenia evaluable for assess12% 6% Nausea/Vomiting ment of pathological (Grade 3/4) complete response Alopecia (Grade 3/4) 51% 55% (pCR). Despite a Congestive Heart Failure greater percentage of 0% 0% (Grade 3/4) T3/T4 tumors in the ED-treated patients Abbreviations: ED = epirubicin/docetaxel; FEC = 5-fluorouracil/ (44%) than in the epirubicin/cyclophosphamide FEC 100 – treated patients (25%), the were 55% for FEC 100 and 82% for pCR was similar in both treatment ED. Complete responses were similar in FEC 100 – and ED-treated pa- arms, 22.5% and 17.5% for FEC 100 tients; however, more patients who and ED, respectively. When axillary received ED achieved a partial re- lymph nodes were evaluated, pCR was 42.5% in the FEC 100 arm and 55% in the ED arm (Figure 2).
Table 3: Toxicities (% of Cycles)
Toxicity Both ED and FEC 100 were fairly well tolerated. The major hematologic toxicity was neutropenia, which was comparable in each arm (56% of cycles on the FEC 100 arm, 72% of cycles on the ED arm). Febrile neutropenia was more common in the ED arm (9% of cycles) than with FEC 100 (1% of cycles) but was manageable with granulocyte colony-stimulating factor (GCSF). Other common adverse events were nausea/vomiting and alopecia. Cardiac function was determined by left
108 • Clinical Breast Cancer July 2000
ventricular ejection fraction (LVEF) assessment. Clinical congestive heart failure was not observed with either treatment regimen (Table 3).
Conclusion Both ED and FEC 100 are safe and effective as treatment of breast cancer in the neoadjuvant setting. Pathological and clinical responses are encouraging with both regimens. ED had a higher clinical response as compared to FEC 100, despite there being a greater proportion of T3 and T4 tumors in patients on the ED arm. Hematologic toxicity observed was easily manageable with G-CSF. Congestive heart failure was not seen with either regimen. Epirubicin/docetaxel appears to be an active regimen in the neoadjuvant setting in breast cancer.
References
1. Viens P, Roche H, Kerbrat P, et al. Epirubicin in combination with docetaxel as first-line chemotherapy of metastatic breast cancer: results of a dose finding and efficacy study. Breast Cancer Res Treat 1997; 46:57 (Abstract #227). 2. Pagani O. Taxoids in combination with epirubicin: the search for improved outcomes in breast cancer. Semin Oncol 1998; 25 (suppl 12):23-26. 3. Nabholtz JM, Smylie M, Mackey J, et al. Docetaxel and anthracycline polychemotherapy in the treatment of breast cancer. Semin Oncol 1999; 26 (suppl 8):4752. 4. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. The French Epirubicin Study Group. J Clin Oncol 1991; 9:305-312. 5. Luporsi E, Vanlemmens L, Coudert B, et al. 6 cycles of FEC 100 vs 6 cycles of epirubicin-docetaxel (ED) as neoadjuvant chemotherapy in operable breast cancer patients (pts): preliminary results of a randomized phase II trial of GIREC S01. Proc Am Soc Clin Oncol 2000; 19:92a (Abstract #355).
brief
Docetaxel in Combination with Epirubicin as Neoadjuvant Therapy in Operable Breast Cancer Rationale • Docetaxel and epirubicin are both efficacious in the treatment of metastatic breast cancer (MBC). Their different, nonoverlapping mechanisms of action have led to studies of the combination, which has been shown to be safe and effective in MBC.1-3 • The 5-fluorouracil/epirubicin/cyclophosphamide (FEC) regimen is effective as first-line treatment of advanced breast cancer.4 • The results of a randomized phase III trial to evaluate and compare the efficacy and safety of the docetaxel/epirubicin and FEC 100 regimens in the neoadjuvant setting, presented by Dr. Luporsi and colleagues at the 2000 American Society of Clinical Oncology Meeting held in New Orleans, LA, are discussed below.5
Study Design Eligibility Criteria Patients between 18 and 65 years of age with histologically proven, unilateral, noninflammatory, operable T2, T3 N0, T3 N1 M0, or T4 breast tumors
were eligible for this study. A WHO performance status ≤ 1 and normal hematologic, renal, liver, and cardiac function were required.
Treatment Schema
5-Fluorouracil, 500 mg/m2, I.V.
(n = 112) Maximum of 6 cycles
ED (n = 48)
Age Median
Efficacy FEC 100
Patients with operable T2, T3 N0, T3 N1 M0, or T4 breast tumor
FEC 100 (n = 48)
45 years 48 years One hundred twelve paRange 27-60 years 27-65 years tients were randomized to re0 ceive either 5-fluorouracil WHO PS 45 47 500 mg/m2, epirubicin 100 1 3 1 mg/m2, cyclophosphamide T1 Clinical Tumor 2 – 500 mg/m2, each given intraT Stage T2 34 27 venously (I.V.) every 3 weeks (No. of patients) T3 (FEC 100), or epirubicin 100 10 20 mg/m2 I.V. bolus and doceT4 2 1 taxel 75 mg/ m2 I.V., given Clinical Lymph N0 21 21 every 3 weeks (ED) (Figure Node Status 27 27 (No. of patients) N1 1). Six chemotherapy cycles were administered. A biopsy Abbreviations: ED = epirubicin/docetaxel; FEC = 5-fluorouracil/ was performed after cycle 2, epirubicin/cyclophosphamide; PS = performance status; and response was evaluated WHO = World Health Organization before cycle 4 and after cycle 6. Surgery was performed 3 weeks after chemotherapy was com- FEC 100 regimen was 45 years and for pleted and was followed by radiation those given ED it was 48 years. Most (96%) patients had a WHO performtherapy. ance status of 0. The majority (95%) of tumors were T2 or T3 and patients Results had clinical lymph node status of N0 Patient Characteristics or N1 (Table 1). The median age of patients on the
Figure 1: Treatment Schema
R A N D O M I Z E
Table 1: Patient Characteristics
Epirubicin, 100 mg/m2, I.V. Cyclophosphamide, 500 mg/m2, I.V. q. 3 weeks
Clinical response, evaluated in 38 patients on each regimen, was higher in the ED arm as compared to the FEC 100 arm. The overall response rates
Table 2: Clinical Response FEC 100 ED (n = 38) (n = 38)
(n = 55)
ED Epirubicin, 100 mg/m2, I.V. bolus Docetaxel, 75 mg/m2, I.V., 1 hour q. 3 weeks (n = 57)
Complete Response (CR)
26%
29%
Partial Response (PR)
29%
53%
Overall Response (CR + PR)
55%
82%
Abbreviations: ED = epirubicin/docetaxel; FEC = 5-fluorouracil/ epirubicin/cyclophosphamide
Clinical Breast Cancer July 2000 • 107
research in
brief
sponse (53%) than those given FEC 100 (29%). Table 2 sumTOXICITY FEC 100 ED marizes the clinical response data. 56 % 72% Neutropenia (Grade 3/4) Forty patients on 1% 9% each regimen were Febrile Neutropenia evaluable for assess12% 6% Nausea/Vomiting ment of pathological (Grade 3/4) complete response Alopecia (Grade 3/4) 51% 55% (pCR). Despite a Congestive Heart Failure greater percentage of 0% 0% (Grade 3/4) T3/T4 tumors in the ED-treated patients Abbreviations: ED = epirubicin/docetaxel; FEC = 5-fluorouracil/ (44%) than in the epirubicin/cyclophosphamide FEC 100 – treated patients (25%), the were 55% for FEC 100 and 82% for pCR was similar in both treatment ED. Complete responses were similar in FEC 100 – and ED-treated pa- arms, 22.5% and 17.5% for FEC 100 tients; however, more patients who and ED, respectively. When axillary received ED achieved a partial re- lymph nodes were evaluated, pCR was 42.5% in the FEC 100 arm and 55% in the ED arm (Figure 2).
Table 3: Toxicities (% of Cycles)
Toxicity Both ED and FEC 100 were fairly well tolerated. The major hematologic toxicity was neutropenia, which was comparable in each arm (56% of cycles on the FEC 100 arm, 72% of cycles on the ED arm). Febrile neutropenia was more common in the ED arm (9% of cycles) than with FEC 100 (1% of cycles) but was manageable with granulocyte colony-stimulating factor (GCSF). Other common adverse events were nausea/vomiting and alopecia. Cardiac function was determined by left
108 • Clinical Breast Cancer July 2000
ventricular ejection fraction (LVEF) assessment. Clinical congestive heart failure was not observed with either treatment regimen (Table 3).
Conclusion Both ED and FEC 100 are safe and effective as treatment of breast cancer in the neoadjuvant setting. Pathological and clinical responses are encouraging with both regimens. ED had a higher clinical response as compared to FEC 100, despite there being a greater proportion of T3 and T4 tumors in patients on the ED arm. Hematologic toxicity observed was easily manageable with G-CSF. Congestive heart failure was not seen with either regimen. Epirubicin/docetaxel appears to be an active regimen in the neoadjuvant setting in breast cancer.
References
1. Viens P, Roche H, Kerbrat P, et al. Epirubicin in combination with docetaxel as first-line chemotherapy of metastatic breast cancer: results of a dose finding and efficacy study. Breast Cancer Res Treat 1997; 46:57 (Abstract #227). 2. Pagani O. Taxoids in combination with epirubicin: the search for improved outcomes in breast cancer. Semin Oncol 1998; 25 (suppl 12):23-26. 3. Nabholtz JM, Smylie M, Mackey J, et al. Docetaxel and anthracycline polychemotherapy in the treatment of breast cancer. Semin Oncol 1999; 26 (suppl 8):4752. 4. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. The French Epirubicin Study Group. J Clin Oncol 1991; 9:305-312. 5. Luporsi E, Vanlemmens L, Coudert B, et al. 6 cycles of FEC 100 vs 6 cycles of epirubicin-docetaxel (ED) as neoadjuvant chemotherapy in operable breast cancer patients (pts): preliminary results of a randomized phase II trial of GIREC S01. Proc Am Soc Clin Oncol 2000; 19:92a (Abstract #355).