Lüftner D, Flath B, Akrivakis C, Mergenthaler H G, Ohnmacht U, Arning M, Possinger K
Medizin. Klinik II, Charité, Humboldt-Universität Berlin, Germany.
Invest New Drugs. 1998;16(2):141-6. doi: 10.1023/a:1006121608414.
Gemcitabine has shown single-agent activity in metastatic breast cancer. Epirubicin is also widely used for the adjuvant and treatment of metastatic breast cancer. The toxicity profiles and modes of action are different which provides a good rationale for studying both drugs in combination. In a phase I study gemcitabine at a fixed dose of 1000 mg/m2 on days 1, 8, 15 of a 28 day cycle was combined with escalated weekly doses of epirubicin starting with an initial dose of 10 mg/m2. Patients had stage IV metastatic disease without previous chemotherapy except as adjuvant treatment. Nineteen patients were included in the study which defined the maximum tolerated dose (MTD) of epirubicin at 20 mg/m2. Myelosuppression was the dose limiting toxicity with leucopenia WHO grade 3 and 4 in 40.0% and 20.0%, neutropenia WHO grade 3 and 4 without neutropenic fever in 20.0% and 40.0% and thrombocytopenia WHO grade 4 in 20.0%. At the epirubicin 15 mg/m2 dose level, leucopenia (11.1% WHO grade 3) and neutropenia (12.5 and 37.5% WHO grade 3 and 4) were reported. Symptomatic toxicity was generally mild: nausea/vomiting in about 20% of patients (WHO grade 3 or 4) on both 15 and 20 mg/m2 epirubicin dose levels. Alopecia WHO grade 3 and 4 was seen in 2 patients at MTD. Four of 19 evaluable patients had a partial response. We conclude that the combination of gemcitabine and epirubicin is well tolerated and has promising activity. A phase II study is underway with gemcitabine 1000 mg/m2 and epirubicin 15 mg/m2 on days 1, 8 and 15 of a 28 day cycle.
吉西他滨已在转移性乳腺癌中显示出单药活性。表柔比星也广泛用于转移性乳腺癌的辅助治疗和治疗。两种药物的毒性特征和作用方式不同，这为联合研究这两种药物提供了很好的理论依据。在一项I期研究中，在28天周期的第1、8、15天给予固定剂量1000mg/m²的吉西他滨，并与每周递增剂量的表柔比星联合使用，初始剂量为10mg/m²。患者患有IV期转移性疾病，除辅助治疗外未接受过先前的化疗。19名患者纳入该研究，该研究确定表柔比星的最大耐受剂量（MTD）为20mg/m²。骨髓抑制是剂量限制性毒性，40.0%的患者出现WHO 3级和4级白细胞减少，20.0%的患者出现WHO 3级和4级中性粒细胞减少且无中性粒细胞减少性发热，20.0%的患者出现WHO 4级血小板减少。在表柔比星15mg/m²剂量水平，报告有白细胞减少（11.1%为WHO 3级）和中性粒细胞减少（12.5%和37.5%为WHO 3级和4级）。有症状的毒性一般较轻：在表柔比星15mg/m²和20mg/m²剂量水平上，约20%的患者出现恶心/呕吐（WHO 3级或4级）。在MTD时，2名患者出现WHO 3级和4级脱发。19名可评估患者中有4名患者出现部分缓解。我们得出结论，吉西他滨和表柔比星联合耐受性良好且具有有前景的活性。一项II期研究正在进行，在28天周期的第1、8和15天给予吉西他滨1000mg/m²和表柔比星15mg/m²。
