Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer
Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer
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DOI：
10.1023/a:1026437731354
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发表时间：
1999-05-01
影响因子：
50.5
通讯作者：
Goldhirsch, A
中科院分区：
文献类型：
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作者：
Pagani, O;Sessa, C;Goldhirsch, A
背景资料：蒽环类和紫杉烷类是最有效的抗乳腺癌药物，在晚期和早期疾病环境中，对它们的最佳组合的研究正在进行深入调查。在晚期乳腺癌（ABC）中进行表阿霉素（E）和多西他赛（D）的剂量探索研究，以确定联合使用和不使用粒细胞集落刺激因子（G-CSF）支持的最大耐受剂量（MTD），并验证其毒性和活性特征。42例既未接受姑息化疗也未接受辅助蒽环类药物的患者（55%为显性内脏疾病，66%累及≥ 2个部位）有可测量/可评价病变，从E75 mg/m2和D 75 mg/m2到E120 mg/m2和D85 mg/m2共4个剂量水平。每三周给予最多四个周期的组合，并且在应答患者中允许另外四个周期的单一药物D。结果：发热性中性粒细胞减少症（2例）和长期严重中性粒细胞减少症（1例患者中性粒细胞绝对计数（ANC）< 0.1 × 109/l，持续3天以上）定义了联合用药的MTD，不含G-CSF支持，E90 mg/m2，D 75 mg/m2。随后常规给予G-CSF，剂量水平为E 120 mg/m2和D 75 mg/m2。G-CSF支持的MTD确定为E 120 mg/m2和D 85 mg/m2（1例患者在第21天出现血小板减少性发热伴ANC恢复失败，3例患者ANC低于0.1 × 10（9）/l超过3天，1例患者同时出现两种情况，1例患者在血小板减少性发热时出现4级血小板减少症和盲肠炎中毒性死亡）。未观察到重度神经毒性、粘膜炎或液体潴留，也未观察到心脏毒性的临床体征。抗肿瘤活性不是本研究的主要终点：40例可评价患者的总体缓解率（ORR）为60%（95%置信区间：43%-75%，肝病为58%，软组织为84%），无明显剂量相关效应。经过19个月的中位随访（范围2-30+），在没有维持激素治疗的9例患者的总体进展时间（TTP）为5个月。结论：E和D的组合被证明是一种有效和安全的方案，在预后不良的ABC患者。G-CSF支持允许安全地输送更高剂量，但剂量递增并不能转化为改善的缓解率（RR）。在一项II期试验中使用了无生长因子支持的MTD，该试验还包括既往接受过含蒽环类药物辅助治疗方案的患者。
Background: Anthracyclines and taxanes are the most active drugs against breast cancer and the search after their optimal combination is under intensive investigation in both the advanced and early disease settings. A dose-finding study of epidoxorubicin (E) and docetaxel (D) was conducted in advanced breast cancer (ABC) to define the maximum tolerated dose (MTD) of the combination with and without granulocyte colony-stimulating factor (G-CSF) support and to characterise its toxicity and activity profile.Patients and methods: Forty-two patients who received neither palliative chemotherapy nor adjuvant anthracyclines (55% with dominant visceral disease and 66% with greater than or equal to 2 sites involved) with measurable/evaluable lesions, were treated at four dose levels starting from E 75 mg/m(2) and D 75 mg/m(2) to E 120 mg/m(2) and D 85 mg/m(2). A maximum of four cycles of the combination was given every three weeks and four additional cycles of single agent D were allowed in responding patients. Cardiac function was monitored at baseline and at every second course by echocardiography.Results: Febrile neutropenia (two patients) and prolonged, severe neutropenia (absolute neutrophil count (ANC) < 0.1 x 109/l for more than three days; one patient) defined the MTD of the combination without G-CSF support at E 90 mg/m(2) and D 75 mg/m(2). G-CSF was then routinely administered from the subsequent dose level of E 120 mg/m(2) and D 75 mg/m(2). The MTD with G-CSF support was established at E 120 mg/m(2) and D 85 mg/m(2) (one patient with neutropenic fever together with failure of ANC recovery at day 21, three patients with ANC less than 0.1 x 10(9)/l for more than three days, one patient with both and one patient with grade 4 thrombocytopenia and toxic death from typhlitis while neutropenic). No severe neurotoxicity, mucositis, or fluid retention were observed and there were no clinical signs of cardiotoxicity. Antitumour activity was not a primary endpoint of the study: the overall response rate (ORR) in 40 evaluable patients was 60% (95% confidence interval: 43%-75%, 58% in liver disease, 84% in soft tissue) with no apparent dose-related effect. After a median follow-up of 19 months (range 2-30+), the overall time to progression (TTP) in nine patients without maintenance hormonal therapy was five months.Conclusions: The combination of E and D proved to be an effective and safe regimen in poor- prognosis patients with ABC. G-CSF support allowed higher doses to be delivered safely but dose escalation did not translate into improved response rates (RR). The MTD without growth factors support was used, in a phase II trial, which also included patients with previous anthracycline-containing adjuvant regimens.