Pagani O, Sessa C, Martinelli G, Crivellari D, Buonadonna A, Thürlimann B, Hess D, Borner M, Bauer J, Zampino G, Zimatore M, Graffeo R, Riva A, Goldhirsch A
Istituto Oncologico della Svizzera Italiana, Ospedale S. Giovanni, Bellinzona, Switzerland.
Ann Oncol. 1999 May;10(5):539-45. doi: 10.1023/a:1026437731354.
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.
Forty-two patients who received neither palliative chemotherapy nor adjuvant anthracyclines (55% with dominant visceral disease and 66% with > or = 2 sites involved) with measurable/evaluable lesions, were treated at four dose levels starting from E 75 mg/m2 and D 75 mg/m2 to E 120 mg/m2 and D 85 mg/m2. 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.
Febrile neutropenia (two patients) and prolonged, severe neutropenia (absolute neutrophil count (ANC) < 0.1 x 10(9)/l for more than three days; one patient) defined the MTD of the combination without G-CSF support at E 90 mg/m2 and D 75 mg/m2. G-CSF was then routinely administered from the subsequent dose level of E 120 mg/m2 and D 75 mg/m2. The MTD with G-CSF support was established at E 120 mg/m2 and D 85 mg/m2 (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. Antitumor 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.
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.
蒽环类药物和紫杉类药物是治疗乳腺癌最有效的药物，目前正在对它们的最佳联合方案进行深入研究，研究对象包括晚期和早期乳腺癌患者。我们开展了一项关于表柔比星（E）和多西他赛（D）的剂量探索性研究，旨在确定晚期乳腺癌（ABC）患者在联合使用或不使用粒细胞集落刺激因子（G-CSF）支持的情况下，该联合方案的最大耐受剂量（MTD），并明确其毒性和活性特征。
42例未曾接受过姑息化疗或辅助蒽环类药物治疗的患者（55%存在主要内脏疾病，66%有≥2个部位受累），其病灶可测量/可评估，治疗起始剂量为E 75mg/m²和D 75mg/m²，共设四个剂量水平，最高至E 120mg/m²和D 85mg/m²。每三周给予最多四个周期的联合治疗，对有反应的患者允许额外给予四个周期的单药D治疗。在基线期及每两个疗程时通过超声心动图监测心功能。
在未使用G-CSF支持的情况下，发热性中性粒细胞减少（2例患者）和持续性严重中性粒细胞减少（绝对中性粒细胞计数（ANC）<0.1×10⁹/L超过三天；1例患者）确定了该联合方案的MTD为E 90mg/m²和D 75mg/m²。随后从E 120mg/m²和D 75mg/m²的后续剂量水平开始常规给予G-CSF。使用G-CSF支持时的MTD确定为E 120mg/m²和D 85mg/m²（1例患者出现中性粒细胞减少性发热且在第21天ANC未恢复，3例患者ANC低于0.1×10⁹/L超过三天，1例患者同时出现上述两种情况，1例患者出现4级血小板减少并在中性粒细胞减少期间因盲肠炎导致中毒性死亡）。未观察到严重的神经毒性、黏膜炎或液体潴留，也没有心脏毒性的临床迹象。抗肿瘤活性并非本研究的主要终点：40例可评估患者的总缓解率（ORR）为60%（95%置信区间：43%-75%，肝脏疾病患者为58%，软组织患者为84%），未观察到明显的剂量相关效应。在中位随访19个月（范围2-30+）后，9例未接受维持激素治疗患者的总疾病进展时间（TTP）为五个月。
对于预后较差的ABC患者，E和D联合方案被证明是一种有效且安全的治疗方案。G-CSF支持可使更高剂量得以安全使用，但剂量递增并未转化为更高的缓解率（RR）。在一项II期试验中使用了未使用生长因子支持时的MTD，该试验纳入了既往接受过含蒽环类药物辅助治疗方案的患者。
