Bookman M A, McGuire W P, Kilpatrick D, Keenan E, Hogan W M, Johnson S W, O'Dwyer P, Rowinsky E, Gallion H H, Ozols R F
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
J Clin Oncol. 1996 Jun;14(6):1895-902. doi: 10.1200/JCO.1996.14.6.1895.
To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma.
Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity.
Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months.
Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.
制定一种可耐受的、高剂量强度的卡铂和紫杉醇方案用于治疗原发性上皮性卵巢癌。
患者接受初始手术评估及肿瘤减瘤术。Ⅲ/Ⅳ期疾病患者按计划每21天进行一个周期，共接受六个周期的化疗。卡铂剂量根据浓度随时间变化的曲线下面积（AUC，mg·mL⁻¹·min）计算得出，并逐步增加剂量以确定最大耐受剂量（MTD）。紫杉醇剂量也作为3小时、24小时或96小时输注进行逐步增加。在选定的剂量水平需要使用粒细胞集落刺激因子（G-CSF），或可根据血液学毒性添加。
39例患者入组并可评估毒性和反应。剂量限制性毒性（DLT）为血液学毒性，主要是中性粒细胞减少。以3小时或24小时输注紫杉醇的所有周期中，不到2%与4级血小板减少或发热性中性粒细胞减少相关。卡铂的MTD为AUC 7.5（相当于中位剂量471mg/m²）。在未初始使用G-CSF的情况下，紫杉醇的MTD为24小时输注135mg/m²和3小时输注175mg/m²。以120mg/m²剂量进行96小时的紫杉醇输注与过度的单周期和累积骨髓抑制相关，未进一步评估。测量的卡铂AUC与计算的AUC吻合良好。24例可测量疾病患者的总体完全缓解（n = 16）和部分缓解（n = 2）率为75%，无进展生存期的中位数为15个月。
使用基于预计肾脏清除率的剂量公式，卡铂可与紫杉醇安全联合使用。推荐的门诊方案是卡铂AUC 7.5和紫杉醇175mg/m²在3小时内输注，不初始使用G-CSF。该治疗安全地实现了比基于体表面积的传统给药更高的卡铂剂量强度。
