Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
Cancer Chemother Pharmacol. 2010 Oct;66(5):927-33. doi: 10.1007/s00280-010-1242-z. Epub 2010 Jan 28.
This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid.
Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m(2)/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks.
Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60-90%) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m(2)/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs.
The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m(2)/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.
本研究旨在确定固定剂量他莫昔芬和卡铂联合递增剂量拓扑替康的剂量限制性毒性（DLT）和最大耐受剂量，并确定拓扑替康在血浆和脑脊液中的药代动力学。
他莫昔芬 100 mg 口服，bid；拓扑替康 0.25、0.5、0.75 或 1.0 mg/m(2)/d IV，72 h 持续输注，于第 1-3 天给药，随后于第 3 天给予卡铂 AUC = 3 IV。每 4 周重复一个周期。
17 例患者接受了 39 个周期的治疗：中位 2 个（范围 1-5）。肿瘤包括胶质母细胞瘤（6）、间变性星形细胞瘤（2）、转移性非小细胞肺癌（3）、小细胞肺癌（2），还有 1 例为髓母细胞瘤、室管膜瘤和转移性乳腺癌或结肠癌。中位卡氏功能状态评分为 70%（范围 60-90%），年龄为 52 岁（范围 24-75 岁）。11 例为女性，6 例为男性。毒性包括血小板减少症（2）、无发热性中性粒细胞减少症持续 6 天（1）、深静脉血栓形成（2）和呕吐（1）。在输注结束前，测量了血浆和脑脊液（CSF）中拓扑替康的水平，包括总浓度和内酯浓度。在 1.0 mg/m(2)/d 剂量下，CSF/血浆比中位数为 19.4%（范围 15.1-59.1%）。在两名出现 DLT 的患者中，总血浆拓扑替康浓度分别为 4.63 和 5.87 ng/ml，在同一剂量水平下，无 DLT 的 3 名患者的平均总血浆拓扑替康浓度为 3.4 ng/ml（范围 3.02-3.83）。血浆内酯浓度为总浓度的 33%；CSF 穿透率为总血浆浓度的 20%。8 例高级别胶质瘤患者中有 4 例病情稳定（中位数：3 个周期（范围 2-5））。2 例患者有轻微反应。1 例转移性非小细胞肺癌和 1 例小细胞肺癌患者有客观缓解。
推荐的 II 期剂量为：他莫昔芬 100 mg 口服，bid；拓扑替康 0.75 mg/m(2)/d IV 持续输注 72 h，随后于第 3 天给予卡铂 AUC = 3 IV。可在 CSF 中检测到可测量的拓扑替康水平，包括总浓度和内酯浓度。
