Department of Medical Oncology, Albert Einstein Cancer Center, Bronx, NY, USA.
Cancer Chemother Pharmacol. 2011 Aug;68(2):457-63. doi: 10.1007/s00280-010-1510-y. Epub 2010 Nov 11.
Most ovarian cancers recur after first-line treatment. We studied the pharmacology, tolerability, and therapeutic potential of intraperitoneal (IP) topotecan, alone and with IP cisplatin.
Patients received IP topotecan 1.5 mg (flat dose) daily on days 1-5 (level 0) via IP catheter. Subsequent cohorts received IP cisplatin 50 mg/m(2) on day 1 added to topotecan 1.5 mg on days 1-3 (level I), topotecan 1.25 mg on days 1-3 (level II), or topotecan 1.25 mg on days 1-5 (level III). Plasma and IP concentrations of total and lactone (E-ring closed) topotecan were measured on days 1 and 2 in cycles 1 and 2.
Sixteen patients (15 tubo-ovarian, 1 gastric cancers) were entered at levels 0 (3), I (4), II (4), or III (5). Dose-limiting neutropenias occurred in seven patients at dose levels I and III; grade 3 thrombocytopenia occurred in two at level III. Other toxicities included grade 1 hives in two, serum creatinine elevations in two, and Staphylococcus epidermidis and chemical peritonitis (one each). A median progression-free survival of 13 months was recorded among ovarian cancer patients who had minimal (6) or no residuum (3) after platinum-based induction; 5 are alive at 4 years. Topotecan's AUC IP/AUC plasma ratios ranged from 13 to 119.
Topotecan IP for 3-5 days is tolerable; occasionally, myelosuppression is dose-limiting. Topotecan 1.25 mg (days 1-3) with IP cisplatin 50 mg/m(2) (day 1) is a regimen suitable for consolidation in phase 3 trials.
大多数卵巢癌在一线治疗后复发。我们研究了腹腔内（IP）拓扑替康的药理学、耐受性和治疗潜力，单独使用和与 IP 顺铂联合使用。
患者通过 IP 导管每天接受 IP 拓扑替康 1.5 毫克（平剂量），连续 5 天（第 0 级）。随后的队列接受 IP 顺铂 50mg/m²，第 1 天添加到拓扑替康 1.5mg/d，第 1-3 天（第 1 级），拓扑替康 1.25mg/d，第 1-3 天（第 2 级），或拓扑替康 1.25mg/d，第 1-5 天（第 3 级）。在第 1 和第 2 周期的第 1 和第 2 天测量总拓扑替康和内酯（E 环闭合）的血浆和 IP 浓度。
16 名患者（15 名输卵管卵巢癌，1 名胃癌）分别进入 0 级（3 名）、I 级（4 名）、II 级（4 名）或 III 级（5 名）。7 名患者在 I 级和 III 级出现剂量限制中性粒细胞减少症；3 级血小板减少症发生在 2 名患者中。其他毒性包括 2 例 1 级荨麻疹、2 例血清肌酐升高、1 例表皮葡萄球菌和化学性腹膜炎。铂类诱导后残留最小（6 例）或无残留（3 例）的卵巢癌患者中位无进展生存期为 13 个月；5 例患者在 4 年后仍存活。拓扑替康的 IP/AUC 血浆比范围为 13 至 119。
拓扑替康 IP 治疗 3-5 天是可耐受的；骨髓抑制偶尔是剂量限制因素。拓扑替康 1.25mg/d（第 1-3 天）联合 IP 顺铂 50mg/m²（第 1 天）是适合 3 期试验巩固治疗的方案。
