Division of Gynecologic Oncology, Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania, USA
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
Int J Gynecol Cancer. 2019 Jan;29(1):147-152. doi: 10.1136/ijgc-2018-000055.
Intraperitoneal (IP) chemotherapy improves survival in ovarian cancer but its use has been limited by toxicity with cisplatin-based regimens. The primary objective of this study was to define the maximum tolerated dose and dose-limiting toxicity of intravenous (IV) oxaliplatin and IP docetaxel in women with recurrent ovarian, fallopian tube or peritoneal cancer. Secondary objectives were response rate, time to progression, symptom interference with quality of life, and pharmacokinetics.
Patients received a constant dose of oxaliplatin 75 mg/m IV on day 1 and docetaxel escalating from 50 mg/m IP on day 2 every 3 weeks using a 3 + 3 design. Treatment continued until disease progression, remission, or intolerable toxicity occurred. Plasma and IP samples were taken to determine drug concentrations. Patients completed the MD Anderson Symptom Inventory weekly.
Twelve patients were included. The median number of cycles was 4 (range 2-6) with a median time to progression of 4.5 months. Among eight patients with measurable disease, the best responses were partial response in two patients, stable disease in five, and progressive disease in one. A total of 14 grade 3-4 toxicities were noted, most commonly hematologic. Four patients, all dose level 3, had six dose-limiting toxicities: two with prolonged neutropenia, one with infection, one with hyponatremia, and two with abdominal pain. Dose level 3 was therefore considered intolerable. The mean±SD ratio of docetaxel area under the curve (AUC) in IP fluid to AUC in plasma was 229±111. Symptom interference with life activities steadily decreased from cycle 1 to 5.
Oxaliplatin 75 mg/m IV on day 1 and docetaxel 75 mg/m IP on day 2 was the maximum tolerated dose. Most patients had partial response or stable disease, even in a heavily pre-treated population. At this dose level, patient-reported outcomes demonstrate temporary but tolerable decrements in quality of life.
腹腔内（IP）化疗可提高卵巢癌患者的生存率，但由于顺铂类方案的毒性，其应用受到限制。本研究的主要目的是确定复发性卵巢癌、输卵管癌或腹膜癌患者静脉注射（IV）奥沙利铂和 IP 多西他赛的最大耐受剂量和剂量限制毒性。次要目标是反应率、无进展生存期、对生活质量的症状干扰以及药代动力学。
患者在第 1 天接受 75mg/m2 的固定剂量 IV 奥沙利铂，第 2 天接受 50mg/m2 的递增剂量 IP 多西他赛，每 3 周 1 次，采用 3+3 设计。治疗持续到疾病进展、缓解或不可耐受的毒性发生为止。采集血浆和腹腔内样本以确定药物浓度。患者每周完成 MD 安德森症状量表。
共纳入 12 例患者。中位周期数为 4 个（范围 2-6 个），中位无进展生存期为 4.5 个月。在 8 例可测量疾病的患者中，最佳反应为 2 例部分缓解，5 例疾病稳定，1 例疾病进展。共有 14 例 3-4 级毒性，最常见的是血液学毒性。4 例患者（均为剂量水平 3）出现 6 例剂量限制毒性：2 例中性粒细胞减少延长，1 例感染，1 例低钠血症，2 例腹痛。因此，剂量水平 3 被认为是不可耐受的。腹腔内多西他赛 AUC 与血浆 AUC 的平均比值（SD）为 229±111。从第 1 个周期到第 5 个周期，生活活动症状干扰逐渐下降。
第 1 天静脉注射奥沙利铂 75mg/m2，第 2 天腹腔内注射多西他赛 75mg/m2 是最大耐受剂量。大多数患者有部分缓解或疾病稳定，即使在预处理较多的患者中也是如此。在这个剂量水平，患者报告的结果显示生活质量暂时但可耐受的下降。
