Stiff P J, McKenzie R S, Alberts D S, Sosman J A, Dolan J R, Rad N, McCloskey T
Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
J Clin Oncol. 1994 Jan;12(1):176-83. doi: 10.1200/JCO.1994.12.1.176.
To develop an active high-dose chemotherapy regimen for the treatment of ovarian carcinoma. Due to the rapid development a drug resistance, conventional chemotherapy cures only 20% of patients with advanced disease. However, in vitro data demonstrate a steep dose-response curve to a variety of agents, most notably mitoxantrone.
A phase I study of escalated bolus mitoxantrone (10 to 25 mg/m2 x 3) and cyclophosphamide (30 to 50 mg/kg x 3) with a 5-day infusion of carboplatin (1,500 mg/m2) and an autologous bone marrow transplant (ABMT) was performed. Mitoxantrone pharmacokinetics were performed to document levels required to kill platinum-resistant ovarian carcinoma in vitro.
We treated 25 patients; the maximum-tolerated total doses (MTD) were 75 mg/m2 for mitoxantrone, 120 mg/kg for cyclophosphamide, and 1,500 mg/m2 for carboplatin. The dose-limiting toxicity was gastrointestinal, with severe diarrhea, ileus, and resulting sepsis. Transient partial deafness was seen in four patients, and acute renal failure (ARF) occurred in one patient at the first dose level, but was eliminated in subsequent patients with aggressive hydration. There were four early deaths due to ARF (n = 1), Legionella pneumonia (n = 1), and sepsis (n = 2). Peak mitoxantrone levels at the MTD were 623 to 2,810 ng/mL, and the area under the curve (AUC) values of the concentration versus time measurements were 560 to 1,700 ng/mL/h. Of 20 assessable patients, 65% responded, with a 45% complete remission (CR) rate. All six of the assessable patients with ovarian cancer responded: CR in five (83%) and partial remission (PR) in one (17%); the CRs have lasted 7 to 30+ months. Responses were also seen in testicular and breast carcinoma.
This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.
研发一种用于治疗卵巢癌的积极的高剂量化疗方案。由于耐药性迅速发展，传统化疗仅能治愈20%的晚期疾病患者。然而，体外数据显示多种药物存在陡峭的剂量反应曲线，最显著的是米托蒽醌。
进行了一项I期研究，采用递增剂量的大剂量米托蒽醌（10至25mg/m²×3）和环磷酰胺（30至50mg/kg×3），联合5天输注卡铂（1500mg/m²）及自体骨髓移植（ABMT）。进行米托蒽醌药代动力学研究以记录体外杀死铂耐药卵巢癌细胞所需的水平。
我们治疗了25例患者；米托蒽醌的最大耐受总剂量（MTD）为75mg/m²，环磷酰胺为120mg/kg，卡铂为1500mg/m²。剂量限制性毒性为胃肠道毒性，表现为严重腹泻、肠梗阻及由此导致的败血症。4例患者出现短暂性部分听力丧失；1例患者在首个剂量水平出现急性肾衰竭（ARF），但在随后积极补液的患者中未再出现。有4例早期死亡，原因分别为ARF（1例）、军团菌肺炎（1例）和败血症（2例）。MTD时米托蒽醌的峰值水平为623至2810ng/mL，浓度与时间测量的曲线下面积（AUC）值为560至1700ng/mL/h。在20例可评估患者中，65%有反应，完全缓解（CR）率为45%。所有6例可评估的卵巢癌患者均有反应：5例（83%）CR，1例（17%）部分缓解（PR）；CR持续了7至30多个月。在睾丸癌和乳腺癌患者中也观察到了反应。
该方案在MTD时耐受性良好，对于复发/难治性卵巢癌似乎很有前景，所达到的米托蒽醌水平在体外对铂耐药卵巢癌细胞具有活性。
