Lyass O, Hubert A, Gabizon A A
Department of Oncology, Hadassah-Hebrew University Medical Center, Kiryat Hadassah, Jerusalem 91120, Israel.
Clin Cancer Res. 2001 Oct;7(10):3040-6.
Our first objective was to evaluate the feasibility of administering a combination of Doxil, a pegylated liposome formulation of doxorubicin, and cisplatin and to determine the maximum tolerated dose of the combination. A secondary objective was to examine Doxil peak and 7-day postinjection plasma levels at the various dose levels tested.
Patients with advanced solid tumors were treated every 4 weeks with cisplatin on day 1 and Doxil on day 2. In the first three dose levels, the dose of Doxil was fixed at 40 mg/m(2), whereas the dose of cisplatin was escalated from 40 to 50 and 60 mg/m(2). At the fourth and fifth dose levels, the dose of cisplatin was fixed at 60 mg/m(2), whereas the dose of Doxil was escalated to 50 and to 60 mg/m(2). Plasma Doxil (doxorubicin-equivalent) levels were measured by a high-performance liquid chromatography assay with fluorescence detection at 1 h and 7 days after infusion of Doxil.
Twenty-six patients entered the study. Twenty-four patients completed a minimum of 2 courses and were fully assessable for toxicity and efficacy. Eighteen patients had received prior chemotherapy, 11 of them with anthracycline-containing regimens. A total of 177 courses were administered within the study. In 12 patients, cisplatin was discontinued after 1 to 13 courses, and Doxil was continued alone for 1-22 courses. All other patients received both drugs until discontinuation of therapy. The dose-limiting toxicities were neutropenia and mucositis. Grade 4 neutropenia was seen in 3 patients (one with neutropenic fever) at dose levels 4 and 5. Grade 3 mucositis was observed in 4 patients at dose levels 3, 4, and 5. In contrast, the most severe palmar-plantar erythrodysesthesia manifestation was grade 2 seen in 1 patient only. Tumor responses included seven partial responses, of which three were in ovarian cancer patients. In four of seven responders, the time to disease progression exceeded 1 year. Doxil 1-h (C(max) equivalent) levels were assessed in 20 patients. The mean Doxil C(max) (mg/l plasma) increased gradually with dose escalation from 14.7 +/- 1.9 for 40 mg/m(2), to 17.3 +/- 3.0 for 50 mg/m(2), and 23.3 +/- 5.5 for 60 mg/m(2). The 60 mg/m(2) C(max) was similar to data obtained in parallel clinical studies at our institution with single-agent Doxil at 60 mg/m(2). However, the 7-day Doxil postinfusion levels were significantly lower in patients receiving the Doxil-cisplatin combination than in those receiving single-agent Doxil.
Doxil can be administered at full maximum tolerated dose (50 mg/m(2) every 4 weeks) in combination with 60 mg/m(2) cisplatin, with no evidence of major overlapping toxicities. Palmar-plantar erythrodysesthesia incidence and severity appears to be diminished, in comparison with data available for single-agent Doxil. Plasma concentration data point to an accelerated clearance of Doxil when administered after cisplatin.
我们的首要目标是评估阿霉素聚乙二醇脂质体制剂（多柔比星脂质体注射液，Doxil）与顺铂联合给药的可行性，并确定该联合用药的最大耐受剂量。次要目标是检测在不同测试剂量水平下Doxil的峰值及注射后7天的血浆水平。
晚期实体瘤患者每4周接受一次治疗，第1天给予顺铂，第2天给予Doxil。在前三个剂量水平中，Doxil的剂量固定为40mg/m²，而顺铂的剂量从40mg/m²逐步增至50mg/m²和60mg/m²。在第四和第五个剂量水平，顺铂的剂量固定为60mg/m²，而Doxil的剂量增至50mg/m²和60mg/m²。通过高效液相色谱荧光检测法在输注Doxil后1小时和7天测量血浆中Doxil（多柔比星等效物）水平。
26例患者进入本研究。24例患者至少完成了2个疗程，可全面评估毒性和疗效。18例患者曾接受过化疗，其中11例接受过含蒽环类药物的方案。本研究共给药177个疗程。12例患者在接受1至13个疗程后停用顺铂，单独继续使用Doxil 1至22个疗程。所有其他患者在治疗终止前均接受两种药物治疗。剂量限制性毒性为中性粒细胞减少和粘膜炎。在第4和第5剂量水平，3例患者（1例伴有中性粒细胞减少性发热）出现4级中性粒细胞减少。在第3、4和5剂量水平，4例患者出现3级粘膜炎。相比之下，仅1例患者出现2级最严重的手足红斑性感觉异常表现。肿瘤反应包括7例部分缓解，其中3例为卵巢癌患者。7例缓解患者中有4例疾病进展时间超过1年。对20例患者评估了Doxil 1小时（Cmax等效物）水平。随着剂量增加，Doxil的平均Cmax（mg/L血浆）逐渐升高，从40mg/m²时的14.7±1.9升高至50mg/m²时的17.3±3.0，以及60mg/m²时的23.3±5.5。60mg/m²的Cmax与我们机构在平行临床研究中使用60mg/m²单药Doxil获得的数据相似。然而，接受Doxil - 顺铂联合用药的患者输注Doxil后7天的水平显著低于接受单药Doxil的患者。
Doxil可与60mg/m²顺铂联合，以完全最大耐受剂量（每4周50mg/m²）给药，无主要重叠毒性的证据。与单药Doxil的现有数据相比，手足红斑性感觉异常的发生率和严重程度似乎有所降低。血浆浓度数据表明，顺铂给药后Doxil的清除加快。
