Heidenreich Axel, Sommer Frank, Ohlmann Carsten H, Schrader Andres J, Olbert Peter, Goecke Joachim, Engelmann Udo H
Department of Urology, University of Cologne, Germany.
Cancer. 2004 Sep 1;101(5):948-56. doi: 10.1002/cncr.20455.
Liposomal encapsulation of doxorubicin has been shown to reduce nonspecific delivery of this agent to normal tissue and to increase specific delivery to malignant cells. On the basis of doxorubicin's demonstrated clinical efficacy against hormone-refractory prostate carcinoma (HRPCA), the authors conducted a prospective, randomized Phase II clinical trial to evaluate the feasibility, toxicity, and therapeutic efficacy associated with the pegylated form of this agent.
Forty-eight patients with symptomatic HRPCA were randomized to receive pegylated liposomal doxorubicin at either 25 mg/m2 every 2 weeks for 12 cycles (Group A) or 50 mg/m2 every 4 weeks for 6 cycles (Group B). Thirty-eight of these 48 patients (79%) presented with severe pain (corresponding to a pain score of 7.5 on a visual analog scale [VAS] ranging from 0 to 10) due to osseous metastases. Therapeutic efficacy was assessed by serial evaluation of serum prostate-specific antigen (PSA) concentrations and by serial measurement of pain levels (using a VAS ranging from 0 to 10). Toxicity data were obtained using the National Cancer Institute of Canada/Cancer and Leukemia Group B criteria and the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.
The median patient age was 68.9 years (range, 58-79 years), and the mean follow-up duration was 42 months. The mean pretreatment PSA level was 660.4 ng/mL (mean, 8-6340 ng/mL); an objective decrease in PSA levels (i.e., a decrease of > 50%) was observed in 8 of 31 patients (25.8%) in Group B, whereas no other patient in either group experienced such a decrease. The mean time to disease progression was 6.5 months, and the mean survival duration was 13.4 months. Patients in Group B had a significantly higher rate of response with respect to pain (52.6% vs. 28.6%; P = 0.04), and the mean 1-year survival rate also was significantly higher in Group B (42% vs. 15%; P = 0.02). Severe side effects were observed, with 24 patients (50%) experiencing World Health Organization Grade 3/4 toxicity. Toxicity types differed significantly between Group A and Group B; palmar-plantar erythrodysesthesia developed in 60% of patients in the former group (P < 0.0005), whereas tachycardia was more common in the latter group (39% of patients; P < 0.0005). No dose-limiting cardiotoxicities or hematotoxicities were documented.
Pegylated liposomal doxorubicin yielded a noteworthy objective palliative response rate and a mean survival of 13 months for patients with symptomatic HRPCA. The dosage tested in the current study should be used in future Phase II and Phase III trials of pegylated liposomal doxorubicin-containing combination regimens for patients with HRPCA.
已证明阿霉素脂质体包封可减少该药物向正常组织的非特异性递送，并增加向恶性细胞的特异性递送。基于阿霉素对激素难治性前列腺癌（HRPCA）已证实的临床疗效，作者开展了一项前瞻性、随机II期临床试验，以评估该药物聚乙二醇化形式的可行性、毒性和治疗效果。
48例有症状的HRPCA患者被随机分组，分别接受每2周25mg/m²共12个周期的聚乙二醇化脂质体阿霉素治疗（A组）或每4周50mg/m²共6个周期的治疗（B组）。这48例患者中有38例（79%）因骨转移出现严重疼痛（对应视觉模拟评分[VAS]为7.5，VAS范围为0至10）。通过连续评估血清前列腺特异性抗原（PSA）浓度和连续测量疼痛水平（使用范围为0至10的VAS）来评估治疗效果。使用加拿大国家癌症研究所/癌症与白血病B组标准以及欧洲癌症研究与治疗组织生活质量问卷30项版获取毒性数据。
患者中位年龄为68.9岁（范围58 - 79岁），平均随访时间为42个月。治疗前PSA平均水平为660.4ng/mL（范围8 - 6340ng/mL）；B组31例患者中有8例（25.8%）观察到PSA水平客观下降（即下降>50%），而两组中其他患者均未出现这种下降。疾病进展的平均时间为6.5个月，平均生存时间为13.4个月。B组患者在疼痛方面的缓解率显著更高（52.6%对28.6%；P = 0.04），B组的平均1年生存率也显著更高（42%对15%；P = 0.02）。观察到严重副作用，24例患者（50%）出现世界卫生组织3/4级毒性。A组和B组的毒性类型有显著差异；前一组60%的患者出现手足红斑性感觉异常（P < 0.0005），而后一组心动过速更常见（39%的患者；P < 0.0005）。未记录到剂量限制性心脏毒性或血液毒性。
聚乙二醇化脂质体阿霉素对有症状的HRPCA患者产生了值得注意的客观姑息缓解率和13个月的平均生存期。当前研究中测试的剂量应在未来针对HRPCA患者的含聚乙二醇化脂质体阿霉素联合方案的II期和III期试验中使用。
