Chang A Y, Kim K, Glick J, Anderson T, Karp D, Johnson D
Department of Medicine, University of Rochester Cancer Center, N.Y. 14607.
J Natl Cancer Inst. 1993 Mar 3;85(5):388-94. doi: 10.1093/jnci/85.5.388.
Patients with metastatic (stage IV) non-small-cell lung cancer usually have a poor prognosis and disease refractory to chemotherapy. Three new agents--taxol, merbarone, and piroxantrone--have shown promising antitumor treatment in vitro and in animals. Taxol is an antimicrotubular agent that interferes with mitosis during cell division. Merbarone, a conjugate of thiobarbituric acid and aniline, is a topoisomerase II inhibitor, which thus inhibits DNA synthesis and tumor growth. Piroxantrone, an anthracenedione derivative, is a DNA intercalating agent that has shown potent antitumor activity in animal studies.
Our randomized phase II study was designed to evaluate the efficacy and toxicity of these agents in the treatment of stage IV metastatic non-small-cell lung cancer.
Eligible patients (119) were randomly assigned to receive one of the three treatments given every 3 weeks: 250 mg/m2 taxol by a 24-hour intravenous infusion, 1000 mg/m2 merbarone by continuous intravenous infusion through a central catheter daily for 5 days, or 150 mg/m2 piroxantrone by intravenous infusion over 1 hour. Patients had received no chemotherapy. Response and toxicity were evaluated every 3 weeks.
Twenty-five patients were randomly assigned to receive taxol, 47 to receive merbarone, and 47 to receive piroxantrone. One of 44 assessable patients (2.3%) treated with piroxantrone had a complete response. Rates for partial response were 20.8% (five of 24 patients) and 5.7% (two of 35) for assessable patients treated with taxol or merbarone, respectively. One-year survival rates were 41.7%, 21.6%, and 22.6%, and median survival times were 24.1, 19.9, and 29.3 weeks for taxol, merbarone, and piroxantrone, respectively. These differences were not statistically significant, but this study was not designed to compare survival. In general, toxicity was manageable. With premedication, no anaphylaxis was observed with taxol. The most common toxic effects were leukopenia with taxol or piroxantrone treatment and thromboembolic complications with merbarone. Death directly related to treatment occurred in 4% (one patient), 11.4% (four), and 5% (two) of the assessable patients receiving taxol, merbarone, and piroxantrone, respectively. Cardiotoxicity and neurotoxicity occurred only occasionally in all three arms.
On the basis of the response rate (20.8% partial response) and 1-year survival rate (41.7%), taxol is an active agent for the treatment of metastatic non-small-cell lung cancer. Merbarone and piroxantrone are relatively inactive.
Further study of taxol is warranted. In future studies, taxol should be combined with other agents, and granulocyte colony-stimulating factor should be used to ameliorate myelosuppression.
转移性（IV期）非小细胞肺癌患者通常预后较差，且疾病对化疗耐药。三种新型药物——紫杉醇、美巴龙和吡罗昔康——已在体外和动物实验中显示出有前景的抗肿瘤治疗效果。紫杉醇是一种抗微管药物，可在细胞分裂过程中干扰有丝分裂。美巴龙是硫代巴比妥酸与苯胺的共轭物，是一种拓扑异构酶II抑制剂，因此可抑制DNA合成和肿瘤生长。吡罗昔康是一种蒽二酮衍生物，是一种DNA嵌入剂，在动物研究中已显示出强大的抗肿瘤活性。
我们的随机II期研究旨在评估这些药物治疗IV期转移性非小细胞肺癌的疗效和毒性。
符合条件的患者（119例）被随机分配接受三种治疗方案之一，每3周给药一次：250mg/m²紫杉醇通过24小时静脉输注，1000mg/m²美巴龙通过中心静脉导管每日持续静脉输注5天，或150mg/m²吡罗昔康静脉输注1小时。患者此前未接受过化疗。每3周评估反应和毒性。
25例患者被随机分配接受紫杉醇治疗，47例接受美巴龙治疗，47例接受吡罗昔康治疗。接受吡罗昔康治疗的44例可评估患者中有1例（2.3%）完全缓解。接受紫杉醇或美巴龙治疗的可评估患者的部分缓解率分别为20.8%（24例患者中的5例）和5.7%（35例中的2例）。紫杉醇、美巴龙和吡罗昔康的1年生存率分别为41.7%、21.6%和22.6%，中位生存时间分别为24.1周、19.9周和29.3周。这些差异无统计学意义，但本研究并非设计用于比较生存率。总体而言，毒性是可控的。通过预处理后，使用紫杉醇未观察到过敏反应。最常见的毒性反应是紫杉醇或吡罗昔康治疗导致的白细胞减少以及美巴龙治疗导致的血栓栓塞并发症。接受紫杉醇、美巴龙和吡罗昔康治疗的可评估患者中，分别有4%（1例患者）、11.4%（4例）和5%（2例）的死亡与治疗直接相关。在所有三个治疗组中，心脏毒性和神经毒性仅偶尔发生。
基于缓解率（20.8%部分缓解）和1年生存率（41.7%），紫杉醇是治疗转移性非小细胞肺癌的一种有效药物。美巴龙和吡罗昔康相对无效。
有必要对紫杉醇进行进一步研究。在未来的研究中，紫杉醇应与其他药物联合使用，并且应使用粒细胞集落刺激因子来改善骨髓抑制。
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