Langer Corey J
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Clin Lung Cancer. 2003 Jan;4 Suppl 2:S45-9. doi: 10.3816/clc.2003.s.003.
The median survival for patients with locally advanced non-small-cell lung cancer (NSCLC) remains 18 months, at best, in cooperative group efforts. Integrating new agents into the standard combined modality treatment paradigm is a daunting challenge. Gemcitabine has activity in advanced NSCLC and is a potent radiosensitizer, but preclinical trials did not delineate an optimal dose or schedule, and early attempts to graft full-dose gemcitabine (1000 mg/m2/week) onto standard radical thoracic radiation therapy (RT) were marked by significant grade 4 and 5 toxicity. More recent trials, however, have shown that attenuated doses of 150-300 mg/m2/week during radiation (XRT) are safer and potentially efficacious. Higher doses produce dose-limiting esophageal and pulmonary toxicities. Using a twice-weekly schedule, the maximum tolerated dose is 35 mg/m2. The use of 3 dimensional conformal RT may enable significant dose escalations while substantially reducing esophageal exposure and minimizing toxicity. The cooperative oncology groups are just beginning to evaluate gemcitabine in this setting. Cancer and Leukemia Group B, in a randomized phase II study, assessed combination gemcitabine and cisplatin in both the induction and radiosensitizing setting. During the induction phase, gemcitabine was given 1250 mg/m2 on days 1 and 8 every 3 weeks for 2 cycles in combination with cisplatin 80 mg/m2 every 3 weeks, and then reduced to 600 mg/m2 days 1 and 8 every 3 weeks during XRT. The overall response rate was 63% with median survival of 18.3 months and 1-year and 3-year survival rates of 68% and 28%, respectively. Radiation Therapy Oncology Group is currently spearheading a phase I study of concurrent radiation and weekly gemcitabine in combination with either weekly carboplatin or paclitaxel. Ongoing efforts will also evaluate the role of gemcitabine either alone or in combination with docetaxel in the consolidation setting after definitive chemoradiation has been completed. Whether gemcitabine in combination with radiation, with or without other agents, will ultimately prove superior to standard chemoradiation regimens remains to be determined.
在协作组的研究中，局部晚期非小细胞肺癌（NSCLC）患者的中位生存期最多仍为18个月。将新药物纳入标准的综合治疗模式是一项艰巨的挑战。吉西他滨对晚期NSCLC有活性，且是一种有效的放射增敏剂，但临床前试验并未确定最佳剂量或给药方案，早期将全剂量吉西他滨（1000mg/m²/周）与标准根治性胸部放疗（RT）联合应用的尝试出现了显著的4级和5级毒性反应。然而，最近的试验表明，放疗（XRT）期间每周150 - 300mg/m²的减毒剂量更安全且可能有效。更高剂量会产生剂量限制性的食管和肺部毒性。采用每周两次的给药方案，最大耐受剂量为35mg/m²。使用三维适形放疗可在显著减少食管受照剂量并将毒性降至最低的同时实现剂量大幅增加。肿瘤协作组才刚刚开始在这种情况下评估吉西他滨。癌症与白血病B组（Cancer and Leukemia Group B）在一项随机II期研究中，评估了吉西他滨联合顺铂在诱导治疗和放射增敏治疗中的应用。在诱导期，吉西他滨每3周的第1天和第8天给予1250mg/m²，共2个周期，联合每3周80mg/m²的顺铂，然后在XRT期间减至每3周第1天和第8天600mg/m²。总体缓解率为63%，中位生存期为18.3个月，1年和3年生存率分别为68%和28%。放射肿瘤学组（Radiation Therapy Oncology Group）目前正在牵头开展一项I期研究，评估同步放疗联合每周一次的吉西他滨，再联合每周一次的卡铂或紫杉醇。正在进行的研究还将评估吉西他滨单独或与多西他赛联合在确定性放化疗完成后的巩固治疗中的作用。吉西他滨联合放疗，无论是否联合其他药物，最终是否优于标准放化疗方案仍有待确定。
