Koyfman Shlomo A, Agrawal Manish, Garrett-Mayer Elizabeth, Krohmal Benjamin, Wolf Elizabeth, Emanuel Ezekiel J, Gross Cary P
Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA.
Cancer. 2007 Sep 1;110(5):1115-24. doi: 10.1002/cncr.22878.
Although aggressive dose escalation strategies were designed to improve the risk-benefit profile of phase 1 oncology trials, they have not been adequately studied. The prevalence of several novel trial designs and their association with a variety of clinical endpoints was evaluated.
A review of the literature was performed to identify phase 1 oncology studies of cytotoxic agents published from 2002 through 2004.
Of 955 phase 1 oncology articles initially identified, 149 studies, comprising 4532 patients, were analyzed. Only 34% of studies utilized aggressive dose escalation schemes, 22% permitted intrapatient dose escalation, and only 28% enrolled fewer than 3 patients to any dose level. Studies that allowed intrapatient dose escalation or used fewer than 3 patients per dose were not associated with different rates of response or toxicity, nor did they increase the number of patients who received the recommended phase 2 dose. However, aggressive dose escalations were associated with increased rates of both hematologic (17% vs 10%) and nonhematologic (17% vs 13%) toxicity with similar response rates. Only studies that used conservative dose escalation designs and those that studied U.S. Food and Drug Administration (FDA)-approved agents required fewer patients to complete a trial. Trials of FDA-approved agents were also associated with higher response rates than trials of non-FDA-approved agents (10% vs 2%), without an increased risk of toxicity.
Several novel aggressive design strategies intended to improve the risk-benefit profile of phase 1 oncology trials are not associated with improved clinical outcome, and may be harmful in certain instances.
尽管积极的剂量递增策略旨在改善1期肿瘤学试验的风险效益状况，但尚未得到充分研究。评估了几种新型试验设计的流行情况及其与各种临床终点的关联。
对文献进行综述，以确定2002年至2004年发表的细胞毒性药物1期肿瘤学研究。
在最初确定的955篇1期肿瘤学文章中，分析了149项研究，共4532例患者。只有34%的研究采用了积极的剂量递增方案，22%允许患者内剂量递增，只有28%在任何剂量水平纳入的患者少于3例。允许患者内剂量递增或每剂量使用少于3例患者的研究与不同的缓解率或毒性率无关，也未增加接受推荐2期剂量的患者数量。然而，积极的剂量递增与血液学毒性（17%对10%）和非血液学毒性（17%对13%）发生率增加相关，缓解率相似。只有采用保守剂量递增设计的研究以及研究美国食品药品监督管理局（FDA）批准药物的研究完成试验所需的患者较少。FDA批准药物的试验与非FDA批准药物的试验相比，缓解率也更高（10%对2%），且毒性风险未增加。
旨在改善1期肿瘤学试验风险效益状况的几种新型积极设计策略与改善临床结局无关，在某些情况下可能有害。
