Department of Investigational Cancer Therapeutics, Phase I Program, MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Clin Cancer Res. 2010 Feb 15;16(4):1289-97. doi: 10.1158/1078-0432.CCR-09-2684. Epub 2010 Feb 9.
To safely assess new drugs, cancer patients in initial cohorts of phase I oncology studies receive low drug doses. Doses are successively increased until the maximum tolerated dose (MTD) is determined. Because traditional chemotherapy is often more effective near the MTD, ethical concerns have been raised about administration of low drug doses to phase I patients. However, a substantial portion of oncology trials now investigate targeted agents, which may have different dose-response relationships than cytotoxic chemotherapies.
Twenty-four consecutive trials treating 683 patients between October 1, 2004, and June 30, 2008, at MD Anderson Cancer Center were analyzed. Patients were assigned to a low-dose (<or=25% MTD), medium-dose (25-75% MTD), or high-dose (>or=75% MTD) group, and groups were compared for response rate, time-to-treatment failure, progression-free survival, overall survival, and toxicity. To remove negatively biasing data from the high-dose group, in a second analysis, patients treated above the MTD were excluded (high-dose group, 75-100% MTD). Of the 683 patients, 97.7% received targeted agents.
Even when excluding patients above the MTD, there was an early trend favoring the low- versus high-dose group in time-to-treatment failure, with 32.9% versus 25.2% of patients on therapy at 3 months (P = 0.08). In addition, the low-dose group fared at least as well as the other groups in all other outcomes, including response rate, progression-free survival, overall survival, and toxicity.
These data may help alleviate concerns that patients who receive low drug doses on contemporary phase I oncology trials fare worse and suggest targeted agents may have different dose-response relationships than cytotoxic chemotherapies.
为了安全地评估新药，在 I 期肿瘤学研究的初始队列中，癌症患者接受低剂量药物。剂量逐渐增加，直到确定最大耐受剂量（MTD）。由于传统化疗在接近 MTD 时通常更有效，因此人们对给 I 期患者给予低剂量药物提出了伦理方面的担忧。然而，现在相当一部分肿瘤学试验都在研究靶向药物，这些药物的剂量反应关系可能与细胞毒性化疗药物不同。
对 2004 年 10 月 1 日至 2008 年 6 月 30 日期间在 MD 安德森癌症中心进行的 24 项连续试验共 683 例患者进行了分析。将患者分为低剂量（≤25% MTD）、中剂量（25%-75% MTD）或高剂量（≥75% MTD）组，并对各组的反应率、治疗失败时间、无进展生存期、总生存期和毒性进行比较。为了消除高剂量组中存在的负偏数据，在第二次分析中，排除了接受 MTD 以上剂量治疗的患者（高剂量组，75%-100% MTD）。在 683 例患者中，97.7%接受了靶向药物治疗。
即使排除接受 MTD 以上剂量的患者，在治疗失败时间方面，低剂量组仍较高剂量组有早期趋势，3 个月时仍有 32.9%和 25.2%的患者接受治疗（P = 0.08）。此外，低剂量组在所有其他结局方面至少与其他组一样，包括反应率、无进展生存期、总生存期和毒性。
这些数据可能有助于缓解人们的担忧，即接受当代 I 期肿瘤学试验低剂量药物的患者预后较差，并表明靶向药物的剂量反应关系可能与细胞毒性化疗药物不同。
