Pediatric ethics and early-phase childhood cancer research: conflicted goals and the prospect of benefit.
Pediatric ethics and early-phase childhood cancer research: conflicted goals and the prospect of benefit.
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DOI：
10.1080/08989620300502
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Kodish, Eric
中科院分区：
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作者：
Kodish, Eric
癌症导致的儿童死亡人数比其他任何疾病都要多。因此，在儿科肿瘤学进行临床研究的道德要求是强大的。过去40年来进行了数百项临床试验，在降低儿童癌症死亡率和发病率方面取得了长足进步，但仍有许多工作要完成。新的“靶向治疗”的出现，基于对分子细胞信号的复杂理解，为加速儿童癌症的进展带来了实质性的希望。然而，这些发现的成果不会使儿童受益，除非首先在严格的临床试验中对他们进行评估。对于许多深思熟虑的批评者来说，第一阶段肿瘤学研究在研究伦理领域提出了最棘手的两难境地。根据定义，第一阶段的研究是首次将一种新的制剂引入人体受试者。传统的临床试验架构要求首先在剂量递增模型中检查药物的安全性和剂量考虑因素。安全性研究先于疗效的逻辑对肿瘤药物特别有意义，因为治疗窗口很窄。不幸的是，典型的细胞毒性化疗药物表现出剂量和毒性以及剂量和疗效之间的直接关系。正是这种基本关系为第一阶段-第二阶段序列提供了理论基础，并要求为了人体受试者的安全，疗效问题要等到安全性和剂量问题得到回答后再进行。在这些传统的第一阶段研究中，任何特定的子-
Cancer kills more children than any other disease. The moral imperative to conduct clinical research in pediatric oncology is accordingly powerful. Great strides against mortality and morbidity from childhood cancer have resulted from hundreds of clinical trials that have been performed over the past 40 years, yet much remains to be accomplished. The advent of new “targeted therapies,” based on a sophisticated understanding of molecular cell signaling, brings substantial hope for accelerated progress against childhood cancer. Yet, the fruits of these discoveries will not benefit children without first evaluating them in rigorous clinical trials.For many thoughtful critics, Phase I oncology research poses the thorniest of dilemmas in the realm of research ethics. Phase I studies are, by definition, the first time a new agent is introduced into a human subject. The traditional architecture of clinical trials requires that a drug first be examined for safety and dosing consideration in a dose-escalation model. The logic of safety studies preceding efficacy made particular sense for oncology drugs, where the therapeutic window is narrow. Unfortunately, typical cytotoxic chemotherapy drugs exhibit a direct relationship between dose and toxicity and between dose and efficacy. It is this basic relationship that provides the rationale for the Phase I-Phase II sequence and demands, for the safety of human subjects, that efficacy questions wait until safety and dosing questions have been answered. In these traditional Phase I studies, the chance that any particular sub-