Dorris Kathleen, Liu Chunyan, Li Dandan, Hummel Trent R, Wang Xia, Perentesis John, Kim Mi-Ok, Fouladi Maryam
Section of Pediatric Hematology, Oncology, Bone Marrow Transplantation, Children's Hospital Colorado, Aurora, Colorado.
Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Pediatr Blood Cancer. 2017 Mar;64(3). doi: 10.1002/pbc.26258. Epub 2016 Sep 22.
Prior reviews of phase I pediatric oncology trials involving primarily cytotoxic agents have reported objective response rates (ORRs) and toxic death rates of 7.9-9.6% and 0.5%, respectively. These data may not reflect safety and efficacy in phase I trials of molecularly targeted (targeted) drugs.
A systematic review of pediatric phase I solid tumor trials published in 1990-2013 was performed. The published reports were evaluated for patient characteristics, toxicity information, and response numbers.
A total of 143 phase I pediatric clinical trials enrolling 3,896 children involving 53 targeted and 48 cytotoxic drugs were identified. A meta-analysis demonstrated that the ORR is 2.1-fold higher with cytotoxic drugs (0.066 vs. 0.031 per subject; P = 0.007). By contrast, the pooled estimate of the stable disease rate (SDR) is similar for cytotoxic and targeted drugs (0.2 vs. 0.23 per subject; P = 0.27). The pooled estimate of the dose-limiting toxicity rate is 1.8-fold larger with cytotoxic drugs (0.24 vs. 0.13 per subject; P = 0.0003). The hematologic grade 3-4 (G3/4) toxicity rate is 3.6-fold larger with cytotoxic drugs (0.43 vs. 0.12 per treatment course; P = 0.0001); however, the nonhematologic G3/4 toxicities and toxic deaths occur at similar rates for cytotoxic and targeted drugs.
In phase I pediatric solid tumor trials, ORRs were significantly higher for cytotoxic versus targeted agents. SDRs were similar in targeted and cytotoxic drug trials. Patients treated with cytotoxic agents were more likely to experience hematologic G3/4 toxicities than those patients receiving targeted drugs.
先前对主要涉及细胞毒性药物的I期儿科肿瘤试验的综述报告称，客观缓解率（ORR）和毒性死亡率分别为7.9 - 9.6%和0.5%。这些数据可能无法反映分子靶向（靶向）药物I期试验的安全性和有效性。
对1990 - 2013年发表的儿科I期实体瘤试验进行系统综述。对已发表的报告进行患者特征、毒性信息和缓解病例数评估。
共确定了143项I期儿科临床试验，纳入3896名儿童，涉及53种靶向药物和48种细胞毒性药物。荟萃分析表明，细胞毒性药物的ORR高2.1倍（每位受试者分别为0.066和0.031；P = 0.007）。相比之下，细胞毒性药物和靶向药物的疾病稳定率（SDR）合并估计值相似（每位受试者分别为0.2和0.23；P = 0.27）。细胞毒性药物的剂量限制毒性率合并估计值高1.8倍（每位受试者分别为0.24和0.13；P = 0.0003）。细胞毒性药物的血液学3 - 4级（G3/4）毒性率高3.6倍（每个治疗疗程分别为0.43和0.12；P = 0.0001）；然而，细胞毒性药物和靶向药物的非血液学G3/4毒性及毒性死亡发生率相似。
在I期儿科实体瘤试验中，细胞毒性药物的ORR显著高于靶向药物。靶向药物试验和细胞毒性药物试验中的SDR相似。接受细胞毒性药物治疗的患者比接受靶向药物治疗的患者更易出现血液学G3/4毒性。
