Department of Biostatistics, Institut Curie, Paris U900, INSERM, Paris CIC1401-Clinical Epidemiology, INSERM U897, Bordeaux Division of Public Health, University Hospital, Bordeaux CIC1401-Clinical Epidemiology, Bordeaux University, Bordeaux
CIC1401-Clinical Epidemiology, INSERM U897, Bordeaux Division of Public Health, University Hospital, Bordeaux CIC1401-Clinical Epidemiology, Bordeaux University, Bordeaux Labex Vaccine Research Institute, Bordeaux.
Ann Oncol. 2015 Feb;26(2):422-8. doi: 10.1093/annonc/mdu523. Epub 2014 Nov 17.
Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per-cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period.
Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib + radiotherapy in brainstem gliomas with longer time on treatment) and one 3 + 3 design (T3: liposomal doxorubicin + cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM.
Eighty-three patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 [P = 0.04; per-cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D]. At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3.
Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.
在剂量限制毒性评估期之外进行安全性评估可为确定新治疗方案的推荐 II 期剂量（RP2D）提供相关信息。我们回顾性分析了三项 I 期临床试验，以说明两个指标：每个治疗周期中分级毒性的概率和治疗期间严重毒性的累积概率。
从两项连续评估方法（CRM）试验（T1：短时间治疗的固体肿瘤中的 aviscumine；T2：长时间治疗的脑干胶质瘤中的厄洛替尼+放疗）和一项 3+3 设计试验（T3：卵巢癌中的脂质体多柔比星+环磷酰胺联合治疗）中收集数据。采用混合比例优势模型估计每个剂量水平下每周期严重和中度或严重毒性的概率。采用时间事件 CRM 估计严重毒性的累积概率。
三项试验共纳入 83 例患者；T1、T2 和 T3 分别接受了 94、96 和 72 个治疗周期。中度毒性至少是严重毒性的两倍。在 T3 中检测到随着时间的推移毒性增加的趋势 [P=0.04；RP2D 时严重毒性的每周期概率：27%（第 1 周期）至 59%（第 6 周期）]。在 RP2D，T2 中 37%的患者在前 6 个周期中至少经历了一次严重毒性，T3 中则有 78%的患者出现了这种情况。
专门的方法可用于分析整个治疗周期的毒性。它们不会延迟入组，并且应该纳入 I 期剂量发现试验的分析和报告中。
