BACKGROUND The National Cancer Institute Moonshot℠ research initiative calls for improvements in the analysis and reporting of treatment toxicity to advise key stakeholders on treatment tolerability and inform regulatory and clinical decision-making. This study illustrates alternative approaches to toxicity evaluation using the National Surgical Adjuvant Breast and Bowel Project (NSABP-R04) clinical trial as an example. METHODS NSABP-R04 was a neoadjuvant chemo-radiation trial in stage II-III rectal cancer patients. A 2x2 factorial design was used to evaluate whether the addition of oxaliplatin (Oxa) to 5-fluorouracil (5FU) or capecitabine (Cape) with radiation therapy improved local-regional tumor control. The toxicity index (TI), which accounts for the frequency and severity of toxicities, was compared across treatments using multivariable probabilistic index models (PIMs), where Pr A < B indicates the probability that higher values of TI were observed for A when compared to B. Baseline age, gender, performance status (PS), body mass index (BMI), surgery type and stage were evaluated as independent risk factors. RESULTS A total of 4,560 toxicities from 1,558 patients were analyzed. Results from adjusted PIMs indicate that oxaliplatin-containing regimens had statistically significant (p < 0.001) probability for higher TI compared to regimens without oxaliplatin: Pr 5FU < 5FU + Oxa = 0.619 (95% CI 0.560-0.674); Pr 5FU< Cape + Oxa = 0.627 (95% CI 0.568-0.682); Pr Cape < 5FU + Oxa =0.587 (95% 0.527-0.644); and Pr Cape < Cape+ Oxa = 0.596 (95% 0.536-0.653).When compared to other existing toxicity analysis methods, TI provided greater power to detect differences between treatments. CONCLUSIONS This paper uses standard data collected in a cancer clinical trial to introduce descriptive and analytic methods that account for the additional burden of multiple toxicities. These methods may provide a more accurate description of a patient's treatment experience that could lead to individualized dosing for better toxicity control. Future research will evaluate the generalizability of these findings in trials with similar drugs.

中文翻译：

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使用毒性指数评估癌症临床试验中的治疗耐受性。

背景 美国国家癌症研究所 Moonshot℠ 研究计划呼吁改进治疗毒性的分析和报告，以就治疗耐受性向主要利益相关者提供建议，并为监管和临床决策提供信息。本研究以国家外科辅助乳房和肠道项目 (NSABP-R04) 临床试验为例，说明了毒性评估的替代方法。方法 NSABP-R04 是一项针对 II-III 期直肠癌患者的新辅助放化疗试验。使用 2x2 析因设计来评估将奥沙利铂 (Oxa) 添加到 5-氟尿嘧啶 (5FU) 或卡培他滨 (Cape) 是否能改善局部肿瘤控制。毒性指数 (TI)，它说明了毒性的频率和严重程度，使用多变量概率指数模型 (PIM) 对不同治疗进行比较，其中 Pr A < B 表示与 B 相比，A 观察到更高 TI 值的概率。 基线年龄、性别、体能状态 (PS)、体重指数 ( BMI）、手术类型和分期作为独立危险因素进行评估。结果 共分析了 1,558 名患者的 4,560 种毒性。调整后的 PIM 结果表明，与不含奥沙利铂的方案相比，含奥沙利铂的方案具有统计学显着性 (p < 0.001) 的更高 TI 概率：Pr 5FU < 5FU + Oxa = 0.619 (95% CI 0.560-0.674)；Pr 5FU< Cape + Oxa = 0.627 (95% CI 0.568-0.682)；Pr Cape < 5FU + Oxa =0.587 (95% 0.527-0.644)；和 Pr Cape < Cape+ Oxa = 0.596 (95% 0.536-0.653)。与其他现有毒性分析方法相比，TI 提供了更大的能力来检测治疗之间的差异。结论 本文使用在癌症临床试验中收集的标准数据来介绍描述性和分析性方法，以解释多重毒性的额外负担。这些方法可以更准确地描述患者的治疗经验，从而可以进行个体化给药，从而更好地控制毒性。未来的研究将评估这些发现在类似药物试验中的普遍性。s 治疗经验，可以导致更好的毒性控制的个体化给药。未来的研究将评估这些发现在类似药物试验中的普遍性。s 治疗经验，可以导致更好的毒性控制的个体化给药。未来的研究将评估这些发现在类似药物试验中的普遍性。