PURPOSE The goal of this study was to assess whether a model-based approach applied retrospectively to a completed randomized controlled trial (RCT) would have significantly altered the selection of patients of the original trial, using the same selection criteria and endpoint for testing the potential clinical benefit of protons compared to photons. METHODS AND MATERIALS A model-based approach, based on three widely used normal tissue complication probability (NTCP) models for radiation pneumonitis (RP), was applied retrospectively to a completed non-small cell lung cancer RCT (NCT00915005). It was assumed that patients were selected by the model-based approach if their expected ΔNTCP value was above a threshold of 5%. The endpoint chosen matched that of the original trial, the first occurrence of severe (grade ≥3) RP. RESULTS Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for lung cancer using RP as the normal tissue endpoint. The analyzed lung trial showed that less than 19% (32/165) of patients enrolled in the completed trial would have been enrolled in a model-based trial, prescribing photon therapy to all other patients. The number of patients enrolled was also found to be dependent on the type of NTCP model used for evaluating RP, with the three models enrolling 3%, 13% or 19% of patients. This result does show limitations in NTCP models which would affect the success of a model-based trial approach. No conclusion regarding the development of RP in patients randomized by the model-based approach could statistically be made. CONCLUSIONS Uncertainties in the outcome models to predict NTCP are the inherent drawback of a model-based approach to clinical trials. The impact of these uncertainties on enrollment in model-based trials depends on the predicted difference between the two treatment arms and on the set threshold for patient stratification. Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for specific treatment sites, such as lung cancer, depending on the chosen normal tissue endpoint.

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基于模型的质子治疗试验方法展望：肺癌随机试验的回顾性研究

目的 本研究的目的是评估基于模型的方法回顾性应用于已完成的随机对照试验 (RCT) 是否会显着改变原始试验的患者选择，使用相同的选择标准和终点来测试潜在的质子与光子相比的临床益处。方法和材料 基于三种广泛使用的放射性肺炎 (RP) 正常组织并发症概率 (NTCP) 模型的基于模型的方法被回顾性应用于已完成的非小细胞肺癌 RCT (NCT00915005)。如果患者的预期 ΔNTCP 值高于 5% 的阈值，则假设他们是通过基于模型的方法选择的。选择的终点与原始试验的终点相匹配，即首次出现严重（≥3 级）RP。结果 我们的分析表明，质子治疗和光子治疗之间的 NTCP 差异可能太小，无法支持使用 RP 作为正常组织终点的基于模型的肺癌试验方法。经分析的肺部试验表明，参加完成试验的患者中，只有不到 19% (32/165) 会参加基于模型的试验，为所有其他患者开出光子疗法。还发现招募的患者数量取决于用于评估 RP 的 NTCP 模型的类型，三种模型招募了 3%、13% 或 19% 的患者。该结果确实显示了 NTCP 模型的局限性，这会影响基于模型的试验方法的成功。无法从统计学上得出关于通过基于模型的方法随机化的患者发生 RP 的结论。结论 预测 NTCP 的结果模型的不确定性是基于模型的临床试验方法的固有缺陷。这些不确定性对参加基于模型的试验的影响取决于两个治疗组之间的预测差异以及患者分层的设定阈值。我们的分析表明，质子和光子治疗之间的 NTCP 差异可能太小，无法支持针对特定治疗部位（如肺癌）的基于模型的试验方法，具体取决于所选的正常组织终点。这些不确定性对参加基于模型的试验的影响取决于两个治疗组之间的预测差异以及患者分层的设定阈值。我们的分析表明，质子和光子治疗之间的 NTCP 差异可能太小，无法支持针对特定治疗部位（如肺癌）的基于模型的试验方法，具体取决于所选的正常组织终点。这些不确定性对参加基于模型的试验的影响取决于两个治疗组之间的预测差异以及患者分层的设定阈值。我们的分析表明，质子和光子治疗之间的 NTCP 差异可能太小，无法支持针对特定治疗部位（如肺癌）的基于模型的试验方法，具体取决于所选的正常组织终点。