Cancer Research Institute, University of South Australia, Adelaide, Australia.
Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, Australia.
Med Phys. 2022 Jan;49(1):742-755. doi: 10.1002/mp.15360. Epub 2021 Dec 13.
Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/β ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT).
Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/β ratio.
IMPT plans resulted in lower NTCP compared to IMRT across all models (p < 0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (> 20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p < 0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p < 0.0001) across tested α/β as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/β of these pediatric tissues is higher than expected (α/β ∼ 3), the risk of tinnitus for IMRT can significantly increase (p < 0.0001).
Due to the scarcity of pediatric NTCP data available, sensitivity analyses were performed using plausible ranges based on published adult data. In the clinical scenario where, if female pediatric patients were 20% more radiosensitive (lower TD50 value), they could be up to twice as likely to experience side-effects of brainstem necrosis and cochlea tinnitus compared to males, highlighting the need for considering the sex in NTCP models. Based on our sensitivity analyses, age and sex of a pediatric patient could significantly affect the resultant NTCP from cranial radiotherapy, especially at higher α/β values.
质子治疗（PT）被广泛认为是儿童颅癌患者的护理金标准。与光子放射治疗相比，PT 的优越剂量分布降低了危及器官的正常组织并发症概率（NTCP）。由于儿科器官的 NTCP 尚未得到很好的理解，临床通常基于成人数据来预测放射反应。然而，有证据表明放射反应强烈依赖于患者的年龄甚至性别。此外，还存在有关个体固有放射敏感性（α/β 比值）对儿科 NTCP 影响的问题。虽然临床儿科 NTCP 数据稀缺，但放射生物学建模和敏感性分析可用于研究 NTCP 趋势及其对个体建模参数的依赖性。本研究的目的是对 NTCP 模型进行敏感性分析，以确定放射敏感性、儿童的性别和年龄以及强度调制质子治疗（IMPT）和强度调制放射治疗（IMRT）后的颅侧效应的依赖性。
此前，我们在 Varian Eclipse 治疗计划系统（版本 13.7）中为 6 名性别匹配的儿科颅部数据集（5、9 和 13 岁）进行了计划。我们回顾性地为一系列模拟的靶区和位置优化了多达 108 个扫描束 IMPT 计划和 108 个 IMRT 计划。在这项工作中，从剂量-体积直方图中提取并导入到 BioSuite 软件中进行放射生物学建模。使用相对序列和 Lyman-Kutcher-Burman 模型来计算毒性终点的 NTCP 值，其中 TD50（基于报告的成人临床数据）变化以模拟 NTCP 的性别依赖性。基于成人文献的合理参数范围用于建模。除了敏感性分析外，我们还使用 20%的 TD50 差异来表示男女之间的放射敏感性（认为女性更敏感），以便作为参数（例如 α/β 比）的函数轻松比较数据。
在所有模型中，IMPT 计划导致的 NTCP 均低于 IMRT（p<0.0001）。对于髓母细胞瘤治疗，如果考虑到女性的 TD50 值较低，女性发生脑干坏死（>10%）和耳蜗耳鸣（>20%）的风险可能会被低估。敏感性分析表明，男女之间的 NTCP 差异具有统计学意义（p<0.0001）。同样，脑干坏死和耳蜗耳鸣的 NTCP 也随着测试的α/β值显著变化（p<0.0001），这取决于 TD50 值（假设女性的 TD50 值低 20%）。如果这些儿科组织的真实 α/β 值高于预期（α/β∼3），则 IMRT 的耳鸣风险可能会显著增加（p<0.0001）。
由于儿科 NTCP 数据稀缺，因此使用基于已发表的成人数据的合理范围进行了敏感性分析。在临床情况下，如果女性儿科患者的放射敏感性提高 20%（TD50 值较低），与男性相比，她们患脑干坏死和耳蜗耳鸣等副作用的可能性可能增加一倍，这突出了在 NTCP 模型中考虑性别的必要性。基于我们的敏感性分析，儿科患者的年龄和性别可能会显著影响颅放射治疗的结果 NTCP，尤其是在更高的α/β 值下。
