Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Consortium (DKTK) Core-Center Heidelberg, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Molecular and Translational Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.
Med Phys. 2024 May;51(5):3782-3795. doi: 10.1002/mp.17045. Epub 2024 Apr 3.
Interpatient variation of tumor radiosensitivity is rarely considered during the treatment planning process despite its known significance for the therapeutic outcome.
To apply our mechanistic biophysical model to investigate the biological robustness of carbon ion radiotherapy (CIRT) against DNA damage repair interference (DDRi) associated patient-to-patient variability in radiosensitivity and its potential clinical advantages against conventional radiotherapy approaches.
The "UNIfied and VERSatile bio response Engine" (UNIVERSE) was extended by carbon ions and its predictions were compared to a panel of in vitro and in vivo data including various endpoints and DDRi settings within clinically relevant dose and linear energy transfer (LET) ranges. The implications of UNIVERSE predictions were then assessed in a clinical patient scenario considering DDRi variance.
UNIVERSE tests well against the applied benchmarks. While in vitro survival curves were predicted with an R > 0.92, deviations from in vivo RBE data were less than 5.6% The conducted paradigmatic patient plan study implies a markedly reduced significance of DDRi based radiosensitivity variability in CIRT (13% change of in target) compared to conventional radiotherapy (62%) and that boosting the LET within the target further amplifies this robustness of CIRT (8%). In the case of heightened tumor radiosensitivity, a dose de-escalation strategy for photons allows a reduction of the maximum effective dose within the normal tissue (NT) from a of 2.65 to 1.64 Gy, which lies below the level found for CIRT ( = 2.41 Gy) for the analyzed plan and parameters. However, even after de-escalation, the integral effective dose in the NT is found to be substantially higher for conventional radiotherapy in comparison to CIRT ( of 0.75, 0.46, and 0.24 Gy for the conventional plan, its de-escalation and CIRT, respectively).
The framework offers adequate predictions of in vitro and in vivo radiation effects of CIRT while allowing the consideration of DRRi based solely on parameters derived from photon data. The results of the patient planning study underline the potential of CIRT to minimize important sources of interpatient divergence in therapy outcome, especially when combined with techniques that allow to maximize the LET within the tumor. Despite the potential of de-escalation strategies for conventional radiotherapy to reduce the maximum effective dose in the NT, CIRT appears to remain a more favorable option due to its ability to reduce the integral effective dose within the NT.
尽管肿瘤放射敏感性的个体间差异对治疗结果具有重要意义，但在治疗计划过程中很少考虑这种差异。
应用我们的机制生物物理模型，研究碳离子放射治疗（CIRT）对与 DNA 损伤修复干扰（DDRi）相关的放射敏感性个体间变异性的生物学稳健性，及其对常规放射治疗方法的潜在临床优势。
“UNIfied and VERSatile bio response Engine”（UNIVERSE）通过碳离子得到扩展，并将其预测结果与包括各种终点和 DDRi 设置的体外和体内数据进行比较，涵盖了临床相关剂量和线性能量传递（LET）范围内。然后，考虑到 DDRi 变化，在临床患者情况下评估 UNIVERSE 预测结果的意义。
UNIVERSE 很好地验证了应用基准。尽管体外生存曲线的预测 R 值>0.92，但与体内 RBE 数据的偏差小于 5.6%。进行的范例化患者计划研究表明，与常规放射治疗（62%）相比，CIRT 中基于 DDRi 的放射敏感性变异性的显著性显著降低（靶区变化的 13%），并且在靶区内提高 LET 进一步放大了 CIRT 的这种稳健性（8%）。在肿瘤放射敏感性增加的情况下，对于光子的剂量下调策略可将正常组织（NT）内的最大有效剂量从 2.65 Gy 降低到 1.64 Gy，这低于分析计划和参数下 CIRT 的水平（=2.41 Gy）。然而，即使在下调后，与 CIRT 相比，常规放射治疗中 NT 内的积分有效剂量仍然显著更高（常规计划为 0.75 Gy，下调后为 0.46 Gy，CIRT 为 0.24 Gy）。
该框架提供了对 CIRT 的体外和体内辐射效应的充分预测，同时允许仅基于来自光子数据的参数考虑 DDRi。患者计划研究的结果强调了 CIRT 能够最小化治疗结果中重要的个体间差异源的潜力，尤其是当与允许最大化肿瘤内 LET 的技术相结合时。尽管常规放射治疗的下调策略有降低 NT 内最大有效剂量的潜力，但由于 CIRT 能够降低 NT 内的积分有效剂量，因此 CIRT 似乎仍然是更有利的选择。
