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Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

机译：通过不均匀的每日剂量分布最大限度地提高质子剂量随扫描束传递的生物学效应

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>Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning.>Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery.>Results: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE.>Conclusions: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled.
机译：>目的：通过超分割，局部剂量递增以及在粒子疗法中，通过优化线性能量转移（LET）的分布，可以增强辐射的生物效应。作者描述了一种构建不均匀分数剂量（IFD）分布的方法，并评估了通过笔形束扫描进行质子治疗时从其传递中获得的治疗效果的潜在收益。>方法：在癌症中，作者考虑了60 Gy的超分割疗程，分20步进行。 （以Gy表示的所有剂量均包括1.1的质子平均相对生物有效性（RBE）。）使用两个相对的侧向光束优化了两种类型的计划，以通过扫描向靶标均匀递送每份3 Gy的剂量：（1）在常规的全目标计划（FTP）中，每个光束都照射整个腺体；（2）在分割目标计划（STP）中，光束仅照射相应的近半球（前列腺矢状裂开）。反向计划会产生强度图，其中为扫描光束（点）的离散位置控制点分配了最佳强度值。 FTP计划优先要求目标远侧的斑点强度更高，而STP通过设计采用近侧斑点。为了评估IFD交付的实用性，通过从FTP或STP强度图中分别重新排列斑点强度并使用各种混合权重进行组合来生成IFD计划。对IFD疗程进行设计，以便以交替的分数，前列腺的一个半球将接受剂量增加，而另一个半球接受较低的剂量，而来自IFD疗程的总物理剂量在整个前列腺上大致是均匀的。对IFD计划进行了标准化，因此与基线FTP计划相比，直肠和膀胱的等效均等剂量（EUD）不会增加，基线FTP计划在各个部位均均匀地照射了前列腺。然后将基于EUD的模型应用于估计肿瘤控制概率（TCP）和正常组织并发症概率（NTCP）。为了评估潜在的本地RBE变化，使用Monte Carlo计算LET分布，并比较不同的计划。根据对模型参数和分娩不确定性的敏感性来评估结果。>结果： IFD课程包括相等数量的分数促进任一半球，因此，整个前列腺的综合物理剂量接近均匀。但是，在整个过程中，IFD中的前列腺EUD比传统的FTP高出14％，相当于TCP的估计值从88％增加到96％。增益的程度取决于混合因子，即用于组合FTP和STP点权重的相对权重。 STP权重的增加通常会产生更高的目标EUD，但也会导致剂量对质子范围变化的敏感性增加。直肠和膀胱EUD相同或更低（按标准化），两者的NTCP均保持在1％以下。 IFD中的LET分布还强烈取决于混合权重：使用更高重量的STP点的计划产生的LET更高，表明潜在的局部RBE更高。>结论：在通过笔形束扫描进行的质子治疗中，通过在整个疗程中对目标给药规定的准均匀剂量，可能会随着IFD分布的传递而达到预期的治疗效果。通过优化LET分布，可以进一步提高IFD的生物学有效性。 IFD分布的特征是位于前列腺中平面附近的剂量梯度，因此，传递的保真度将关键取决于质子范围可控制的精度。

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