Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Med Phys. 2013 May;40(5):051708. doi: 10.1118/1.4801897.
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.
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.
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.
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.
通过分次剂量降低、局部剂量递增以及在粒子治疗中优化线性能量传递（LET）分布，可以增强辐射的生物学效应。作者描述了一种构建不均匀分次剂量（IFD）分布的方法，并评估了在质子笔形束扫描治疗中，通过递送这些分布来提高治疗效果的潜力。
对于 13 例前列腺癌患者，作者考虑了 60 Gy 的 20 次分割疗程，每次分割剂量为 3 Gy。（所有剂量均以质子的平均相对生物效应（RBE）1.1 表示。）使用两个相对的侧向射束优化两种类型的计划，以通过扫描将每个射束的整个腺体的目标剂量均匀照射为 3 Gy：（1）在传统全靶区计划（FTP）中，每个射束照射整个腺体，（2）在靶区分割计划（STP）中，射束仅照射各自的近端半球（前列腺矢状面分割）。逆向计划生成强度图，其中离散的扫描射束（光斑）位置控制点被分配优化的强度值。FTP 计划优先要求在目标的远端部分使用更高强度的光斑，而 STP 则通过设计使用近端光斑。为了评估 IFD 输送的实用性，分别通过重新排列来自 FTP 或 STP 强度图的光斑强度以及结合使用各种混合权重来生成 IFD 计划。IFD 疗程的设计方式是，在交替的分次中，前列腺的一个半球将接受剂量提升，而另一个半球将接受较低的剂量，同时整个 IFD 疗程的物理剂量在前列腺中大致均匀。IFD 计划通过归一化，使得直肠和膀胱的等效均匀剂量（EUD）与基线 FTP 计划相比不会增加，该计划在每个分次中均匀照射前列腺。然后应用基于 EUD 的模型来估计肿瘤控制概率（TCP）和正常组织并发症概率（NTCP）。为了评估潜在的局部 RBE 变化，使用蒙特卡罗计算了 LET 分布，并比较了不同的计划。结果根据模型参数和输送的不确定性进行了评估。
IFD 疗程包括等量的分次剂量提升，因此，整个疗程的前列腺总物理剂量接近均匀。然而，对于整个疗程，IFD 的前列腺 EUD 比传统的 FTP 高出多达 14%，这对应于 TCP 从 88%估计增加到 96%。增益的程度取决于混合因子，即用于组合 FTP 和 STP 光斑权重的相对权重。STP 的权重增加通常会导致目标 EUD 更高，但也会导致剂量对质子射程变化的敏感性增加。直肠和膀胱 EUD 相同或更低（归一化后），并且两者的 NTCP 均保持在 1%以下。IFD 的 LET 分布也强烈依赖于混合权重：使用更高权重的 STP 光斑的计划会产生更高的 LET，表明潜在的局部 RBE 更高。
在通过笔形束扫描进行质子治疗时，通过递送 IFD 分布，可以预期潜在地改善治疗效果，同时在整个疗程中向目标给予规定的准均匀剂量。通过优化 LET 分布，可以进一步提高 IFD 的生物学效应。IFD 分布的特点是在前列腺中平面附近存在剂量梯度，因此，输送的保真度将取决于质子射程的控制精度。
