Treatment Planning and Delivery of Whole Brain Irradiation with Hippocampal Avoidance in Rats
Treatment Planning and Delivery of Whole Brain Irradiation with Hippocampal Avoidance in Rats
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DOI：
10.1371/journal.pone.0143208
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发表时间：
2015-12-04
期刊：
影响因子：
3.7
通讯作者：
Oldham, M.
中科院分区：
文献类型：
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作者：
Cramer, C. K.;Yoon, S. W.;Oldham, M.
背景尽管全脑放射治疗(WBRT)具有临床益处，但其对认知功能的长期影响一直是患者和医生关注的问题。许多研究WBRT的分子和细胞影响的研究都使用了啮齿动物模型。然而，还没有一个啮齿动物方案可以与最近报道的放射治疗肿瘤组(RTOG)方案相媲美，用于WBRT伴海马回避(HA)，旨在免除认知功能。本研究的目的是在Wistar大鼠中建立一种保留海马区的WBRT方案。确定了三个关键挑战：海马区定位、治疗计划和治疗定位。海马区定位是通过复杂的成像技术实现的，需要将大鼠MRI图谱与高分辨率MRI可变形地配准，然后通过刚性配准融合到CBCT。治疗计划采用了SMART-PLAN中的蒙特卡罗剂量计算，并创建了定制的0.5厘米厚的铅块，以匹配DRR投影。治疗定位需要XRAD C225Cx微CT/微辐照仪(精密X射线)的车载图像引导能力。治疗采用相对侧向磁场，225kVP X射线，电流13 mA，用40x40 mm正方形准直器和铅块过滤通过0.3 mm的铜。单次照射4Gy2GY/侧野，每野照射41s，剂量率为304.5 cGymin。用放射变色胶片进行海马区保护的剂量学验证。采用伽玛-H_2AX染色方法，对接受HA、WBRT或假照射(阴性对照)的大鼠的DNA损伤进行体内验证。结果海马区下放射致变色胶片的平均剂量为0.52Gyvs3.93Gyvs3.93Gy.这一差异与蒙特卡罗剂量计算预测的剂量一致。通过蒙特卡罗模拟生成的剂量体积直方图(DVH)显示，由于侧方阻断技术保留了一些中线丘脑和皮质下组织，靶区体积(脑减去海马体)的剂量不足，50%的靶区体积得到100%的等剂量处方。脑切片抗磷化组蛋白H_2A.X染色(反映双链DNA断裂)表明，这种治疗方案限制了体内海马区的辐射剂量。大脑皮质γ-H_2AX染色的平均信号强度与放射线照射组大鼠大脑皮质的平均信号强度差异无统计学意义(5.40vs.5.75，P=0.32)。与之相比，透明质酸治疗组大鼠海马区的信号强度明显低于对照组(4.55vs6.93，P=0.012)。结论尽管小体积适形放射治疗对啮齿动物具有挑战性，但我们的剂量学和体内数据表明，透明质酸治疗大鼠的适形放射治疗在大鼠是可行的。本研究为该技术的进一步应用和完善提供了有益的平台。
BackgroundDespite the clinical benefit of whole brain radiotherapy (WBRT), patients and physicians are concerned by the long-term impact on cognitive functioning. Many studies investigating the molecular and cellular impact of WBRT have used rodent models. However, there has not been a rodent protocol comparable to the recently reported Radiation Therapy Oncology Group (RTOG) protocol for WBRT with hippocampal avoidance (HA) which is intended to spare cognitive function. The aim of this study was to develop a hippocampal-sparing WBRT protocol in Wistar rats.MethodsThe technical and clinical challenges encountered in hippocampal sparing during rat WBRT are substantial. Three key challenges were identified: hippocampal localization, treatment planning, and treatment localization. Hippocampal localization was achieved with sophisticated imaging techniques requiring deformable registration of a rat MRI atlas with a high resolution MRI followed by fusion via rigid registration to a CBCT. Treatment planning employed a Monte Carlo dose calculation in SmART-Plan and creation of 0.5cm thick lead blocks custom-shaped to match DRR projections. Treatment localization necessitated the on-board image-guidance capability of the XRAD C225Cx micro-CT/micro-irradiator (Precision X-Ray). Treatment was accomplished with opposed lateral fields with 225 KVp X-rays at a current of 13mA filtered through 0.3mm of copper using a 40x40mm square collimator and the lead blocks. A single fraction of 4Gy was delivered (2Gy per lateral field) with a 41 second beam on time per field at a dose rate of 304.5 cGy/min. Dosimetric verification of hippocampal sparing was performed using radiochromic film. In vivo verification of HA was performed after delivery of a single 4Gy fraction either with or without HA using gamma-H2Ax staining of tissue sections from the brain to quantify the amount of DNA damage in rats treated with HA, WBRT, or sham-irradiated (negative controls).ResultsThe mean dose delivered to radiochromic film beneath the hippocampal block was 0.52Gy compared to 3.93Gy without the block, indicating an 87% reduction in the dose delivered to the hippocampus. This difference was consistent with doses predicted by Monte Carlo dose calculation. The Dose Volume Histogram (DVH) generated via Monte Carlo simulation showed an underdose of the target volume (brain minus hippocampus) with 50% of the target volume receiving 100% of the prescription isodose as a result of the lateral blocking techniques sparing some midline thalamic and subcortical tissue. Staining of brain sections with anti-phospho-Histone H2A.X (reflecting double-strand DNA breaks) demonstrated that this treatment protocol limited radiation dose to the hippocampus in vivo. The mean signal intensity from gamma-H2Ax staining in the cortex was not significantly different from the signal intensity in the cortex of rats treated with WBRT (5.40 v. 5.75, P = 0.32). In contrast, the signal intensity in the hippocampus of rats treated with HA was significantly lower than rats treated with WBRT (4.55 v. 6.93, P = 0.012).ConclusionDespite the challenges of planning conformal treatments for small volumes in rodents, our dosimetric and in vivo data show that WBRT with HA is feasible in rats. This study provides a useful platform for further application and refinement of the technique.