Pediatric VMAT total body irradiation (TBI) in the treatment of B-cell acute lymphoblastic leukemia (B-ALL)

Total Body Irradiation (TBI) is used in the treatment of certain diseases, such as multiple myeloma, lymphoma, leukemia, and in preparation for bone marrow transplantation (BMT). The purpose of TBI is to destroy residual cancer cells, to destroy the patient’s own bone marrow prior to receiving stem cells, or to prevent donor bone marrow from being rejected (by immunosuppression). TBI has high efficacy, with the ability to penetrate areas, such as the central nervous system (CNS) and testicles, where traditional chemotherapy is ineffective.

Drawbacks of classical TBI techniques include possible dose heterogeneity, a lack of organ-at-risk (OAR) protection, and high delivery uncertainties. The volumetric modulated arc therapy (VMAT) technique was favored for implementing TBI at our hospital due to the accurate and precise dose calculation, OAR protection, and homogenous dose distributions that can be achieved using Monaco’s Monte Carlo dose calculation algorithm.

VMAT TBI was implemented at this hospital in 2015 for 40-50 patients annually. We use VMAT TBI prior to BMT in the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and aplastic anemia. It is applied in patients with brain or testicular involvement and, generally, where chemotherapy alone is insufficient. A TBI regimen is also applied for a second BMT, where the first transplant was unsuccessful.

Based on published guidelines and recommendations1-5, our usual TBI plan delivers 12 Gy in 6 fractions over 3 days, ensuring that the interval between fractions is at least 8 hours. Lung and kidney mean doses are limited to between 9-10 Gy and lens doses to <5 Gy. We aim for target dose homogeneity index (HI) of <1.15.

The following case study demonstrates how OAR-sparing TBI was applied prior to a second BMT in a 6-year-old male patient who experienced early extramedullary relapse (testis) of CALLA-positive B-cell acute lymphoblastic leukemia (B-ALL).

This B-ALL patient received his first bone marrow transplant (without TBI) from a fully compatible sibling in March 2017. He experienced an isolated bone marrow relapse 8 months after the initial transplant and was then started on chemotherapy (single dose etoposide 60 mg/kg). While on chemotherapy, the patient experienced a number of complications, including hepatosplenic candidiasis, long QT syndrome, liver dysfunction, cholelithiasis, and BK virus-associated hemorrhagic cystitis. In addition, the patient has congenital kidney atrophy (single kidney). The patient had an orchidectomy in June 2018.

2019年3月，决定使用TBI方案进行第二个BMT。同样，发现了一个相对供体，具有9/10人类白细胞抗原（HLA）兼容性。

病人定位使用C-RAD Sentinel surface guidance system and simulated for TBI on a Siemens® Biograph mCT PET-CT scanner (5 mm slice thickness) in the head-first and feet-first positions, since he was over 115 cm in height. Immobilization was achieved with a head-neck mask and the Elekta BodyFIX vacuum bed. Optimum scanning parameters were selected to ensure minimal dose to a pediatric patient.

Contouring of the patient's skin, lenses, kidneys and lungs were performed at a Prosoma workstation. The vacuum bed was included in the external patient contour so that we could calculate the maximum/minimum dose distributions that may occur outside the patient's skin.

计划是使用5.11.0摩纳哥版本执行2 with the Monte Carlo dose calculation algorithm. A VMAT TBI plan was generated for a Versa HD linear accelerator to deliver 12 Gy to the whole body in 6 fractions over 3 days. Dose constraint targets were determined as mean 9-10 Gy for lung, mean 8 Gy for single kidney and mean 4 Gy for lenses. For optimization purposes, the aim was to obtain the desired dose distribution in the PTV, giving priority to lung, kidney and lens constraints.

在约束优化模式下准备了VMAT计划。使用多准则优化（MCO）更精确地实现了对关键器官的均匀剂量分布和剂量局限性。我们能够通过基于MCO的计划来确保计划效率和剂量分配质量。

Thanks to Elekta Agility’s 40 cm x 40 cm field size, we created the treatment plan using just four isocenters, allowing us to shorten the treatment time as much as possible. The patient volume was divided into four parts in Monaco: PTVHead, PTVThorax, PTVAbdomen and PTVFoot. For this plan, one VMAT field (two arcs) was used at each of the four isocenters. Three isocenters were used in the head-first position (PTVHead, PTVThorax, PTVAbdomen) and a single isocenter was used in the feet-first position (PTVFoot). Overlapping regions of 8 cm are created to avoid hot and cold spots in the intersection zones.

A composite plan was made by fusing the head-first and feet-first plans and using the Monaco Bias Dose feature to manage potential high or low dose points at the junction.

VMAT TBI planning details and dosimetric parameters for this patient are shown in tables 1-3. Dose distributions and DVH curves and shown in figure 1.

Table 1. VMAT TBI planning details

Isocenters	4 isocenters 3 in head-first position; one in feet-first position 8 cm overlap region Bias Dose at composite plan junction
VMAT arcs	2 per isocenter
Photon beam	6 MV Beamlet width: 0.3 cm
计算参数	网格间距：0.4厘米 Statistical uncertainty: 1.0% per calculation
测序参数	最小段宽度：1厘米 Maximum control points per arc: 240 Fluence smoothing: Medium Auto flash margin: 0.5 cm
MLC parameters	有效叶速度为6.5 cm/s 叶子在中央轴上行驶15厘米 横跨动态段的下颌速度为9 cm/s

Table 2. TBI target volume doses

	D95 (cGy)	DMean (cGy)	DMax (cGy)	你好
PTVHead	1153	1230	1379	1.09
PTVThorax	1078	1206	1393	1.19
PTVAbdomen	1171	1230	1359	1.11
PTVFoot	1151	1213	1438	1.14

Table 3. Critical organ doses

	DMean (cGy)	V60 (cGy)
Lungs	975	942
Kidney (left only)	786	743
Left Lens	497
右镜头	478

使用IBA MATRIXX 2D阵列执行了脚步第一单一同性恋计划的质量标准和首先组合计划（一项计划中收集的三个等级中心计划）。伽马分析证明了> 90％的有效结果，标准为5％剂量差（DD）和5 mm的一致性（DTA）。我们还确保平均伽马指数值<0.6。

使用C-RAD前哨表面图像指导，将患者定位为用于模拟的治疗。在治疗前，对每种同学进行了XVI CBCT扫描，如下：

3D CBCT scanning was performed on the first head-first region and, following corrections, the VMAT field at the first isocenter was delivered. After sliding the table 32 cm longitudinally, the procedure was repeated for the second isocenter and, after sliding the table longitudinally for another 32 cm, it was repeated again for the last head-first isocenter. These three isocenters were treated with a maximum deviation of 2 mm in the longitudinal axis. The patient was then rotated to the foot-first position. A 3D CBCT scan was performed to ensure correct positioning for the fourth isocenter in the lower leg region and the last VMAT field was delivered.

为了减少儿科患者的CBCT剂量，使用了一种特殊的CBCT方案：管势能量为100 kV；每架20 mA的标称管电流；S20准直仪;F0过滤器；和183帧。

The patient was treated twice daily for three days, with an inter-fraction gap of at least 8 hours. The total treatment time for each fraction was approximately 30-35 minutes. Beam on time was 10.13 minutes in the head-first position and 2.91 minutes in the foot-first position. MU values were 2250 in the head-first position and 508 in the foot-first position.

This patient was successfully treated using VMAT TBI, with minimal side effects. Twenty-one months following the second transplant, the patient has experienced no problems or complications.

使用摩纳哥和敏捷性多动物准直仪中的金标准蒙特卡洛剂量计算算法实现了VMAT TBI的准确和同质剂量分布。此外，对于患者定位，使用C-RAD前哨表面跟踪系统而无需辐射，并且使用低剂量CBCT可提供最大的设置可重复性和准确性。

敏捷性是40厘米x 40厘米大小,它的能力achieve a virtual 1 mm leaf width with its dynamic leaf guide feature, the long travel distance of the MLC leaves and their ability to form islands on opposite sides simultaneously, are extremely advantageous in achieving the desired dose distributions and OAR protection.

In Monaco, we can achieve homogeneous dose distributions using multiple arcs within a single VMAT field. A composite plan is obtained using the Bias Dose feature in Monaco to prevent hot and cold dose points in the junction areas of the head-first and foot-first plans.

根据我们的经验，所有患者的VMAT TBI方案在早期和中期都非常成功，患者没有与白内障，肾功能或呼吸功能有关的副作用。

由于被诊断出患者的患者的预期存活率是好的，因此应考虑接受TBI的患者的辐射的长期副作用。应该对剂量均匀性，器官保存和准确剂量计算的更多关注，这可以使用VMAT TBI技术来实现。与替代性TBI技术相比，该方法可提供更高的准确性，可靠性和OAR保护，并减少不确定性。可以通过最小的副作用来实现同质剂量的递送，从而导致BMT成功和长期无疾病生存。

Institution:
Yeni Yuzyil大学Gaziosmanpasa医院

Location:
Istanbul, Turkey

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