A Study of Dose Painting Guided by Three-Dimensional Arterial Spin Labeling for Non-Enhancing Low-Grade Gliomas During Radiotherapy

doi:10.21203/rs.3.rs-1496172/v1

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A Study of Dose Painting Guided by Three-Dimensional Arterial Spin Labeling for Non-Enhancing Low-Grade Gliomas During Radiotherapy

https://doi.org/10.21203/rs.3.rs-1496172/v1

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Background: The purpose of this study was to investigate the feasibility and dosimetric characteristics of dose painting for non-enhancing low-grade gliomas (NE-LGGs) guided by three-dimensional arterial spin labeling (3D-ASL).

Methods: Eighteen patients with NE-LGGs were enrolled. 3D-ASL, T2 fluid-attenuated inversion recovery (T2 Flair) and contrast-enhanced T1-weighted magnetic resonance images were obtained. The gross tumor volume (GTV) was delineated on the T2 Flair. The hyper-perfusion region of the GTV (GTV-ASL) was determined by 3D-ASL, and the GTV-SUB was obtained by subtracting the GTV-ASL from the GTV. The clinical target volume (CTV) was created by isotropically expanding the GTV by 1cm. The planning target volume (PTV), PTV-ASL were obtained by expanding the external margins of the CTV, GTV-ASL, respectively. PTV-SUB was generated by subtracting PTV-ASL from PTV. Three plans were generated for each patient: a conventional plan (plan1) without dose escalation delivering 95%-110% of 45-60Gy in 1.8–2Gy fractions to the PTV and two dose-painted plans (plan2 and plan3) with dose escalating by 10%-20% (range, 50-72Gy) to the PTV-ASL based on plan1. The plan3 was obtained from plan2 without the maximum dose constraint. The dosimetric differences among the three plans were compared.

Results: The volume ratio of the PTV-ASL to the PTV was (23.49±11.94) % (Z=-3.724, P=0.000). Compared with plan 1, D_2%, D_98% and D_mean of PTV-ASL increased by 14.67%,16.17% and 14.31% in plan2 and 19.84%,15.52% and14.27% in plan3, respectively (P<0.05); the D_2% of the PTV, PTV-SUB increased by 11.89% and 8.34% in plan2, 15.89% and 8.49% in plan3, respectively (P<0.05). The PTV coverages were comparable among the three plans (P>0.05). In plan2 and plan3, the conformity indexes decreased by 18.60% and 12.79%; while the homogeneity index increased by 1.43 and 2 times (P<0.05). Compared with plan1, the D_0.1cc of brain stem and D_max of optic chiasma were slightly increased in plan 2 and plan 3, and the absolute doses met the dose constraint. The doses of the other organs at risk (OARs) were similar among the three plans (P>0.05).

Conclusions: The dose delivered to hyper-perfusion region derived from 3D-ASL can increased by 10-20% while respecting the constraints to the OAR, which provides a basis for future individualized and precise radiotherapy for NE-LGGs.

low-grade gliomas

non-enhancing

three-dimensional arterial spin labeling

dose painting

radiotherapy

Non-enhancing low-grade gliomas (NE-LGGs) are a special type of LGGs. Grade II Astrocytoma was the most common histological type. The vast majority of NE-LGGs are LGGs, and LGGs enhanced as commonly as they lacked enhancement [1, 2]. These NE-LGGs was not enhanced on conventional enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Their blood vessel wall composition is similar to that of brain-healthy tissue, with a complete blood-brain barrier. Macromolecules used for tumor enhancement cannot pass through the blood-brain barrier to enhance these lesions. Therefore, the lesions show low density on enhanced CT and T1 hypointensity and T2 hyperintensity on enhanced MRI (the manifestation of edema) [3, 4]. Radiotherapy is one of the effective treatment methods for NE-LGGs, which is usually the first option for patients who are unable to operate.

Most LGGs recurrence after radiotherapy predominantly occur in the radiation field in conventional radiotherapy, which is significantly associated with insufficient doses to the tumor target region [5, 6]. Based on conventional anatomical MR images for homogeneous dose boosting, the dose of healthy tissue increases simultaneously, and the occurrence of radiation damage is inevitable. In contrast, the dose-painted radiotherapy guided by functional images such as functional MR and positron-emission tomography (PET) which prescripts heterogeneous dose distribution to the target volume, is expected to achieve a safe dose boost on the premise of ensuring the safety and the accuracy of dose transmission. In a prospective phase II randomized clinical trial, it investigated the region of hyperperfused/hypercellular (TV_HCV/TV_CBV) > 1 cm³ in high b-value diffusion-weighted MRI and dynamic contrast enhanced perfusion (DCE) MRI for glioblastoma with dose boosting (75 Gy/30 f) and found that patients treated to the combined hypercellular/ hyperperfused tumor volume had significantly improved 12-month overall survival (OS) (92%; 95% CI, 78%-100%) compared with historical control (P = 0.03). However, there was no significant difference in 12-month OS between patients boosted to the hypercellular tumor volume alone vs historical control (P = 0.9) with favorable outcomes for neurocognitive function, symptom burden, and quality of life [7].

At present, the abnormal hyperintensity (edema area) on T2 fluid-attenuated inversion recovery (T2 Flair) is usually used as the standard for delineating gross tumor volume (GTV), which can ensure the coverage of radiotherapy dose to tumor, but it is difficult to increase the radiotherapy dose due to the large irradiation range. Although the tumor boundary of NE-LGGs is difficult to identify in conventional imaging, the blood flow and metabolism of the tumor are still significantly different from those of the brain tissue in the edema area in biology [8]. Quantifying this difference through functional imaging can clarify the distribution of tumor cell enrichment areas, which could guide the delineation of target volume during radiotherapy. Commonly functional imaging, including dynamic susceptibility contrast MRI (DSC), DCE or PET, requires intravenous administration of a contrast agent and is therefore somewhat limited.

As a non-invasive blood perfusion imaging technology, three-dimensional arterial spin labeling (3D-ASL) generates an image by magnetically labeling water molecules as an endogenous tracer. It does not require the destruction of the blood–brain barrier and can reflect microscopic changes in tissue blood perfusion and micro-vessel density [9, 10]. 3D-ASL perfusion imaging can effectively distinguish intracranial tumors from non-neoplastic lesions, and the tumor cerebral blood flow (CBF) value is significantly negatively correlated with survival [11, 12]. ASL has been used to guide stereotactic biopsy and operation for glioma. Jin et al. [13] showed that compared with conventional MRI, combined magnetic resonance spectroscopy (MRS) and ASL improved the accuracy of target selection for the stereotactic biopsy of intracranial tumors, especially three cases each of low-enhancing and non-enhancing gliomas. Lindner et al. [14] concluded that intraoperative ASL was a feasible, reproducible, and reliable tool to map CBF in brain tumors and seemed to give beneficial information compared to conventional intraoperative MRI in partial resection.

3D-ASL has been widely used in the diagnosis, grading and efficacy evaluation of gliomas [15, 16]. However, there are few reports on its application in guiding the radiotherapy planning of NE-LGGs. In this study, we investigated whether dose painting for NE-LGGs can achieve dose escalation to hyper-perfusion region derived from 3D-ASL without increasing the dose to cranial organs at risk (OARs).

2.1 Patients

This study enrolled 18 patients with pathologically confirmed, newly diagnosed glioma from Shandong Cancer Hospital between December 2018 and May 2021. Patients, including 12 (67%) males and 6 (33%) females, with an average age of 42 ± 21 years (5 to 74 years), showed nonenhancement on diagnostic brain MRI that strongly suggested a diagnosis of World Health Organization (WHO) grade I or II glioma. Radiological studies performed on the patients were accessed by 2 neuroradiologists from Picture Archiving and Communication Systems (PACS). WHO grading was reviewed by 3 neuropathologists according to the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5) [17]. Patient’s characteristics are presented in Table 1.

Table 1

Clinical characteristics of the patients
Characteristics	Number of patients (%)
Age type
Adults	15 (83%)
Pediatric	3 (17%)
Tumor location
Unilateral	7 (39%)
Midline ^* (H3 K27-altered status)	8 (44%)
Altered	0 (0%)
Non-altered	7 (39%)
NOS	1 (5%)
Bilateral (diffuse distribution)	3 (17%)
Type of histopathology
Astrocytoma	18 (100%)
WHO classification
Grade II	18 (100%)
IDH mutation status
Mutant	1 (6%)
Wild type	13 (72%)
NOS	4 (22%)
1p/19q deletion status
Codeletion	0 (0%)
No deficiencies	4 (22%)
NOS	14 (78%)
Concurrent temozolomide chemoradiotherapy
Yes	14 (78%)
No	4 (22%)
^* Midline location included brainstem, thalamus, cerebellum. NOS, Not Otherwise Specified. WHO, World Health Organization; IDH, isocitrate dehydrogenase.

Our retrospective study followed medical ethics guidelines, and the Institutional Review Board of Shandong Cancer Hospital approved this study (NO. 20211109). All patients signed informed consent forms. We protected patient privacy and excluded patient identification information from our analysis.

2.2 CT and MRI images acquisition

2.2.1 CT

A CT scanner (Brilliance Big Bore, Philips, Netherlands) with a slice thickness of 3 mm and no interslice gap width was used, scanning from the foramen magnum to the end of the skull in a caudocranial direction.

2.2.2 MRI

All MR images (T2 Flair, 3D-ASL and contrast-enhanced T1-weighted (CE-T1W)) were acquired with the same 3.0T MR scanner (Discovery 750W, GE Healthcare, USA) using a standard 8-channel cranial coil. For CE-T1W images, gadopentetate dimeglumine was injected at doses standardized by patient’s body weight (0.2 mL/kg) at 2 mL/s, and the scan was started 3–5 min after the injection. The common scan parameters for all sequences are shown in Table 2.

Table 2

Parameters of multi-sequence MR
Parameters	T2 Flair	3D-ASL	CE-T1WI
TR (ms)	11000	5160	8.5
TE (ms)	120	11.5	3.2
Layer thickness(mm)	3	3	3
FOV (cm)	26	25.6	25.6
Matrix	320×320	512×512	256×256
T2 Flair, T2 fluid attenuated inversion recovery; 3D-ASL, three-dimensional arterial spin
labeling; CE-T1WI, contrast-enhanced T1-weighted imaging; TR, repetition time; TE, echo time; FOV, field of view.

2.2.3 3D-ASL data acquisition and postprocessing

Setting a marking plane on the neck in advance, labeling with pseudo-continuity, image acquisition with single-shot gradient-echo echo planar imaging (EPI), labeling duration = 1500 ms, post spin labeling delay (PLD) = 2025 ms, number of excitation (NEX) = 3, forty pairs of control/label images were acquired and averaged. The scan duration was 5:27. For measurement of the magnetization of arterial blood and also for segmentation purposes, an M0 calibration image was acquired separately with the same geometry and the same imaging parameters as the ASL without labeling. Background suppression technology was used in the process of image acquisition.

The raw 3D-ASL data were transferred to the GE Advantage Workstation 4.7 and post-processed in the FuncTool environment. The motion correction, temporal and spatial filtering, and partial volume effect correction were performed. Subsequently, the CBF values were calculated by intensity normalization. A quantitative CBF map was generated based on the following equation [18]:

$$\text{C}\text{B}\text{F}=\frac{6000\bullet {\lambda }\bullet \left({\text{S}\text{I}}_{\text{c}\text{o}\text{n}\text{t}\text{r}\text{o}\text{l}}{-\text{S}\text{I}}_{\text{l}\text{a}\text{b}\text{e}\text{l}}\right)\bullet {\text{e}}^{\frac{\text{P}\text{L}\text{D}}{{\text{T}}_{1,\text{b}\text{l}\text{o}\text{o}\text{d}}}}}{2\bullet {\alpha }\bullet {\text{T}}_{1,\text{b}\text{l}\text{o}\text{o}\text{d}}\bullet {\text{S}\text{I}}_{\text{P}\text{D}}\bullet (1-{\text{e}}^{-\frac{{\tau }}{{\text{T}}_{1,\text{b}\text{l}\text{o}\text{o}\text{d}}}})}\left[\text{m}\text{l}/100\text{g}/\text{m}\text{i}\text{n}\right]$$

Where λ is the brain/blood partition coefficient in ml/g, SI_control and SI_label are the time-averaged signal intensities in the control and label images, respectively, T_1,blood is the longitudinal relaxation time of blood in seconds, α is the labeling efficiency, SI_PD is the signal intensity of a proton density-weighted image, τ is the label duration, and PLD is the post-labeling delay. The parameters used in the present study were: λ = 0.9, T_1,blood = 1650 ms, α = 0.85, τ = 1500 ms and PLD = 2025 ms. The SI_PD was derived from the echo planar imaging M0 images. The factor of 6000 converts the units from ml/g/s to ml/100g/ min, which is customary in the physiological literature

2.3 Target volume delineation

All MRI images were imported into MIM Maestro software (6.8.8, USA). The tumor target volume and organs at risk (OARs) were delineated by two senior radiologists, and another senior radiologist confirmed the target volume and modified it as needed. Axial T2 flair sequences were used to contour the hyperintense abnormality as the GTV. The GTV-ASL was defined as a high-perfusion region under the guidance of 3D-ASL sequence that was free of cysts, necrosis, calcifications, hemorrhage, and large vessels. The GTV-SUB was obtained by subtracting the GTV-ASL from the GTV.

Clinical target volumes (CTV) were created by isotropically expanding the GTV by 1 cm. The planning target volume (PTV) and PTV-ASL were generated by adding a 0.5 and 0.3 cm margin to CTV and GTV-ASL, respectively. The PTV-SUB was obtained by subtracting the PTV-ASL from the PTV. The PTV-ASL was used to generate simultaneous integrated boost (SIB) volume. OARs used for treatment planning were: eyeballs, lenses, optic nerves, optic chiasma and brain stem. Figure 1(A) and Fig. 1(B) show the target volumes delineated for two patients with NE-LGGs.

2.4 Radiotherapy planning

All treatment plans were designed in the Eclipse (Version 15.6, Varian, USA) treatment planning system using intensity-modulated radiotherapy (IMRT). Three plans were generated for each patient: a conventional plan (plan 1) without dose escalation delivering 95%-110% of 45–60 Gy in 1.8–2 Gy fractions to the PTV and two dose-painted plans (plan 2 and plan 3) with dose escalating by 10%-20% (range, 50–72 Gy) to the PTV-ASL based on plan 1. The plan 3 was obtained from plan 2 without the maximum dose constraint. The prescription dose ultimately depended on the location of tumor. Seven patients with unilateral hemispheric tumors were prescribed 60 Gy in plan 1, and the dose of PTV-ASL increased by 20% (72 Gy) in plans 2 and 3. For other patients, the prescription doses were relatively limited because the tumors were located in important functional areas such as the midline of the brain or widely distributed. The prescription doses were 45–54 Gy in plan 1, and the dose of PTV-ASL increased by 10% − 20% (50–60 Gy) in plan 2 and plan 3.

The field angles were constant for all three treatment plans. Dose calculation was performed in anisotropic analytical algorithm optimization mode (AAA, version 15.512) using 6 MV X-rays. The calculated grid size was 2.5 mm × 2.5 mm, and the prescription covered 95% of the target volume.

The doses of OARs were restricted as following: brain stem D_0.1cc (the dose to 0.1cc target volume) ≤ 54 Gy, eyeballs D_max (the maximum dose) < 45 Gy, lens D_max < 10 Gy, and optic nerves and optic chiasm D_max ≤ 55 Gy.

2.5 Evaluation of treatment plans

To compare the three treatment plans, cumulative dose–volume histograms (DVHs) were calculated for all target volumes and OARs for all patients. The D_2% and D_98% (where D_x indicates the dose to x% of the target volume) as well as average dose (D_mean) were compared for the PTV, PTV-SUB and PTV-ASL. Furthermore, the target coverage, conformity index (CI) and homogeneity index (HI) were calculated. A CI close to 1 indicates that the shape of the region receiving the reference dose closely matches the shape of the target region, and an HI close to 0 indicates good uniformity. The formulas for calculating CI and HI are as follows:

$\text{C}\text{I}=\frac{{\left({\text{V}}_{\text{t},\text{r}\text{e}\text{f}}\right)}^{2}}{{\text{V}}_{\text{t}}\bullet {\text{V}}_{\text{r}\text{e}\text{f}}}$, $\text{H}\text{I}=\frac{{\text{D}}_{2\text{\%}}-{\text{D}}_{98\text{\%}}}{{\text{D}}_{50\text{\%}}}$

where V_t represents the volume of the target region, V_t,ref represents the volume of the target region covered by the reference dose, and V_ref represents the volume of all regions covered by the reference dose. The flow chart of this study is as shown in Fig. 2.

2.6 Statistical analyses

Statistical analyses were performed using SPSS (IBM, version 25.0). Comparisons between two groups were done with paired t-tests or Wilcoxon tests, depending on the distribution defined by the Shapiro–Wilk normality test. Comparisons of multiple groups were performed by 2-way analysis of variance (ANOVA), followed by least significant difference (LSD) and Friedman two-way ANOVA, followed by Friedman multiple comparison tests, depending on Levene’s test of variance homogeneity. All datas were expressed as mean ± standard deviation, and P < 0.05 was considered as a significant difference.

3.1 Comparison of target volumes

The volumes of the PTV and PTV-ASL were 383.95 ± 255.69 cm³ and 90.06 ± 92.03 cm³, respectively. The volume ratio of the PTV-ASL to the PTV was (23.49 ± 11.94) % (Z = -3.724, P = 0.000). Technically, it was feasible to escalate the dose to hyper-perfusion target volume up to 72 Gy without violating dose constraints of normal tissues and, meanwhile, to ensure prescribed doses to the PTVs. Figure 3 shows an example of the dose distribution for the three plans for a sample patient. Figure 4 shows the DVHs of sample target volumes and OARs.

3.2 Dosimetric comparison of target volumes among the three plans

3.2.1

The doses of the PTV, PTV-SUB and PTV-ASL increased in plan 2 and plan 3 than plan 1. The D_2% increased by 11.89%, 8.34%, and 14.67% in plan 2 and 15.89%, 8.49%, and 19.84% in plan 3, respectively, with statistically significant differences (P < 0.05); the D_98% increased by 1.12%, 0.93%, and 16.17% in plan 2 and 0.7%, 0.49%, 15.52% in plan 3, respectively, but only increased significantly for the PTV-ASL in plans 2 and 3 (P < 0.05); and D_mean increased by 5.15%, 3.60%, and 14.31% in plan 2 and 4.62%, 2.71%, and 14.27% in plan 3, respectively, with statistically significant differences (P < 0.05) except for the PTV in plan 3.

3.2.2

Compared with plan 2, the D_2% of the PTV, PTV-SUB and PTV-ASL increased by 3.58%, 0.51% and 4.52% in plan 3, respectively, with statistically significant differences for the PTV and PTV-ASL (P < 0.05); D_98% and D_mean decreased by 0.41%, 0.43%, and 0.56% and 0.50%, 0.86%, and 0.03%, respectively, with no statistically significant differences (P > 0.05), as shown in table 3 (provided as an additional file) and Fig. 5.

3.3 Plan evaluation

The PTV target coverages for plan 1, plan 2 and plan 3 were comparable (98.45%±2.16% vs. 98.70%±2.31% vs. 98.20%±2.31%, P > 0.05). Compared with plan 1, the CIs decreased by 18.60% in plan 2 and 12.79% in plan 3, respectively, with statistically significant differences (P < 0.05), while the CIs were comparable between plan 2 and plan 3 (P > 0.05). Compared with plan 1, the HIs increased by 1.43 times in plan 2 and 2 times in plan 3, respectively; and increased by 23.53% in plan 3 than in plan 2 (P < 0.05).

3.4 Dosimetric comparison of OARs among three plans

Compared to plan 1, the brain stem D_0.1cc and optic chiasma D_max were slightly increased by 3.98% and 4.33% in pan 2, and 4.52% and 6.27% in plan 3 respectively, with statistically significant differences (P < 0.05), while the absolute doses were safe. The D_max of the eyeballs, lens, and optic nerves were comparable among plan 1, plan 2, and plan 3 (P > 0.05), as shown in table 4 (provided as an additional file).

Many LGGs inevitably develop into malignant high-grade gliomas, and even with effective treatment, the survival rate of patients with LGGs remains poor [19, 20]. Radiotherapy can delay the malignant transformation of LGGs, improve the local control rate of tumor, and improve the survival rate and quality of life of patients.

European Organization for Research and Treatment of Cancer (EORTC) 22,844 included over 300 patients with Grade 2 astrocytoma and randomized them to 45 Gy or 59.4 Gy. With a median follow up of over 6 years, there was no significant difference in survival rates between the two groups [21]. Another randomized trial the North Central Cancer Treatment Group (NCCTG) assessed over 200 patients with grade II gliomas. This study, which classified the low-dose group as 50.4 Gy/28 fractions and the high dose group as 64.8 Gy/36 fractions, found no significant difference in OS or progression free survival, but a doubling of radiation necrosis (2.5–5%) with higher dose [22]. An important finding to explore is that patients receiving higher doses had worser survival than lower radiation doses. One potential reason for this discovery could be that these trials were mainly based on conventional anatomical MR images for homogeneous dose boosting, with a simultaneous dose increase for healthy tissues, as resulted in radiation toxicity. Radiation on the brain, although used as a therapy, has its consequences.

NE-LGGs, as a special type of LGGs with significant heterogeneity, require an individualized radiotherapy dose for the tumor target volume. Jakola et al. [23] showed that the blood–brain barriers of NE-LGGs were disrupted after malignant transformation, and the region that appeared to be enhanced was much smaller than the edema area. Although coverage of the radiotherapy dose to the tumor can be guaranteed if the edema area is directly defined as the GTV of the NE-LGGs, it is difficult to increase the radiotherapy dose due to the large irradiation range. However, we found that NE-LGGs showed no abnormalities on CE-T1W MRI but showed local high perfusion on 3D-ASL. And all the local hyper-perfusion regions were within edema areas through the fusion images of T2 Flair and 3D-ASL. The study also found that the volume of the hyper-perfusion region (GTV-ASL) was significantly smaller than the volume of the edema area (GTV) by analyzing target volumes. The target volume of dose escalation guided by 3D-ASL was smaller than conventional radiotherapy. Under the same prescription dose, the dose of surrounding healthy tissues is lower. Therefore, it is more conductive to dose escalation ensuring that surrounding healthy tissues were not damaged.

3D-ASL is a functional MRI that does not depend on the destruction of the blood-brain barrier and the paramagnetic contrast agent. It has the advantages of being non-invasive, low cost, simple to operate, and repeatable, and effectively avoids the potential risks caused by an exogenous contrast agent [24]. Related studies have shown that the CBF determined by 3D-ASL is significantly positively correlated with micro-vessel density (ρ = 0.567; P = 0.029) and vascular endothelial growth factor expression (r = 0.604; P < 0.001) but significantly negatively correlated with survival (r=-0.714, P < 0.001) and can be an independent risk factor for OS (HR = 1.028; P = 0.010) [12, 25]. We defined the high-perfusion region derived from 3D-ASL in GTV as a high-risk region, which was conducted SIB.

In this study, plan 1 was the conventional plan and plan 2 and plan 3 were dose-painted plans. Compared with plan 1, the D_2%, D_98% and D_mean of the PTV-ASL increased by more than 14% in plan 2 and plan 3; however, these values increased by less than 9% in the PTV-SUB, with D_98% increased by less than 1%. This suggested that under the guidance of 3D-ASL, the dose-painted plan can achieve a significant dose boost in hyper-perfused sub-volume region for NE-LGGs while having less impact on the peripheral dose and avoiding dose boost blindness. This is similar to the study of Thureau et al., which was based on 18Flourodeoxyglucose (¹⁸FDG) PET-CT image-guided dose boost for locally advanced non-small-cell lung cancer [26]. The dose to high recurrence risk areas increased by 12.12% without increasing the radiation dose to OARs, whereas the doses to other areas of the GTV only increased by 2.88%. We also found that the D_2% of the PTV, PTV-SUB and PTV-ASL gradually increased in plan 1, plan 2 and plan 3, while the D_98% and D_mean of each target region were comparable between plan 2 and plan 3. Thus, the elimination of maximum dose constraints is favorable to boost the maximum dose but has no significant effect on the minimum or average dose.

The target coverages of the PTV were comparable among plan 1, plan 2 and plan 3, with the prescribed isodose line wrapping around approximately 95% of the PTV, indicating that all treatment plans for plan 2 and plan 3 met the minimum dose requirements of the target region. Because only the local hyper-perfused regions on 3D-ASL were escalated in plan 2 and plan 3, whereas the edema areas surrounding the hyper-perfused regions received standard doses, the HIs were larger in plan 2 and plan 3 than in plan 1. In this study, the conformality and homogeneity of plan 2 and plan 3 decreased, however, the dose to the tumor target region was significantly increased. Therefore, reducing the homogeneity of the radiation dose is beneficial for dose escalation and protecting OARs.

During radiotherapy for patients with NE-LGGs, radiation damage to surrounding healthy tissues should not be ignored. The dose boost to the tumor target region must be balanced with protecting OARs. The results of this study showed that the dose delivered to OARs were comparable among the three treatment plans, except for brain stem and optic chiasma. However, the absolute doses of all OARs were within a safe range. In addition, the constrained boost plan outperformed the unconstrained plan in terms of OAR protection.

The main limitations of our study were as follows: (1) the number of enrolled patients is relatively small, due to the low incidence of NE-LGGs. Meanwhile, most of patients were operated. Due to the destruction of the blood-brain barrier, the post-operative area was frequently enhanced on enhanced MRI, which cannot be enrolled in the study. (2) Although this is a preclinical technical study, it lays a foundation for future studies on the impact of this technology on the progression free survival (PFS) and OS.

The dose delivered to hyper-perfusion region derived from 3D-ASL can increased by 10–20% while respecting the constraints to the OAR, which provides a basis for future individualized and precise radiotherapy for NE-LGGs.

LGGs: non-enhancing low-grade gliomas; CT: computed tomography; MRI: magnetic resonance imaging; PET: positron-emission tomography; DCE: dynamic contrast enhanced; OS: overall survival; T2 Flair: T2 fluid-attenuated inversion recovery; GTV: gross tumor volume; DSC: dynamic susceptibility contrast; 3D-ASL: three-dimensional arterialspin labeling; CBF: cerebral blood flow; MRS: magnetic resonance spectroscopy; PACS: Picture Archiving and Communication Systems; WHO CNS5: the fifth edition of the WHO Classification of Tumors of the Central Nervous System; NOS: not otherwise specified; IDH: isocitrate dehydrogenase; CE-T1W: contrast-enhanced T1-weighted; EPI: echo planar imaging; PLD: post spin labeling delay; NEX: number of excitation; TR: repetition time; TE: echo time; FOV: field of view; OARs: organs at risk; CTV: Clinical Target Volume; PTV: planning target volume; SIB: simultaneous integrated boost; IMRT: intensity-modulated radiotherapy; DVHs: dose–volume histograms; D_x: the dose to x% of the target volume; D_max: the maximum dose; D_min: the minimum dose; D_mean: the average dose; CI: conformity index: HI: homogeneity index; ANOVA: analysis of variance; LSD: least significant difference: ¹⁸FDG: 18Flourode oxyglucose.

Ethical approval and consent to participate

Consent for publication

Not applicable.

Availability of data and materials

The data set used and analysed during the current study were available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by Cultivation Project of Shandong Cancer Hospital (Grant No. YYPY2020-016).

Authors’ Contributions

Guanzhong Gong conceived and designed the study. Lizhen Wang and Ya Su collected data. Zihong Zhu made a statistical analysis, performed the experiments and wrote the paper. Yong Yin and Jie Lu reviewed and edited the manuscript. All authors read and approved the manuscript.

Acknowledgments

Not applicable.

Author details

¹ Department of Oncology, Affiliated Hospital of Southwest Medical University, No.25 Taiping Street, Jiangyang District, Luzhou City, 646000, Sichuan Province, China

² Department of Radiation Oncology Physics and Technology, Shandong Cancer Hospital and Institute, 338 Shandong First Medical University and Shandong Academy of Medical Sciences, No.440 Jiyan Road, 339 Huaiyin district, Jinan City, 250117, Shandong Province, China

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No competing interests reported.

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A Study of Dose Painting Guided by Three-Dimensional Arterial Spin Labeling for Non-Enhancing Low-Grade Gliomas During Radiotherapy

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Abstract

Figures

1 Introduction

2 Materials And Methods

2.1 Patients

2.2 CT and MRI images acquisition

2.2.1 CT

2.2.2 MRI

2.2.3 3D-ASL data acquisition and postprocessing

2.3 Target volume delineation

2.4 Radiotherapy planning

2.5 Evaluation of treatment plans

2.6 Statistical analyses

3 Results

3.1 Comparison of target volumes

3.2 Dosimetric comparison of target volumes among the three plans

3.3 Plan evaluation

3.4 Dosimetric comparison of OARs among three plans

4 Discussion

5 Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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