Dosimetric feasibility analysis and presentation of an isotoxic dose-escalated radiation therapy concept for glioblastoma used in the PRIDE trial (NOA-28; ARO-2022-12)

Highlights • The presented dose escalation strategy doubles the risk of radiation necrosis.• While Literature suggests that Bevacizumab can halve its risk.• Dose constraints of organs at risk were adhered to.• Therefore, isotoxicity might be achieved in the upcoming PRIDE trial.

Background and purpose: The PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023.Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions.To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach.The current study aims to assess the dosimetric feasibility of the proposed concept.Materials and methods: A total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis.Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline.The Abbreviations: 4-miRNA, 4-micro-ribunucleoid-acid; BEV, bevacizumab; BTV, biological target volume; CT, computed tomography; CTV, clinical target volume; CTV60, clinical target volume of the reference plan; CTV60ex, clinical target volume of the experimental plan; D0.03cc, dose covering 0.03cc; D2, dose which is covered by 2 % of the respective volume; D50, dose which is covered by 50 % of the respective volume; D98, dose which is covered by 98 % of the respective volume; Dmax, maximum irradiation dose; Dmean, mean irradiation dose; DVH, dose volume histogram; EUD, Equivalent Uniform Dose; FET, O-(2-18F-fluoroethyl)-Ltyrosine positron emission; GTV, gross tumor volume; GTVu, union of the biological tumor volume, the gross tumor volume (including resection cavity); IDH, isocitrate dehydrogenase; IDH wt, isocitrate dehydrogenase wild-type; IR, increased risk; MGMT, methylguanine methyltransferase; MRI, magnet resonance imaging; NTCP, Normal Tissue Complication Probability; OAR, organ at risk; OS, overall survival; PET, positron emission tomography; PFS, progression-free survival; PTV, planning target volume; PTV60, planning target volume of the reference plan; PTV60ex, planning target volume of the experimental plan; PTV75, planning target volume of the 75 Gy simultaneous integrated boost volume; PTV75opt, the 75 Gy volume cropped at the brainstem, the optic nerves and the chiasma with a 5 mm margin; PRV, planning organ at risk volume; RN, radiation necrosis; RT, radiation therapy; SIB, simultaneous integrated boost; TMZ, temozolomide; VEGF, vascular endothelial growth factor.

Introduction
The current standard of care for glioblastoma involves performing a maximum safe resection followed by radiochemotherapy delivered at a dose of 60 Gy in 30 fractions or 40 Gy in 15 fractions depending on the patient ś age and clinical condition [1][2][3][4].Concurrent and sequential chemotherapy is administered following either the EORTC 26981/ 22981 or the NOA-09 regimen, depending on the methylguanine methyltransferase (MGMT) promoter methylation status [1,5].Despite the aggressive nature of the current treatment regimens, the overall survival (OS) of patients with glioblastoma remains poor, emphasizing the need for novel and improved treatment strategies.
A major challenge in the treatment of glioblastoma is the insufficiency of the standard radiation dose to effectively control the tumor.Supporting this notion is the observation of many publications that 75-93 % of recurrences/progressions manifest within the primary tumor area [6][7][8][9][10].To address this concern, several trials have explored dose escalation concepts, with some studies reporting favorable outcomes in terms of OS and progression-free survival (PFS) [11][12][13][14][15][16][17][18][19].However, these benefits are mostly accompanied by an elevated risk of treatmentrelated toxicity such as radiation necrosis (RN).
To address this issue of increased RN risk, the PRIDE trial ("Protective VEGF Inhibition for Isotoxic Dose Escalation in Glioblastoma"; NCT05871021; NOA-28; ARO-2022-12) aims to incorporate the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (BEV) into dose-escalated radiation therapy (RT), with doses up to 75 Gy (Fig. 1).BEV is known to be effective in treating steroid-refractory edema and RN [20,21].Its protective potential during re-irradiation treatment was shown in a study by Fleischmann et al, reducing the one-year risk of RN and symptomatic edema from 54.1 % to 23.9 %, p = 0.013; the percentage of patients with RN was substantially reduced in patients receiving BEV compared to patients not receiving BEV (4.8 % vs. 13.5 %; p = 0.078) [22].Assuming that the risk of RN doubles with the proposed dose escalation schedule and that the protective effects of BEV are consistent in primary RT, dose-escalated RT with concurrent BEV could potentially achieve isotoxicity compared to standard RT, while potentially improving PFS and possibly extending OS.
The PRIDE trial is designed as a, single-arm, open-label, nonrandomized, multicenter phase IIa study.It is intended to include a total of 146 patients from ten different centers as depicted in Fig. 2. The cohort for the PRIDE trial will consist of patients with glioblastoma who meet the following criteria: isocitrate dehydrogenase wild-type (IDH wt), MGMT non-methylated, aged between 18 and 70 years, and clinically eligible to receive temozolomide (TMZ) and BEV.The complete inclusion and exclusion criteria are shown in Table 1, while a visual representation of the patient selection process is provided in Fig. 3.The primary endpoint of the PRIDE trial is OS, which will be the main measure of treatment effectiveness.The trial also includes several secondary endpoints, including treatment safety and tolerability of the treatment, PFS, quality of life assessment, and evaluation of cognitive function.In addition to these endpoints, there is a translational exploratory objective in the study to validate a 4-micro-ribunucleoidacid (4-miRNA) signature-based risk subgroup classification [23,24].This objective aims to investigate the potential of a specific 4-miRNA signature in predicting treatment response or prognosis.Recruitment for the study is planned to start on October 1st, 2023, and continue until October 1st, 2024.The end of the study is scheduled for October 1st, 2026 ensuring a minimum follow-up period of 24 months for the enrolled patients.
The primary objective of this dosimetric feasibility study is to conduct a comparative analysis between the standard treatment approach and the experimental treatment protocol which will be utilized in the PRIDE trial.The results obtained from this study will contribute to determining the feasibility of the proposed treatment concept for the upcoming phase II trial.

Material and methods
For this dosimetric feasibility study, a total of ten patients, who had previously undergone treatment for glioblastoma, were selected from Fig. 2. A map of Germany depicting the ten centers, who will be participating in the PRIDE trial.
R. Bodensohn et al. the internal clinical database MOSAIQ® (Elekta, Stockholm, Sweden).The contrast-enhanced T1 and T2 FLAIR weighted magnet resonance imaging (MRI) sequences, the planning computed tomography (CT) scans, and the O-(2-18F-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) scans from the primary treatment were utilized to generate two distinct RT treatment plans.The first plan, serving as the reference, was generated following the ESTRO-EANO contouring guidelines of 2023 [25].The second plan was a modified plan generated in accordance with the specific study guidelines outlined for the PRIDE trial.

Target definition
The gross tumor volume (GTV) was created by delineating the contrast-enhanced tumor and the resection cavity in the T1 MRI sequence.Highly suspicious T2 FLAIR enhancements were also included in the GTV.In addition to the GTV, a biological tumor volume (BTV) was generated using the target-to-background ratio (TBR) threshold of 1.8, based on the FET PET scan with the assistance of nuclear medicine experts (further details provided in the subsequent section) [26,27].The union of the GTV and the BTV was defined as GTVu.In the reference plan, the clinical target volume (CTV) receiving 60 Gy (CTV60) was generated by expanding the GTVu with a 15 mm margin, following the 2023 ESTRO-EANO contouring guidelines, and anatomical adjustements [25]: The contour was cropped at the skull, the falx cerebri, the tentorium cerebelli, the optic nerves, the optic chiasm and the brainstem allowing no overlap (except in the case of direct/midbrain involvement); at the ventricles an overlap of 5 mm was allowed.In the experimental plan the CTV receiving 60 Gy (CTV60ex), was created by expanding the GTVu with a 10 mm margin (5 mm less than in the reference plan); the anatomical adjustments were equivalent to the CTV60.To generate the corresponding planning target volumes (PTV) the CTV60 and the CTV60ex were expanded with a 3 mm margin resulting in the PTV60 and the PTV60ex, respectively, without further modifications.In the experimental treatment plan, an additional PTV was created specifically for the dose escalation to 75 Gy (PTV75); it was generated by expanding the GTVu with a 3 mm margin, with no further adjustments.If the PTV75 was adjacent to or infiltrating critical structures, such as the brainstem, the chiasm or the optic nerves, a PTV75opt was generated by subtracting the mentioned organs at risk (OAR) with a safety margin of 5 mm from the PTV75.All target volumes were delineated by three radiation oncology consultants, who reached a consensus on the contours of the structures.

Definition of BTV on FET PET
BTV on FET PET was defined as recommended in the joint nuclear medicine/neuro-oncology procedural guidelines on amino acid PET.Summation PET images acquired 20-40 min post injection were used [26].The mean background activity was assessed using crescent-shaped regions-of-interest in the brain hemisphere contralateral to the target lesion, as previously established [27].BTV was semi-automatically delineated using a cut-off threshold of 1.8× background activity (target-to-background ratio, TBR); all voxels above a TBR of 1.8 were included into the BTV.In case of multifocal disease, all BTVs were summed up.Each BTV was individually controlled for potential spill-in uptake of adjacent structures, such as vessels and the skull, and manually adjusted if necessary.

Dose planning
All plans were generated by a medical physicist using the inverse planning software MONACO® by Elekta (Stockholm, Sweden), which utilizes a Monte Carlo dose calculating algorithm.The prescription details for the experimental and reference plan are presented in Table 2. OAR constraints were used as given per ESTRO-EANO guideline 2023 by Niyazi et al with slight adaptations and summarized in Table 3 [25].To optimize the dose distribution and achieve a balance between adequate target coverage and minimizing radiation exposure to the OAR, the medical physicist was encouraged to employ non-coplanar arcs.

Equivalent uniform dose (EUD)
The EUD concept introduced by Niemierko et al. was employed to evaluate and compare the quality of the reference and experimental treatment plans [28].The EUD represents the radiation dose that would result in the same clinical effect as achieved by the actual heterogeneous

Table 1
The Inclusion and exclusion criteria of the PRIDE-trial (AST = aspartate aminotransferase; ALT = alanine aminotransferase; IDH = Isocitrate dehydrogenase; MGMT = methylguanine methyltransferase; ECOG = Eastern Cooperative Oncology Group; ULN = upper limit of normal; NYHA = New York Heart Association; NCI-CTC = National cancer institute common terminology criteria).
The EUD is calculated by using the formula depicted below, which takes into account the irradiated partial volumes (V i ) and doses (D i ) in each bin, and the volume-effect parameter a (a ∊ [1… ∞[).For a->∞ and a = 1 the EUD would be equivalent to the maximum dose (Dmax) and the mean dose (Dmean), respectively.

Normal tissue complication probability (NTCP) model
The NTCP model developed by Niyazi et al. was applied for comparison of the RN risk assuming no differences between photon and proton dose distributions, since the effects appear to be independent of the linear energy transfer [33,34].The NTCP model used in this study is based on the EUD of the brain (pure brain tissue excluding cavernous sinuses, brainstem, optic chiasm, optic nerves, pituitary, mammillary bodies, Meckel's caves and GTVu) with a = 9 and converted to 30 fractions: As we hypothesize that BEV can reduce the risk of RN by a factor of 2-3, similar as what has been shown for patients receiving reirradiation [22], we aim to achieve a similar factor for the ratio of the two NTCP values (NTCP ref , NTCP ex : the NTCP of the reference and the experimental treatment plan, respectively): A more precise estimation to assess the increased risk (IR) of the experimental plan was performed with the following logarithmical formula: A value of "1", "2" or "3" would mean that the risk of RN is identical, increased by a factor two, or by a factor three, respectively, for the experimental plan compared to the reference plan.

Plan comparison
The ProKnow® cloud-based platform (Elekta, Stockholm, Sweden), was employed for the comparison and analysis of both treatment plans.The anonymized images, registrations, structure sets, and dose distributions of the reference and experimental plan were uploaded to the platform for further analysis.Using the prescription and constraints provided in Tables 2 and 3, scorecards were created enabling the assessment and comparison of plan quality.

Discussion
Historically, the primary goal of RT for glioblastoma has been to effectively treat the extensive non-visible tumor cell population, given the infiltrative nature of glioblastoma.In fact, up to the 1990 s glioblastoma was treated with whole-brain RT in addition to RT to the tumor volume or resection cavity [35].With the advancement of imaging techniques, the size of the treatment volumes gradually decreased.The 2016 ESTRO-ACROP guideline recommended expanding the GTV with 2.0 cm and optionally including the entire visible edema in the T2 sequence of the MRI [36].Despite the considerable reduction of the treatment volume compared to the historical whole-brain RT, volumes were still quite large.The introduction of advanced imaging techniques, such as amino acid PET (e.g.FET PET), which enables the delineation of a Biological Tumor Volume (BTV), offered the potential for further refinement of treatment volumes [37].Several studies investigating FET-based planning and recurrence analyses have reported on the reduction of treatment margins.For instance, a recurrence pattern analysis by Fleischmann et al. described a feasible reduction in the margin to 1.5 cm, while Laack et al. went even further by reducing the margin to 1.0 cm [38,39].Following these observations, the recent ESTRO-EANO guideline from 2023 recommends a GTV-to-CTV-margin of 1.5 cm (1.0-1.5 cm for "molecularly defined" tumors); additionally, the edema is no longer included in the CTV [25].In addition to margin reduction, PET-based planning has been explored as a strategy for dose escalation in glioblastoma treatment.Notably, Piroth et al and Kim et al have conducted studies exploring the concept of escalating the radiation dose to 72 Gy and 75 Gy, respectively [16,19].
Piroth et al. implemented dose escalation guided by PET imaging in their study.Their hypothesis was that utilizing FET PET could optimize

Table 4
The dose values of the target volumes for both plans of every patient: the green values are completely within protocol, the yellow values are acceptable variations, the orange values are above or below the margin of acceptance; the ranges are shown in Table 2.The numbers in the brackets with the asterisk (*) show the corresponding numbers of the PTV75opt, which was generated in this cases due to adjacency to critical organs at risk (D98, D50, D2 = the dose covering 98 %, 50 % and 2 % of the volume standing for the near minimal, mean and near maximal dose, respectively; GTVu = the union of the gross tumor volume and the biological tumor volume; PTV60, PTV60ex = the planning target volume prescribed with 60 Gy of the reference plan and of the experimental plan; PTV75 = the planning target volume prescribed with 75 Gy of the experimental plan).

Table 5
The dose exposure of the organs at risk (OAR): the green values are completely within protocol, the yellow values are acceptable variation, the orange values are above or below the margin of acceptance, the non-colored values do not have any specific constraints; the accepted ranges are shown in Table 3 (   coverage and allow regional dose escalation the areas containing viable tumor tissue.They conducted a phase II trial involving 22 patients, administering radiotherapy through MRI-and FET PET-guided integrated-boost intensity-modulated radiotherapy.Interestingly, the authors concluded that their concept did not yield an OS benefit.However, they noted the significant presence of MGMT unmethylated patients who underwent subtotal tumor resection, a factor the authors acknowledged but did not take into account in their analysis.In contrast to the planned PRIDE study dose-escalation was done up to 72 Gy and the resection cavity was excluded from the volume which received doseescalation [16].Kim et al. conducted a study investigating doseescalated radiotherapy in glioblastoma patients recruited between 2016 and 2018 [19].In this single-arm phase II study, dose escalation to hypercellular/hyperperfused tumor regions showed promising improvements in OS, along with positive impacts on short-term neurocognitive function, symptomatic burden, and quality of life.This study enrolled 26 patients and employed MRI along with 11C-Methionine (MET) PET imaging to delineate at-risk brain areas.Two patients exhibited late grade 3 neurologic toxicity.Among the cohort, only five out of 22 patients experienced central-to-in-field recurrence.Notably, the 1-year survival rate stood at 92 %, with a median OS of 20 months observed among the 13 patients who had received a radiation boost targeting both hypercellular and hyperperfused tumor regions [19].The most recently published trial exploring dose escalation is the SPECTRO GLIO trial using a slightly different approach by utilizing MRI spectroscopy to define the region which should receive dose escalation to 72 Gy [40].Median OS and median PFS was 22.6 months and 22.2 months, and 8.6 and 7.8 months, in the cohort with and without dose escalation, respectively.Despite the lack of a clear benefit for the dose-escalated cohort, there are still several reasons why PRIDE could potentially be successful.Firstly, the cohort, viewed through the lens of the WHO 2021 criteria, exhibits heterogeneity with partially unknown IDH status and a mixed MGMT methylation status [41].Additionally, MR spectroscopy might be somewhat less suitable for boost delineation compared to FET PET.An intriguing aspect of the study's results is the high OS outcome observed in the control cohort, as noted by Shu et al. in a letter [42], and the absence of a difference in the rate of radiation necrosis [40].Compared to these results, Tsien et al. (2019) presented encouraging outcomes regarding dose-escalation in their study [11].The primary aim of this phase I trial was to demonstrate the feasibility and assess the toxicity of dose-escalated radiotherapy alongside chemotherapy among patients diagnosed with primary supratentorial glioblastoma.A cohort of 209 patients were included in this study, showcasing the viability of administering radiotherapy doses exceeding the standard 60 Gy, concurrently with chemotherapy for primary glioblastoma.Importantly, the study indicated an acceptable risk profile for late central nervous system toxicity.Despite not being explicitly designed for this outcome, the higher dose arms exhibited a noteworthy extension in median overall survival (OS) [11].In a study by Laack et al. 75 patients with a FET-PET based dose-escalated RT were compared to 139 patients treated with standard RT at the same institution [38].Median PFS was significantly improved by dose-escalation (8.7 vs. 6.6 months; p = 0.017), OS was non-significantly improved in MGMT unmethylated patients (16.0 vs. 13.5 months; p = 0.13) and significantly improved in MGMT methylated patients (35.5 vs 23.3 months; p = 0.049) [38].
The PRIDE trial takes advantage of PET-based planning techniques and implements a reduction in the GTV-to-CTV margins to 1.0 cm.Simultaneously, the dose administered to the morphologically and biologically defined tumor volume is escalated to 75 Gy delivered in 30 fractions.The idea of this concept is to minimize radiation exposure to potentially unaffected brain tissue while intensifying treatment to the true tumor volume, aiming for a more aggressive approach.The addition of BEV is intended to mitigate the potentially increased RN risk from dose escalation.
The feasibility of the PRIDE concept relies on ensuring that the increased risk of RN from dose-escalated RT does not exceed the protective potential of BEV.The logarithmical NTCP-comparison of the experimental and reference plan led to a median value of 2.00 (range 1.66-2.35),meaning the risk of RN is increased by a median factor of 2 in the dose-escalated RT compared to the reference plan.Having the described protective effect of BEV with a factor of 2-3 in mind, the concept appears to be feasible.Furthermore, the concept of margin reduction may provide additional benefits to OARs despite of the dose escalation: Upon reviewing the dose values in Table 5 and examining the dose-volume histograms (DVH) graphs in Fig. 6, it becomes evident that the critical OARs are exposed to lower levels of radiation in the majority of experimental plans compared to their corresponding reference plans.There are, however, two exceptions to this trend, specifically in the cases of Patient_03 and Patient_07.In both cases, the GTVu is either infiltrating (Patient_03) or adjacent (Patient_07) to critical structures such as the brainstem and/or the optic tract (see Fig. 5).Although both patients (Patient_03 and Patient_07) exceeded the constraints given by the protocol for the brainstem and partly the optic system, it is important to note that they did neither exceed their acceptance range nor the constraints for the brainstem center (Table 5).The dose prescription requirements (Table 2) were found to be outside of the acceptance range in two cases (Table 4): in Patient_03 due to the aforementioned circumstances in the experimental plan, and Patient_01 only in the reference plan.In the reference plan for Patient_01, the elevated dose peaks were observed due to attempts to achieve a higher dose gradient.However, it is worth noting that in the majority of cases, the dose prescription requirements were within the acceptable range.In summary, the results of

Table 6
The parameters related with the risk of radiation necrosis; the numbers in the brackets with the asterisk (*) show the corresponding volumes of the PTV75opt, which was generated in this cases due to adjacency to critical organs at risk (EUD = equivalent uniform dose; NTCP = normal tissue complication probability; Ref = the reference plan; Ex = the experimental plan; GTVu = the union of the gross tumor volume and the biological tumor volume; PTV60, PTV60ex = the planning target volume prescribed with 60 Gy of the reference plan and of the experimental plan; PTV75 = the planning target volume prescribed with 75 Gy of the experimental plan; V40, V45 = the percentage of brain volume covered by 40  this study indicate that the PRIDE is capable of meeting its constraints and achieving adequate dose coverage.Furthermore, the increase of RN risk, estimated by the logarithmical NTCP comparison, is within the acceptable range.Therefore, if the risk of RN through BEV by the same factor as it increased by dose escalation holds true, isotoxicity could be achievable in the PRIDE trial.

Conclusion
The concept of the PRIDE trial holds promise for a significant improvement in the recurrence rate and OS in glioblastoma patients.By escalating the radiation dose to the morphologically and biologically defined tumor volume, while reducing margins and implementing the protective application of BEV, the PRIDE trial aims to enhance treatment outcomes without increasing treatment-related toxicity.The dosimetric feasibility, demonstrated in the presented data, even for critical tumor locations, is encouraging.It remains to be seen whether the PRIDE trial will be able to validate its hypothesis of achieving isotoxicity through the concomitant application of BEV, despite dose escalation.R. Bodensohn et al.

EUD9 ) 10 Fig. 3 .
Fig. 3.A Flow-Chart showing the inclusion and treatment plan for patients in the upcoming PRIDE trial (BTV = biological target volume; GTV = gross tumor volume; IDH wt = Isocitrate dehydrogenase wild type; MGMT = methylguanine methyltransferase).
maximum dose in a measurable volume) was 55.1 Gy (17.8-56.0Gy) and 48.5 Gy (17.3-57.5 Gy) for the brainstem, and 45.1 Gy (13.8-53.7 Gy) and 32.2 Gy (10.2-53.8Gy) for the brainstem center (brainstem minus 3 mm inner margin) in the reference and the experimental plan, respectively.The exact values of each patient and plan of the critical OARs are listed in Table 5.The corresponding dose-volume histograms are shown in Fig. 6.The dose values for all OARs are listed in the Supplement Table.

Fig. 4 .
Fig. 4. A diagram comparing the D98 (vertical axis in Gy) between the standard plan (PTV60) and the experimental plan (PTV60ex) of each patient.

Fig. 5 .
Fig. 5. MRI images including dose distribution of two patients, which required a PTVopt due to adjacency to the brainstem and/or optical tract; A1 + 2 are reference plans, B1 + 2 are the experimental plans; A1/B1 is Patient_3; A2/B2 is Patient_7; the red lines is are PTV60 or PTV60ex, dark violet the GTVu, magenta the PTV75, and pink the PTV75opt (MRI = magnet resonance imaging; GTVu = the union of the gross tumor volume and the biological tumor volume; PTV60, PTV60ex = the planning target volume prescribed with 60 Gy of the reference plan and of the experimental plan; PTV75 = the planning target volume prescribed with 75 Gy of the experimental plan; PTV75opt = the optimized PTV75 for patients adjacent to the brainstem or the optic tract).
D0.03 cc = the dose covering 0.03 cc; Dmean = the mean dose received by the volume; Ref = the reference plan; Ex = the experimental plan).R.Bodensohn et al.

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.Bodensohn et al.

Fig. 7 .
Fig. 7. Diagrams depicting the EUD (A) and NTCP (B) values of each patient in the reference and experimental plan.The third diagram (C) shows the results of the logarithmical comparison mentioned in the methods section (EUD = equivalent uniform dose; NTCP = normal tissue complication probability; ref = the reference plan; ex = the experimental plan).

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R.Bodensohn et al.

Table 2
Prescription Details for Experimental Plan and Reference Plan (PD = prescription dose; GTVu = the union of the gross tumor volume and the biological tumor volume; PTV60, PTV60ex = the planning target volume of the reference plan and the experimental plan prescribed with 60 Gy; PTV75 = the planning target volume of the experimental plan prescribed with 75 Gy; PTV75opt = the optimized PTV75 for volumes adjacent to the brainstem or the optic tract; D98, D50, D2 = the dose covering 98 %, 50 % and 2 % of the volume, standing for the near minimal, mean and near maximal dose, respectively).

Table 3 Organs
at risks (OAR) and their dose constraints (PTV = planning target volume; V40, V45 = the percentage of brain volume covered by 40 Gy and 45 Gy; D0.03 cc = the dose covering 0.03 cc; Dmean = the mean dose received by the volume; EUD = equivalent uniform dose; PRV = planning organ at risk volume).