Brain volume loss after cranial irradiation: a controlled comparison study between photon vs proton radiotherapy for WHO grade 2-3 gliomas

doi:10.21203/rs.3.rs-4973431/v1

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Research Article

Brain volume loss after cranial irradiation: a controlled comparison study between photon vs proton radiotherapy for WHO grade 2-3 gliomas

https://doi.org/10.21203/rs.3.rs-4973431/v1

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Journal Publication

published 14 Oct, 2024

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Purpose

Radiation therapy (RT) is an integral treatment component in patients with glioma but associated with neurotoxicity. Proton RT (PRT), as compared with photon RT (XRT), reduces excess radiation to nontarget tissue. We used a retrospective method to evaluate brain imaging metrics of neurotoxicity after treatment with PRT and XRT for glioma.

Methods

We analyzed brain volume change in thirty-four patients with WHO grade 2–3 gliomas treated with either PRT (n = 17) or XRT (n = 17). Both groups were carefully matched by demographic/clinical criteria and assessed longitudinally for two years post-radiotherapy. Brain volume change was measured as ventricular volume expansion in the tumor free hemisphere (contralateral to RT target) as a proxy indicator of brain volume loss. We further assessed the impact of volumetric changes on cognition in PRT patients, who completed neuropsychological testing as part of an outcome study.

Results

We found significant ventricular volume increases in the contralesional hemisphere in both groups at two years post-RT (F(1, 31) = 18.45, p < .000, partial η2 = .373), with greater volume change observed in XRT (26.55%) vs. PRT (12.03%) (M = 12.03%, SD = 16.26; F(1,31) = 4.26, p = 0.048, partial η2 = 0.121). Although, there was no group-level change on any cognitive test in PRT treated patients, individual changes on cognitive screening, working memory, processing speed and visual memory tasks correlated with contralesional brain volume loss.

Conclusion

This study suggests progressive brain volume loss following cranial irradiation, with greater severity after XRT vs PRT. Radiation-induced brain volume loss appears to be associated with measurable cognitive changes on an individual level. Prospective studies are warranted to validate these findings and their impacts on long-term cognitive function and quality of life. An improved understanding of the structural and functional consequences of cranial radiation is essential to develop neuroprotective strategies.

Glioma

Radiation Therapy

Magnetic Resonance Imaging

Neurotoxicity

Cognition

Gliomas are infiltrative primary central nervous system (CNS) tumors that are classified by histologic and molecular criteria [1–5]. Treatment typically consists of maximal safe tumor resection followed by additional tumor directed treatments to slow progression and delay recurrence. Despite advances in cancer therapy to prolong patient survival, WHO grade 2–4 glial tumors are considered incurable neoplasms [6, 7]. The treatment for many gliomas includes combined chemotherapy and radiation therapy (RT) [8, 9]. While such treatments have been shown to prolong survival, there are known neurotoxic sequelae of such treatments.

Neurotoxic effects following RT to the brain include cerebral volume loss [10–11], injury to white matter [12, 13], vascular disruption [14–16], and radiation necrosis [17–19], which can greatly impact an individual’s quality of life (QoL). Previous studies from our group have shown that patients with glioblastoma (GBM) who were treated with photon RT (XRT) combined with systemic chemotherapy experience progressive whole brain volume loss as well as grey matter volume loss and white matter integrity changes in the hemisphere contralateral to the tumor/radiation target, suggesting a diffuse neurotoxic effect of such therapy on the brain [20–22]. Cerebral atrophy after RT appears to be irreversible and can contribute to cognitive dysfunction [23–26] through a pattern of progressive cognitive decline [27–29]. Balancing the antineoplastic benefit of cancer directed therapy with these neurotoxic adverse effects is a challenge, given the ultimate goal to improve both quantity and quality of life in glioma survivors [5–7].

There have been mixed outcomes in studies of neurotoxic effects of treatment in patients with lower grade gliomas (LGG) following radiation therapy (RT). While many studies have revealed cognitive deterioration after RT [30–32], some studies have suggested that minimal to no decline occurred [33] or that confounding variables (e.g., tumor location or laterality) [34] influenced cognitive performance to a greater extent than treatment-related changes [33, 35, 36].

Indeed, variation in RT characteristics may influence neurotoxicity patterns and degree, including fraction size and total dose [35, 37–41]. Studies examining the type of RT used in patients with WHO grade 2–3 glioma and the associated treatment-related sequalae over time are warranted.

The dosimetric and radiobiological advantages of proton RT (PRT), as compared with photon RT (XRT), restrict radiation delivery to the target region, potentially sparing healthy brain tissue [42–45]. The superior dose distribution of protons [46, 47] is due to a radiation beam that travels a finite length and disproportionately delivers much of its dose at the end its path, known as the Bragg Peak, placed in the intended target [48]. In a prospective study, Brown et al. compared PRT to XRT in patients with GBM, seeking to determine whether PRT would prolong time to cognitive deterioration [50]. The study found a substantial reduction in radiation dose to brain structures critical to cognitive outcome (e.g., left hippocampus) in the PRT group compared to the XRT cohort. Despite reduced radiation dose to healthy brain tissue in the PRT cohort, there was no difference in cognitive deterioration between groups. Because of the aggressive nature of GBM, the study had limited power due to the rapid deterioration and tumor progression seen in both groups. A prospective, longitudinal study examining cognitive function in adults with LGG receiving PRT showed no decline in cognitive performance at 5 years after treatment, suggesting the possibility of long-term cognitive stability after PRT, but without comparison to XRT treated individuals [51]. Whether PRT may reduce diffuse neurotoxicity when compared to conventional XRT in patients with LGG remains an area of active investigation.

The primary purpose of this study was to longitudinally explore treatment-induced structural and functional neurotoxic complications in adults with lower grade glioma (WHO grades 2–3) following partial cranial radiation treatment. Specifically, we compared brain volume changes for up to two years following PRT vs XRT treatment in carefully matched patient cohorts. We hypothesized that PRT would be associated with less neurotoxicity than XRT, as assessed by brain volume loss contralateral to the glioma target. In addition, taking advantage of prospective longitudinal neuropsychological assessment that had been conducted in the cohort of PRT patients, we sought to explore the relationships between contralesional volumetric changes and cognitive performance over a two-year time period following treatment.

A secondary retrospective case-control study design was used to investigate demographic, clinical (e.g., treatment variables), and histopathological data in a total of 34 adult patients with lower grade glioma (WHO grades 2–3) treated with either XRT or PRT at the Massachusetts General Hospital (MGH) between 11/1998–10/2017. Patients treated with PRT were identified from ongoing longitudinal single-arm outcome studies at our institution (NCT01358058, NCT03286335), which included routine brain MRI and serial neuropsychological assessments. Patients treated with XRT were identified from an archival database from the Departments of Radiation Oncology and the Division of Neuro-Oncology at MGH. All PRT patients signed informed consent for participation in the outcome studies enumerated above. The XRT patient data was gathered under a Mass General Brigham IRB approved research protocol for secondary retrospective analyses of medical record data. All research procedures were conducted in accordance with the Declaration of Helsinki [52] As indicated above, patients treated with XRT had not completed neuropsychological assessment as part of their routine care, so only PRT patients were included in the detailed cognitive analyses.

Inclusion criteria for all patients were: (a) pathologically confirmed grade 2 or grade 3 glioma as defined by the World Health Organization (pathology records included the WHO classification criteria that were in place at the time of diagnosis and were re-classified to meet the 2021 classification based on available data), (b) tumor burden limited to one hemisphere (e.g., tumors did not cross midline to minimize brain volume changes associated with tumor growth or regression after treatment), (c) age 18 years or older, (d) partial cranial radiation therapy (PRT or XRT) delivered at MGH, (e) availability of contrast-enhanced axial brain magnetic resonance imaging scans (e.g., MPRAGE, BRAVO, or thick slice T1 weighted MRI) at baseline (within eight weeks after completion of radiation therapy) as well as at yearly intervals or more frequently (part of routine cancer surveillance screening), and (f) a minimum of two years progression free survival following RT.

To limit sampling bias, XRT patients were closely matched to “case-control” PRT patients using a carefully developed eleven-tiered set of criteria: age, sex, tumor type, tumor location, laterality of tumor, isocitrate dehydrogenase (IDH) 1 mutation status, 1p/19q co-deletion status, concurrent chemotherapy, adjuvant chemotherapy, total radiation dose, and number of radiation fractions. Participants were first matched on an individual level, followed by a group match for patients (n = 6) that did not match on all eleven variables.

Structural MRI scans were collected for patients at baseline, one year, and at two years after RT. When available, thin-slice (1mm) imaging (e.g., MPRAGE, BRAVO, and T1) was used for volume quantification; thick-slice (6mm) images were used for those cases without thin-slice imaging. As in our prior studies [20, 53], we measured volume change in the lateral ventricle in the hemisphere contralateral to the tumor as an index of diffuse cerebral volume loss. Ventricular segmentation was performed manually using Slicer (Version 4.10.2) to generate a 3D model of the contralesional ventricle, as illustrated in Fig. 1. The manual segmentation process was carried out by two trained research technicians following extensive training from board-certified neuro-oncologists (J.D. and E.G.) to ensure accurate identification of the limits of the ventricle. Each researcher identified the area of interest or ventricular space on a single axial slice using a “point and click” method to place a “seed” in the ventricular space and then used the “grow from seeds” function in Slicer to fill in all areas of the ventricle across slices. The program computed volume as the product of voxel size in the individual patient’s image space multiplied by the number of voxels labeled as included in the ventricle. Inter-rater reliability was evaluated by random selection of ventricular measurements for ten patients at each time point using the same method.

INSERT FIGURE 1 HERE

As noted above, PRT patients completed neurocognitive assessment at baseline (e.g., after the surgical resection and before start of radiotherapy) and follow-up (e.g., two years after baseline). All neuropsychological evaluations were carried out by a neuropsychologist (J.S.) with testing assistance from a psychometrist. The detailed neuropsychological evaluation included cognitive screening measures, attention/working memory, processing speed, executive functioning, language, memory, and measures of depression and anxiety (See Supplemental Table 1 for complete list of tests). Embedded within the assessment was the "clinical trial battery composite” (CBTC) which generates a composite score routinely used in large scale clinical trials of cognitive outcomes in patients with brain tumors [54, 55]. The CTBC is the mean of the Z-scores of the following six metrics: Controlled oral word association (COWA), Trail Making Test parts A and B (TMT-A and B), and total recall, delayed recall, and recognition discrimination scores from the Hopkins Verbal Learning Test-Revised (HVLT-R)[54] Normative data (e.g., conversion to z-scores using published test norms) for neuropsychological assessment allows for a standardized comparison of individual performance while controlling for demographic factors (e.g., age, education). In repeat or serial cognitive assessment, it is controversial whether discrete norms yield invalid or additional error [56, 57]; therefore, raw scores were used in analyses assessing change over time. Linear regression and correlation coefficients were calculated to examine the relationship between change in ventricular volumes and change in cognitive performance in patients treated with PRT. Non-parametric tests were used for binary variables indicating cognitive deterioration.

Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS-29). Descriptive statistics were calculated for demographic, diagnostic and treatment data for the two study groups (PRT and XRT) and compared with non-parametric analyses including the Mann-Whitney U-test of independence to evaluate their equivalence. Percent change in lateral ventricle volume between the two study groups was evaluated using a repeated-measures ANOVA with treatment as the between groups factor (XRT and PRT) and time (year 1 and 2 from baseline) as the within patients variable. Paired t-tests and simple linear regression analyses were used to test overall change from baseline to follow-up. Associations between lateral ventricle volume changes and measures of neurocognitive functioning, mood and anxiety were explored using correlations and linear regressions. To examine the relationship between ventricular volume and cognitive decline, the mean change in raw scores for each cognitive test was determined and those patients whose cognitive decline was 1 standard deviation or more below the mean change for the group were defined as “decliners” on that test. The number of cognitive tests showing a decline was tabulated for each individual and plotted into a simple linear regression. An alpha of .01 was used to control for multiple comparisons of the neurocognitive baseline and follow-up analyses and should be interpreted as exploratory.

3.1. Demographics

Over 80% (n = 28/34) of patients were precisely matched at an individual level based on all eleven specified criteria. Six additional patients differed in no more than two of the eleven variables and were added to the total sample (shown in Table 1). Following this matching process, 34 patients with progression-free WHO grade 2 or 3 gliomas were included with 17 patients in each cohort (17 PRT matched with 17 XRT). As shown in Table 1, there were no statistically significant differences between groups on demographics, tumor characteristics or treatment variables. Review of clinically acquired brain imaging confirmed that patients remained free from tumor progression during the two-year study period.

INSERT Table 1 HERE

Table 1

Summary of patient characteristics, treatment specifics, and clinical outcome.
Patient characteristics	Total cohort	XRT	PRT	p value for difference between groups
No of patients included	34	17	17
Demographics
% sex ratio (m/f)	56 / 44	59 / 41	53 / 47	X² = 0.119, p = 0.730
Median Age at diagnosis (yrs)	39.6	38.6	39.6	t=-0.115, p = 0.126
Tumor specifics
Intracranial Location				X² = 4.877, p = 0.431
% left / right	56 / 44	47 / 53	65 / 35	X² = 1.074, p = 0.300
% frontal (N)	50.0 (17)	47.1 (8)	52.9 (9)
% temporal (N)	32.4 (11)	41.2 (7)	23.5 (4)
% insular (N)	5.9 (2)	0 (0)	11.8 (2)
% thalamic (N)	5.9 (2)	5.9 (1)	5.9 (1)
% parietal (N)	2.9 (1)	0 (0)	5.9 (1)
% cerebellopontine angle (N)	2.9 (1)	5.9 (1)	0 (0)
WHO Grade % (N)				X² = 0.582, p = 0.748
2	64.7 (22)	58.8 (10)	70.6 (12)
3	29.4 (10)	35.3 (6)	23.5 (4)
low grade, not otherwise specified	5.9 (2)	5.9 (1)	5.9 (1)
Histopathology				X² = 0.183, p = 0.913
% astrocytoma* (N)	73.5 (25)	76.5 (13)	70.6 (12)
% oligodendroglioma (N)	20.6 (7)	17.6 (3)	23.5 (4)
% low grade astrocytoma, not otherwise specified	5.9 (2)	5.9 (1)	5.9 (1)
Molecular-genetic profile
% IDH1 mutant (N)	82.4 (28)	76.5 (13)	88.2 (15)	X² = 0.81, p = 0.368
% 1p19q co-deleted (N)	37.0 (10/27)	38.5 (5/13)	35.7 (5/14)	X² = 0.02, p = 0.883
% p53 mutated (N)	37.0 (10/27)	54.5 (6/11)	25.0 (4/16)	X² = 6.367, p = 0.041
% ATRX loss	42.1 (8/19)	33.3 (2/6)	46.2 (6/13)	X² = 6.085, p = 0.048
% MGMT promoter methylated (N)	50.0 (6/12)	42.9 (3/7)	60.0 (3/5)	X² = 1.238, p = 0.538
Clinical status
% w/ cardiovascular comorbidities	61.8	70.6 (12)	52.9 (9)	X² = 3.84, p = 0.147
% w/ recurrence prior to RT (N)	35 (12)	24 (4)	47 (8)	X² = 2.06, p = 0.151
Median KPS baseline pre-RT	90	90	90	t = 1.343, p = 0.165
Median KPS 2 years post-RT	90	95	90	t=-0.026, p = 0.475
Treatment details
Extent of surgical resection				X² = 5.727, p = 0.126
% GTR (N)	8.8 (3)	5.9 (1)	11.8 (2)
% NTR (N)	17.6 (6)	0 (0)	35.3 (6)
% STR (N)	32.4 (11)	29.4 (5)	35.3 (6)
% PR (N)	17.6 (6)	17.6 (3)	17.6 (3)
% Biopsy only (N)	23.5 (8)	41.2 (7)	5.9 (1)	X² = 5.1, p = 0.024
Radiotherapy Regimen				n/a
% Photons (N)	50 (17)	100 (17)	N/A
% IMRT (N)		29.4 (5/17)	N/A
% VMAT (N)		17.7 (3/17)	N/A
% 3D CRT (N)		5.9 (1/17)	N/A
% IFRT, not otherwise specified		47.1 (8/17)
% Protons (N)	50 (17)	N/A	100 (17)
Median Dose in Gy (range)	54 (9)	59.4 (9)	54(RBE) (5.4)	t = 1.92, p = 0.065
Median No. Fractions (range)	30 (5)	33 (5)	30 (3)	t = 1.41, p = 0.167
Median Fraction size in Gy	1.8	1.8	1.8(RBE)	t = 1.00, p = 0.325
Systemic Treatment
% w/ neoadjuvant Ctx (N)	14.7 (5)	17.6 (3)	11.8 (2)	X² = 5.034, p = 0.412
% w/ concurrent Ctx (N)	32.4 (11)	35.5 (6)	29.4 (5)	X² = 0.134, p = .714
% w/ adjuvant Ctx (N)	67.6 (23)	58.8 (10)	76.5 (13)	X² = 1.209, p = 0.271
Clinical outcome
Median PFS post-RT in years (SD)	5.0 (3.69)	4.7 (4.95)	5.1 (1.26)	p = .134, CI-5.52 -8.3
% w/ recurrence post-RT (N)	44.1 (15)	58.8 (10)	29.4 (5)	X² = 2.43, p = 0.119
Abbreviations: ATRX = alpha-thalassemia/mental retardation, X-linked; Ctx = chemotherapy; f = female; GTR = gross total resection; IDH1 = isocitrate dehydrogenase 1; IFRT = involved-field radiation therapy; IMRT= intensity-modulated radiation therapy; KPS = Karnofsky Performance Satus Scale; m = male; MGMT = Methylguanine methyltransferase; NTR = near total resection; PFS = progression-free survival; PR = partial resection; RT = radiotherapy; SD = standard deviation; STR = subtotal resection; VMAT = volumetric modulated arc therapy; WHO = World Health Organization; yrs = years
*The majority (n = 21) of tumors were classified as “Astrocytoma, IDH mutant” as per WHO 2021 classification. In the remainder (n = 4), imaging, histopathology, and disease course were consistent with grade 2/3 astrocytoma although detailed molecular information were not available given the retrospective nature of the study.
Table 1 reproduced with permission from Winter et al., 2024 [58]

3.2. Volumetric Analysis

The preferred brain MRI sequence for measurement of ventricular volume is a 3-dimensional high resolution T1-weighted image with 1mm slice thickness (e.g., MPRAGE, BRAVO). However, this sequence was not always obtained in standard clinical brain MRI studies between 1998 and 2017. Although the PRT cohort had high resolution T1-weighted images with 1mm slices available for all 17 patients at both time points (i.e., baseline and follow-up), seven XRT patients did not have high resolution imaging available at both time points. Ventricular volumes for these seven XRT patients were measured using T1-weighted images with 6 mm slice thickness. The Shapiro-Wilk tests revealed the raw volumetric MRI data at baseline (p = 0.069 and 0.046) was normally distributed. However, the difference between ventricular volume measurements in those with 1mm MRI slices vs 6mm MRI slices was statistically significant (F([1, 32] = 6.66, p = .015).

To control for the systematic difference in raw volumes between different imaging types, we used the same image type (e.g., thick slice images) at both the baseline and follow up time points for the 7 patients who did not have thin slice imaging available at one of those points. For subsequent analyses, we calculated the percent change in ventricular volume for each patient using images with identical geometry at baseline and two-year follow up (ventricular volume at two years minus ventricular volume at baseline divided by ventricular volume at baseline * 100). An ANOVA showed no significant difference between image types (thick vs thin slice) using percent volume change at one year (F[1, 32] = 0.077, p = .783) as the dependent variable, with a normal distribution and no outliers. Ventricular volume calculations using high resolution (thin slab) images were highly reliable, with intra-class correlations coefficients (ICC) showing excellent agreement between raters at baseline (ICC = .969) and follow-up (ICC = .931).

A repeated-measures ANOVA found a main effect of time, whereby overall ventricular volume was significantly greater (F(1, 31) = 18.45, p = < .000, partial η2 = .373) in all patients after two years. There was also a main effect of treatment type; the XRT group had greater percent change in volume of the contralesional lateral ventricle (M = 26.55%, SD = 13.46%) than the PRT group (M = 12.03%, SD = 16.26; F(1,31) = 4.26, p = 0.048, partial η2 = 0.121). A statistically significant interaction effect (1,31) = 10.16, p = 0.003 partial η2 = .247 was found between PRT and XRT over time, where patients treated with photons showed greater change at 2 years, as shown in Fig. 2.

INSERT FIGURE 2 HERE

3.3. Neurocognitive, emotional, and behavioral assessment

Exploratory analyses were conducted to examine changes in neuropsychological performance over time (i.e., from baseline to follow-up) for 16 of the 17 patients in the PRT group (one patient did not undergo cognitive testing). Descriptive statistics are presented in Table 2.

INSERT Table 2 HERE

Table 2

Neurocognitive domains and tests scores for exploratory analyses
	Baseline Mean (SD)	Follow-up Mean (SD)	Cognitive Δ Mean (SD)	Correlation with Δ Volume (r, p)
Cognitive Domain Cognitive test(s)	N = 16	N = 16	N = 16
Cognitive Screen
MMSE	29.19 (1.33)	29.19 (1.33)	-0.06 (1.53)	(r=-0.459, p = 0.073)
ACE-R	93.63 (6.1)	93.63 (6.1)	0.69 (4.13)	(r = − .793, p = < 0.001)
Language
Boston Naming Test	55.5 (4.32)	55.5 (4.32)	1.13 (2.34)	(r = − .606, p = 0.013)
Auditory Naming Test	49.25 (1.29)	49.25 (1.29)	0.25 (1.13)	(r=-0.316, p = 0.234)
Semantic Fluency: Animal Naming	22.19 (6.42)	22.19 (6.42)	0.38 (4.38)	(r=-0.308, p = 0.246)
Attention \| Working Memory
WAIS-IV ; Digit Span	27.13 (6.12)	27.13 (6.12)	-1.13 (3.4)	(r = − .609, p = 0.012)
WMS-III Spatial Span	16.25 (3.61)	16.25 (3.61)	-0.44 (2.87)	(r=-0.328, p = 0.215)
Auditory Consonant Trigrams	34.75 (6.83)	32.38 (8.72)	-2.37 (5.84)	(t = 1.626, p = 0.125)
Executive Function \| Processing speed
WAIS-IV; Coding	70.5 (20.77)	70.5 (20.77)	-2.38 (9.97)	(r = − .704, p = 0.002)
Trail Making Test; Part A	26.81 (9.36)	26.81 (9.36)	-0.06 (6.65)	(r = 0.258, p = 0.335)
Trail Making Test; Part B	59.63 (26.15)	59.63 (26.15)	1.25 (19.77)	(r = 0.473, p = 0.064)
Controlled Oral Word Association Test	43.75 (12.41)	43.75 (12.41)	4.13 (7.86)	(r=-0.06, p = 0.826)
Verbal Memory
HVLT-R Total Recall	24.56 (5.45)	24.56 (5.45)	-2.06 (6.48)	(r=-0.48, p = 0.06)
HVLT-R Delayed Recall	8.06 (2.57)	8.06 (2.57)	0.06 (4.19)	(r=-0.433, p = 0.094)
HVLT-R Recognition Index	10.81 (1.38)	10.81 (1.38)	0.13 (1.54)	(r=-0.479, p = 0.061)
Visual Memory	24.11 (6.8)	30.06 (2.7)	-3.40
BVMT-R Total Recall	23.56 (6.89)	23.56 (6.89)	-0.44 (5.93)	(r=-0.447, p = 0.082)
BVMT-R Delayed Recall	8.81 (2.23)	8.81 (2.23)	-0.38 (2.36)	(r=-.549, p = 0.027)
BVMT-R Recognition Index	5.81 (0.75)	5.81 (0.75)	-0.13 (0.81)	(r=-.596, p = 0.015)
Clinical Trial Battery Composite Score †	-0.18 (0.84)	-0.19 (0.74)	-0.01 (0.72)	(r=-0.47, p = 0.066)
Emotional & Behavioral Functioning
Beck Anxiety Inventory	3.63 (3.96)	3.63 (3.96)	-1 (4.24)	(r = .325, p = 0.219)
Beck Depression Inventory	5.13 (6.33)	5.13 (6.33)	-0.69 (3.74)	(r = 0.163, p = 0.546)
Abbreviations (PRT cohort only): MMSE = Mini Mental State Examination; ACE-R = Addenbrooke's Cognitive Examination - Revised; WAIS-IV = Wechsler Adult Intelligence Scale − 4th edition; WMSIII = Wechsler Memory Scale—3rd edition; ACT = Auditory Consonant Trigrams; HVLT-R = Hopkins Verbal Learning Test – Revised; BVMT-R = Brief Visuospatial Memory Test – Revised; Change = Δ
Statistically significant (p < 0.05) †Standardized z scores

Contralesional ventricular volume and baseline neurocognitive scores did not significantly correlate prior to the start of treatment. Paired t-tests showed that there was no statistically significant change between baseline and follow-up on any of the neurocognitive assessment measures at the group level. However, at an individual level significant associations were observed between ventricular volume increases and declines on several cognitive test scores. As shown in Fig. 3, volume change was moderately to strongly inversely associated with changes in ACE-R (r = − .793, p = < 0.001), digit span (r = − .609, p = 0.012), coding (r = − .704, p = 0.002), naming (r = − .606, p = 0.013), visual memory delayed recall (r = − .549, p = 0.027) and visual recognition discrimination index (r = − .596, p = 0.015). Increase in ventricular volume showed a moderate negative correlation approaching statistical significance with the CTBC Z-score (r = -0.470; p = 0.066). Emotional and behavioral functioning tests did not show a significant relationship with volumetric change at any time point (baseline or follow-up).

INSERT FIGURE 3 HERE

Ventricular enlargement also demonstrated sensitivity to the number of tests on which an individual showed cognitive decline (defined as a decline of greater than 1 SD more than the group mean change). Linear regression indicated that ventricular enlargement accounted for 60.3% of the variation in cognitive deterioration (F(1,14) = 21.3, p < 0.001) from baseline to follow-up. The strongest relationships between volume loss and cognitive deterioration were seen on the coding and digit span tests (partial r’s = -0.70 and − .61, respectively; p’s < 0.01; see Table 3).

INSERT Table 3 HERE

Table 3

Neurocognitive domains and tests scores for exploratory analyses
	Baseline Mean (SD)	Follow-up Mean (SD)	Cognitive Δ Mean (SD)	Correlation with Δ Volume (r, p)
Cognitive Domain Cognitive test(s)	N = 16	N = 16	N = 16
Cognitive Screen
MMSE	29.19 (1.33)	29.19 (1.33)	-0.06 (1.53)	(r=-0.459, p = 0.073)
ACE-R	93.63 (6.1)	93.63 (6.1)	0.69 (4.13)	(r = − .793, p = < 0.001)
Language
Boston Naming Test	55.5 (4.32)	55.5 (4.32)	1.13 (2.34)	(r = − .606, p = 0.013)
Auditory Naming Test	49.25 (1.29)	49.25 (1.29)	0.25 (1.13)	(r=-0.316, p = 0.234)
Semantic Fluency: Animal Naming	22.19 (6.42)	22.19 (6.42)	0.38 (4.38)	(r=-0.308, p = 0.246)
Attention \| Working Memory
WAIS-IV ; Digit Span	27.13 (6.12)	27.13 (6.12)	-1.13 (3.4)	(r = − .609, p = 0.012)
WMS-III Spatial Span	16.25 (3.61)	16.25 (3.61)	-0.44 (2.87)	(r=-0.328, p = 0.215)
Auditory Consonant Trigrams	34.75 (6.83)	32.38 (8.72)	-2.37 (5.84)	(t = 1.626, p = 0.125)
Executive Function \| Processing speed
WAIS-IV; Coding	70.5 (20.77)	70.5 (20.77)	-2.38 (9.97)	(r = − .704, p = 0.002)
Trail Making Test; Part A	26.81 (9.36)	26.81 (9.36)	-0.06 (6.65)	(r = 0.258, p = 0.335)
Trail Making Test; Part B	59.63 (26.15)	59.63 (26.15)	1.25 (19.77)	(r = 0.473, p = 0.064)
Controlled Oral Word Association Test	43.75 (12.41)	43.75 (12.41)	4.13 (7.86)	(r=-0.06, p = 0.826)
Verbal Memory
HVLT-R Total Recall	24.56 (5.45)	24.56 (5.45)	-2.06 (6.48)	(r=-0.48, p = 0.06)
HVLT-R Delayed Recall	8.06 (2.57)	8.06 (2.57)	0.06 (4.19)	(r=-0.433, p = 0.094)
HVLT-R Recognition Index	10.81 (1.38)	10.81 (1.38)	0.13 (1.54)	(r=-0.479, p = 0.061)
Visual Memory	24.11 (6.8)	30.06 (2.7)	-3.40
BVMT-R Total Recall	23.56 (6.89)	23.56 (6.89)	-0.44 (5.93)	(r=-0.447, p = 0.082)
BVMT-R Delayed Recall	8.81 (2.23)	8.81 (2.23)	-0.38 (2.36)	(r=-.549, p = 0.027)
BVMT-R Recognition Index	5.81 (0.75)	5.81 (0.75)	-0.13 (0.81)	(r=-.596, p = 0.015)
Clinical Trial Battery Composite Score †	-0.18 (0.84)	-0.19 (0.74)	-0.01 (0.72)	(r=-0.47, p = 0.066)
Emotional & Behavioral Functioning
Beck Anxiety Inventory	3.63 (3.96)	3.63 (3.96)	-1 (4.24)	(r = .325, p = 0.219)
Beck Depression Inventory	5.13 (6.33)	5.13 (6.33)	-0.69 (3.74)	(r = 0.163, p = 0.546)
Abbreviations (PRT cohort only): MMSE = Mini Mental State Examination; ACE-R = Addenbrooke's Cognitive Examination - Revised; WAIS-IV = Wechsler Adult Intelligence Scale − 4th edition; WMSIII = Wechsler Memory Scale—3rd edition; ACT = Auditory Consonant Trigrams; HVLT-R = Hopkins Verbal Learning Test – Revised; BVMT-R = Brief Visuospatial Memory Test – Revised; Change = Δ
Statistically significant (p < 0.05) †Standardized z scores

To our knowledge, the current study represents the first controlled comparison of PRT and XRT effects on brain volume and associated cognitive change over two years in patients with LGG. This study found that both PRT and XRT treatment for LGG were associated with substantial and progressive ventricular volume expansion over two years following treatment. This change was significantly greater in patients treated with XRT, with a mean percent change in lateral ventricular volume expansion contralateral to the tumor of 26.55% compared to 12.03% in the PRT group. Exploratory analyses examining correlations between ventricular volume change and cognition over time showed significant relationships on tests of global cognitive function, attention, working memory, processing speed, language, and visual memory. Measures of working memory and processing speed were strongly associated with volume change, whereas changes on a commonly used verbal memory measure, the HVLT-R, were not associated with volumetric change. This finding is of particular interest given the CTBC score includes measures from the HVLT-R but not from coding and digit span. Thus, studies limited to only the CTBC measures may be missing diffuse changes that impact attention/working memory and processing speed. Further dissection of simple attention (digit span forward) vs. working memory (digit span backward/sequencing) is warranted.

The progressive brain volume loss in LGG patients treated with RT identified in this study supports previous findings from studies in GBM patients, which have demonstrated progressive brain volume loss following combined XRT and chemotherapy [20, 21]. Our findings are also consistent with a study conducted by Petr et al. (2017), examining brain volume loss and cerebral perfusion patterns in patients with GBM treated with either XRT or PRT. However, in the Petr et al. (2017) study, significant cerebral atrophy was seen only in the non-tumor hemisphere of patients treated with XRT but not in patients treated with PRT [11]. The location of high and low dose regions across conditions (PRT and XRT) predicted regional volume loss, although the authors identified that patient age was a confounding variable contributing to this finding. The careful age-match in our study suggests that greater ventricular volume increase is likely related to XRT treatment rather than age. Furthermore, in a concurrent study using this sample of patients, we have demonstrated unique patterns of white matter damage associated with each radiation modality, with increased evolution of diffuse leukoencephalopathy and cerebral microbleeds in the contralesional hemisphere in XRT as compared with PRT treated patients [58]. It is likely that both white and grey matter changes are contributing to the overall cerebral volume loss and ventricular expansion demonstrated here.

Few studies have integrated cognitive outcomes in the examination of radiation-associated neurotoxicity. A recent phase II trial did not find a difference in cognitive failure rates following proton compared to photon therapy 6 months after treatment in patients with glioblastoma (GBM) when assessed at a group level [59]. Despite the limited follow period (6 months), a significant difference in patient reported fatigue was observed, favoring the PRT (24%) over XRT (58%) arm. Our study suggests that the effects of treatment may become more apparent over time in progression free survivors of lower grade gliomas, with relative reduction of neurotoxic sequelae in those treated with PRT.

Given the significant ventricular enlargement in the XRT group two years after treatment, analysis of the associated changes in cognitive functioning is a critical consideration. It is important to highlight that there was substantial variability in lateral ventricular volume changes over 2 years in both the PRT and XRT cohort. Our findings suggest that individuals who experience a higher degree of brain volume loss are more likely to have cognitive deterioration. Given the relationship between volume change and cognition, further examination of risk factors for lateral ventricular volume increase/brain volume loss in people undergoing RT is needed. Neurotoxicity of treatment is an important factor to consider in optimizing long term outcomes. RT has been a core component of treatment for patients with LGG for many years [60], yet the treatment landscape is evolving [61] and the value of PRT over XRT-based therapies is actively being investigated in the context of their relative risks and costs [62]. Observing a cohort of patients with less aggressive gliomas (i.e., grade 2–3, IDH-mutant), putatively less toxic treatment (e.g., IDH inhibitor therapy or temozolomide without radiation therapy) or favorable demographic variables (e.g., age, cognitive reserve, cardiovascular risk factors) would provide additional data on the effects of brain volume loss on a population with expected prolonged overall survival rates. It is also important to evaluate if changes in ventricle volume and the associated changes in cognitive functioning generalize across conditions (e.g., at different timepoints as well as domain specific cognitive change and at what timepoint).

Limitations of our study include its retrospective design, relatively small sample size, and the fact that cognitive assessment was available only for the PRT group. Consideration for tumor laterality and its relationship with cognitive performance or additional treatment related variables (e.g., extent of surgical history at baseline) would be beneficial. Future designs would benefit from securing uniform imaging and comparing the absolute volumetric change between groups. Integration of more advanced imaging, such as diffusion tensor imaging to evaluate white matter integrity and resting state functional MRI to measure functional connectivity, would further elucidate the underlying mechanisms of these brain changes [63]. Additionally, extending volumetric surveillance past two years would inform researchers and healthcare providers about the long-term implications and progressive pattern of treatment related neurotoxicity. A randomized controlled trial is considered the gold standard for comparing two groups when evaluating the effectiveness and impact of treatment interventions as it offers the most rigorous method for hypothesis testing. While randomization was not feasible in this study, it is important to note that a randomized controlled trial is not always achievable as the treating physicians ethically must maintain clinical equipoise in addition to following known treatment standards. The ongoing cooperative group NRG Oncology BN005 study addresses this concern by randomizing IDH-mutant LGG patients between photon and proton therapy [64] and includes cognitive assessment measures, which may provide further opportunity to study these issues.

Understanding the pattern of progressive neural injury following RT is a critical step to develop future neuroprotective strategies and to ultimately improve QoL and survivorship in patients with glioma. This retrospective case-matched study identified that ventricular volume in patients with WHO grade 2–3 gliomas receiving radiation therapy increased over two years following treatment. Patients treated with XRT had significantly greater change over time than those treated with PRT. The secondary analyses suggest that volume change correlated significantly with cognitive deterioration in the PRT group. Prospective studies are warranted to validate these findings in larger cohorts and understand the long-term impacts of different radiation modalities on brain structure and function.

Funding Statement

This research received no external funding.

Competing Interest Statement

Michael W. Parsons serves as a consultant to Servier Pharmaceuticals.

Author Contribution Statement:

All authors contributed to the study conception and design, and results interpretation. Material preparation, data collection and analysis were performed by Melissa M. Gardner, Sebastian F. Winter, Franziska Stahl and Michael W. Parsons. The first draft of the manuscript was written by Melissa M. Gardner and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability Statement

Research data for this work are available upon request to the corresponding author by any qualified investigator.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. All research procedures were conducted with the approval of the Institutional Review Board of Mass General Brigham.

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Competing interest reported. Michael W. Parsons serves as a consultant to Servier Pharmaceuticals.

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Brain volume loss after cranial irradiation: a controlled comparison study between photon vs proton radiotherapy for WHO grade 2-3 gliomas

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