The impact of brain lesions on quality of life in patients with WHO CNS grade 3 or 4 glioma: A lesion-function and resting-state fMRI analysis

doi:10.21203/rs.3.rs-2435579/v1

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The impact of brain lesions on quality of life in patients with WHO CNS grade 3 or 4 glioma: A lesion-function and resting-state fMRI analysis

https://doi.org/10.21203/rs.3.rs-2435579/v1

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Journal Publication

published 07 Feb, 2023

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Purpose

Following multimodality therapy, glioma patients may suffer from reduced health-related quality of life (QoL). It is largely unknown how different types and locations of tumor- and treatment-related brain lesions, as well as their relationship to white matter tracts and functional brain networks, affect QoL.

Methods

In 121 patients with pretreated gliomas of WHO CNS grades 3 or 4, structural MRI, O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) PET, resting-state functional MRI (rs-fMRI) and self-reported QoL questionnaires (EORTC QLQ-C30/BN20) were obtained. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and lesions with pathologically increased FET uptake were delineated. Effects of tumor lateralization, affection of white matter tracts and rs-fMRI network nodes by different types of lesions, and within rs-fMRI functional connectivity on QoL were analyzed.

Results

Gliomas of the right hemisphere were associated with significantly less favorable outcomes in physical, role, emotional and social functioning, compared to left-sided tumors. Most QoL scores correlated significantly with the affection of right-sided white-matter tracts by T2/FLAIR hyperintensities and with the loss of within-network functional connectivity of right-sided functional nodes. Tumors of the left hemisphere caused significantly more communication deficits.

Conclusion

In pretreated high-grade gliomas, right hemisphere rather than left hemisphere lesions are associated with decreased quality of life in most domains, except communication ability. These impairments are associated mainly with T2/FLAIR lesions affecting white matter tracts and functional nodal connectivity in the right hemisphere. The data suggest that sparing the right hemisphere from treatment-related tissue damage may improve quality of life in glioma patients.

glioma

quality of life

brain networks

functional magnetic resonance tomography

positron emission tomography

radiotherapy

Gliomas of the WHO central nervous system (CNS) grades 3 or 4 are the most common primary brain tumors in adults. They are characterized by rapid and infiltrative growth resulting in a mostly unfavorable prognosis despite therapeutic efforts [1, 2]. Patients suffer not only from brain damage due to destructive tumor growth but also from possible side effects of various therapies such as tumor resection, radiation, chemotherapy, and their combinations, which affect the patients' functioning and well-being. [3, 4]. As a result, long-term survivors endure a significant symptom burden leading to a reduced health-related quality of life (QoL) [5, 6]. In these patients, QoL can therefore be considered as important as the survival time. Consequently, the assessment of patients’ quality of life has become an important aspect in the evaluation of treatment strategies in addition to well-established outcome parameters such as overall survival, progression-free survival, or imaging response [7].

One of the most commonly used instruments to evaluate QoL in clinical trials related to brain tumors is the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) with its accompanying brain-specific module BN20 [2]. It is based on a multidimensional concept of health-related QoL comprising physical, mental, emotional, and social domains. However, it remains unclear how the QoL and its domains are linked to tumor location or regional or network-based brain damage. However, such knowledge is critical for clinical decision-making and provides valuable information on the relationship between brain lesion location and dysfunction [8].

So far, studies of higher brain functions in glioma patients have mainly focused on cognitive performance. In a longitudinal study on patients with high-grade gliomas, Dallabona et al. [9] found that, among other factors, tumor lateralization and overall mass effect can contribute to the prediction of postoperative cognitive performance. Patients with major deficits in language and verbal memory tasks predominately suffered from left lateralized tumors. These findings align with data from Habets et al. [8] who investigated the impact of tumor location on neurocognitive functioning (including six cognitive domains) by applying MRI-based lesion-symptom mapping. They suggested that deficits in the different cognitive domains might be related predominantly to the left hemisphere with patients suffering from left hemispheric gliomas showing the highest likelihood of cognitive deficits.

Furthermore, a recent study showed that multimodal imaging can predict cognitive deficits in glioma patients [10]. T2/FLAIR abnormalities correlated best with cognitive outcomes. Moreover, most functional cortical nodes and white matter tracts related to cognitive performance were left-hemispheric. In particular, deficits in language-related functions could be linked to T2/FLAIR hyperintensities in the nodes and tracts of the left temporal lobe.

However, it remains unclear how these findings relate to the patients’ health-related QoL since this construct comprises additional domains such as emotional and social functioning as well as aspects of physical well-being. Emotional processing has been notably related to the right hemisphere. The so-called “right hemisphere hypothesis” posits a general dominance for emotional processing irrespective of the type of emotional valence [11–14]. Based on this theory, we hypothesized involvement of the right hemisphere in the neural correlates of health-related QoL in pretreated high-grade glioma patients. Therefore, we analyzed the effect of location and extent of MRI-assessed resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and regions with pathologically increased O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) uptake on several QoL domains as determined by the EORTC questionnaires QLQ-C30 and BN20. Moreover, we assessed the correlation of within-network node connectivity of seven major functional magnetic resonance imaging (fMRI) resting-state networks with the QoL scores.

Study population

The study population was identical to that investigated in a previous study undertaken by our group [10]. Briefly, it originated from a prospective, cross-sectional study and comprised 121 patients (February 2018 to September 2020) suffering from WHO CNS grade 3 or 4 gliomas, according to the 2016 WHO classification [15]. Patients were referred for hybrid MR/PET imaging for treatment monitoring or suspicion of recurrent tumor. The inclusion criteria were: an ECOG performance score of 0–1, no major depression, no seizures, and fluency in the German language. The local ethics committee approved the protocol, and all patients provided informed written consent according to the Declaration of Helsinki. Patient characteristics are shown in Table 1. The median interval between therapy initiation and imaging was 14 months (mean, 30 months; range, 1–214 months), and 105 patients had

Table 1 Patient Characteristics

Median (Range) unless otherwise stated; ECOG-PS: Eastern Cooperative Oncology Group Performance Score; ISCED: International Standard Classification of Education (1997); GBM: glioblastoma; NOS: not otherwise specified; AA: anaplastic astrocytoma; AOD: anaplastic oligodendroglioma; IDH: Isocitrate-Dehydrogenase; 1p19q codel: 1p19q codeleted; FET: O-(2-[18F]fluoroethyl)-L-tyrosine

completed tri-modality primary treatment, including biopsy/resection, definitive/postoperative radiotherapy, and concomitant/adjuvant chemotherapy with alkylating agents. Most patients had already received one series (100 patients) or two series (14 patients) of local radiotherapy (dose range 59–62 Gy in 92% of patients), with a median interval of 13 months (mean, 32 months; range, 2–213 months) between the start of irradiation and imaging. All patients except one were right-handed.

Assessment of quality of life

Quality of life was assessed at the date of imaging using the validated German version of the EORTC Quality of Life Questionnaire QLQ-C30 and the EORTC QLQ-BN20 (https://qol.eortc.org) [16, 17]. The EORTC QLQ-C30 comprises 30 questions covering five functional domains: physical functioning (Physical), role functioning (Role), cognitive deficits (Cognitive), emotional functioning (Emotional), social functioning (Social), and a global measure of health status (QL). The EORTC QLQ-BN20 is more explicitly adapted to brain cancer and has 20 questions from four domains: future uncertainty (Future), visual disorder (Visual), motor dysfunction (Motor), and communication deficit (Communication). The scores for each domain were computed according to the EORTC QLQ scoring manuals, where the raw scores from 2-5 questions are averaged and rescaled to a range of 0-100 points. Additionally, sociodemographic variables comprising age, gender, and education (International Standard Classification of Education, ISCED, (http://uis.unesco.org/sites/default/files/documents/international-standard-classification-of-education-1997-en_0.pdf) were recorded.

Multimodal imaging, image segmentation, and determination of lesion-specific damage to functional cortical regions and white matter tracts

These procedures have been described in detail before [10]. Briefly, FET positron emission tomography (PET) and MR data were acquired simultaneously using a high-resolution 3T hybrid PET/MR scanner (Siemens Tim-TRIO/BrainPET, Siemens Medical Systems, Erlangen). Structural MR imaging included a 3D T1-weighted magnetization-prepared rapid acquisition gradient-echo (MPRAGE) anatomical scan, a contrast-enhanced T1-weighted image (T1-CE) obtained from a second MPRAGE scan following the injection of gadolinium, or high-resolution T1-weighted, contrast-enhanced MR scans available from the referring institution. Moreover, T2-weighted and T2-weighted fluid-attenuated inversion recovery (FLAIR) structural images were acquired. In addition to these imaging procedures, all patients underwent resting-state fMRI (rs-fMRI), where 300 functional volumes were acquired within 11 minutes using a gradient-echo echo planar imaging (GE-EPI) pulse sequence (36 axial slices, slice thickness 3.1 mm, repetition time TR = 2200 ms, echo time TE = 30 ms, flip angle = 90°, FoV = 200 ×200 mm², in-plane voxel-size 3.1 ×3.1 mm²). The patients were instructed to relax and to let their minds wander but not to fall asleep [10].

Lesion masks were generated for resection cavities, T1-CE enhancing lesions, T2/FLAIR hyperintensities, and lesions with pathologically increased FET uptake. Resection cavities were manually contoured by a radiation oncologist (M.K.), whereas the T1-CE-enhancing lesions and T2/FLAIR hyperintensities were automatically segmented (deep-learning-based software HD-GLIO-AUTO, https://github.com/NeuroAI-HD/HDGLIO-AUTO). FET PET segmentation was implemented by an FSL (https://fsl.fmrib.ox.ac.uk) custom script using a tumor-to-brain ratio (TBR) of > 1.6 as the threshold for pathological FET uptake [18]. All segmentations were visually inspected and manually corrected if needed. For lesion-function mapping, the rs-fMRI-based cortical parcellation atlas of Schaefer et al. [19], comprising 2x50 functional nodes belonging to 7 resting-state networks (visual, somato-motor, dorsal attention, ventral attention, limbic, fronto-parietal control, and default mode), and an atlas of white matter tracts (2 × 24 tracts) from the Stereotaxic White Matter Atlas of the Johns Hopkins University (JHU) [20] were applied. All images were spatially normalized by elastic registration to the MNI-152 brain template by means of the SPM12 toolbox (www.fil.ion.ucl.ac.uk/spm/software/spm12) and, finally, the partial overlapping volume of the nodes or tracts with each of the lesion segments was computed, see Fig. 1.

Determination of resting-state functional connectivity

The determination of resting-state functional connectivity (RSFC) was performed similarly to Kocher et al. [21]. Briefly, functional images were subjected to the standard pre-processing steps of the SPM12/CONN toolbox comprising motion correction with removal of outliers and cerebro-spinal fluid/ white matter signals, slice timing correction, smoothing with 5 mm FWHM, bandpass-filtering to 0.008–0.09 Hz and denoising. All structural and functional images were non-rigidly co-registered to the MNI-152 standard brain template using the SPM12/CONN unified segmentation/registration algorithm. For the determination of RSFC, the cortical parcellation of Schaefer et al. [19] was imported into the CONN toolbox and used to compute full connectivity matrices from the z-transformed Pearson correlation coefficients between the respective nodes. From these z-values, the within-network connectivity for each node of the respective network [22] was computed.

Statistical Analysis

SPSS (IBM SPSS Statistics version 27, IBM Corporation, Armonk, NY, USA) and the Python software package scipy.stats (version 1.5.4, https://scipy.org) were used for all analyses. Correlation coefficients between EORTC QLQ domain scores and the volumetric overlap between lesions and functional nodes or white matter tracts were computed using a 2-sided Kendall tau-b rank correlation that corrects for ties and is less sensitive to outliers. Moreover, the Pearson correlation coefficients between within-network functional connectivity of individual nodes and the EORTEC QLQ domain scores were calculated. In general, p-values <0.05 were regarded significant. No formal correction was applied for massive univariate testing [23]. However, only correlations with p<0.001 for lesion-QoL and p<0.01 for RSFC-QoL analysis were considered significant.

EORTC quality-of-life scores

As shown in Fig. 2, patients with right-hemispheric gliomas had lower EORTC quality-of-life scores in 9/10 domains and scored significantly lower for physical, role, emotional, and social functioning. Conversely, communication deficits were significantly more pronounced in patients with left-sided gliomas. Of note, except for the prevalence of (mild) aphasia, patients with left or right hemispheric gliomas showed no significant differences in disease-related, treatment-related, or sociodemographic characteristics (Table 1). Apart from a weak association of an increased age with a reduction in (self-reported) cognitive functioning (ρ= -0.18, p = 0.045) and a correlation of higher educational status with a lowered future perspective (ρ= -0.20, p = 0.027), the sociodemographic status did not impact the QoL measures.

Impact of lesion volume and location on EORTC quality-of-life scores

Regarding the total volumes of each lesion type, only the global measure of health status (QL) was inversely correlated with the volumes of the lesions (FLAIR hyperintensities: ρ= -0.25, p = 0.05, T1-enhancing lesions: ρ= -0.24, p = 0.009, pathological FET uptake: ρ= -0.27, p = 0.003). The p-value maps for the correlation analysis between the partial volumetric affection of tracts or nodes by the different kinds of lesions and the QoL measures are depicted in Figs. 3 and 4.

As shown in Fig. 3, quality-of-life scores mainly correlated (p < 0.001) with the affection of white-matter tracts of the right hemisphere by T2/FLAIR hyperintensities. In particular, physical functioning, role functioning, social functioning, and global health status were associated with an affection of the right anterior and posterior limbs of the internal capsule, the right anterior corona radiata, and the right striae terminales of the fornix. Conversely, communication deficits were more strongly associated with the left corona radiata and left striae terminales of the fornix. Other types of lesions showed only weaker correlations, which, however, still prevailed in the right hemisphere.

The same principal correlation patterns were observed when analyzing the affection of functional cortical areas (nodes). Physical and role functioning and global health status were mainly associated (p < 0.001) with the affection of the right somato-motor region and other nodes of the right hemisphere, while communication correlated with several nodes of both hemispheres. As shown in Fig. 5a, the within-network functional connectivity of several nodes of the right hemisphere also correlated significantly with the QoL scores. Reduced connectivity of most of the nodes of the right somato-motor network and the right ventral attention network was associated with a significant decline in physical, role, and motor function, as well as global health status. A representative example of the correlation between the functional connectivity of a right-hemispheric somato-motor node and the physical functioning score is depicted in Fig. 5b.

Main findings

In the present analysis, pretreated patients with high-grade gliomas of the right hemisphere had significantly lower self-reported QoL scores in the domains of physical, role, emotional, and social functioning compared to patients with left hemispheric tumors. These QoL impairments were mainly associated with the affection of the right-sided anterior and posterior limbs of the internal capsule, corona radiata, and striae terminales of the fornix by T2/FLAIR lesions and reduced connectivity of most of the nodes of the right somato-motor and ventral attention networks. In contrast, patients with left-sided gliomas were more prone to aphasia and suffered from communication deficits to a greater extent, which were more strongly associated with the left corona radiata and striae terminales of the fornix.

Health-related quality of life in high-grade glioma patients

While most clinical studies on malignant glioma focus on oncologic outcomes, such as overall and progression-free survival, few reports deal with the detailed evolution of QoL subdomains in the course of the disease [5, 24–29]. In newly diagnosed high-grade gliomas, Klein et al. [26] observed a significant decrease in physical and social functioning, vitality, general health perception, and general mental health and increased role limitations compared to a group of healthy subjects. In 2017, Gately et al. [5] reviewed the evidence on QoL outcomes in long-term survivors of glioblastoma [24, 28, 30]. In a study that applied the modern EORTC-QLQ C30 instrument, the most noticeable reductions of QoL were observed in the domains of role and physical functioning, while the mean global health status was largely preserved [28]. Furthermore, Flechl et al. [24] reported that social functioning and cognition were mostly impaired, in contrast to the global health score. These results and the present study suggest that apart from global measures of QoL, specific domains, including physical, role, and social functioning, may be predominantly disturbed in glioma patients.

Impact of glioma laterality on quality of life

Few reports have attempted to determine the cause of decreased QoL concerning lesion location or other tumor-related properties. In newly diagnosed high-grade glioma patients, Klein et al. [26] found that although tumor lateralization significantly affected self-reported difficulties in specific neurocognitive functions such as reasoning, problem-solving, reaction time, forgetfulness, and concentration, two higher-order QoL component scores (physical component scale, mental component scale) did not depend on the side of the affected hemisphere. Several other studies have also not shown any prominent differences in overall QoL between left- and right-sided brain tumors in the preoperative or early postoperative phase [31–33]. However, as expected, patients with left-sided tumors reported suffering more often from disturbances in verbal fluency, verbal learning, memory problems, and communications deficits, while tumors in the right hemisphere caused greater difficulties in process skills when performing everyday tasks [32, 33].

In contrast, a group from Finland investigated 101 newly diagnosed benign and malignant (41%) brain tumors and found close relations between the right hemispheric tumor load and several QoL measures. In detail, the right-sided tumors induced a larger overall QoL reduction than the left-sided tumors for all domains except speech and were associated with significantly higher scores for social isolation and emotional deficits. Also, overall QoL depended on the histological grade and location of the tumor in only the right hemisphere and not in the left [34].

Neural correlates of quality of life in glioma patients

While several studies have been performed to elucidate the underlying causes of neurocognitive deterioration in glioma patients by modern neuroimaging methods, including voxel-wise lesion-symptom mapping, fMRI, and tractography [35–40], these approaches have rarely been applied to self-reported QoL data [41]. It is reasonable to assume that quality of life depends on many different abilities, such as perception of physical and emotional stimuli, attention, planning of complex actions, language, speech, and memory. In neurocognitive testing, more specialized functions are measured in isolation, while by answering a set of questions from a questionnaire, the patient merely self-assesses the interaction of several abilities.

Hemispheric specialization has recently been reviewed from theoretical [42], clinical [43], and neurosurgical perspectives [44], pointing to sets of tasks predominantly processed in the left (communicative speech and language, mathematical and logical reasoning, encoding episodic memory) or right hemisphere (attentional reorientation, emotional processing, nonverbal semantic processing, spatial cognition, mentalizing, affective prosody, face processing, episodic memory retrieval). In line with these findings, the present results suggest that the tracts and nodes in the right hemisphere are important for daily functioning, which is probably the prerequisite for a good subjective quality of life.

Concerning the type of lesions, we found that the affection of right-sided white-matter tracts by T2/FLAIR hyperintensities was most strongly correlated with several QoL domains. Whether these lesions were caused by radiation-induced astrogliosis or by perifocal edema in the presence of a recurrent tumor is challenging to decide. However, in a recent analysis, we found that both types of lesions reduce the fiber density in the underlying white matter by approximately 50% [45].

In pretreated high-grade glioma patients, QoL measures for most domains except communication abilities were less favorable in right hemisphere compared to left hemisphere tumors. These impairments were mainly associated with T2/FLAIR lesions affecting white-matter tracts and the functional node connectivity of the right hemisphere. Thus, sparing the right hemisphere from treatment-induced tissue damage should be considered to improve QoL in glioma patients.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.”

Author Contributions

All authors contributed to the study conception and design. Imaging methods were developed by Philipp Lohmann, Nadim J. Shah and Karl-Josef Langen. Image data acquisition was done by Christian Filss and Gabriele Stoffels. Data collection and analysis were performed by Alexander Heinzel and Martin Kocher. The first draft of the manuscript was written by Alexander Heinzel and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Hospital of Cologne (14.11.2017, 17-365)

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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No competing interests reported.

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published 07 Feb, 2023

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The impact of brain lesions on quality of life in patients with WHO CNS grade 3 or 4 glioma: A lesion-function and resting-state fMRI analysis

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Journal Publication

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Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Patients And Methods

Results

EORTC quality-of-life scores

Impact of lesion volume and location on EORTC quality-of-life scores

Discussion

Main findings

Health-related quality of life in high-grade glioma patients

Impact of glioma laterality on quality of life

Neural correlates of quality of life in glioma patients

Conclusion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1