The Role of Subventricular Zone Irradiation in High-Grade Gliomas – a Narrative Review

2. Introduction

High-grade gliomas (HGGs) are a group of aggressive malignant brain tumours with dismal prognosis and treatment outcomes. According to the World Health Organization 2021 classification, adult-type HGGs include IDH mutant gliomas (oligodendrogliomas grade 3, astrocytomas grade 3, astrocytomas grade 4) and IDH wild-type glioblastoma (GBM) (1,2). These tumours are characterized by cellular atypia, increased mitotic activity, vascular

proliferation and necrosis, making them highly invasive and resistant to conventional treatment modalities, which include surgery whenever it is possible, followed by radiotherapy and/or chemotherapy.

Among HGGs, GBM is the most common and aggressive primary brain tumour in adults (3). Standard treatment for newly diagnosed GBM consists of maximal safe resection followed by radiation therapy and concurrent and adjuvant temozolomide (4,5).Tumour Treating Fields is a new therapeutic strategy that can also be added to the maintenance therapy, as it had been shown to prolong overall survival (OS)(6).

Despite all the therapeutic efforts, the median OS for newly diagnosed GBM is 8-15 months, while for recurrent GBM it is 6-9 months (7). Hence, it is of utmost importance to find novel therapeutic strategies to improve treatment outcomes.

One approach currently under investigation is targeting the subventricular zone (SVZ), a specialized region of neural stem and progenitor cells in the adult brain.

In this review, we discussed the role of the SVZ in gliomagenesis and preclinical and clinical studies investigating the effects of SVZ irradiation, highlighting the potential mechanisms underlying its efficacy. Finally, we also discussed future directions for research and clinical translation.

3. Role of the SVZ in gliomagenesis

Over the last decade, it emerged that within the brain there are zones of neural stem cells (NSCs), multipotent cells that have the ability to self-renew and differentiate into neurons, astrocytes, and oligodendrocytes. They play a crucial role in brain development from the embryonic stage throughout adulthood by generating new neurons and glial cells, being increasingly considered an important source of neuronal plasticity(8).

NSCs are primarily found in two regions of the adult brain: the SVZ of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. The SVZ were shown to play a role in tissue repair and prevention of neurodegenerative diseases, while the SGZ generates NSCs that are involved in pathways of learning and memory (8).

However, studies also revealed intriguing connections between the NSCs and HGGs. Glioma cells were shown to originate from these zones, where they exhibit a remarkable ability to migrate along the specialized pathways provided by these neurogenic niches (9).

The SVZ is the major site of neurogenesis in the brain and the richest zone in NSCs. Research showed that NSCs in the SVZ share similar molecular profiles and several distinctive characteristics to proliferative glioblastoma stem cells (GSCs), suggesting that NSCs are potential initiators of gliomagenesis and are responsible for the aggressive behaviour of this disease (10,11,12). Moreover, the SVZ was hypothesized to be implicated in tumour recurrence, as delocalized residual GSCs can further maintain a malignant state even after extensive surgical resection and standard treatment approaches. These findings highlight the importance of understanding the role of the SVZ in HGGs and exploring its potential as a therapeutic target.

4. Clinical relevance of the SVZ

The anatomical contact with the SVZ gained significant attention in the context of HGGs. The first evidence that underlines the negative impact of the SVZ on the treatment outcomes came from a retrospective clinical study describing that a GBM directly in contact with the SVZ on the preoperative MRI has a more invasive character and was associated with multifocal disease in adults(13). The authors also delineated four distinct patterns that provided a comprehensive characterization of the involvement of the SVZ: GBM in contact with the SVZ and the cortex, GBM invading just the cortex, GBM invading just the SVZ and GBM invading neither structure. They concluded that anatomical contact of the tumour with the SVZ correlates with lower survival rates in GBM. This was further confirmed by Mistry et al in a meta-analysis(14) where contact with the SVZ was found to be an independent negative prognostic factor.

5. Rationale for considering the SVZ during radiotherapy planning

There are several potential treatments that target the SVZ in HGGs. One such treatment is irradiating the SVZ, which may improve outcomes by directly targeting this putative sanctuary site. Irradiation of the SVZ holds the potential in reducing tumour-initiating cells, disrupting the tumour microenvironment, and improving treatment response. Considering their role in glioma growth, targeting these cells may slow GBM growth and potentially improve survival outcomes. Contradictory, irradiating these sites could also damage the auto-repair capacity of the human brain and lead to greater cognitive deficits and poorer survival outcomes. As a consequence, there is a continuous debate over whether irradiating or sparing the SVZ is more beneficial for patients with HGGs.

The hypothesis that manipulating the irradiation doses on the NSC niches was also applied to the treatment of brain metastasis. Traditional treatment approaches such as wholebrain radiation therapy (WBRT) were associated with cognitive decline and neurocognitive deficits, which can significantly impact the quality of life of these patients. Recognizing the importance of preserving NSC function, researchers explored novel techniques to spare these essential cells while targeting metastatic lesions (15). Current research is exploring the feasibility of selectively sparing these NSC compartments during WBRT and prophylactic cranial irradiation for brain metastases (16) and of avoiding the hippocampus during WBRT (17).

6. Review of the retrospective studies

There are already numerous studies that evaluated the hypothesis that irradiating the SVZ can have a role in slowing HGG growth and decreasing its recurrence rate. They examined the relationship between the incidental radiation dose to the SVZs delivered during the radiotherapy sequence and survival in HGG patients.

The methodology of these studies was similar: dividing the patient cohort into low and high SVZ dose groups and comparing the doses with survival metrics, such as OS and progression-free survival (PFS).

We summarized the findings of these studies in Table 1 and 2.

6.1 Studies favoring targeting the SVZ

Evers et al.(18) retrospectively evaluated for the first time 55 patients with HGGs in a study where the high-dose group included patients who received a mean dose of 43 Gy or higher to the bilateral SVZ (biSVZ) region. This value represented the median mean dose in the biSVZ across the entire cohort. The results indicated that the high-dose group showed a significant improvement in PFS (15 vs 17.2 months P=0.028). It is worth noting that no correlation was found between the incidental dose to the hippocampus and PFS, suggesting that irradiation of other neurogenic niches in the brain does not provide any benefit.

Gupta et al.(19) analysed a group of 40 GBM patients, divided based on the median dose to the ipsilateral SVZ (iSVZ) of 59.9 Gy. The study demonstrated that the mean dose to the ipsilateral SVZ was an independent predictive factor for improved OS (HR = 0.87, 95% CI 0.77-0.98; P = 0.025), but not for PFS. In this patient cohort, high radiation doses (>57.9 Gy) to the contralateral SVZ (cSVZ) were associated with a decrease in PFS (P=0.02) and OS (P=0.05).

Lee et al.(20) analysed a larger cohort of 173 GBM patients in a similar manner. Instead of using the median iSVZ dose to divide the patients, they decided that a higher radiation dose would be warranted to induce the death of GSCs and applied a threshold of 59.4 Gy. The results of the study showed that a high iSVZ dose significantly correlated with longer PFS (12.6 vs 9.9 months, P=0.042) and remained significant in the multivariate analysis (P=0.009; HR=0.45, 95% CI=0.25-0.82). A high dose of radiation to the SVZ was also correlated with improved OS, but this correlation was not significant (25.8 vs 19.2 months, P=0.173). These data were reanalysed using different threshold values, including the threshold value used by the first group of researchers of 43 Gy for the biSVZ, as well as 50 and 55 Gy for the iSVZ, but the analysis following the establishment of these threshold values did not result in significant differences in PFS and OS.

Chen et al. (21) similarly evaluated 116 GBM patients. Among patients who received a high iSVZ mean dose (>40 Gy), no significant difference in OS and PFS was observed compared to the group of patients who received a lower dose. It is important to note that among the 41 patients who underwent gross total resection (GTR), those who received a high dose of radiation to the iSVZ had a significant increase in PFS (15.1 vs 10.3 months, P=0.028) and OS (17.5 vs 15.6 months, P=0.027).

In a more recent abstract, Ravind et al.(22) conducted a retrospective analysis of 50 GBM patients and reported that in the group of patients who received a mean dose of over 50 Gy to the iSVZ, OS was higher (19.83 vs 6.07 months, P=0.031), while cSVZ doses over 37 Gy were associated with an improvement in OS, although not significant (19.83 vs 8.73 months, P=0.118).

A study by Foro et al.(23) on 65 GBM patients was the only one to find an improvement in PFS in patients who received a cSVZ dose higher than 48.8 Gy (75th percentile) (HR 0.46; 95% CI=0.23-0.91 P=0.028), but no association with OS.

In a retrospective study evaluating a doseescalated radiotherapy regime in a group of 72 GBM patients, Kusumawidjaja et al.(24) found an association between a higher iSVZ and an improvement in PFS (HR=0.95; CI=0.9-1; P=0.052). Furthermore, patients who received 50 Gy to the entire SVZ volume had a better PFS (HR =0.52; 95% CI =0.27–1.02; P=0.055).

The most recent evidence comes from Ermis et al (25), who demonstrated that an iSVZ dose ≥ 50 Gy was correlated with better PFS (8 vs 6 months; P < 0.001) and OS (16 vs 11 months; p < 0.001). Lower doses to the contralateral SVZ (<32 Gy) were also associated with improved PFS (8 vs 6 months; P=0.03) and OS (15 vs 11 months; P=0.001).

Table 1. Retrospective studies favouring irradiation of the SVZ

^* Dmean – mean dose, PFS – progression-free survival, OS – overall survival, GBM – Glioblastoma, GTR – gross total ressection, NA – not available, NR – not reached, biSVZ – bilateral subventricular zone, cSVZ – contralateral subventricular zone, iSVZ – ipsilateral subventricular zone

5.2. Studies not favoring targeting the SVZ

Slotman et al.(26) attempted to replicate the findings of Evers et al. in a cohort of 40 GBM patients. The threshold used to separate the cohort into a high-dose and a low-dose radiation group was also set at 43 Gy. The study did not find any correlation between the doses to the bilateral, ipsilateral, or contralateral SVZ and PFS or OS. However, they did observe a correlation between the low dose to the contralateral SVZ and an increased number of distant recurrences (outside the radiation field).

A subsequent study conducted by Elicin et al.(27) suggested that the correlation between the SVZ dose and survival outcomes is much more complex. The cohort of 60 patients was analysed using different threshold values for the iSVZ and cSVZ doses, based on the 25th, 50th, and 75th percentiles. Univariate analysis showed that a higher dose of 59.2 Gy (75th percentile) to the cSVZ is a negative prognostic factor for PFS (7.1 vs 10.3 months, P=0.009), but this effect lost its statistical significance in the multivariate analysis. In the subgroup with subtotal resection or biopsy only, the same cSVZ dose was a negative prognostic factor for OS (HR: 4.83 [95% CI 1.71–13.97], p = 0.004). Similarly, an iSVZ dose above 62.25 Gy (75th percentile) was correlated with a decrease in PFS in the subgroups of patients with a KPS > 90 (HR: 2.58 [95% CI 1.03–6.05], p = 0.044) and those with tumours not invading the SVZ (HR: 10.57 [95% CI 2.04–49], p = 0.008). Although this result could be explained by the effects of a large tumour mass, there were no correlations found between the clinical target volume (CTV) and PFS or OS in both univariate and multivariate analyses.

Sakuramachi et al.(28) studied a cohort of 74 glioma patients and found that high iSVZ radiation doses did not affect PFS or OS. In the subgroup of 58 GBM patients, an iSVZ dose higher than 58.2 Gy was correlated with a reduced PFS, without any significant effect on OS.

In the largest retrospective study to this date, including 370 GBM patients, Murchison et al.(29) did not find any correlation between iSVZ, cSVZ, biSVZ doses and PFS or OS. Even more recently, in a retrospective analysis of 95 patients diagnosed with anaplastic gliomas, Valiyaveettil et al.(30) also found no significant association between the dose delivered to the SVZ and PFS or OS.

In 2022, Bruil et al.(31) conducted a study on 226 HGG patients, which also included an evaluation of the ipsilateral SGZ (iSGZ) doses. In their analysis an iSVZ dose greater than 30.33 Gy was correlated with a lower median OS (10.7 vs 14 months, P=0.011) and an iSGZ dose greater than 29.11 Gy was also associated with a lower median OS (10.7 vs 15.5 months, P<0.001), further underscoring a potential role for sparing the iSVZ and iSGZ during radiotherapy.

Table 2. Retrospective studies not favouring the irradiation of the SVZ

^* prospective study

Dmean – mean dose, PFS – progression-free survival, OS – overall survival, GBM – Glioblastoma, HGG – high-grade glioma, biSVZ – bilateral subventricular zone, cSVZ – contralateral subventricular zone, iSVZ – ipsilateral subventricular zone

6. Review of the prospective studies

In an originally planned prospective study to evaluate the effectiveness of hypofractionated high-dose IMRT for newly diagnosed GBM(32), the researchers observed improved OS outcomes specifically in cases of radionecrosis occurring in the SVZ (36.2 vs 13.3 months, P=0.0001), but also significant decrease in Karnofsky Performance Status in long-term survivors. Radionecrosis surrounding the tumour site was also correlated with better survival outcomes, but this correlation did not reach statistical significance.

The first prospective clinical study investigating the irradiation of NSC niches in GBM was conducted on 74 patients who underwent total surgical resection followed by radiotherapy and chemotherapy (33). The CTV included the ipsilateral periventricular zone (PVZ), defined as a 5 mm expansion all around the lateral ventricles, and it included the SVZ, defined as a 5 mm lateral expansion of the lateral ventricles. The mean doses for the iSVZ and biPVZ were 55.1 Gy and 56.2 Gy, respectively, and the median OS for the entire group was 13 months. The group was dichotomized according to the median SVZ and PVZ doses and the results did not show a correlation between OS and PFS and the doses delivered to the iPVZ, cPVZ, bPVZ iSVZ or cSVZ, bPVZ.

7. Discussion

Comparing these studies can be challenging due to their retrospective nature and the fact that they do not control for important variables such as patient selection, radiation dose, threshold values, and treatment planning strategies. Additionally, classical prognostic factors like O6-methylguanine DNA methyl transferase (MGMT) or isocitrate dehydrogenase (IDH) status were often disregarded.

There is also room for improvement in determining the value of survival metrics, as PFS and OS were not collected in all the studies. Considering the lethality of GBM, OS is the most reliable parameter for assessing treatment efficacy, and the value of PFS should be reflected in OS since disease recurrences do not extend beyond the central nervous system (34). However, evaluating OS, in this case, can be ambiguous and challenging due to the effect of salvage therapy administered to patients at the time of progression or recurrence of the disease. Salvage therapy options include surgical reintervention, reirradiation, TMZ, lomustine (CNNU) and bevacizumab, but at the moment there is no consensus for selecting it (2,35,36).

The relationship between the neurogenic niches and the CNS tumours remains a complex one, which also deserves a more detailed study of the hippocampus and the neurocognitive functions. Routinely assessing cognitive impairment could also provide clues for further treatment optimization.

A recent preclinical study was conducted to identify whether the tumour microenvironment in the brain influences the response of GSCs to radiation therapy (37). It showed that GSCs that migrated to the olfactory bulb are more radioresistant than those that migrated to the corpus callosum or the striatum. Therefore, the olfactory bulb also harbors a niche of radioresistant GSCs, and correlating radiation doses at the olfactory bulb with survival outcomes would also be worth studying.

In the studies considered in this review, there is significant variation in the delineation of the SVZ. It can be assumed that it cannot be accurately and uniformly done due to the significant variability in shape and volume of the lateral ventricles among patients and between the simulation CT and MR images. This becomes challenging when the tumour invades the entire thickness of the lateral ventricle. When the lateral ventricle is not visible, it is difficult to determine if the tumour invaded it, and whether the ipsilateral SVZ can be considered symmetrical to the contralateral one, or if the lateral ventricle is compressed and located in the immediate vicinity of the midline of the cerebral hemispheres, in which case the SVZs are no longer symmetrical.

There has been no guideline regarding the anatomical delineation of the SVZ until 2022, when Bruil et al. (31) provided along with their study a SVZ atlas, including its subregions, where the thickness of the zone is only 3 mm, significantly smaller than what others considered before. A subregion analysis would also be critical as the SVZ was demonstrated to be a highly heterogeneous zone. The atlas is openly available, which enables reproducibility and makes further assessments of the doses to the SVZ and its subregions easier.

The evaluation of the benefit-risk balance specific to targeting the SVZ in children has not been conducted yet and requires further investigation.

A randomized phase II clinical study is underway that examines PFS in patients with newly diagnosed GBM treated with a radiation treatment plan that intentionally prescribes 60 Gy to the iSVZ compared to a standard radiotherapy regimen (NCT02177578)(38).

8. Conclusions

The potential benefits and risks of targeting the SVZ in adult patients were examined in numerous studies so far. However, a definitive conclusion cannot be drawn based on the current literature review. We still need other prospective and randomized studies to establish which type of patients may benefit from the irradiation or avoidance of the SVZ and what are its subregions worth considering during radiotherapy delivery.

Abbreviations:

biSVZ – bilateral subventricular zone

cSVZ – contralateral subventricular zone

GBM – glioblastoma

GTR – gross total resection

GSC – glioblastoma stem cell

HGG – high-grade glioma

iSGZ – ipsilateral subgranular zone

iSVZ – ipsilateral subventricular zone

NSC – neural stem cells

OS – overall survival

PFS – progression-free survival

SGZ – subgranular zone

SVZ – subventricular zone

WBRT – whole-brain radiation therapy

NA – not available

NR – not reached

Statements:

Author’s contribution: OC gathered the data and wrote the article.

Conflict of interest: I declare having no conflict of interest.

Funding Sources: None.

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