|Year : 2019 | Volume
| Issue : 3 | Page : 145-152
Impact of stereotactic radiosurgery on first recurrence of glioblastoma
Maciej Harat1, Sebastian Dzierzecki2, Katarzyna Dyttus-Cebulok3, Miroslaw Zabek4, Roman Makarewicz5
1 Department of Oncology and Brachytherapy, Nicolaus Copernicus University, Ludwik Rydygier Collegium Medicum; Department of Radiotherapy, Unit of Radiosurgery and Radiotherapy of Central Nervous System, Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland
2 Department of Neurosurgery, Postgraduate Medical Center; Gamma-Knife Center, Warsaw, Poland
3 Gamma-Knife Center; Department of Radiotherapy, Maria Sklodowska Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
4 Department of Neurosurgery, Postgraduate Medical Center; Department of Radiotherapy, Maria Sklodowska Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
5 Department of Oncology and Brachytherapy, Nicolaus Copernicus University, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
|Date of Submission||25-May-2019|
|Date of Decision||22-Jun-2019|
|Date of Acceptance||22-Aug-2019|
|Date of Web Publication||26-Sep-2019|
Dr. Maciej Harat
Romanowskiej 2 Street, 85-796, Bydgoszcz
Source of Support: None, Conflict of Interest: None
Background and Aim: The benefit of stereotactic radiosurgery (SRS) in recurrent glioblastoma multiforme (GBM) remains unclear, partly due to disease heterogeneity. Subventricular zone (SVZ) invasion is a prognostic factor for primary GBM, but whether SVZ involvement is also prognostic in recurrent GBM treated with SRS is unknown. Here, we aimed to determine prognostic factors after first GBM recurrence. Materials and Methods: Thirty-nine consecutive patients with a first recurrence of glioblastoma treated at the Gamma Knife Center, Warsaw, Poland and the Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland, between 2012 and 2016 were retrospectively reviewed. Magnetic resonance images were reviewed according to SVZ invasion by primary tumors and at the time of recurrence. Outcomes were evaluated using univariable and multivariable analyses. The study protocol was approved by the Ludwik Rydygier Collegium Medicum of Nicolas Copernicus University Institutional Review Board (approved No. KB 494/2018) on June 19, 2018. Results: SRS was the only prognostic factor for overall survival after recurrence in multivariable analysis. The median overall survival after the first recurrence was 18 months in the SRS group versus 6.5 months in the non-SRS group (P = 0.02). Survival after the first recurrence treated with SRS was shorter when recurrences were localized to the SVZ. Conclusion: SRS appears to be an effective salvage modality for small recurrent GBMs. Although SVZ-positive tumors have a worse prognosis, these tumors may benefit from SRS.
Keywords: Glioblastoma multiforme, overall survival, personalized therapy, prognostic factors, radiotherapy, recurrence, stereotactic radiosurgery, subventricular zone
|How to cite this article:|
Harat M, Dzierzecki S, Dyttus-Cebulok K, Zabek M, Makarewicz R. Impact of stereotactic radiosurgery on first recurrence of glioblastoma. Glioma 2019;2:145-52
|How to cite this URL:|
Harat M, Dzierzecki S, Dyttus-Cebulok K, Zabek M, Makarewicz R. Impact of stereotactic radiosurgery on first recurrence of glioblastoma. Glioma [serial online] 2019 [cited 2022 May 17];2:145-52. Available from: http://www.jglioma.com/text.asp?2019/2/3/145/267917
| Introduction|| |
Glioblastoma multiforme (GBM) is the most malignant primary central nervous system tumor and inevitably recurs. In addition to other factors, subventricular zone (SVZ) invasion has been shown to be a prognostic factor for primary GBM,,, and SVZ invasion status is associated with distinct GBM progression patterns.,,
At recurrence, improving overall survival (OS) must be balanced against the risk of neurological morbidity,, and more aggressive cytoreduction is associated with adverse treatment outcomes. Stereotactic radiosurgery (SRS) is a promising noninvasive modality that allows for limited number of small volume tumors treated as day cases. However, there is insufficient evidence on whether SRS has a positive impact on different GBM types, and controversies remain regarding the use of salvage SRS. In particular, the highly invasive nature of GBM and possibility of edema after reirradiation are of major concern in the recurrent setting.
Therefore, little is known about how tumors with SVZ invasion behave after progression when treated. Here, we evaluated clinical prognostic factors associated with survival after the first recurrence of GBM including SVZ invasion status.
| Materials and Methods|| |
Patient population and study design
This was a retrospective analysis of 39 patients at the time of the first GBM recurrence treated at the Gamma Knife Center in Warsaw and Franciszek Lukaszczyk Oncology Center in Bydgoszcz, between July 2012 and December 2016. The study protocol was approved by the Ludwik Rydygier Collegium Medicum of Nicolas Copernicus University Institutional Review Board (approved No. KB 494/2018) on June 19, 2018. Written informed consent was obtained from each patient before enrollment as for standard therapy.
The patients received either SRS or other non-SRS standard of care treatments according to Franciszek Lukaszczyk Oncology Center and 10th Military Research Hospital in Bydgoszcz. Patients referred to above centers without SRS equipment were treated with surgery, procarbazine, lomustine, and vincristine (PCV), or supportive care. Only patients with Karnofsky performance status (KPS) >60 were evaluated.
The eligibility criteria for SRS were as follows: (i) patients with pathologically confirmed GBM at first recurrence; SRS recommended by a multidisciplinary neuro-oncology tumor board; and KPS >60. The eligibility criteria for resection were as follows: (i) first progression of glioblastoma defined on T1-Gad magnetic resonance imaging (MRI) sequence in location permitting safe gross total resection without increased risk of postoperative decrease in quality of life. The decision was left at the discretion of the neurosurgeon.
Patients with large tumors (>45 cm 3) and/or tumors with a mass effect were excluded from the analysis.
All available magnetic resonance (MR) images were reviewed according to SVZ invasion by primary tumors and at the time of recurrence. Patients were evaluated according to the period from GBM diagnosis to the first recurrence; number of patients treated with 60 Gy; patient age; and extent of resection. All patients receiving chemotherapy at primary diagnosis (n = 36) also received adjuvant temozolomide. Six patients were diagnosed with disease progression during adjuvant chemotherapy. Histopathological confirmation of the recurrence was not mandatory for inclusion.
The extent of tumor excision was classified as either gross or subtotal. Unresectable lesions were biopsied. Recurrent tumors at the time of SRS planning were categorized as involving or not involving the SVZ. O-6-methylguanine-DNA methyltransferase (MGMT) promoter gene methylation status was not a standard in this study, but time to first progression was used as a surrogate of MGMT methylation. Tumors that progressed up to 10 months from diagnosis were considered MGMT unmethylated, and those that progressed over 10 months were considered MGMT methylated according to Hegi et al.
Magnetic resonance imaging scan and stereotactic radiosurgery treatment
Treatment was offered using the Gamma Knife Perfexion (Elekta Instrument AB, Stockholm, Sweden) to patients with progressive disease measured by contrast-enhanced MRI. All MRI scans were performed on a GE Signa HDxt 1.5T MRI System (General Electric Medical Systems, Milwaukee, WI, USA). Each patient was scanned with a contrast-enhanced T1-weighted MRI, T2 fast spin echo, and a fast imaging employing steady-state acquisition MRI protocol. After contrast injection (15 mL Gd-diethylenetriamine pentaacetic), three-dimensional T1-weighted MR images of the entire head were obtained. T1-weighted gradient echo data were acquired at 256 × 256 matrix, 1 mm thickness, with no overlap. Axial T2-weighted fast spin echo and fast imaging employing steady-state acquisition MR images were used at a section thickness of 1 mm and no section gap. A neurosurgeon and a radiation oncologist planned treatment and determined target volumes in all 19 patients. The target for radiosurgery was defined using T1-post Gd-contrast and T2-fast imaging employing steady-state acquisition sequences. No additional margins were added for clinical target volume or planning target volume. The mean time from initial diagnosis to salvage radiosurgery was 15.6 months (range 1–66 months).
After primary radiochemotherapy and after recurrence, follow-ups were performed every 3 months or whenever the patient presented with new neurological deficits. Therapeutic effect was evaluated according to Response Assessment in Neuro-Oncology Criteria, or failure was confirmed on subsequent follow-up MRI. New or progressive lesions after SRS were also defined in relation to pre-SRS images as local or distant progression with or without SVZ invasion. SVZ infiltration was defined when the contrast-enhancing tumor contacted the ventricles. Recurrence patterns were evaluated and considered either local (within 2 cm of the treated volume) or distant.
OS was calculated in months as time from date of surgery to the date of death. Survival after recurrence was calculated in months as time from the recurrence as defined by MRI to the date of death. Progression-free survival (PFS) was calculated in months as time from the date of salvage SRS treatment to the date of disease progression.
Statistical analyses were performed using PQStat (version 184.108.40.206, Poznan International Fair, Poznan, Poland). All study group and subgroups treated with or without SRS were described according to age, volume, KPS, time to first progression, OS, PFS, and survival after the first recurrence (Student's t-test or Chi-squared dependence test and Fisher's exact test).
OS and survival after first recurrence were analyzed using Kaplan–Meier survival curves, and all survival data, depending on the subgroup, were compared using the log-rank or Wilcoxon–Breslow–Gehan. Cox proportional hazards regression model was used to estimate the association between survival and various clinical factors (age, primary resection, time from diagnosis to SRS, volume, and SVZ involvement at diagnosis and at recurrence). For multivariate analysis, various categorical and continuous variables were tested to assess their influence on OS using the log-rank Mantel-Cox proportional hazards regression analysis.
Failure site after SRS was analyzed by logistic regression. P <0.05 was considered as statistically significant. The hazard ratios and 95% confidence intervals were calculated for the survival data.
| Results|| |
Characteristics of glioblastoma Apatients with a first recurrence
Nineteen patients underwent SRS for recurrent GBM and 20 patients were treated with surgery, PCV chemotherapy, or best supportive care [Table 1]. The median age was 56 years (range 25–83 years), KPS = 80, and biopsy or subtotal resection was performed in 21 primary tumors and gross total resection in 17. Median time to recurrence was 9 months (range 3–66 months).
|Table 1: Demographics and outcomes of glioblastoma patients with first recurrence|
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Mean tumor volume at the time of recurrence was 9 cm 3 (range 1–43 cm 3) and was significantly different between SRS and non-SRS subgroups [median 4 vs. 10 cm 3; P = 0.004; [Table 1]. SVZ invasion of the primary tumor was present in 28 cases and was more frequent in the SRS subgroup than the non-SRS subgroup (89% vs. 55%; P < 0.05). SVZ invasion was present in 20 cases at the time of recurrence (57% vs. 50% in each subgroup; P > 0.05). In the SRS subgroup, five primary tumors were not treated with chemotherapy while all primary tumors in the non-SRS subgroup were treated with radiochemotherapy.
In the SRS subgroup, the margin dose was 18 Gy (range 15–20 Gy), mean dose 24 Gy (range 19.6–28 Gy), and mean PFS after SRS was 5.5 months (range 2–15 months). SRS was generally used as a salvage treatment for first GBM recurrence; however, in five patients, this was a second overall tumor recurrence, with four patients originally diagnosed with World Health Organization II astrocytoma and one patient with anaplastic astrocytoma. The median period between GBM diagnosis and SRS treatment was 11 months. The total primary radiotherapy dose was 60 Gy (range 42–60 Gy). There were volumetric responses to SRS treatment during follow-up in nine patients [Figure 1].
|Figure 1: MRI scans (T1+ contrast enhancement) of two patients before and 5 months after SRS. Patient 1: Male, age 40 years, initially treated with gross total resection and radiochemotherapy (60 Gy + temozolomide). The primary tumor was invading the SVZ, and distant recurrence (1.17 cm3) occurred 23 months after diagnosis also invading the SVZ but due to the deep brain location was considered unresectable. SRS was 20 Gy prescribed to 50% isodose (yellow circle, mean dose 27.9 Gy). Five months after SRS, he developed a local recurrence and lived for 12 months after retreatment. Patient 2 was another male, age 40 years, initially treated with gross total resection and radiochemotherapy (60 Gy + temozolomide). The primary tumor did not invade the SVZ, and a late recurrence (10 cm3) occurred 66 months after primary treatment. The recurrence also did not invade the SVZ but considered unresectable. An 18 Gy SRS dose was prescribed to 50% isodose (yellow circle, mean dose 23.7 Gy). The patient was still alive 25 months after SRS. Red lines– positioning markers pointing to the same area of both images after coregistration. SRS: Stereotactic radiosurgery, SVZ: Subventricular zone, MRI: Magnetic resonance imaging|
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Survival outcomes of glioblastoma patients with a first recurrence
The mean OS for all patients was 29.7 months after initial diagnosis (median 23 months, range 9–91 months). The median OS was 31 months in the SRS group and 15.5 months in the non-SRS group [Figure 2].
|Figure 2: Kaplan–Meier survival curves of glioblastoma patients with first recurrence. (A and B) Overall survival (A) and survival after recurrence (time in months) (B) for the SRS group and non-SRS group. SRS: Stereotactic radiosurgery|
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No significant difference was observed in survival to the first recurrence between subgroups (P = 0.3). The mean survival to the first recurrence was 15.9 months (median 9 months, range 3–66 months).
OS after the first recurrence was 13.6 months (median 11 months, range 2–36 months). The median was 6.5 months in the non-SRS group and 18 months in the SRS group, while the 1-year survival after recurrence was 20% vs. 63% (log-rank test, P = 0.038). The median PFS after SRS was 5.5 months.
Survival in relation to subventricular zone involvement in glioblastoma patients with a first recurrence
The median OS and PFS with respect to a first recurrence were not significantly different between subgroups with and without SVZ invasion at primary diagnosis (OS: 23.5 vs. 23 months, P = 0.67; PFS: 10 vs. 8 months, P = 0.67). Survival after first recurrence was shorter when the recurrence was localized to the SVZ; however, it failed to gain statistical significance in univariate analysis (9 months vs. 18 months for SVZ+ at recurrence vs. SVZ− at recurrence; P = 0.12) [Figure 3].
|Figure 3: Kaplan–Meier of survival after recurrence in relation to SVZ involvement (time in months). SRS (SVZ) involved and SVZ uninvolved subgroups treated with SRS (A) and in whole study group (B). SRS: Stereotactic radiosurgery, SVZ: Subventricular zone|
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Recurrence location of glioblastoma patients with a first recurrence
There was a trend toward distant recurrences with SVZ invasion at primary diagnosis [20% vs. 30%, SVZ− vs. SVZ+; [Table 2]. In the SRS subgroup, the majority (89%) of primary tumors were SVZ+ on initial MRI. Nevertheless, only 53% of these SVZ+ primary tumors recurred within the SVZ. After SRS, tumors recurred in the SVZ in half of cases. Interestingly, recurrences after SRS were local in 44% and distant in 56% of patients, whereas first recurrences were distant in 25% of patients.
Evaluation of factors determining patient survival
In a Cox proportional hazards regression model, age, volume, failure site at recurrence, SVZ at the time of first recurrence, SVZ involvement at primary diagnosis, SRS (P = 0.054), chemotherapy, and primary resection status were not predictive of OS but the time to first recurrence (MGMT surrogate) was. In multivariate analysis, only SRS was associated with extended OS after a first recurrence [Table 3]. Uninvolved SVZ was predictive for survival after recurrence in a subgroup of patients treated with SRS in a Cox proportional hazards regression model [Table 4].
|Table 3: Multivariate analysis of different prognostic factors for survival after first recurrence and overall survival|
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|Table 4: Multivariate analysis of different prognostic factors for survival after first recurrence in patients treated with stereotactic radiosurgery|
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| Discussion|| |
SVZ invasion may represent subependymal spread, so patients with these tumors are less likely to benefit from SRS and are frequently considered ineligible. Here, we explored the impact of SRS on survival after recurrence and whether SVZ involvement may be predictive of SRS efficacy. To the best of our knowledge, this is the first study analyzing survival after GBM recurrence in relation to SVZ invasion and SRS. The current study focuses on whether it is beneficial to incorporate SRS at the time of first GBM recurrence.
Surgery is considered as the treatment of choice at recurrence in many centers and has been shown to be associated with improved survival after complete resection. However, total and safe gross removal of a contrast-enhancing mass is frequently difficult or impossible when recurrent. When resurgery is performed, complications may arise in over 20% of cases.
In patients undergoing surgery at recurrence, the reported survival is 13 months after gross total reresection and 6.5 months after incomplete reresection, with volumes of 9.5 cm 3 before resurgery at recurrence. Similar survival (6.5 months) was noted in our group not treated with SRS. Survival after SRS of recurrent GBM is reported to be 10–18 months, depending on the series; our result of 18 months matches the best of other reported results. For hypofractionated SRS in Phase I–II trials, survival is between 7 months  and 12 months after salvage. These confounding results emphasize the need for prognostic factors to guide SRS.
Smaller reirradiation target volumes have been shown to be prognostic in some studies. However, different studies report different volumes in hypofractionated stereotactic radiotherapy, SRS, and reresection. In hypofractionated stereotactic radiotherapy studies, volumes range up to 636 cm 3, whereas in SRS, the median volume is about 5 cm 3. In particular, Moller et al. found that biological tumor volume and MRI volume (cystic/necrotic cavities subtracted) derived from baseline 18 F-fluoroethyltyrosine-positron emission tomography, and MRI scans were both independent prognostic factors for OS following reirradiation with various SRS protocols, which may in part explain differences with our results (4 cm 3vs. 32 cm 3). Furthermore, tumor volumes at recurrence were also prognostic with systemic therapy, with significant survival advantages in recurrent GBM patients with enhancing tumor volume < 5 cm 3 compared to patients with larger tumor volumes.
Although volume may be an important factor that determines outcomes, important studies on glioblastoma reirradiation have failed to support this hypothesis.,,,, In particular, Scholtyssek et al. reirradiated very large median volumes > 100 cm 3 and found no difference in outcomes between volumes > 110 cm 3 and < 110 cm 3. One explanation for this is that size might be important when comparing small with very large tumors but not when very large volumes are irradiated. However, the threshold at which the volume effect is lost is unknown.
The volume at the time of recurrence was different between the groups in our study, but this parameter was also not associated with survival. Larger volumes in the non-SRS group were frequently treated with surgery, while those in the SRS group were not. In general, our study confirms that SRS of smaller volumes is effective. Therefore, early imaging and treatment of smaller tumors may have a role in the management of recurrent GBM. Future studies should stratify based on volume to provide more data on recurrence sizes favorable for irradiation.
A number of other prognostic factors at the time of reirradiation are also associated with survival, in particular age, KPS, and histology., Niyazi et al. recently made an effort to validate predictive factors for hypofractionated stereotactic radiotherapy and found that histology and age at diagnosis most significantly impacted survival after reirradiation. As far as we know, no predictive factors have yet been validated for recurrent GBM patients eligible for radiosurgery. KPS, resurgery, MGMT methylation status, sex, World Health Organization grade, tumor volume, and age were not significant predictors of either postrecurrence survival or postrecurrence PFS. There is a growing body of evidence that malignant gliomas infiltrating the SVZ and multifocal lesions at initial diagnosis have a dismal prognosis, with the natural history of these tumors being quite different to those in contact with primary tumor. Rapid and multifocal progression may be a negative predictive factor for radiosurgery. SVZ-positive tumors were identified as poor candidates for recurrence surgery due to their dismal prognosis. An analysis of recurrent GBM in relation to the SVZ after repeat surgery found an association between SVZ involvement during progression and worse survival after retreatment, so noninvasive treatment strategies for this group are needed. OS and survival after repeated surgery in SVZ tumors were 16 and 10 months, respectively, compared to 22 and 14 months for SVZ-negative recurrences. These data cannot be compared directly with our results due to the significant number of patients treated with SRS in the study by Sonoda et al. Furthermore, the most favorable results were observed in patients without SVZ involvement at the time of recurrence treated with SRS. However, the OS of patients treated with SRS for SVZ-positive tumors was better than that of patients not treated with SRS during the course of disease, regardless of SVZ invasion. These data support stratification on the basis of SVZ invasion for further radiosurgery trials in this indication.
The radioresistant nature of SVZ tumors limits fractionated radiotherapy efficacy, but we could not confirm whether this was similarly true for patients treated with SRS. Due to increased radioresistance of tumor stem cells within the SVZ, higher doses may be necessary to control SVZ tumors. In the primary setting, high-dose fractionated radiation of the whole ipsilateral SVZ was associated with a significant improvement in PFS and OS after gross total GBM resection. It has been proposed that GBM lesions may benefit from radiotherapy that includes the SVZ during primary treatment, and this strategy has been examined retrospectively with encouraging results. Two ongoing trials are currently testing the hypothesis of bilateral SVZ (NCT02177578) and ipsilateral SVZ alone (NCT02039778) irradiation. The limitation of whole, elective SVZ irradiation with 40–60 Gy is that it may produce delayed neurological deficits. Nevertheless, targeted radiosurgery at the time of recurrence is an effective treatment strategy when a high radiation dose is necessary, not limited by radioresistance, and to help preserve quality of life.
Khalifa et al. noted distant recurrences in 14% of cases after primary treatment, with the majority of all recurrences (distant and local) located within the SVZ. Recurrences more often occur within the SVZ than outside SVZ,, so the optimal management of such recurrences should be defined. For primary SVZ tumors, we noticed a substantial number of distant recurrences, and the number of distant recurrences was even greater after recurrence. There was further distant dissemination in 55% of cases. It is unclear what the efficacy of SRS retreatment is in second or more distant recurrences. As far as we know, this is the first study of the behavior of SVZ+ recurrent tumors treated with SRS. The high frequency of distant failure after SRS in SVZ-positive tumors did not, however, impact OS.
Our study has a number of limitations, including a lack of MGMT status and a relatively small study sample. We have used time to first progression as an MGMT methylation surrogate, perhaps indirect evidence of the different biology of these tumors. This marker was prognostic for OS. MGMT methylation status at recurrence is not thought to be prognostic, and MGMT methylation affects OS by increasing PFS but not postprogression survival., This is consistent with our results. Conversely, one study reported different outcomes from salvage radiosurgery according to methylation status; 14 months of survival after SRS for methylated MGMT tumors and 8 months for nonmethylated tumors. Further, methylation status was prognostic in recurrent tumors treated with implanted wafers  and in patients treated with temozolomide rechallenge. Thus, MGMT methylation status should be included in future studies examining the role of SRS in recurrent glioblastoma.
Another limitation was is that we did not have detailed information about the number of further reresections and/or salvage chemotherapy. Gross total resection of recurrent tumors, but not further resections, may extend survival. In our study, gross total resection of recurrent tumor, when possible, was part of treatment in the non-SRS arm but overall resulted in worse outcomes. Only two salvage chemotherapy schemes were used: PCV and temozolomide. There is no clear advantage to either of these treatments, so we do not expect large differences in outcomes in terms of type of salvage chemotherapy used.
The standard of care for patients with progressive glioblastoma has not been established. One single-arm study  and the randomized BRAIN trial  accelerated bevacizumab's approval in the United States; in Europe, bevacizumab is not routinely used. It has been shown that bevacizumab, a monoclonal antibody that targets the vascular growth factor receptor, decreases glucocorticoid needs and improves PFS. Data from the phase 3 BELOB trial support its use with lomustine. However, a recent randomized Phase 3 trial that compared lomustine alone with a combination of lomustine and bevacizumab at first progression of glioblastoma after standard chemoradiotherapy did not show an additional survival benefit of adding bevacizumab. Patients in this trial had a 31%–35% survival range at 12 months, with a median survival of 9 months after the first recurrence, similar to the non-SRS-treated subgroup in our study.
| Conclusion|| |
This study supports the use of SRS as an effective salvage modality for small recurrent GBMs. SVZ-positive tumors at the time of recurrence have a worse prognosis. Frequent distant failure may favor multiple, noninvasive treatment strategies. More prospective studies will be required to definitively confirm the value of SRS in recurrent GBM considering SVZ infiltration as prognostic factor.
Financial support and sponsorship
Institutional review board statement
The study protocol was approved by the Ludwik Rydygier Collegium Medicum of Nicolas Copernicus University Institutional Review Board (approved No. KB 494/2018) on June 19, 2018.
Declaration of patient consent
The authors certify that they have obtained the appropriate patient consent forms. In the forms, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understood that their names and initials would not be published and due efforts would be made to conceal their identity.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]