Prospective comparative study of intraoperative balloon electronic brachytherapy versus resection with multidisciplinary adjuvant therapy for recurrent glioblastoma
- Department of Neurosurgery, Novosibirsk State Medical University, Novosibirsk, Russian Federation,
- Department of Neurosurgery, Peoples’ Friendship University of Russia, Moscow, Russian Federation,
- Department of Neurosurgery, European Medical Center, Moscow, Russian Federation,
- Department of Neurosurgery, Klinik Hirslanden, Zürich, Switzerland,
- Department of Neurosurgery, Meshalkin National Medical Research Center, Novosibirsk, Russian Federation.
Aleksey Gaytan, Department of Neurosurgery, Peoples’ Friendship University of Russia, Moscow, Russian Federation.
DOI:10.25259/SNI_494_2021Copyright: © 2021 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Aleksey Krivoshapkin1, Aleksey Gaytan2, Orkhan Abdullaev3, Nidal Salim3, Gleb Sergeev3, Ilya Marmazeev3, Evaldas Cesnulis4, Tim Killeen4, Vladimir Tyuryn1, Roman Kiselev5, Pavel Syomin5, Aldo Spallone3. Prospective comparative study of intraoperative balloon electronic brachytherapy versus resection with multidisciplinary adjuvant therapy for recurrent glioblastoma. 11-Oct-2021;12:517
How to cite this URL: Aleksey Krivoshapkin1, Aleksey Gaytan2, Orkhan Abdullaev3, Nidal Salim3, Gleb Sergeev3, Ilya Marmazeev3, Evaldas Cesnulis4, Tim Killeen4, Vladimir Tyuryn1, Roman Kiselev5, Pavel Syomin5, Aldo Spallone3. Prospective comparative study of intraoperative balloon electronic brachytherapy versus resection with multidisciplinary adjuvant therapy for recurrent glioblastoma. 11-Oct-2021;12:517. Available from: https://surgicalneurologyint.com/surgicalint-articles/11166/
Background: Intraoperative balloon electronic brachytherapy (IBEB) may provide potential benefit for local control of recurrent cerebral glioblastomas (GBMs).
Methods: This is a preliminary report of an open-label, prospective, comparative cohort study conducted in two neurosurgical centers with ongoing follow-up. At recurrence, patients at one center (n = 15) underwent reresection with IBEB while, at the second center (n = 15), control subjects underwent re-resection with various accepted second-line adjuvant chemoradiotherapy options. A comparative analysis of overall survival (OS) and local progression-free survival (LPFS) following re-resection was performed. Exploratory subgroup analysis based on postoperative residual contrast-enhanced volume status was also done.
Results: In the IBEB group, median LPFS after re-resection was significantly longer than in the control group (8.0 vs. 6.0 months; log rank χ2 = 4.93, P = 0.026, P 2 = 4.23, P = 0.04, P
Conclusion: These hypothesis-generating results from a small cohort of subjects suggest putative clinical benefit in OS and LPFS associated with maximal safe re-resection of recurrent GBM with IBEB versus re-resection and standard adjuvant therapy, a hypothesis that deserves further testing in an appropriately powered clinical trial.
Keywords: Brachytherapy, Glioblastoma, Glioma resection, Intraoperative radiation therapy, Radiation therapy
Glioblastoma (GBM) is the most frequently occurring malignant intracerebral neoplasm in adults. It is characterized by significant infiltrative growth and an aggressive clinical course.[
Because of the obvious difficulty in conducting a randomized trial of gross total versus lesser resection in GBM, level 1 data supporting the value of gross total tumor resection for prolonging OS are rather spare,[
Level 1 data strongly support the role of radiation therapy in the management of newly diagnosed malignant gliomas; however, the use of EBRT in recurrent malignant glioma is often limited by the relatively high risk of radiation-related complications. The value of re-irradiation on OS, progression-free survival, and quality of life is still not well documented and needs to be investigated in future prospective trials.[
Attempts to use various intraoperative radiation therapy (IORT) techniques in patients with malignant gliomas have been undertaken for several decades. Several studies have shown improved survival rates in subjects treated with IORT compared with retrospective controls; however, these studies were performed in small groups of subjects, and exhibits significant limitations.[
Intraoperative balloon electronic brachytherapy (IBEB) is a new method that has been successfully applied in oncological practice over the past few years to treat breast cancer as well as other neoplasms.[
This prospective cohort study was performed at two tertiary referral neurosurgical centers in the Russian Federation. The study enrolled in total 30 ≥18 years old patients with recurrent GBM (imaging-defined, using brain magnetic resonance imaging [MRI] with contrast enhancement and MR-perfusion) with Karnofsky Performance Status (KPS) ≥60%. Ineligibility criteria included contraindications to general anesthesia, decompensated chronic illness, acute infectious and non-infectious inflammatory processes, inability to undergo MRI with contrast enhancement and/or positron emission tomography-computed tomography (PETCT) with amino acid tracers, pregnancy, or breastfeeding. The final decision on subject inclusion was made by a multidisciplinary team with the mandatory participation of a neurosurgeon, a radiologist, a radiation oncologist, and a medical oncologist.
The electronic brachytherapy device used in this study is a miniaturized X-ray source that applies electronic brachytherapy (Xoft® Axxent® Electronic Brachytherapy (eBx®) System; Xoft®, a subsidiary of iCAD, Inc., San Jose, CA USA). The device enables highly focused therapeutic radiation to the target tissue with very rapid dose fall-off, which spares surrounding tissue. The X-ray source is complemented by a range of balloon applicators to be filled with varying volumes of saline to optimally fit the contour of the surgical cavity. This provides a well-defined geometry for the miniaturized X-ray source and allows the delivery of a more conformal radiation dose.
This study was approved by the local ethics committees and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its amendments.[
At Moscow, 15 consecutive subjects with recurrent GBM underwent maximum safe microsurgical resection of their recurrent tumor in combination with IBEB (IBEB Group). These subjects received no further adjuvant treatment. In the same period, Novosibirsk also recruited 15 consecutive subjects with recurrent GBM. These subjects underwent the same maximally safe resection, followed by routine postoperative adjuvant chemotherapy with or without radiotherapy, based on investigator preference (Control Group).
GBM recurrences were confirmed by contrast-enhanced MRI perfusion and additional PET-CT with amino acid tracers in selected cases. In case of questionable results, intraoperative pathomorphological examination (frozen section analysis) was performed. Ultimately, the presence of tumor recurrence was confirmed by pathological examination after surgery.
Preoperatively, the radiation oncologist, medical physicist, and neurosurgeon developed in all cases the IBEB plan (BrachyVision™; Varian Medical Systems, Inc., Palo Alto, CA). To provide this preoperative dosimetric estimate, reliable preoperative neuroimaging techniques were utilized to estimate the volume of the predicted post-operative surgical cavity and the appropriate balloon size to fit it. This allowed also the estimation of the IBEB X-ray source dose delivery to be applied [
(a) T1-weighted contrast-enhanced axial magnetic resonance imaging image demonstrates local glioblastoma recurrence prior to resection followed by intraoperative balloon electronic brachytherapy (IBEB). (b) IBEB isodose distribution based on computed tomography (CT) scans covers tumor bed sparing surrounding brain tissue. (c) External beam radiotherapy plan in comparison to IBEB. Isodose distribution based on the same CT scans affects extensively surrounding brain tissue which was irradiated after first surgery. (d) An overview of the post-resection cavity. (e) Intraoperative ultrasound demonstrates configuration of the postresection cavity which is free of macroscopic disease. (f) Deflated applicator balloon being introduced into the post-resection cavity. (g) Final position of the inflated applicator balloon with its dense adherence to the walls of the post-resection cavity. (h) Proper position of the balloon confirmed by intraoperative ultrasound.
Resection in both groups of subjects was conducted under general anesthesia, targeting maximal and safe resection under computed frameless MRI with contrast enhancement guidance, metabolic navigation with 5-aminolevulinic acid (5-ALA), and neurophysiological monitoring of evoked motor potentials. No “awake surgery” resection was conducted in the present patients. In the cases of multifocal tumor, only the largest neoplastic focus was resected, since it usually was responsible for the greatest mass effect. As described above IBEB was performed using the electronic brachytherapy device. After microsurgical removal of the neoplasm, the resection cavity was measured by filling it with isotonic sodium chloride solution. An empty IBEB applicator balloon was then introduced into this cavity and filled with the known volume of sodium chloride solution to give it a spherical shape, tightly adhering to the walls of the tumor bed. This was confirmed ultrasonographically [
A baseline postoperative MRI scan with and without contrast was obtained within 24 h. Following IBEB, subjects did not receive any other adjuvant treatment except for those subjects with multifocal tumors, where additional stereotactic conformal fractionated irradiation was performed to treat the remaining lesions. Two patients in the IBEB group received additional surgery and IBEB treatment to deal with multifocal tumor growth. One subject with multifocal lesions (Nr. 10) did not receive any additional radiation therapy.
In the control group, 13 subjects received adjuvant therapy by preference of the treating neurosurgeon. The systemic treatment regimens included temozolomide, bevacizumab, lomustine, and mustophoran. Eight subjects received additional EBRT with doses between 36 and 60 Gy and one subject underwent another surgery.
Follow-up and analysis
All subjects were followed monthly according to the protocol. This included clinical visits and evaluation for performance status, toxicities, and clinical evidence of progression, with imaging controls every 3 months. This included MR imaging with and without contrast, perfusion-weighted MR to assess cerebral blood volume, and PET-CT with 18-FDOPA.
Contrast-enhanced tumor volume before and after resection was evaluated with automated volumetric analysis based on DICOM MR images (NeuroSegment Software; Novosibirsk, Russia).[
This is a hypothesis-generating small pilot study with two contemporaneous cohorts enrolled simultaneously at two centers, without randomization. The endpoints included OS, local progression-free survival (LPFS) and the impact of the residual postsurgical tumor volume on OS and LPFF. OS was defined as the interval from the day of the recurrent GBM surgery to death for any reason or to the last documented follow-up, whichever occurred first; LPFS was defined as the time between surgery to any Local Progression/Tumor reoccurrence within 20 mm of the cavity margin or to the last documented follow-up, whichever occurred first. Based on the suggestion of the literature regarding the impact of the extent of residual tumor volume determined by MRI within 24 h after surgery on OS,[
Statistical analyses of the treatment groups, including appropriate measures of central tendency and distribution, were performed using commercial software (IBM SPSS Statistics®; Armonk, NY and XLSTAT; Addinsoft, New York, NY). The effect of IBEB and the extent of tumor resection on OS and LPFS were assessed using Kaplan–Meier curves and the Log-rank test. A multivariate analysis (MANOVA) was carried out for both treatment groups. Independent variables evaluated for their impact on the efficacy endpoints included volume of residual disease, adjuvant therapy, gender, KPS, and IDH1/2 status. A univariate Cox proportional hazards model was used to calculate the hazard ratio (HR) for radical resection and IBEB therapy and a MANOVA was performed with corresponding adjustments for variables with potential confounding effects.
Baseline demographics and clinical characteristics
Thirty subjects were treated in the IBEB Group (Subjects 1-15) and Control Group (Subjects 16-30). Subjects in the IBEB Group had recurrent GBM (Grade IV, WHO 2016) with a mean age of 52.9 years (range, 40.0–71.0 years). Six (40%) were male. Median KPS was 90% (range, 60–100%). Other subject and tumor characteristics are summarized in [
The Control Group included 15 subjects with recurrent GBM (Grade IV, WHO 2016). Two subjects did not receive any further adjuvant therapy due to postoperative complications, but they were included in the intent-to-treat analysis. The mean age of the control group subjects was slightly younger at 48.6 years (range 24.0–74.0 years). The majority, (67.7%) were male unlike what observed in the IBEB Group. Subjects in the control group had a median KPS of 85.3% (range, 60–100%). Other subject and tumor characteristics are summarized in [
Subjects in both treatment groups had a ≥6-month period between the last day of the initial radiation and any subsequent radiotherapy for the recurrent tumor [
The location of the tumor resections is presented in [
Ten IBEB Group subjects had local tumor recurrence in the immediate vicinity of the resection cavity without signs of multifocal growth. In the remaining five (Patients 4, 5, 8, 10, and 11) cases, distant tumor growth was observed in addition to the main GBM focus. Mutation in the 132nd codon of the IDH1 was detected in three subjects. No subject presented with any mutation of the IDH2 gene. Analysis of the MGMT gene promoter methylation was performed in 11 subjects. The promotor was methylated in only three cases, one of which was in combination with the mutation of the IDH1 gene.
In 14 control group subjects, local tumor recurrence occurred in the immediate vicinity of the resection cavity without signs of multifocal growth. In one case with multifocal GBM (Subject 25), there was relapse at and distant to the site of operation. The median duration of the disease-free period after the initial surgery was 8.0 months (range 0–14 months). The localization of tumor foci, subjected to resection, is presented in [
IBEB and control arm results
The postoperative residual contrast-enhanced volume (PCEV) values of the main lesion for each subject in the IBEB group are shown in [
In a subgroup of subjects of the IBEB group (n = 7) with PCEV >2.5 cm3, the median LPFS was 5.0 months (range 3.5– 8.0 months). It should also be noted that in this subgroup, four subjects showed multifocal growth of their GBM. In the subgroup of subjects with PCEV ≤2.5 cm3 (n = 8), the median LPFS was 16.5 months (range 7.5–54.0 months). This subgroup included one subject with multifocal GBM. Whereas five (4, 5, 8, 10, and 11) patients experienced multifocal tumor growth before IBEB treatment, two patients (2 and 13) presented multifocal lesions after IBEB, outside the radiation treatment field. Patients with multifocal lesions in the IBEB group were treated after IBEB with EBRT, or surgery followed by a second course of IBEB. Therapeutic approaches used to control the multifocal tumors in the IBEB group are given in [
The PCEV values of all subjects of the control group are shown in [
The median LPFS for the entire Control Group (n = 15) was 6.0 months (range, 2.0–10.0 months) and 33% (n = 5) of these subjects had a LPFS >6 months. In a subgroup of subjects (n = 8) with PCEV >2.5 cm3, the median LPFS was 2.0 months (range, 2.0–6.0 months). In the subgroup of subjects with PCEV ≤2.5 cm3 (n = 7), the median LPFS was 8.0 months (range, 6.0–10.0 months).
Median OS for the IBEB group was 11.0 months (range, 4.0–54.0 months). In the subgroup of subjects with PCEV >2.5 cm3 (n = 7), the median OS was 7.5 months (range, 4.0–11.0 months). In the subgroup of subjects with PCEV ≤2.5 cm3 (n = 8), median OS was 21.2 months (range, 7.5– 54.0 months). Relatively rapid progression was noted in all subjects with PCEV >2.5 cm3, irrespective of multifocal tumor growth. The Kaplan–Meier analysis of OS after reresection of recurrent GBM in combination with IBEB is shown in [
Kaplan-Meier curves for overall survival in the intraoperative balloon electronic brachytherapy group stratified according to postoperative residual contrast-enhanced volume (PCEV): the subgroup of subjects with PCEV >2.5 cm3 marked in red, the subgroup of subjects with PCEV ≤2.5 cm3 marked in green; log rank χ2 = 8.03, P = 0.005, P < 0.05.
Median OS for the entire control group of subjects (n = 15) was 8.0 months (range, 2.0–22.5 months). In the subgroup of subjects with PCEV >2.5 cm3, median OS was 2.8 months (range, 2.0–9.0 months). In the subgroup of subjects with PCEV ≤2.5 cm3, median OS was 11.0 months (range, 8.0– 22.5 months). The median OSin after initial surgery for the control group was 21.0 months (range, 4.5–38.5 months) [
Treatment group comparisons
Data analysis of the CEV and PCEV, KPS, MGMT in these groups showed a normal distribution of values and the equality of variances (Livin criterion for dispersions equality, P > 0.05). Analysis of variance testing did not reveal statistically significant differences between IBEB and control groups (Pillai multivariate trace = 0.153, P = 0.390).
The results of a univariate Cox proportional hazards model to calculate the HR for PCEV and IBEB therapy are listed in [
Among subjects in the IBEB, both the median LPFS and the median OS were significantly higher than those in control group (8.0 vs. 6.0 months and 11.0 vs. 8.0 months, respectively). The Kaplan–Meier curve confirmed statistically significant increased OS and LFPS for the IBEB group of subjects compared to the control group (OS: log rank χ2 = 4.23, P = 0.04, P < 0.05; LPFS: log rank χ2 = 4.93, P = 0.026, P < 0.05) [
The results of the study confirmed the important role of the extent of tumor resection in cases of GBM recurrence. Kaplan– Meier curves [
Kaplan-Meier curves for local progression-free survival in the subgroups of subjects with postoperative residual contrast-enhanced volume ≤2.5 cm3: the intraoperative balloon electronic brachytherapy group marked in green, the control group marked in red; Log Rank χ2 = 7.24, P = 0.007, P < 0.05.
The treatment of recurrent GBM is still matter of debate. The role of re-resection has become widely accepted in the last decade provided some clinical parameters would seem to justify this, including age, relatively good Karnofsky status and no invasion of functionally relevant areas.[
However, others factors such as MGMT methylation, IDH 1/2 mutation, and comorbidities are known to play a role in the outcome of GBM patients. This means that evaluation of newly proposed therapeutic protocols requires unavailable extreme caution, and preliminary though encouraging results, if convincing, should be considered only a suggestive base for properly designed future studies.
In our study, we proposed for the first time the use of IBEB technique in GBM patients. This technique was recently introduced and has become a widely accepted form of local radiation therapy for malignant tumors of several organs which seems to offer the advantage of increasing the radiation dosage delivered to the malignancy while sparing almost completely the surrounding healthy tissue. We designed an open-label, not randomized study because the IBEB technology was available only in one center. For the recruitment of the control group of patients, another independent center was chosen to eliminate bias. However, the two institutions share several members of the medical staff and have strictly similar treatment protocols for GBM patients. In particular, criteria for reoperation were absolutely the same, and postoperative management in no-IBEB group of patients followed the most updated therapeutic recommendations.
The present results indicate improved, LPES in the IBEB treated group which reached statistical significance (8.0 months vs. 6.0 months) which appeared also more evident in the cases in which near-total removal had been achieved (16.5 months vs. 8.0 months). Consequently also OS was significantly longer in the IBEB group.
We collected from the relevant literature previously published outcomes data for the treatment of recurrent GBMs. These are summarized in [
Our study reports two cases of radionecrosis in the IBEB Group with only one CTCAE Grade 3 toxicity. No other grade ≥3 adverse events occurred in the IBEB group. This is in the same range as RTOG 1205, which reported 5% grade ≥3 events.[
In our patients the IBEB treatment took approximately 30 min, with a duration of <20 min in the vast majority of the patients, thus IBEB treatment did not significantly increase the total surgery time [
The effect of any adjuvant therapy decreases with the amount of residual tumor. GBM is an aggressively growing tumor, with the potential to increase substantially in volume within a short period.[
As mentioned previously, metabolic guidance using 5-ALA was used intraoperatively. Protoporphyrin IX (PpIX, a 5-ALA metabolite) selectively accumulates in cancer cells and was characterized as a radio-responsive compound. As in vitro studies and in vivo studies in small animals have shown, PpIX produces reactive oxygen species upon X-ray irradiation, which induces DNA double-strand breaks resulting in cell cycle arrest.[
We did not operate any of the present patients on awake surgery, a treatment protocol of which we have extensive experience particularly in recurrent GBM. Awake surgery would give immediate, functional control to the operating surgeon, and might encourage more aggressive, thought safe, surgical conduct. However, highly developed technology such as sophisticate neuromonitoring and metabolic navigation in anesthetized patients can offer equivalent safety standards to the operating surgeon who is so encouraged to perform maximally aggressive though safe resection.
Study limitations include an open-label study design, inability to control for all the factors contributing to outcome, inclusion of subjects with multifocal disease, sample size, and limited follow-up period. In addition, patients were not allocated randomly to either treatment regiments as they were treated in two different Institutions. However, we believe that the present results are appealing and should encourage further investigations by properly designed clinical trials in order determine if the innovative IBEB protocol which we used in this study might be helpful to other subjects with similar characteristics.
The results of this prospective, two-center, and comparative cohort pilot study suggest that a significant improvement in median LPFS and OS may occur in subjects undergoing IBEB following repeated resection of recurrent GBM in comparison with a control group who received standard adjuvant chemo-radiotherapy following re-resection. IBEB was associated with manageable toxicity. Subjects with a PCEV <2.5 cm3 and free of concurrent multifocal disease showed particular benefit from IBEB. This first comparative study, while limited by small sample size and its open-label nature, provides hypothesis-generating data that may warrant further investigation on the potential use of IBEB in malignant gliomas and its risk/benefit/ratio.
Institutional Review Board (IRB) permission obtained for the study.
There are no conflicts of interest.
Institutional Review Board (IRB) permission obtained for the study.
There are no conflicts of interest.
The authors acknowledge the editorial assistance of Dr. Carl S. Hornfeldt, Apothekon, Inc., during the preparation of this manuscript.
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