Relation between residual tumor volume after surgery and overall survival in patients with glioblastoma – a single neuro-oncology center study

Overview

Aim: The aim of this study is to demonstrate the technical feasibility of volumetric assessment of residual tumor volume and to evaluate the effect of a precisely defined residual tumor volume on overall survival (OS) in patients with glioblastoma (GBM). Materials and methods: Adult patients who underwent surgical resection for GBM in the University Hospital Olomouc from 2012 to 2016 were selected retrospectively. Patients attended regular clinical and MRI follow-up every three months. Early postoperative MRI scans were used in the study. In each patient, tumor segmentation was performed followed by creating a 3D model of tumor volume, which allowed the calculation of its volume both before and after surgery. Results: Results of 50 patients were available for a retrospective analysis. Our study showed a significant prolongation of OS only in the group with no contrast-enhancing residue (median OS = 16.1 vs. 6.3 months) Patients with a combination of radical resection and oncological treatment with the Stupp protocol achieved further prolongation of OS with a mean of 19.6 months and a median of 14 months. Conclusion: Our paper describes the process of calculating the volume of the postoperative residual component of GBM using easily available software. According to the study findings, significantly better therapy results were achieved in patients with complete removal of the contrast-enhancing GBM component, supplemented by the most possible radical resection of the contrast non-enhancing components of the tumor.

Keywords:

overall survival – glioblastoma – postoperative residue

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

 

Introduction

Glioblastoma (GBM) is the most common and most malignant primary CNS tumour of WHO classification grade 4 with an unfavourable overall survival (OS) of 16-24 months [1,2]. The 2016 WHO classification [1] divided the most malignant forms of astroglial tumors into predominant GBM without isocitrate dehydrogenase (IDH) mutation (GBM IDH wild-type) and low-frequency GBM with IDH mutation (GBM IDH mutant), which in 5-10% arise secondary to malignant transformation from diffuse astrocytoma or anaplastic astrocytoma. However, advances in the understanding of the genotype-phenotypic characteristics of gliomas soon necessitated further modification of the nomenclature [2,3]. The 2021 WHO classification [4] assigned the name GBM to all astrogliomas without IDH mutation that meet the genetic characteristics of so-called molecular glioblastomas [3]. Gliomas without IDH mutation are referred to as IDH wild-type astrocytomas, WHO group 4.

The best results are achieved by aggressive multimodal therapy of GBM [4,5], which includes maximal radical safe resection. As shown above, one of the few confirmed positive prognostic factors is the radicality of surgical resection [6-13].

The aim of this study was to demonstrate the technical feasibility of volumetric assessment of postoperative residual volume in GBM and to evaluate the impact of a well-defined residual tumor volume on the OS of GBM patients.

 

Patients

Adult patients who underwent GBM resection at the Olomouc University Hospital from 2012 to 2016 and for whom the necessary data were available were selected retrospectively. Recurrent GBM and tumors diagnosed by needle biopsy were excluded. The goal of surgical treatment was maximal radical safe resection followed, if possible, by standard aggressive oncotherapy according to the Stupp protocol [5]. All patients underwent early postoperative MRI within 48 h of surgery to assess the radicality of the procedure. Tumor tissue was evaluated by a local pathologist as glioblastoma in all patients according to the 2016 WHO classification [1]. Subsequently, patients attended regular clinical and MR follow-ups every 3 months until death. Tumor tissue samples were stored both as formalin-fixed and paraffin-embedded blocks and as unfixed, deep-frozen samples stored in liquid nitrogen.

 

Evaluation methodology

All patients with histologically confirmed GBM complemented by molecular biology examination of IDH mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in the given period had access to preoperative and postoperative MR examination on a 1.5T MR machine (Siemens MAGNETOM SYMPHONY or Siemens MAGNETOM AVANTO, Munich, Germany). Postoperative MR examination was performed within 48 h after surgery. Both preoperative and postoperative examinations included fluid attenuated inversion recovery (FLAIR) sequences and postcontrast T1-weighted sequences (voxel size 0.4 × 0.4 × 6 mm³ to 0.7 × 0.7 × 6.5 mm³) so that we were able to differentiate postoperative changes from postcontrast tumor and noncontrast tumor residual. The presence of postoperative residual tumor was independently assessed by the radiologist and the two neurosurgeons who performed the surgery.

For each patient, a segmentation of the tumor process was performed, followed by the creation of a 3D model and calculation of its volume in three planes based on semi-automatic evaluation. Post-contrast T1-weighted images were used as the source, which were extracted from the hospital system viewer and then converted from DICOM format to NIFTI format. These images were subsequently entered into FSLeyes software, a multiplatform tool (Wellcome Centre for Integrative Neuroimaging [FMRIB], University of Oxford, UK) [14] (Figure 1). From these sequences, masks containing the tumor in three mutually perpendicular planes were created using the aforementioned software and then checked by another neurosurgeon who assessed the complexity of the created masks (Figure 2).

Using the ITK-SNAP software (Penn Image Computing and Science Laboratory [PICSL], University of Pennsylvania, USA), we were able to semi-automatically create a 3D model of the tumor from these masks [15] (Figure 3). Subsequently, the 3D tumor volume was calculated to three decimal places. Postoperatively, if a postoperative residual was identified and described, the same procedure was used to calculate its volume based on the created masks. Again, the residual masks were independently checked by neurosurgeons (Figures 4 and 5). The ratio of the calculated postoperative residual volume to the preoperative MRI finding volume indicates the percentage of surgical radicality of the surgical resection.

 

IDH and MGMT mutation testing

Examination of IDH mutation and MGMT promoter methylation was performed using standard techniques at the Olomouc Neuro-Oncology Centre [16-18]. The first step was immunohistochemical examination of the canonical IDH mutation (anti-IDH1R132H), complemented by IDH genotyping using Next-Generation Sequencing (Nextera XT kit, Illumina, San Diego, CA, USA), and MGMT promoter methylation examination using Real-time methylation-specific PCR (Zymo Research, Irvine, USA).

 

Statistical analysis

The description of the observed parameters was performed using frequency tables and descriptive statistics (mean, median, minimum, maximum). Kaplan-Meier curves were used to show patient survival. All analyses and graphical outputs were performed in the statistical software R, ver. 3.5.2 (Core Team, R Foundation for Statistical Comput-ing, Vienna, Austria 2018). Tests were performed at the 5% level of statistical significance. Results with a p-value less than 0.05 were considered statistically significant.

 

Results

The results of 50 patients, 32 men and 18 women, whose age ranged between 33 and 82 years with a median age of 62 years, were available for retrospective analysis. Follow-up time varied from 1.2 months to 92 months (7.6 years), with a mean of 13.1 months and a median of 7.9 months. All patients were operated with a histological diagnosis of GBM, supplemented by immunohistochemical and molecular genetic analysis where available. GBM without IDH mutations was confirmed in 41 patients, GBM with IDH mutations in 4 patients. In five cases, it was not possible to investigate the IDH mutation due to insufficient quality of the collected sample. MGMT promoter methylation was confirmed in 12 patients. For technical reasons, MGMT promoter methylation was not investigated in 19 patients.

A total of 13 patients underwent radiotherapy alone at a total dose (60 Gy/30 Gy), either in the form of intensity modulated radiotherapy (iMRT) or 3D conformal radiotherapy. Another 23 patients underwent complete concomitant chemoradiotherapy according to the Stupp protocol. Only three of these patients required a dose reduction of continued chemotherapy due to hematotoxicity. At the beginning of the analysis, it was determined that the application of more than 40 Gy of radiotherapy in normofractionation would be considered as performed oncotherapy. In the end, however, no patient received a radiotherapy dose between 40 and 59 Gy. Fourteen patients did not complete or did not undergo any oncological treatment due to unsatisfactory clinical status.

The operated patients were divided into groups according to the residual volume based on the postoperative residual volume (Table 1). Group 1 was also added with patients with so-called supramaximal resection [11], which was defined by complete removal of both the postcontrast-enhancing portion of the tumor and resection of noncontrast-enhancing tissue (MR/T1 hyposignal, MR/T2/FLAIR hypersignal) with a residual volume below 5 cm³. Group 2A included patients with complete resection characterized by complete removal of the postcontrast-enhancing component of the tumor. Group 2B was defined by a residual tumor volume ≤ 1 cm³. Group 3A was characterized by a residual postcontrast tissue volume ≤ 5 cm³. Group 3B was characterized by a residual postcontrast tissue volume greater than 5 cm³. One patient in group 4 had a resection procedure prematurely terminated due to cardiovascular instability. The resulting radicality of the resection was more consistent with an extended biopsy.

The extent of the resection performed in the case of partial resection ranged from 15%, which is at the level of a biopsy, to resection of 99% of the volume, including the postcontrast non-contrasting component of the tumour. The largest preoperative tumor had a volume of 117.74 cm³, and the smallest had a volume of 10.76 cm³ (median 22.23 cm³ and mean 29.49 cm³). The average radicality of resection among all operated patients was 92%.

A statistically significant effect of resection radicality on OS prolongation was found only in patient groups 1 and 2A. That is, in the group without the finding of postcontrasting GBM residue, or supplemented with resection of the postcontrasting part of the tumor (Figure 6). This was a group of 6 patients with supramaximal resection, with OS between 16.8 and 92.1 months (7.6 years), with a mean of 35.6 months and a median of 18 months. Group 2A included a total of 23 patients with OS between 4.6 and 39.4 months (3.3 years), with a mean of 10.8 months and a median of 5.8 months. When the two groups were combined, the mean OS was 16.1 months, with a median of 10.7 months.

In group 2B, there were 7 patients with OS between 1.3 and 38.6 months (3.2 years), with a mean of 13.2 months and a median of 9.3 months, the shortest being 0.4 months and the longest 38.6 months. In group 3A, there were 5 patients with OS between 2 and 19 months, with a mean OS of 10.7 months and a median of 9.6 months. Group 3B contained 8 patients with OS between 1.3 and 17.3 months, with a mean OS of 6.7 months and a median of 4.8 months. Group 4 included only 1 patient with an OS of 1.2 months. In the combined group 2B, 3A, 3B and 4 evaluated as partial resection, the mean OS was 9.6 months, with a median of 5.9 months.

When evaluating the impact of oncotherapy, patients with better resection, good postoperative clinical status and the ability to complete the complete oncological treatment (Stupp protocol) achieved a clearly better OS (Figure 7). In groups 1 and 2A with complete resection (29 patients in total), 15 patients completed the Stupp protocol with a mean OS of 19.6 months and a median OS of 14.1 months. Five patients underwent postoperative radiotherapy alone with a mean OS of 13.5 months and a median of 5.4 months. Nine patients remained cancer-free with a mean OS of 11.2 months and a median of 3.8 months.

In the remaining partial resection groups (21 patients in total), 8 patients underwent the Stupp protocol with a mean OS of 14.9 months and a median of 13.2 months. Eight patients underwent radiotherapy alone with a mean OS of 9.2 months and a median of 8.2 months. There were 5 patients without cancer treatment with a mean OS of 1.7 months and a median of 1.3 months.

 

Discussion

Surgical resection of the tumour is an essential part of glioma treatment and radicality of resection has been repeatedly confirmed as a positive prognostic factor affecting OS [6-13]. Based on postoperative MRI performed within 72 h of surgery, the radicality of resection has been evaluated in several ways [9,10]. One option was to subdivide according to the radiological, MR postcontrast image, residual tumor: gross total resection (GTR) = complete removal of the postcontrast tumor component, near total resection (NTR) = postcontrast thin margin of tumor on the wall of the resection cavity, subtotal resection (STR) = postcontrast small nodules on the wall of the resection cavity, and partial resection (PR) = presence of a large postcontrast residual tumor.

Another option was to assess the extent of resection by comparing the preoperative and postoperative volumes and determining the percentage reduction of the original tumor volume: GTR = complete removal of the postcontrasting tumor component, NTR = more than 90% reduction of the original tumor volume, STR = removal of 51-90% of the original tumor volume, and PR = with extirpation less than or equal to 50% of the original tumor volume. In the case of extirpation of less than 10% of the original tumor volume, this operation was considered as a mere biopsy. However, both of the aforementioned methods of postoperative residual assessment have their shortcomings. The first system dividing the postoperative MRI findings according to radiological grades of radicality is burdened with considerable subjectivity, and the system using percentage assessment of resection radicality is burdened with bias based on the different preoperative volume of individual tumors.

One of the first major studies was the 2011 paper by Sanaia and Berger [10], which focused on volumetric analysis of the extent of resection in 500 patients̊ with newly̌ diagnosed supratentorial GBMs. The median postoperative residual tumor volume was 2.3 cm³ and the median extent of resection was 96%. This study demonstrated a significant prolongation of survival with a reduction of more than 78% of the original tumor volume.

In a retrospective study, Orringer and Lau et al. [13] used a semi-automated technique to assess the extent of resection in GBM. The median extent of resection was 91%. Again, the extent of resection was associated with significantly longer survival (76.5%), with resection greater than or equal to 90% compared to resection less thaň 90%.

Another 2014 paper by Grabowski et al [19] showed that the volume of residual post-contrast GBM was a much more significant predictor of OS prolongation than the percentage of resection. A volume of 2 cm^{(3) of} residual tumor was determined as the cutoff volume for a significant impact of resection on OS prolongation.

In 2023, papers were published [12,20,21] showing the impact of complete extirpation of post-contrast GBM tissue on significantly prolonging OS. Efforts to identify the volume of residual tumor that would still significantly prolong OS led to a study organized by EANO [12], which confirmed the above conclusions and pushed the threshold to 1 cm^{(3) of} residual post-contrast GBM tissue.

Based on our study, for our clinical practice, we assigned the following threshold residual tumor volumes to the original radiological radicality grades: supramaximal resection, GTR: no postcontrasting residual, NTR: ≤ 1 cm³ residual, STR: > 1 cm³ and ≤ 5 cm³, and PR: > 5 cm³.

Our study showed a clearly significant prolongation of OS only in the groups without post-contrast residual (median OS = 16.1 vs. 6.3 months). In the group with residual tumor volume up to 1 cm³, there was already a reduction in OS prolongation (median OS = 10.7 months). Our study demonstrated that the actual size of the residual tumor is a more significant prognostic factor for OS than the percentage of resection.

A recurrently discussed topic in the literature is the question of the so-called supramaximal resection of the MR/T1 hyposignal area around the postcontrast tumour [11]. This area consists of the peritumoral infiltration zone [22], which is formed when migrating tumor cells penetrate into the brain tissue and is the pathobiological basis of residual tumor disease in GBM [23]. Conclusions suggest that the effect of complete extirpation of postcontrasting GBM tissue on OS prolongation can be further enhanced when at least 50% reduction of the postcontrasting non-contrasting part of the tumor is achieved [11,24, 25]. Our study also demonstrated a positive prognostic effect of resection of the peritumoral infiltration zone, with a median OS of 18 months in these patients.

The increasing radicality of resection is necessarily associated with an increasing risk of permanent neurological deficit, which compromises the application of standard cancer therapy [26] and ultimately shortens OS [27]. On the contrary, it has been shown that the positive prognostic effect of oncotherapy in the Stupp regimen is multiplied by radical resection of GBM [5]. Also in our cohort, patients with radical resection and oncotherapy in the Stupp regimen achieved the best outcome with a mean OS of 19.6 months and a median OS of 14.1 months. The limited percentage of patients who were eventually able to undergo standard chemoradiotherapy is consistent with data published in the Czech literature [28].

 

Conclusion

Our work describes a simple procedure to calculate the postoperative tumor residual volume using readily available software. According to the conclusions of our study, the significantly best results were achieved by patients with complete removal of the postcontrasting part of the GBM supplemented by the most radical resection of the postcontrasting part of the tumor. Based on the data obtained on the residual tumor volumes, we could precisely define the radicality grades.

There are only a few controllable factors in GBM that have been shown to influence treatment outcomes, and maximal radical safe resection is one of them. Conversely, adverse postoperative clinical status of the patient may minimize this effect. Therefore, finding a balance between radicality of resection and postoperative quality of life must be an integral part of a patient-centered individualized surgical treatment strategy.

 

Ethical aspects

The study was conducted in accordance with the 1975 Declaration of Helsinki (and its 2004 and 2008 revisions). Patients were treated according to the standard procedure. The study is not subject to ethics committee approval. All patients signed an informed consent for the anonymized analysis of the data obtained and consented to the diagnostic and treatment process.

 

Grant support

This study was partially supported by a grant from the Ministry of Health of the Czech Republic -⁠ AZV (NU21-03-00195). This study was supported by the conceptual development funds of the FNOL research organization, 00098892.

 

Conflict of interest

The authors declare that they have no conflict of interest in relation to the subject of the study.

 

Group	1	2A	2B	3A	3B	4
number of patients (%)	6 (12 %)	22 (44 %)	8 (16 %)	9 (18 %)	4 (8 %)	1 (2 %)

Table 1. Groups of patients according to the radicality of resection.