Sub-lobectomy for IDH Wild-type and TERT Promoter Mutant Glioblastoma

Glioblastoma is recognized as the most common and aggressive form of primary malignant brain tumor, with treatment options that are limited and prognosis that is extremely poor, showing median progression-free survival of 12 months and median overall survival of less than 18 months. Surgical resection plays a critical role in the treatment, with the extent of resection significantly impacting patient outcomes. Historical approaches to surgical resection have evolved, moving from radical strategies to more conservative ones that aim to preserve normal brain function while removing the tumor as completely as possible. Recent studies have suggested that increasing the extent of surgical resection, particularly along the T2 FLAIR border rather than the traditional T1-enhanced border, can significantly improve patient prognosis. There is, however, a lack of consensus on the optimal surgical approach, and the heterogeneity of tumors presents challenges in standardizing surgical strategies. Extended resection has been shown to prolong survival, and novel intraoperative molecular diagnostics have emerged to improve accuracy in tumor classification and prognosis. Building on these advancements, a multicenter, prospective, randomized controlled trial is proposed to evaluate the efficacy of sub-lobectomy in treating IDH wild-type/TERTp-mutant glioblastoma, aiming to improve evidence levels and establish standardized surgical practices for this devastating disease.

Glioblastoma is the most prevalent and aggressive type of primary malignant brain tumor\[1\]. Treatment options are limited and often include surgical resection followed by radiation therapy or electric field therapy\[2\]. Prognosis is very poor, with median progression-free survival of only 12 months and median overall survival of less than 18 months. The 5-year survival rate is a mere 12% \[3\].

Surgical resection is fundamental to treating patients with glioblastoma, and the extent of resection directly impacts patient prognosis \[4\]. Professor William Stewart Halsted, a renowned surgeon, historically championed "radical" surgical resection as a means of controlling tumours \[5\]. Nevertheless, the majority of neurosurgeons disagreed with this view because of the disruption to normal brain function caused by extreme surgery. However, in 1928, Professor Walter Dandy reported five patients with gliomas who underwent right hemispherectomy \[6\]. These patients showed no significant neurological impairment except for left hemiparesis. Even though no grave complications arise from the complete resection of the nondominant hemisphere, it did not seem to enhance the patients' prognosis either. Only one out of these five patients survived for 3.5 years, and eventually, all of them passed away due to gliomas. After this, the radical surgical strategy of enlarging the resection margin around gliomas was challenged, and neurosurgeons aimed to achieve total resection of imaging gliomas, based on the principle of removing tumour tissue with an abnormal signal on MRI while preserving normal brain function.

Notably, with respect to the complete surgical removal of glioblastoma, the T1-enhanced borders of MRI imaging were commonly used as a criterion in the past. However, various retrospective studies reveal that increasing the extent of surgical resection significantly improves patient prognosis (median survival from 9.8 to 15.2 months) \[7\]. However, a recent study conducted retrospectively discovered that resection along the T2 FLAIR border advanced the prognosis of patients with glioblastoma even further compared to resection along the T1 enhancing border (median survival from 11.6 to 31.7 months) \[8\]. Another study discovered that performing a sub-lobectomy on glioblastoma patients could enhance their prognosis (median survival from 18.7 to 44.1 months) in comparison to T2 FLAIR border resection, as long as normal brain function is not affected \[9\]. Nonetheless, there remains a lack of consensus in the academic community regarding the optimal surgical resection strategy for glioblastoma patients (such as T1 enhancing border, T2 FLAIR border, sub-lobectomy). In addition, the significant heterogeneity in tumour location, size, infiltration extent, and anatomical proximity across different patients makes it difficult to standardise imaging border resection as an "individualised" surgical approach. This places greater demands on the surgical capabilities and knowledge of clinicians in clinical settings. Furthermore, it also introduces multiple confounding factors that hinder the advancement of interventional clinical research.

Therefore, we have thoroughly reviewed recent studies to investigate the prognosis of glioblastoma patients following extended resection. The majority of studies analyzed the prognostic benefits of extended resection beyond T1 enhancement compared to gross total tumor resection, while a few studies evaluated the difference between sub-lobectomy and gross total tumor resection. Extended resection beyond the T1 enhancement region was discovered to prolong the survival of glioblastoma patients, with the prognostic benefits of sub-lobectomy proving significantly pronounced and not associated with further neurological impairment \[9\]. Previous studies have several limitations. Firstly, they are predominantly retrospective, leading to issues with selection bias and retrospective memory bias, among other factors. Furthermore, many of these studies lack a balanced control group. Secondly, factors such as a small number of patient cases, short follow-up time, and poor quality control of follow-up have also contributed to their low level of evidence \[10\]. Furthermore, the classification for glioblastoma were updated in 2021. Patients with gliomas who were included in these studies also await further evaluation to clarify their diagnosis.

Previous studies on the correlation between surgical resection and prognosis of glioblastoma were retrospective due to the absence of molecular pathology. Intraoperative frozen pathology cannot provide real-time diagnosis of glioblastoma. Therefore, molecular testing is crucial for accurate staging and diagnosis. According to the 5th edition of World Health Organization Central Nervous System tumors classification, patients diagnosed with glioblastoma (IDH wild-type) had IDH wild-type adult diffuse glioma accompanied by tissue necrosis, vascular hyperplasia, TERT promoter mutation, +7/-10, or epidermal growth factor receptor (EGFR) amplification \[17\]. TERT promoter mutation, which is the most frequent hotspot mutation observed in glioblastomas, is present in almost 80% of patients with glioblastoma mutations \[18\]. We have conducted a range of innovative studies regarding intraoperative rapid integrated diagnosis of gliomas. Our works include ①simplified integrated diagnostic system for human gliomas that is based on a combination of IDH, TERT, and histopathology. ②We have also developed an accurate method for detecting IDH and TERT mutations through the use of locked nucleic acid-amplification refractory mutation system fluorescence polymerase chain reaction (PCR). ③We have optimized the DNA extraction process and reduced the detection cycle as well. ④Conducting multi-center, prospective clinical trials to verify the feasibility of intraoperative rapid molecular testing. In summary, through combining intraoperative frozen pathology, our technique allows for precise diagnosis of glioblastoma (IDH wild-type) with TERT promoter mutations within 35 minutes intraoperatively, with a sensitivity and specificity of 100.0% when compared with postoperative sequencing data. Furthermore, our prior retrospective study found that a higher degree of surgical resection greatly improved the prognosis of glioblastoma with IDH wild-type/TERTp-mutated, and that sub-lobectomy conferred a more significant prognostic benefit.

Therefore, building on previous work and knowledge in our field, we will conduct a multicenter, prospective, randomized controlled trial to evaluate the efficacy of sub-lobectomy in the treatment of IDH wild-type/TERTp-mutant glioblastoma. Our study aims to enhance the level of evidence, while also establishing a standardized surgical strategy for glioblastoma.

Eligibility Criteria:
Inclusion Criteria:

1. Eligible patients are aged between 18 and 80, have newly diagnosed high-grade diffuse adult-type gliomas, and have not received any other treatment besides puncture biopsy.
2. Preoperative KPS score ≥70.
3. Enhanced MRI can be tolerated.
4. Sign the informed consent form.
5. Patients with supratentorial gliomas and lesions confined to the unilateral frontal, temporal, parietal, and occipital lobes are included.
6. Imaging total resection can be completed after preoperative imaging evaluation.
7. The intraoperative integrative diagnosis was IDH wild-type high-grade glioma with TERT promoter mutation.

Exclusion Criteria:

1. The tumor involves the anterior central gyrus, posterior central gyrus, nigral gyrus, limbic lobe, corpus callosum, basal ganglia, and lateral ventricles.
2. The tumor involves 2 or more lobes of the brain;
3. Developing severe systemic diseases such as renal insufficiency, hepatic insufficiency, cardiac insufficiency, etc.
4. Previously, the patient had experienced other types of malignant tumours.
5. Developing other brain diseases, such as Parkinson's or Alzheimer's disease.
6. Simultaneously participating in other clinical trials.
7. Expected survival is less than 3 months.
8. Not receiving Stupp protocol after surgery.