Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain
High-grade gliomas (HGG), such as glioblastoma, may arise from low grade gliomas (LGG) that have a more indolent course.
They are comprised of a heterogeneous population of tumor cells, immune cells, and extracellular matrix.
Interactions among these different cell types and pro-/anti-inflammatory cytokines may promote tumor development and progression.
During the early 19th century, glioblastoma was considered of mesenchymal origin and was defined as a sarcoma. In 1863, Rudolf Virchow demonstrated its glial origin 1) , and in 1914 Mallory proposed the term glioblastoma multiforme. However, it was not until 1925 that Globus and Strass presented a complete description of the neoplasm, at which point the most common term became spongioblastoma multiforme. Finally, in 1926, Bailey and Cushing successfully reintroduced the term originally proposed by Mallory: glioblastoma multiforme.
Glioblastoma (GBM) occurs in approximately 46% of gliomas 2).
Its incidence continues to increase in the elderly because the older segment of the population is growing faster than any other age group. Most clinical studies exclude elderly patients, and “standards of care” do not exist for GBM patients aged >70 years 4).
Prior malignancies in patients harboring glioblastoma
Patients who develop GBM following a prior malignancy constitute ~8% of patients with GBM. Despite significant molecular differences these two cohorts appear to have a similar overall prognosis and clinical course. Thus, whether or not a patient harbors a malignancy prior to diagnosis of GBM should not exclude him or her from aggressive treatment or for consideration of novel investigational therapies 6).
With the advance of genomics research, there have been a new breakthrough in the molecular classification of gliomas. Glioblastoma (WHO grade Ⅳ) could be subtyped to proneural, neural, classical, and mesenchymal according to the mRNA expression. Low grade gliomas (WHO grade Ⅱ and Ⅲ) could be divided into 5 types using 1p/19q co-deletion, isocitrate dehydrogenase(IDH) mutation, and TERTp (promotor region) mutation. In 2016, a new classification of tumors of the central nervous system was proposed, and some new markers such as IDH1 mutation were introduced into the diagnosis of gliomas. Genotype and phenotype were integrated to diagnose gliomas. In the meantime, precision treatment for gliomas has also been vigorously developed 7).
Glioblastoma IDH wildtype
Glioblastoma IDH mutant
Histologically, they are characterized by hypercellularity, nuclear pleomorphism, microvascular proliferation, and pseudopalisading necrosis.
Glioblastomas are among the most vascularized tumors in humans. There is also an abnormal vascular remodeling process that leads to microvascular proliferation that is a histopathological hallmark of glioblastoma.
Seizures as the presenting symptom of glioblastoma predicted longer survival in adults younger than 60 years. The IDH1 R132H mutation and p53 overexpression (>40%) were associated with seizures at presentation. Seizures showed no relationship with the tumor size or proliferation parameters 11).
Diagnostic tools include computed tomography (CT or CAT scan) and magnetic resonance imaging (MRI). Magnetic resonance imaging (MRI) is the most sensitive and best method of detecting brain tumors. Magnetic resonance spectroscopy (MRS) is used to study the tumor’s chemical profile and determine the nature of the lesions seen on the MRI. Positron emission tomography (PET scan) can help detect recurring brain tumors.
The current standard of care in glioblastoma is not very effective, resulting in tumor recurrence with patients rarely surviving over 2 years. This tumor recurrence is attributed to the presence of chemo and radiation resistant glioma stem cells (GSCs).
Extensive dominant lobe glioblastoma
Thromboembolic events, seizures, neurologic symptoms and adverse effects from corticosteroids and chemotherapies are frequent clinical complications seen in Glioblastoma (GB) patients. The exact impact these have on dismal patient outcome has not been fully elucidated.
Complications significantly decrease GB patient survival. Age, poor functional status, other than standard adjuvant therapy and eloquent tumor location proved as significant risk factors for encountering a therapy associated complication. Not extensive surgery or tumor size but surgery at eloquent locations impacts complication occurrence the strongest with a 2 fold increased complication occurrence risk 12).
A study enrolled 60 glioblastoma patients with more than 5-mm-thick surgical cavity wall enhancement (SCWE)s as detected on contrast-enhanced MR imaging after concurrent chemoradiation therapy. Two independent readers categorized the shape and perfusion state of SCWEs as nodular or non-nodular and as having positive or negative perfusion compared with the contralateral grey matter on arterial spin labeling (ASL). The perfusion fraction on ASL within the contrast-enhancing lesion was calculated. The independent predictability of TTP was analyzed using the Kaplan-Meier method and Cox proportional hazards modelling.
The perfusion fraction was higher in the non-progression group, significantly for reader 2 (P = 0.03) and borderline significantly for reader 1 (P = 0.08). A positive perfusion state and (P = 0.02) a higher perfusion fraction of the SCWE were found to become an independent predictor of longer TTP (P = 0.001 for reader 1 and P < 0.001 for reader 2). The contrast enhancement pattern did not become a TTP predictor.
Assessment of perfusion in early post-treatment MR imaging can stratify TTP in patients with glioblastoma for adjuvant temozolomide therapy. Positive perfusion in SCWEs can become a predictor of a longer TTP 13).
The Medicare database was searched to identify patients 66 years of age and older with glioblastoma, with and without infection, from 1997 to 2010. The primary outcome was survival after diagnosis. The statistical analysis was performed with a graphical representation using Kaplan-Meier curves, univariate analysis with the log-rank test, and multivariate analysis with proportional hazards modeling.
A total of 3784 patients with glioblastoma were identified from the database, and from these, 369 (9.8%) had postoperative infection within 1 month of surgery. In patients with glioblastoma who had an infection within 1 month of surgery, there was no significant difference in survival (median 5 months) compared with patients with no infection (median 6 months; p = 0.17). The study also showed that older age, increased Gagne comorbidity score, and having diabetes may be negatively associated with survival.
Infection after craniotomy within 1 month was not associated with a survival benefit in patients with glioblastoma 14).
Álvarez de Eulate-Beramendi et al. retrospectively included all patients over 70 years of age, who underwent surgery at the Department of Neurosurgery (HUCA and HUMV) and were diagnosed of GBM by pathological criteria from January 2007 to September 2014. Results Eighty-one patients were analysed, whose mean age was 75 (SD 4) and 48 were male. Karnofsky performance status (KPS) was over 70 in 61 patients and 38.3% presented with motor deficit. Sixty-three patients underwent resection, and 18 had only a diagnostic biopsy. The complication rate was 17.28% and mortality rate was 7.4%. Survival was increased in patients who received radiotherapy (n = 41) or additional chemotherapy (n = 26) (p < 0.001). KPS < 70 was an independent factor associated with low-rate survival. Patients with optimal treatment had a median survival of 8 months compared to patients with suboptimal treatment who had a median survival of 4 months (p < 0.001). Conclusions This study suggests that KPS is the most important preoperative prognostic factor. Maximal safe resection followed by radical radiotherapy and temozolomide might be the optimal treatment of choice since glioblastoma-diagnosed patients over 70 years of age showed a statistically significant survival benefit 15)
With the publication of the European Organisation for Research and Treatment of Cancer/National Cancer Information Center EORTC NCIC protocol, concomitant radiochemotherapy followed by intermittent chemotherapy became the new treatment standard for patients with primary glioblastoma.
Eight years after widespread introduction of this protocol, it is of interest to investigate whether this new standard has been established in daily neuro-oncologic practice.
Rapp et al. analyzed primary glioblastoma patients diagnosed between 2005 and 2013 treated at the Heinrich Heine Medical Centre, Düsseldorf, Germany according to the EORTC/NCIC trial. Parameters associated with treatment performance (interruption of radiotherapy, concomitant chemotherapy and intermittent chemotherapy, total number of cycles, and side effects) were retrospectively analyzed and compared with the available data from the EORTC/NCIC trial.
In this single-center retrospective study, they identified 189 patients (116 men, 73 women; median age: 62 years) who were treated according to the EORTC/NCIC trial protocol.
A total of 176 patients received cytoreductive surgery; 13 patients had stereotactic biopsy only (EORTC/NCIC trial: 239 patients and 48 patients, respectively). Radiotherapy had to be interrupted in 9 patients (5%) (EORTC/NCIC trial: 15 patients [5%]) and concomitant chemotherapy in 26 patients (14%) (EORTC/NCIC trial: 37 patients [13%]). In 156 patients (83%), adjuvant TMZ chemotherapy was initiated (6 median temozolomide [TMZ] cycles; range: 1-30). In the EORTC/NCIC trial, 223 patients (47%) received the intermittent chemotherapy protocol (median: 3 cycles; range: 1-7). Overall, 97 patients (62%) completed 6 TMZ cycles (EORTC/NCIC-trial: 105 patients [47%]); dose escalation to 200 mg/qm at the second cycle was performed in 91 patients (58%) (versus 149 patients [67%]). Intermittent TMZ therapy was discontinued in 59 patients (38%) (versus 118 patients [53%]). Median overall survival in our patient cohort was 19 months (versus 14.6 months); median time to progression was 9 months (versus 6.9 months).
Comparison between the feasibility of the treatment protocol established by the EORTC/NCIC trial (performed within the setting of a prospective randomized trial) and the daily routine in a dedicated neurosurgical neuro-oncologic department demonstrates that the protocol is suitable for daily practice within a neurosurgical unit 16).
A total of 126 patients were reviewed. Median progression-free survival was 5 months (95% confidence interval [CI], 4.138 to 5.862 months). Median overall survival (OS) was 8 months (95% CI, 5.950 to 10.050 months). Univariate analysis showed the statistically significant associations between the higher OS and age <70 (P = 0.046), Karnofsky performance status ≥70 (P = 0.001), single lesions (P = 0.007), lesions affecting one lobe (P = 0.007), total resection (P = 0.048), and Charlson Comorbidity Scoring System ≤5. Multivariate analysis identified the completion of 60 Gy radiotherapy and completion of 6 or more cycles of temozolomide chemotherapy as independent prognostic factors positively correlated with increased survival.
Maximal resection and radiochemotherapy treatment completion are associated with longer OS, and age alone should not preclude elderly patients from receiving surgery and adjuvant treatment. However, only a few patients were able to finish the proposed treatments. Poor performance and high comorbidity index status might compromise the benefit of treatment aggressiveness and must be considered in therapeutic decision 17).
Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31).
The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy 18).
A 57-year-old man presented with seizures. Until the seizure onset, he had been treated for thyroid cancer and its metastasis to the thoracic vertebral body with the multi-receptor tyrosine kinase inhibitor (RTK) lenvatinib for 4 years. MRI revealed a slightly high intensity lesion in the left frontal base area on T2-weighted or fluid-attenuated inversion recovery (FLAIR) images, and the lesion showed only faint enhancement on T1-weighted images after gadolinium administration. Total resection was performed and the histopathological diagnosis was glioblastoma. However, grade IV histology was observed in only a limited area, and the majority of the specimen showed lower grade histology with moderate vascularization that lacked microvascular proliferation.
Lenvatinib, which is anti-angiogenic, might have affected the radiological characteristics, as well as the pathology of the tumor. Brain tumors arising during treatment with RTKs for other cancers could show atypical imaging findings 19).