High risk low grade glioma

High risk low grade glioma

On the basis of two randomized studies from the European Organization for Research and Treatment of Cancer (EORTC1) 2). and a synthesis by Pignatti et al, 3) high-risk low grade glioma LGG were defined by any three of five characteristics, including astrocytic histology, large tumor size (> 6 cm in diameter), midline tumor involvement, neurologic deficits ascribed to the tumor and not to surgery, and age older than 40 years.

This definition differ significantly from the definition used in the RTOG 9802 trial4).

Radiation Therapy Oncology Group (RTOG) 9802 has established postoperative radiation therapy (RT) and chemotherapy sequentially as the new standard of care for patients with high-risk low-grade glioma (LGG) meeting trial criteria. Although this trial investigated sequential chemoradiation therapy (sCRT) with RT followed by chemotherapy, it is unknown whether concurrent chemoradiation therapy (cCRT) may offer advantages over sCRT.

The National Cancer Database (NCDB) was queried for newly diagnosed World Health Organization (WHO) grade II glioma. Patients with unknown surgery, RT, or chemotherapy status were excluded, along with patients below 40 years old who underwent gross total resection to coincide with RTOG 9802 exclusion criteria. The χ, the Fisher exact, or Wilcoxon rank-sum tests evaluated differences in characteristics between groups. Kaplan-Meier analysis was used to evaluate overall survival (OS) between groups (sCRT vs. cCRT). Cox proportional hazards modeling determined variables associated with OS.

In total, 496 patients were analyzed (n=416 [83.9%] cCRT, n=80 [16.1%] sCRT). Sequencing or concurrency of therapy did not independently influence survival on univariable/multivariable analysis. Factors associated with worse OS on multivariable analysis included advanced age (P<0.001), whereas mixed glioma (P=0.017) and oligodendroglioma (P=0.005) were associated with better OS than astrocytoma histologies.

This is the only analysis of which we are aware of cCRT versus sCRT for LGG. There is no evidence that cCRT improves outcomes over sCRT 5).


The level of evidence for adjuvant treatment of diffuse WHO grade II glioma (low-grade gliomaLGG) is low. In so-called “high risk low grade glioma” patients most centers currently apply an early aggressive adjuvant therapy after surgery. The aim of a assessment was to compare progression free survival (PFS) and overall survival (OS) in patients receiving radiation therapy (RT) alone, chemotherapy (CT) alone, or a combined/consecutive RT+CT, with patients receiving no primary adjuvant treatment after surgery.

Based on a retrospective multicenter cohort of 288 patients (≥ 18 years old) with diffuse WHO grade II gliomas, a subgroup analysis of patients with confirmed isocitrate dehydrogenase mutation was performed. The influence of primary adjuvant treatment after surgery on PFS and OS was assessed using Kaplan-Meier estimates and multivariate Cox regression models, including age (≥ 40 years), complete tumor resection (CTR), recurrent surgery, and astrocytoma versus oligodendroglioma.

One hundred forty-four patients matched the inclusion criteria. Forty patients (27.8%) received adjuvant treatment. The median follow-up duration was 6 years (95% confidence interval 4.8-6.3 years). The median overall PFS was 3.9 years and OS 16.1 years. PFS and OS were significantly longer without adjuvant treatment (p = 0.003). A significant difference in favor of no adjuvant therapy was observed even in high-risk patients (age ≥ 40 years or residual tumor, 3.9 vs 3.1 years, p = 0.025). In the multivariate model (controlled for age, CTR, oligodendroglial diagnosis, and recurrent surgery), patients who received no adjuvant therapy showed a significantly positive influence on PFS (p = 0.030) and OS (p = 0.009) compared to any other adjuvant treatment regimen. This effect was most pronounced if RT+CT was applied (p = 0.004, hazard ratio [HR] 2.7 for PFS, and p = 0.001, HR 20.2 for OS). CTR was independently associated with longer PFS (p = 0.019). Age ≥ 40 years, histopathological diagnosis, and recurrence did not achieve statistical significance.

In this series of IDH-mutated LGGs, adjuvant treatment with RT, CT with temozolomide (TMZ), or the combination of both showed no significant advantage in terms of PFS and OS. Even in high-risk patients, the authors observed a similar significantly negative impact of adjuvant treatment on PFS and OS. These results underscore the importance of a CTR in LGG. Whether patients ≥ 40 years old should receive adjuvant treatment despite a CTR should be a matter of debate. A potential tumor dedifferentiation by administration of early TMZ, RT, or RT+CT in IDH-mutated LGG should be considered. However, these data are limited by the retrospective study design and the potentially heterogeneous indication for adjuvant treatment 6).


There was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices.

The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma 7).

References

1)

van den Bent MJ, Afra D, de Witte O, et al. (2005) Long term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: The EORTC 22845 randomised trial. Lancet 366:985–990.
2)

Karim AB, Afra D, Cornu P, et al. (2002) Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council Study BRO4—An interim analysis. Int J Radiat Oncol Biol Phys 52:316–324.
3)

Pignatti F, van den Bent M, Curran D, et al. (2002) Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20:2076–2084.
4)

Chamberlain MC. Does RTOG 9802 change practice with respect to newly diagnosed low-grade glioma? J Clin Oncol. 2013 Feb 10;31(5):652-3. doi: 10.1200/JCO.2012.46.7969. Epub 2013 Jan 7. PubMed PMID: 23295807.
5)

Ryckman JM, Appiah AK, Lyden E, Verma V, Zhang C. Concurrent Versus Sequential Chemoradiation for Low-grade Gliomas Meeting RTOG 9802 Criteria. Am J Clin Oncol. 2019 Feb 12. doi: 10.1097/COC.0000000000000519. [Epub ahead of print] PubMed PMID: 30768441.
6)

Paľa A, Coburger J, Scherer M, Ahmeti H, Roder C, Gessler F, Jungk C, Scheuerle A, Senft C, Tatagiba M, Synowitz M, Wirtz CR, Schmitz B, Unterberg AW. To treat or not to treat? A retrospective multicenter assessment of survival in patients with IDH-mutant low-grade glioma based on adjuvant treatment. J Neurosurg. 2019 Jul 19:1-8. doi: 10.3171/2019.4.JNS183395. [Epub ahead of print] PubMed PMID: 31323633.
7)

Reijneveld JC, Taphoorn MJ, Coens C, Bromberg JE, Mason WP, Hoang-Xuan K, Ryan G, Hassel MB, Enting RH, Brandes AA, Wick A, Chinot O, Reni M, Kantor G, Thiessen B, Klein M, Verger E, Borchers C, Hau P, Back M, Smits A, Golfinopoulos V, Gorlia T, Bottomley A, Stupp R, Baumert BG. Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1533-1542. doi: 10.1016/S1470-2045(16)30305-9. Epub 2016 Sep 27. PubMed PMID: 27686943.

Thalamic glioma treatment

Thalamic glioma treatment

Deep-seated astrocytomas within the basal ganglia and the thalamus are considered unfavourable for microsurgical removal since the circumferential neighbourhood of critical structures limits radical resection. On closer assessment, the thalamus has a unique configuration within the basal ganglia.

Its tetrahedric shape has 3 free surfaces and only the ventrolateral border is in contact with vital and critical functional structures, e.g. the subthalamic nuclei and the internal capsule.

see Transcallosal approach.


Tumors here are usually treated with biopsy and adjuvant therapy with relatively poor results. Rarely do patients undergo extensive surgical intervention. It seems reasonable to suggest that successful cytoreduction may help these patients. However, this hypothesis has not been studied due to the general view that it is not possible to remove deep-seated brain tumors with acceptable outcomes.

Through retrospective data collection, Briggs et al., described a small case series undergoing awake contralateral, transcallosal approach surgery for deep-seated brain tumors affecting the basal ganglia. They described the patient cohort, report on patient outcomes, and described the surgical technique.

Four patients underwent awake contralateral, transcallosal surgery for glioblastoma invading the basal ganglia. All four patients demonstrated hemibody weakness contralateral to the side of their tumor, with three patients confined to wheelchairs at presentation. Ages ranged from 25-64 years. Tumor volumes ranged from 14-93 cm3. Greater than 50% resection of each tumor was achieved during surgery. In two cases, approximately 90% resection was achieved. Motor strength improved in one patient who presented with hemiplegia. Two patients required ventriculoperitoneal shunting for complications related to hydrocephalus. When writing this manuscript, two of our patients were still alive, functional, and free of tumor progression.

They presented results attempting to resect large gliomas infiltrating the basal ganglia in four patients. This technique combined a contralateral, transcallosal approach with awake neuromonitoring. The results suggest it is possible to remove these tumors with reasonable outcomes 1).


From May 2011 to Aug 2015, 49 patients with thalamic gliomas underwent microsurgical resection, and received chemotherapy and radiotherapy postoperatively. The postoperative symptoms and complications were documented, and the overall survival (OS) and the progression-free survival (PFS) data were collected. The prognostic factors were evaluated by univariate and multivariate analyses. Finally, there was no perioperative death. Twenty cases, 24 cases and 5 cases were achieved subtotal resection (>90%), partial resection (70-90%) and less than partial resection (<70%) respectively. All patients’ pathological diagnosis was confirmed. The symptoms were improved in 32 cases, unchanged in 11 cases, and worsen in 6 cases. Postoperative complications were absent in 9 cases. The 6-month, 12-month, and 24-month OS were 71.4%, 38.9%, and 12.1% respectively; corresponding PFS were 66.6%, 27.1%, and 10.2% respectively. The median OS time and PFS time were 9.0 months (95% CI 6.9-11.1) and 9.0 months (95% CI 6.6-11.4) respectively. Multivariate analysis revealed extent of resection were independent prognostic factors for OS (p < .05), patients with postoperative adjuvant chemotherapy and radiotherapy had a significant prolonged OS (p < .001) and PFS (p < .001). The study shows that the short-term efficacy of microsurgery for high-grade thalamic gliomas is satisfactory. Microsurgery can effectively alleviate patients’ symptoms and improve life quality. Postoperative adjuvant chemotherapy and radiotherapy are helpful for prolonging the survival time 2).


Series demonstrated the feasibility of the microsurgical concept. Comparison with other treatment modalities, such as brachytherapy, requires future consideration 3).

References

1)

Briggs RG, Nix CE, Conner AK, Palejwala AH, Smitherman AD, Teo C, Sughrue ME. An Awake, Contralateral, Transcallosal Approach for Deep-Seated Gliomas of the Basal Ganglia. World Neurosurg. 2019 Jul 10. pii: S1878-8750(19)31937-0. doi: 10.1016/j.wneu.2019.07.031. [Epub ahead of print] PubMed PMID: 31301441.
2)

Wu B, Tang C, Wang Y, Li Z, Hu S, Hua W, Li W, Huang S, Ma J, Zhang Y. High-grade thalamic gliomas: Microsurgical treatment and prognosis analysis. J Clin Neurosci. 2018 Mar;49:56-61. doi: 10.1016/j.jocn.2017.12.008. Epub 2017 Dec 14. PubMed PMID: 29248381.
3)

Steiger HJ, Götz C, Schmid-Elsaesser R, Stummer W. Thalamic astrocytomas: surgical anatomy and results of a pilot series using maximum microsurgical removal. Acta Neurochir (Wien). 2000;142(12):1327-36; discussion 1336-7. PubMed PMID: 11214625.

Neutrophil to lymphocyte ratio for glioma

Neutrophil to lymphocyte ratio for glioma

Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio, the systemic immune inflammation index (SII), and red blood cell distribution width (RDW), have been recognized as promising predictors for histological grade and prognosis in multiple cancer types.

It is a simple, low-cost and easily measured inflammation marker.

Studies have shown that the peripheral blood pretreatment Neutrophil to lymphocyte ratio(NLR) is a prognostic measure in various cancers. The few studies evaluating NLR in glioblastoma multiforme (GBM) patients yielded inconsistent results.

In the cohort of Brenner et al., GBM patients treated with combined modality therapy, pretreatment NLR was not prognostic. Toxicity of treatment was acceptable. Investigation of the NLR with larger groups of patients selected by MGMT status is warranted 1).

For Weng et al., the preoperative NLR was correlated with glioma grading, and the elevated NLR was an independent predictive factor for poor outcome of glioblastoma patients 2).

For Bao et al., NLR was an independent prognostic factor for overall survival in glioma 3).

For Zadora et al., preoperative NLCR measurement corresponds with a glial brain tumor grading 4).

Case series

Brenner et al., analyzed 89 patients with GBM in a retrospective cohort analysis who were treated in Soroka University Medical Center’s Oncology Department between the years 2005-2016. We analyzed NLR as a dichotomous variable at 3 cut-off points, 2.5, 3 and 4, as a predictor of OS and PFS. Methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was not determined.

No significant correlation was found between NLR and either OS or PFS. Factors that predicted a shorter OS were age and extent of surgery. Patients over 70 years of age had a statistically significant shorter OS, 12.5 months (95% CI: 10.4-14.5 months) versus 17.6 months (95% CI: 14.2-21.1 months) in those 70 years of age and younger (p = 0.004). The OS of patients undergoing partial resection (12.7 months 95% CI: 8.3-17.1 months) or biopsy only (9.3 months 95% CI: 7.8-24.6 months), was significantly shorter than that of patients undergoing total resection (18.9 months, 95% CI: 11.8-26.0 months; p = 0.035). There were no treatment-related deaths. The most common grade III-IV toxicities were thrombocytopenia, 12.4%, and fatigue, 13.5%.

In this cohort of GBM patients treated with combined modality therapy, pretreatment NLR was not prognostic. Toxicity of treatment was acceptable. Investigation of the NLR with larger groups of patients selected by MGMT status is warranted 5).


The preoperative NLR was analyzed retrospectively in 239 gliomas of different grades, and receiver operating characteristic (ROC) curve analysis was adopted to investigate the prediction of glioma grading. Univariate and multivariate analyses were performed to analyze the variables of overall survival (OS) of glioblastoma patients.

There were significant differences in the preoperative NLR values among the four glioma groups, with the highest values observed in the glioblastoma group (p < 0.05). ROC curve analysis showed the NLR value of 2.36 was a cutoff point for predicting glioblastoma. The OS of patients with high NLR (≥ 4.0) was shorter compared with that with low NLR (< 4.0) (mean 11.23 vs. 18.56 months, p < 0.05). Univariate analysis and multivariate analysis indicated age≥ 60, NLR≥ 4.0, Karnofsky Performance Scores (KPS) ≤ 70, incomplete tumor resection, incomplete Stupp protocol accomplishment and the isocitrate dehydrogenase 1 (IDH1) wild-type as independent prognostic indicators for poor outcome (each p < 0.05).

The preoperative NLR was correlated with glioma grading, and the elevated NLR was an independent predictive factor for poor outcome of glioblastoma patients 6).


A retrospective chart review study was conducted for 219 glioma patients between January 2012 and January 2017. The values of the NLR, PLR, MLR and RDW on the prognosis were evaluated. And correlations between these hematologic inflammatory markers were examined.

Patients were divided into high and low groups according to cutoff points from the receiver operating characteristic curve. The high NLR groups were associated with tumor grade (p = 0.000). Kaplan-Meier survival analyses shown that the high NLR group experienced inferior median survival compared with the low NLR group (11 vs. 32 months; p = 0.000). The high PLR group experienced inferior median survival compared with the low PLR group (12 vs. 21 months; p = 0.001). The high MLR group experienced inferior median survival compared with the low MLR group (12 vs. 22 months; p = 0.006). However, there was no significant difference in median survival between the high and low RDW groups (15 vs. 23 months; p = 0.184). Multivariate analysis demonstrated that NLR was an independent predictor for overall survival (OS) (HR 1.758; p = 0.008).

High preoperative NLR, PLR, MLR were predictors of poor prognosis for patients with glioma. NLR was an independent prognostic factor for OS in glioma 7).


A retrospective analysis of NLCR was performed in neurosurgical patients treated for glial brain tumors. The preoperative NLCR was analyzed in accordance with WHO glial tumors’ classification, which distinguishes G1, G2, G3 and G4 (glioblastoma) tumors.

The analysis of NLCR was performed in 424 patients (258 males and 166 females) aged 53 ± 16 years who underwent either an open surgery or stereotactic biopsy for a glial brain tumor. G1 was diagnosed in 22 patients, G2 – in 71 patients, G3 – in 63 patients and G4 – in 268 patients. The highest value of NLCR was noted in G4 patients (5.08 [3.1; 8.7] – median [quartiles 1 and 3, respectively]) and was significantly higher compared to G3 (p<0.01), G2 (p<0.001) and G1 (p<0.01) groups. Moreover, NLCR was significantly higher in group G3 than G2 (p<0.05). ROC curve analysis showed 2.579 as a cut-off point for prediction of glioblastoma.

Preoperative NLCR measurement corresponds with a glial brain tumor grading 8).

References

1) , 5)

Brenner A, Friger M, Geffen DB, Kaisman-Elbaz T, Lavrenkov K. The Prognostic Value of the Pretreatment Neutrophil/Lymphocyte Ratio in Patients with Glioblastoma Multiforme Brain Tumors: A Retrospective Cohort Study of Patients Treated with Combined Modality Surgery, Radiation Therapy, and Temozolomide Chemotherapy. Oncology. 2019 Jul 9:1-9. doi: 10.1159/000500926. [Epub ahead of print] PubMed PMID: 31288238.
2) , 6)

Weng W, Chen X, Gong S, Guo L, Zhang X. Preoperative neutrophil-lymphocyte ratio correlated with glioma grading and glioblastoma survival. Neurol Res. 2018 Aug 3:1-6. doi: 10.1080/01616412.2018.1497271. [Epub ahead of print] PubMed PMID: 30074469.
3) , 7)

Bao Y, Yang M, Jin C, Hou S, Shi B, Shi J, Lin N. Preoperative hematologic inflammatory markers as prognostic factors in patients with glioma. World Neurosurg. 2018 Aug 6. pii: S1878-8750(18)31732-7. doi: 10.1016/j.wneu.2018.07.252. [Epub ahead of print] PubMed PMID: 30092479.
4) , 8)

Zadora P, Dabrowski W, Czarko K, Smolen A, Kotlinska-Hasiec E, Wiorkowski K, Sikora A, Jarosz B, Kura K, Rola R, Trojanowski T. Preoperative neutrophil-lymphocyte count ratio helps predict the grade of glial tumor – a pilot study. Neurol Neurochir Pol. 2015;49(1):41-4. doi: 10.1016/j.pjnns.2014.12.006. Epub 2015 Jan 6. PubMed PMID: 25666772.
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