The Glioma Book

The Glioma Book

Michael E. Sughrue

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Glioblastoma (GBM) is an extremely aggressive and malignant brain tumor, with cell infiltration, rapid invasion, and a high frequency of relapse. The Glioma Book by neurosurgeon Michael Sughrue is a highly personal book — a culmination of two years of writing and more than 1,000 surgeries. It presents a unique viewpoint with the potential to transform the traditional paradigm that too often informs treatment of this universally fatal brain tumor. The book reinterprets the role of the cerebrum and sub-cortex, leverages scientific advances to improve cytoreduction and reduce neurological deficits, and challenges the myth of the “inoperable” glioma.

This is the first step-by-step technical guide focused on aggressively resecting different types of gliomas. The book is logically organized, starting with a foundation of fundamental knowledge, then progressing to practical applications. Chapters focus on the skills necessary to perform glioma surgery, specific techniques, and systematic approaches to gliomas in different brain regions.

Numerous case examples illuminate concepts introduced earlier in the book and explain how to perform these procedures

About 30 high-quality videos posted online provide insightful procedural guidance The role of connectomic imaging in visualizing the cerebrum, and other innovative techniques including awake brain mapping and diffusion tensor tractography

Neurosurgeons who embrace the concepts in this book will realize they can change the glioma treatment paradigm. Continually improving techniques and viewing a glioma diagnosis as a battle for a patient’s life, rather than an exercise in inevitable failure can impart progress in treating this devastating disease.

This book includes complimentary access to a digital copy on https://medone.thieme.com

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.
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