DIAGNOSIS AND TREATMENT OF GLIOMA IN ADULT: CHILEAN CONSENSUS

ABSTRACT

Brain tumors are characterized by high morbidity and mortality. The vast majority are secondary tumors (metastasis). On the other hand, gliomas represent a 30% of primary tumors of the central nervous system. In the US, between 2007-2011, an approximate incidence of 21.4 cases every 100,000 inhabitants was estimated. Recent advances in the molecular biology of these tumors have made possible to substantially improve their classification, thus allowing a better correlation with clinical outcomes and prognosis. Along these lines, today it is possible to rank patients by risk and deliver treatments capable of extending global survival, between 5 to 7 years, for grade II and III gliomas. This consensus was prepared by a multidisciplinary panel of experts, coming from various Chilean Scientific Societies; therefore, involving all medical/surgical therapy specialties. Enlightened from molecular oncology, this proposal offers a clinically useful input which, along with an updated treatment/follow-up review of these patients, allows us to understand the relevance of these biomarkers for an accurate disease management. It should be noted that this paper was prepared by the same team who prepared the Clinical Protocol for Adult Gliomas, in 2019, to be later published by the Ministry of Health, and that differs from it, which offers clinical-operative details, such as flowcharts and dose, our review attempts to reveal imaging and molecular advances and how they impact current management of the disease.

Key words: Glioma, Glioblastoma, Astrocytoma, Oligodendroglioma

GENERAL CONSIDERATIONS

Brain gliomas represent 30% of primary tumors of the central nervous system (SNC)¹. During the last few years, its incidence has been increasing and has become a severe sanitary issue, due to the horrible vital prognosis in high grade lesions and the big impact on quality of life in lower grade lesions. A recent analysis of the SEER Record (Surveillance, Epidemiology and End Results) reported a lower incidence of gliomas in Latin population, with a higher life expectancy from 1 to 5 years, despite the low access to therapies². Local data on encephalon cancer (CIE-OR 70-72) are old (from 2003 to 2007) and report a general adjusted incidence rate per age (TAI) of 1.8 per 100,000 inhabitants for men and 2 for women ³. In regions, it calls out attention that; Antofagasta (4.6, men), Biobío and Valdivia (4.1, men) and 3.6 for women in the 3 aforementioned regions³. Regarding mortality, the most recent data (2016), regarding the group of "Encephalon and SNC" tumors, report 485 cases per year, due to this cause. 265 of them, are men and 220 are women⁴. It is important to highlight that there is a low percentage (50%) of histological confirmation for malignant brain tumors³. A series, coming from a local Hospital, reported a life expectancy of 6 months5 for glioblastoma (GBM), which is lower than usual life expectancy, close to 16 months⁶.

From a clinical standpoint, these patients have progressive or persistent cephalea, epileptic crisis, focal symptoms, such as language/gait/visual disorders and cognitive disorders with a subacute onset. In some cases, the disease is inquired as a finding.

Next, a review is presented, mainly focused on diagnosis progress (at an imagery and molecular level), and how this has achieved reorganization and optimization treatment of these patients, especially for carriers of WHO grade II, III and IV diffused gliomas (in adults). It is important to highlight that technical details and daily clinical performance, as well as surgical techniques, dosage and operational flowcharts may be reviewed in the Clinical Protocol of Adult's Gliomas (Protocolo Clínico de Gliomas de Adulto), published by the Ministry of Health, in September 20197.

IMAGERY DIAGNOSIS

The preferred imagery analysis is brain magnetic resonance (BMR), whose procedure should include the axial acquisition of the T2, FLAIR, diffusion, T2 GRE sequences or another magnetic susceptibility sequence (SWI), T1 SE with/with no Gadolinium contrast. The T2 FLAIR and T1 GAD sequences are the most used for determining infiltrative/increased uptake⁸ tumor component. Diffusion has a role to identify the hyper cellular tumor area. Magnetic susceptibility sequences allow to determine the intratumoral hemorrhage and the presence of calcifications⁸.

Among the leading edge (BMR) techniques, perfusion by T2* (DSC) dynamic susceptibility contrast is the one most useful by using relative cerebral blood volume rCBV. It has a cutoff point of 1.75, thus allowing to differentiate low/high grade gliomas, with a sensitivity of 95% and a specificity of 70%⁹.

Spectroscopy usefulness is low, as it is not specific enough to differentiate between tumoral and non tumoral pathology. Even though the correlation between choline/N-acetyl aspartate and choline/creatine could contribute in tumor gradation of gliomas, perfusion techniques are still the first choice in diagnosis^10,11.

SURGERY

It is recommended to perform a wider surgery, as long as there are no high risks of permanent functional alteration, considering the stereotactic biopsy in the following cases; doubt about the diagnosis regarding pathologies not getting benefits from surgical treatment, such as brain lymphoma, in extended tumors with a significant non-dryable component, thalamic tumors, in patients with a poor functional condition (Karnofsky <70%) or in patients who reject exeresis surgery^19,20.

In case of brainstem stereotactic biopsies, the best scenario is to perform them with a software aimed to plan the pathway of the biopsy cannula, in order to minimize complications¹⁸. The choice between exeresis surgery or stereotactic biopsy should be taken by an oncological committee, on a cases-by-case basis.

HISTOPATHOLOGICAL/MOLLECULAR DIAGNOSIS

Classification of primary WHO 201612 SNC tumors, was included into the WHO gradation I-IV, molecular biomarkers (biological behavior of the disease) as an accuracy strategy, aimed to optimize treatment and comprehension of the clinical prognosis thereof.

Under this paradigm, Table 1 summarizes the main biomarkers, the population suggested to study them, and the chosen techniques^{12,13, 14}.

Regarding previous Table # 1, it is important to highlight the following 5 statements:

• Any gliomas reported in people older than 55 years old should have a IDH1& Ki67 analysis, by IHC.
• For Gliomas Grade II, III or GBM for < 55 years old with native IDH1, by IHC, our suggestion is to study them by means of PCR or GS for IDH 1/2, in order to discard undetectable mutations by IHC.
• Before any inconclusive histology of a GBM with very high Ki67 and negative IHC of IDH1, PCR or GS should be considered for IDH1 and IDH2.
• For tumors with disagreeing studies or those where it is not possible to perform biomarkers, the acronyms NOS is used (not otherwise specified).
• BRAFV600E is an infrequent mutation and its determination should be consi16dered on a cases-by-case basis, before any potential use of specific therapy under study.

Table 1. Addressing Gliomas in Adults, based on Personalized Accurate Oncology (OPP)

Abbreviations: IHC: immunohistochemistry; GS Genome Sequencing; PCR: Polymerase Chain Reaction; FISH: Fluorescence in situ hybridization; ATRX: X-linked alpha-thalassemia/mental retardation syndrome.

TREATMENT

SURGERY
Next, the main surgical considerations for two big groups of tumors, grade II diffused glioma and then, grade II-IV gliomas are described.

A.- Grade II, diffused gliomas
In diffused grade II WHO gliomas, surgery plays a fundamental role in the treatment, thus increasing progression free survival, general life expectancy and it probably reduces the risk of anaplastic transformation¹⁵. In general terms, a full surgery is recommended, as long as risks of permanent functional alteration are not increased.

For surgical planning, in tumors located in eloquent areas, advanced (BMR) techniques, such as functional (BMR) and tractography may be used. Awake surgery and intraoperative brain mapping must be considered as well for those tumors located in more critical areas (for instance, language-related areas). Neurophysiological intraoperative monitoring is suggested for tumors located within the motor area¹⁶.

The exeresis degree will depend on the proximity or on the infiltration of the eloquent cortical/subcortical areas. In these tumors, which usually do not have contrast uptake, the resection objective is to cover all the area reporting hyper intensity in a T2 FLAIR sequence ¹⁷.

B.- Gliomas Grade III and IV
Mass resection will be applied for reported contrast uptake in (BMR) (T1 with GAD) and necrotic lesions. The same considerations must be taken into account for preserving the eloquent area, by using awake surgery and electrophysiological monitoring, when necessary.

RADIOCHEMOTHERAPY (RT-QT)

Gliomas Grade II (Astrocytoma and Oligodendroglioma)

First line MUTED IDH
In terms of clinical risk, the following risk types appear in this classification:

• Low risk – for those patients younger than 40 years old, with full/nearly full exeresis and mutated IDH 1 or 2. Observation and follow up with periodic (BMR) ²¹ is suggested.
• High risk - for those patients younger than 40 years with biopsy or partial resection; patients who are 40 years old or older, regardless of the tumor resection degree; low risk WHO II gliomas, with tumor progression or gliomas Grade II NOS. Starting sequential RT-QT with Procarbazine, Lomustine and Vincristine (PCV), Procarbazine and Lomustine (PC) or Temozolomide^21,22 is suggested.

This behavior is based on the results from the study RTOG 9802, reporting extended global life expectancy (SG) of 5.5 years, in absolute terms (13.3 years of SG with sequential RT-QT versus 7.8 years in the RT group)²¹. High PCV toxicity has made that many centers perform sequential RT-QT with Temozolomide as a first choice drug. Given the shallow penetration of Vincristine in SNC and its associated toxicity, some centers prefer PC treatment. Some retrospective evidence reports results comparable to the scheme with PCV²³.

Treatment with (RT or QT) monotherapy was reviewed by the work EORTC/NCIC-CTG/RTOG/MRC-CTU (EORTC 22033-26033 stage III)²⁴, reporting a progression free survival (PFS) for patients with mutation of IDH and co-deletion 1p/19q of 5 years. Exclusive QT may be considered for young patients, given the cognitive toxicity that is well reported for RT in the long term. However, patients treated with Sequential RT-QT have more than double progression free life expectancy²².

First line native IDH
Given the poor prognosis of this group (progression free survival with monotherapy in the work EORTC 22033-26033 was of only from 19 to 23 months). The discussion is if therapeutical monotherapy alternatives (RT or QT) or sequential RT-QT are enough; therefore, a more aggressive treatment is needed, such as RT-QT, according to Stupp´s Protocol6, similar to GBM treatment. However, this therapeutical choice is not reviewed in stage III studies; therefore, the suggestion is to evaluate this situation on a cases-by-case basis, according to the criterion of each center and its relevant oncological committee²¹.

Second line
Before progression, management will depend on first line treatment received, and it involves evaluation, reoperation, re-irradiation and/or use of alkylant agents (Temozolomide/PC or PCV)²¹. Repetition of the scheme previously used, if progression occurs after 5 months since the previous treatment was completed or else to change the scheme²³ may be considered.  In low grade native IDH gliomas Lomustine may be used thus homologizing GBM treatment ²⁴.

Anaplastic Gliomas, WHO Grade III (Astrocytomas or Oligodendrogliomas)

First line, for Gliomas Grade III with IDH 1 or 2 mutated and co-deletion 1p/19q present or NOS Anaplastic Oligodendroglioma

The suggestion is Sequential RT-QT with PCV, PC or Temozolomide
This is based on results of 2 prospective/randomized/multicentric works that evaluated RT treatment versus sequential RT-QT with PCV, QT post-RT (EORTC 26951) scheme and QT pre RT (RTOG 9402)^{27 28}. Both found benefit in the two sequential schemes when compared with exclusive RT for those patients with co-deletion 1p/19q and mutated IDH. If we take into account RTOG work, patients with co-deletion 1p/19q the combined therapy, improved SG in more than 7 years old (it duplicates medial SG: 14.7 years versus 7.3 years) and progression free survival (PFS) (8.4 years versus 2.9 years) when compared with RT; in patients with no co-deletion, but with mutated IDH. Benefits are observed in SG as well (5.5 versus 3.3 years) ²⁷.

First line, for Grade III Gliomas with IDH 1 or 2 mutated, and with no co-deletion 1p19q.
- The suggestion is Sequential RT-QT, with PCV/PC/Temozolomide.
- The suggestion is RT-QT, concomitant and adjuvant with Temozolomide (Stupp´s Protocol).

The CATNON study is a stage III multicentric study on Anaplastic Gliomas, with no co-deletion 1p19q. It randomized patients in 4 branches: RT with 59.4 Gy, with/with no 12 adjuvant cycles of Temozolomide and concomitant RTQT with/with no 12 adjuvant cycles of Temozolomide. The first report grouped the therapies, according to randomization or not to QT adjuvant. A significant benefit was reported in PFS in patients who received 12 cycles of adjuvant QT with Temozolomide (42 months versus 19 months). Some SG benefits were reported, as well. The median of global life expectancy has not been reached yet in patients with adjuvant QT versus 41 months in those who did not receive it (p<0,003)²⁹.

First line, Grade III Gliomas with IDH 1 and 2 natives, NOS Anaplastic Astrocytoma or NOS Anaplastic Oligoastrocitoma

This subgroup has the worst prognosis, and still there are no data available regarding specific effects in patients with Native IDH (CATNON study). The suggestion is to treat them with RT-QT, according to Stupp´s Protocol, although it could also be treated with sequential RT-QT, with Temozolomide in 12 cycles²⁹.

Second Line
Management of recurrent anaplastic glioma may consider re-operation, re-irradiation and even the use of alkylant agents (Temozolomide/PC or PCV/Lomustine)²⁴.

Glioblastoma (Grade IV Glioma)

First line
The indication of adjuvant therapy must be made based on the patient´s clinical condition and life expectancy probability. This must be made, considering clinical factors such as age, quality of life measured according to Karnofsky´s Scale (KPI) or ECOG, tumor resection grade and mental condition. The definition of weak patient must be taken into account, as for those patients older than 65 years old, and those whose condition do not allow them to perform their self-care (non self-reliant)³⁰.

A.- Non self-reliant Patients
The suggestion is to refer them to palliative care, a hypo fractioned radiotherapy scheme (reduction of dosage and duration of the treatment) or palliative radiotherapy ³⁰ may be considered.

B.- Self-reliant Patients older than 65 years old
For GBM carriers who are elderly people, their life expectancy is lower, as they have more aggressive tumors and further complications with their treatment³¹. For patients older than 65 years old, with a KPI higher or equal to 70%, it is recommended to perform hypo fractioned RT with concomitant and adjuvant Temozolomide, as the study EOTRC 26062-22061 stage III reported higher SG with this scheme, when compared with hypo fractioned RT with no chemotherapy (9.5 versus 7.6 months p<0.0001)³². In case of patients with significant fragility or comorbilities monotherapy may be considered. In RT there is no difference in SG between a hypo fractioned scheme (5.6 months) and the standard scheme (5.1 months)³³. In elderly people with methylated MGMT, QT monotherapy with Temozolomide^34,35 may be considered.

C.- Self-reliant Patients younger than 65 years old
This is based on Stupp´s 6 work EORTC-NCIC, reporting that RT-QT scheme, concomitant and adjuvant with Temozolomide (Stupp´s Protocol) increases global life expectancy, from 12.1 to 14.6 months, increasing life expectancy percentage to 5 years, in 8% absolute (10 versus 2%), when compared with RT exclusive⁶. 

Second Line
Management of recurrent GBM considers re-operation, re-irradiation options and use of alkylant agents. Repeating the previously used Temozolomide scheme may be considered, if the progression occurs 5 months after completion of the treatment23. The EORTC 26101 study compared the treatment with Lomustine (Monotherapy) vs Lomustine plus Bevacizumab, and no advantages in SG24 were reported. The Belob´s study is a Stage II study with three parallel branches. It reported a similar survival rate, before the use of Lomustine and Bevacizumab, as a monotherapy³⁶.

The summary of the aforementioned medical-surgical management is described in Figure 1.

Figure 1.

FOLLOW UP

Follow up is for life²¹. It is recommended to perform control with (BMR) at decreasing intervals.  (BMR) must include axial acquisition of the T2, FLAIR sequences, diffusion, T2 GRE or another magnetic susceptibility sequence (SWI), T1 SE with and with no contrast. If it is possible, include volumetric T1 sequences with contrast and DCE, DSC and/or ASL perfusions. Use of perfusion techniques in follow up of treated gliomas allow to have a better differentiation among phenomena attributable to treatment v/s tumor progression ³⁷.

Encephalon disturbances, secondary to therapy, represent a spectrum including early onset (pseudo progression) as well as late installation (radio necrosis). Pseudo progression is defined as the progression of new contrast uptake lesions, usually associated to edema, which are produced within the first 6 months after completing the treatment, and can improve or heal spontaneously³⁸.  On the other hand, onset of lesions due to radio necrosis usually occurs between 9 to 12 months after completing the treatment. Both processes correspond to the ends of a continuous named as “treatment-related changes”. Even though these are different physio pathological mechanisms, maybe their most relevant clinical differentiations are that those patients who evolve with pseudo progression have a more favorable prognosis, while those who develop radio necrosis experience a more stressed neurological impairment; therefore, with a worse functional prognosis.

GENERAL SYMPTOMATIC MANAGEMENT

The main medicament for managing cephalea and deficit symptoms are corticoids. A dosage of 16, 8 and 4 mg of Dexamethasone have been compared with a very similar effect, after a week of treatment. The suggestion is to start a higher dosage, to be reduced later to one dosage, aimed to mitigate symptoms or the recession³⁹. Paracetamol or anti-inflammatory drugs may be associated on an hourly basis. Drugs derived from opioids must also be considered for this type of pain⁴⁰.

It is very important to state that rehabilitation is aimed to get functional improvement. Managing a healthy exercise program is a suggested. This routine could be performed by kinesiologists or physical education teachers with an expertise on oncological patients³⁹.

On the other hand, regarding infections, pneumonia caused by pneumocistis jirovecii appears between 1.7 and 6.2% of these patients, as a result of a combined treatment of QT and corticoids. Use of prophylaxis with Co-trimoxazole-Sulfamethoxazole is recommended in QT patient, especially if they use corticoids and have lymphopenia³⁹.
Regarding the possibility of epileptogenic activity, use of antiepileptic drugs during the period perioperative is recommended. In case there is no crisis at the onset, the antiepileptic drug must be removed, seven days after surgery. In case of a crisis, use of anticonvulsants with non enzymatic inducing agents⁴¹ is suggested. Valproic acid increases myelosupression, as it is used along with Temozolomide and Lomustine41. In advances stages patients use to have deglutition disorders. Sublingual Clonazepam or subcutaneous Midazolam or the use of endovenous drugs⁴¹ is recommended (See Table 2).

Table 2. Dosage and Frequency of Antiepileptic drugs used

mg: milligram

Fatigue, nauseas and constipation are frequent symptoms. Any action aimed to improve fatigue, such as exercise and use of drugs (Modafinil or Methylphenidate), are partially effective, and have a low level of evidence⁴².

Deliriums can be treated with Olanzapine, Risperidone, Aripiprazole and Haloperidol which have proven their effective use. At final stages sedation^43,44 is recommended.

In case of unconsciousness, use of stomach tubes or gastrostomy is not recommended, as they are useless, because quality of life is not improved and it favors bronchial aspiration^44,45.

CONCLUSIONS AND FUTURE PERSPECTIVES

This joint work, made with a team of national experts, and by selecting the best evidence available, we have reviewed the main progress in diagnosis and management of this sanitary issue. Likewise, we could also detect the main constraints in national/international medical/scientific knowledge, as well as to review current local challenges, in order to update our knowledge regarding integral management of these patients.

In that context, it is important to highlight the following facts; (i) there is a high need to implement an updated record of tumors of the central nervous system (ii) imagery diagnostic techniques are complex and require leading edge technology and highly trained professionals, (iii) development and implementation of molecular/accuracy oncology is a must for current clinical practice and control of gliomas in adults, (iv) modern neurosurgery must be supported by interventional imagery and intraoperative clinical neurophysiology, (v) to date there are just a few therapeutical implementations (biological), if compared with other oncological areas. In this sense, more advances are expected in the short term.

Finally, it is necessary to consolidate multidisciplinary oncological teams aimed to develop, at the same time, a systematic welfare labor, as well as a robust research activity, with a clear basic-clinical and/or translational approach.

ACKNOWLEDGEMENTS

The main author wants to thank specially to the Academic Development & Research Department (Departamento de Desarrollo Académico e Investigación), of the Clínica Alemana, Santiago, for their support to neuro-oncology progress, as a new area of interest for the Institution. Likewise, the other authors want to thank to their relevant Medical/Scientific Societies they represent (SONEPSYN, SOCHINEURCIRUGÍA, SOCHIRA, SOCHIRADI, SCHAP, SOCHIMEDPAL, SOCHCANCEROLOGÍA) and the Department of integral Management of Cancer and other Tumors (Departamento de Manejo Integral de Cáncer y otros Tumores), from the Ministry of Health, Chile, for its willingness to move forward in these matters and try to improve the life of people suffering cancer, using the best evidence available. The second correspondent author (JAR) wants to thank, specially to the School of Medicine of the Universidad Mayor, as he works there as a teacher, for its permanent support and participation in these instances of multidisciplinary cooperation.

REFERENCES

1. Ostrom QT, Glittleman H, Truitt G, Boscia A, Kruchko C and Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011–2015. Neuro-Oncology 2018; 20: iv1-iv86.
   
2. Shanihkhani M, Telesca D, Movassaghi M, Naeini YB, Naeini K; Hojat SA et al. Incidence, survival, pathology and genetics of adult Latino Americans with glioblastoma. J Neurooncol 2017; 32: 351-358.
   
3. Primer informa de registros poblacionales de cancer de Chile. Minsal 2012 https://www.minsal.cl/wp-content/uploads/2019/01/2019.01.23_PLAN-NACIONAL-DE-CANCER_web.pdf
   
4. Series y Gráficos de Mortalidad - DEIS http://www.deis.cl/series-y-graficos-de-mortalidad/
   
5. Quezada C, Peigñan L, Segura R, Riquelme F, Melo R, Rojas D et al. Glioblastoma multiforme y estudio de la resistencia a la quimioterapia mediada por transportadores ABC. Rev Med Chile 2011; 139: 415-424.
   
6. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC et al. Effect of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459-66.
   
7. Protocolo Clínico: Gliomas en personas sobre 15 años. Minsal  2019 https://redcronicas.minsal.cl/wp-content/uploads/2019/10/2019.10.24_PROTOCOLO-GLIOMAS-DEL-ADULTO.pdf.
   
8. Thust S, Heiland S, Falini A, Jäger HR, Waldman AD, Sundgren PC et al. Glioma imaging in Europe: A survey of 220 centres and recommendations for best clinical practice. Eur Radiol 2018; 28: 3306-3317.
   
9. Law M, Yang S, Babb JS, Knopp EA, Golfinos JG, Zagzag D et al. Comparison of cerebral blood volume and vascular permeability from dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade. AJNR Am J Neuroradiol 2004; 25: 746-55.
   
10. Hourani R, Brant LJ, Rizk T, Weingart JD, Barker PB, Hosrka A. Can proton MR spectroscopic and perfusion imaging differentiate between neoplastic and nonneoplastic brain lesions in adults?AJNR An J Neuroradiol 2008; 29: 366-72.
    
11. Usinskiene J, Ulyte A, Bjørnerud A, Venius J, Katsaros VK, Rynkeviciene R et al. Optimal differentiation of high- and low-grade glioma and metastasis: a meta-analysis of perfusion, diffusion, and spectroscopy metrics. Neuroradiology 2016; 58: 339-50.
    
12. Keles GE, Anderson B, Berger MS. The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. Surg Neurol 1999; 52: 371–379.
    
13. Lacroix M, Abi-Said S, DeMonte F, Fourney DR, Gokaslan ZL, Shi W, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 2001; 95: 190–198.
    
14. Kickingereder P, Willeit P, Simon T, Ruge MI. Diagnostic value and safety of stereotactic biopsy for brainstem tumors: A systematic review and meta-analysis of 1480 cases. Neurosurgery 2013; 72: 873–81
    
15. Louis DN, Perry A Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131: 803-20.
    
16. Chen L, Voronovich Z, Clark K, Hands I, Mannas J, Walsch M et al. Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma. Neuro Oncol 2014; 16: 1478-83.
    
17. DeWitt JC, Jordan JT, Frosch MP, Samore WR, Iafrate AJ, Louis DN, Lennerz JK. Cost-effectiveness of IDH testing in diffuse gliomas according to the 2016 WHO classification of tumors of the central nervous system recommendations. Neuro Oncol 2017; 29: 1640-1650.
    
18. Jakola AS, Myrmel KS, Kloster R, Torp SH, Lindal S, Unsgård G, Solheim O. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA 2012; 308: 1881-8.
    
19. De Witt Hamer PC, Berger MS, Duffau H, Robles SG, Zwinderman AH. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol. 2012; 30: 2559–2565.
    
20. Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. 2008; 62: 753–764.
    
21. Weller M, van den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E et al European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol 2017; 18: e315-e329.
    
22. Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer Ket al. Randomized trial of radiation therapy plus procarbazine, lomustine and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol 2012; 30: 3065-70.
    
23. Webre C, ShonkaN, Smith L, Liu D, DeGroot J. PC or PCV, that is the question: Primary anaplastic oligodendroglial tumors treated with procarbazine and CCNU with and without vincristine Anticancer Res 2015; 35: 5467-72.
    
24. Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 2016; 17:1521-1532.
    
25. Franceschi E, Lamberti G, Visani M, Paccapelo A, Mura A, Tallini G et al Temozolomide rechallenge in recurrent glioblastoma: When is it useful? Future Oncol 2018; 14: 1063-1069.
    
26. Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I et al. Lomustine and Bevacizumab in Progressive Glioblastoma. N Engl J Med 2017; 377: 1954-1963
    
27. Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: Long-term results of RTOG 9402. J Clin Oncol 2013; 31: 337-43.
    
28. Van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: Long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 2013; 31: 344-50.
    
29. Van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma:a phase 3, randomised, open label intergroup study. Lancet 2017; 390: 1645-1653.
    
30. Wick W, Osswald M, Wick A and Winkler F. Treatment of glioblastoma in adults Ther adv neurol disord 2018; 11: 1-13
    
31. Wiestler B, Claus R, Hartlieb SA, Schliesser MG, Weiss EK, Hielscher T et al. Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective. Neuro Oncol 2013; 15: 1017-26.
    
32. Perry JR, Laperriere N, O’Callaghan CJ, Brandes AA, Menten J, Phillips C et al. Short course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 2017; 376: 1027-1037.
    
33. Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: A prospective randomized clinical trial. J Clin Oncol 2004; 22:1583-8
    
34. Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H et al Temozolomide versus standard 6week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomized, phase 3 trial. Lancet Oncol 2012; 13: 916-26
    
35. Wick W, Platten M, Meisner C, Felsberg C, Feisberg J, Tabatabai G et al Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA – 08 randomised, phase 3 trial. Lancet Oncol 2012; 13: 707-15
    
36. Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV Hanse MC et al. Single agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (Belob trial): a randomized controlled phase 2 trial. Lancet Oncol 2014; 15: 943-53.
    
37. Sughara T, Korogi Y, Tomiguchi S, Shigematsu Y, Ikushima I, Kira T et al. Posttherapeutic intraaxial brain tumor: The value of perfusion-sensitive contrast enhanced MR imaging for differentiating tumor recurrence from nonneoplastic contrast enhancing tissue. AJNR Am J Neuroradiol 2000; 21: 901-9.
    
38. Radbruch A, Fladt J, Kickingereder P, Wiestler B, Nowosielski M, Bäumer P et al Pseudoprogression in patients with glioblastoma: Clinical relevance despite low incidence. Neuro Oncol 2015; 17: 151-9.
    
39. Pace A, Dirven L, Koekkoek J, Golla H, Fleming J, Rudà R et al. European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma. Lancet Oncol 2017; 18: e330-e340.
    
40. Caraceni A, Hanks G, Kaasa S, Bennett MI, Chernyl N, Dale O et al. Use of opioid analgesics in the treatment of cancer pain: Evidence-based recommendations from the EAPC. Lancet Oncol 2012; 13: e58-e68.
    
41. Weller M, Stupp R, Wick W. Epilepsy meets cancer: When, why, and what to do about it? Lancet Oncol 2012; 13: e375-82.
    
42. Day J, Yust-Katz S, Cachia D, Wefel J, Katz LH, Tremont I et al. Interventions for the management of fatigue in adults with a primary brain tumour. Cochrane Database Syst Rev 2016;4: CD011376.
    
43. Pace A, Metro G, Fabi A. Supportive care in neurooncology. Curr Opin Oncol 2010; 22: 621-6.
    
44. Agudo Tabuenca A, Altemir Trallero J, Gimeno Oma JA, Ocón Bretón MJ. Mortality risk factors after percutaneous gastrostomy: Who is a good candidate? Clin Nutr 2019; 38: 856-861.