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Journal of Neuro-oncology Dec 2015These recommendations apply to adult patients with recurrent low-grade glioma (LGG) with initial pathologic diagnosis of a WHO grade II infiltrative glioma...
TARGET POPULATION
These recommendations apply to adult patients with recurrent low-grade glioma (LGG) with initial pathologic diagnosis of a WHO grade II infiltrative glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma).
QUESTION
Do pathologic and molecular characteristics predict outcome/malignant transformation at recurrence?
RECOMMENDATIONS
IDH STATUS AND RECURRENCE: (Level III) IDH mutation status should be determined as LGGs with IDH mutations have a shortened time to recurrence. It is unclear whether knowledge of IDH mutation status provides benefit in predicting time to progression or overall survival. TP53 STATUS AND RECURRENCE: (Level III) TP53 mutations occur early in LGG pathogenesis, remain stable, and are not recommended as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis. MGMT STATUS AND RECURRENCE: (Level III) Assessment of MGMT status is recommended as an adjunct to assessing prognosis as LGGs with MGMT promoter methylation are associated with shorter PFS (in the absence of TMZ) and longer post-recurrence survival (in the presence of TMZ), ultimately producing similar overall survival to LGGs without MGMT methylation. The available retrospective reports are conflicting and comparisons between reports are limited CDK2NA STATUS AND RECURRENCE: (Level III) Assessment of CDK2NA status is recommended when possible as the loss of expression of the CDK2NA via either methylation or loss of chromosome 9p is associated with malignant progression of LGGs. PROLIFERATIVE INDEX AND RECURRENCE: (Level III) It is recommended that proliferative indices (MIB-1 or BUdR) be measured in LGGs as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival. 1P/19Q STATUS AND RECURRENCE: There is insufficient evidence to make any recommendations.
QUESTION
What role does chemotherapy have in LGG recurrence?
RECOMMENDATIONS
TEMOZOLOMIDE AND RECURRENCE: (Level III) Temozolomide is recommended in the therapy of recurrent LGG as it may improve clinical symptoms. Oligodendrogliomas and tumors with 1p/19q co-deletion may derive the most benefit. PCV AND RECURRENCE: (Level III) PCV is recommended in the therapy of LGG at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas. CARBOPLATIN AND RECURRENCE : (Level III) Carboplatin is not recommended as there is no significant benefit from carboplatin as single agent therapy for recurrent LGGs. OTHER TREATMENTS (NITROSUREAS, HYDROXYUREA/IMANITIB, IRINOTECAN, PACLITAXEL) AND RECURRENCE: There is insufficient evidence to make any recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess these chemotherapeutic agents.
QUESTION
What role does radiation have in LGG recurrence?
RECOMMENDATIONS
RADIATION AT RECURRENCE WITH NO PREVIOUS IRRADIATION: (Level III) Radiation is recommended at recurrence if there was no previous radiation treatment. RE-IRRADIATION AT RECURRENCE: (Level III) It is recommended that re-irradiation be considered in the setting of LGG recurrence as it may provide benefit in disease control.
SURGERY AT RECURRENCE
There is insufficient evidence to make any specific recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess the role of surgery at recurrence.
Topics: Humans; Brain Neoplasms; Evidence-Based Medicine; Glioma; Neoplasm Grading; Neoplasm Recurrence, Local
PubMed: 26530264
DOI: 10.1007/s11060-015-1910-2 -
Journal of Neuro-oncology Dec 2015Adult patients (age ≥18 years) who have suspected low-grade diffuse glioma.
TARGET POPULATION
Adult patients (age ≥18 years) who have suspected low-grade diffuse glioma.
QUESTION
What are the optimal neuropathological techniques to diagnose low-grade diffuse glioma in the adult?
RECOMMENDATION
LEVEL I: Histopathological analysis of a representative surgical sample of the lesion should be used to provide the diagnosis of low-grade diffuse glioma.
LEVEL III
Both frozen section and cytopathologic/smear evaluation should be used to aid the intra-operative assessment of low-grade diffuse glioma diagnosis. A resection specimen is preferred over a biopsy specimen, to minimize the potential for sampling error issues.
TARGET POPULATION
Patients with histologically-proven WHO grade II diffuse glioma.
QUESTION
In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for IDH1 mutation (R132H and/or others) warranted? If so, is there a preferred method?
LEVEL II
IDH gene mutation assessment, via IDH1 R132H antibody and/or IDH1/2 mutation hotspot sequencing, is highly-specific for low-grade diffuse glioma, and is recommended as an additional test for classification and prognosis.
TARGET POPULATION
Patients with histologically-proven WHO grade II diffuse glioma.
QUESTION
In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for 1p/19q loss warranted? If so, is there a preferred method?
LEVEL III
1p/19q loss-of-heterozygosity testing, by FISH, array-CGH or PCR, is recommended as an additional test in oligodendroglial cases for prognosis and potential treatment planning.
TARGET POPULATION
Patients with histologically-proven WHO grade II diffuse glioma.
QUESTION
In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is MGMT promoter methylation testing warranted? If so, is there a preferred method?
RECOMMENDATION
There is insufficient evidence to recommend methyl-guanine methyl-transferase (MGMT) promoter methylation testing as a routine for low-grade diffuse gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the value of this and related markers for this target population.
TARGET POPULATION
Patients with histologically-proven WHO grade II diffuse glioma.
QUESTION
In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is Ki-67/MIB1 immunohistochemistry warranted? If so, is there a preferred method to quantitate results?
LEVEL III
Ki67/MIB1 immunohistochemistry is recommended as an option for prognostic assessment.
Topics: Humans; Brain; Brain Neoplasms; Disease Management; Evidence-Based Medicine; Glioma; Neoplasm Grading
PubMed: 26530263
DOI: 10.1007/s11060-015-1909-8 -
Journal of Neuro-oncology Dec 2015What is the optimal imaging technique to be used in the diagnosis of a suspected low grade glioma, specifically: which anatomic imaging sequences are critical for most...
QUESTION
What is the optimal imaging technique to be used in the diagnosis of a suspected low grade glioma, specifically: which anatomic imaging sequences are critical for most accurately identifying or diagnosing a low grade glioma (LGG) and do non-anatomic imaging methods and/or sequences add to the diagnostic specificity of suspected low grade gliomas?
TARGET POPULATION
These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG.
LEVEL II
In patients with a suspected brain tumor, the minimum magnetic resonance imaging (MRI) exam should be an anatomic exam with both T2 weighted and pre- and post-gadolinium contrast enhanced T1 weighted imaging. CRITICAL IMAGING FOR THE IDENTIFICATION AND DIAGNOSIS OF LOW GRADE GLIOMA:
LEVEL II
In patients with a suspected brain tumor, anatomic imaging sequences should include T1 and T2 weighted and Fluid Attenuation Inversion Recovery (FLAIR) MR sequences and will include T1 weighted imaging after the administration of gadolinium based contrast. Computed tomography (CT) can provide additional information regarding calcification or hemorrhage, which may narrow the differential diagnosis. At a minimum, these anatomic sequences can help identify a lesion as well as its location, and potential for surgical intervention. IMPROVEMENT OF DIAGNOSTIC SPECIFICITY WITH THE ADDITION OF NON-ANATOMIC (PHYSIOLOGIC AND ADVANCED IMAGING) TO ANATOMIC IMAGING:
LEVEL II
Class II evidence from multiple studies and a significant number of Class III series support the addition of diffusion and perfusion weighted MR imaging in the assessment of suspected LGGs, for the purposes of discriminating the potential for tumor subtypes and identification of suspicion of higher grade diagnoses.
LEVEL III
Multiple series offer Class III evidence to support the potential for magnetic resonance spectroscopy (MRS) and nuclear medicine methods including positron emission tomography and single-photon emission computed tomography imaging to offer additional diagnostic specificity although these are less well defined and their roles in clinical practice are still being defined.
QUESTION
Which imaging sequences or parameters best predict the biological behavior or prognosis for patients with LGG?
TARGET POPULATION
These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG.
RECOMMENDATION
Anatomic and advanced imaging methods and prognostic stratification
LEVEL III
Multiple series suggest a role for anatomic and advanced sequences to suggest prognostic stratification among low grade gliomas. Perfusion weighted imaging, particularly when obtained as a part of diagnostic evaluation (as recommended above) can play a role in consideration of prognosis. Other imaging sequences remain investigational in terms of their role in consideration of tumor prognosis as there is insufficient evidence to support more formal recommendations as to their use at this time.
QUESTION
What is the optimal imaging technique to be used in the follow-up of a suspected (or biopsy proven) LGG?
TARGET POPULATION
This recommendation applies to adults with a newly diagnosed low grade glioma.
LEVEL II
In patients with a diagnosis of LGG, anatomic imaging sequences should include T2/FLAIR MR sequences and T1 weighted imaging before and after the administration of gadolinium based contrast. Serial imaging should be performed to identify new areas of contrast enhancement or significant change in tumor size, which may signify transformation to a higher grade.
LEVEL III
Advanced imaging utility may depend on tumor subtype. Multicenter clinical trials with larger cohorts are needed. For astrocytic tumors, baseline and longitudinal elevations in tumor perfusion as assessed by dynamic susceptibility contrast perfusion MRI are associated with shorter time to tumor progression, but can be difficult to standardize in clinical practice. For oligodendrogliomas and mixed gliomas, MRS may be helpful for identification of progression.
Topics: Adult; Humans; Brain; Brain Neoplasms; Evidence-Based Medicine; Glioma; Neoplasm Grading; Neuroimaging
PubMed: 26530262
DOI: 10.1007/s11060-015-1908-9 -
Journal of Neuro-oncology Dec 2015Adult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed...
TARGET POPULATION
Adult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed oligoastrocytoma).
QUESTION
Is there a role for chemotherapy as adjuvant therapy of choice in treatment of patients with newly diagnosed low-grade gliomas?
LEVEL III
Chemotherapy is recommended as a treatment option to postpone the use of radiotherapy, to slow tumor growth and to improve progression free survival (PFS), overall survival (OS) and clinical symptoms in adult patients with newly diagnosed LGG.
QUESTION
Who are the patients with newly diagnosed LGG that would benefit the most from chemotherapy?
LEVEL III
Chemotherapy is recommended as an optional component alone or in combination with radiation as the initial adjuvant therapy for all patients who cannot undergo gross total resection (GTR) of a newly diagnosed LGG. Patient with residual tumor >1 cm on post-operative MRI, presenting diameter of >4 cm or older than 40 years of age should be considered for adjuvant therapy as well.
QUESTION
Are there tumor markers that can predict which patients can benefit the most from initial treatment with chemotherapy?
LEVEL III
The addition of chemotherapy to standard RT is recommended in LGG patients that carry IDH mutation. In addition, temozolomide (TMZ) is recommended as a treatment option to slow tumor growth in patients who harbor the 1p/19q co-deletion.
QUESTION
How soon should the chemotherapy be started once the diagnosis of LGG is confirmed?
RECOMMENDATION
There is insufficient evidence to make a definitive recommendation on the timing of starting chemotherapy after surgical/pathological diagnosis of LGG has been made. However, using the 12 weeks mark as the latest timeframe to start adjuvant chemotherapy is suggested. It is recommended that patients be enrolled in properly designed clinical trials to assess the timing of chemotherapy initiation once diagnosis is confirmed for this target population.
QUESTION
What chemotherapeutic agents should be used for treatment of newly diagnosed LGG?
RECOMMENDATION
There is insufficient evidence to make a recommendation of one particular regimen. Enrollment of subjects in properly designed trials comparing the efficacy of these or other agents is recommended so as to determine which of these regimens is superior.
QUESTION
What is the optimal duration and dosing of chemotherapy as initial treatment for LGG?
RECOMMENDATION
Insufficient evidence exists regarding the duration of any specific cytotoxic drug regimen for treatment of newly diagnosed LGG. Enrollment of subjects in properly designed clinical investigations assessing the optimal duration of this therapy is recommended.
QUESTION
Should chemotherapy be given alone or in conjunction with RT as initial therapy for LGG?
RECOMMENDATION
Insufficient evidence exists to make recommendations in this regard. Hence, enrollment of patients in properly designed clinical trials assessing the difference between chemotherapy alone, RT alone or a combination of them is recommended.
QUESTION
Should chemotherapy be given in addition to other type of adjuvant therapy to patients with newly diagnosed LGG?
RECOMMENDATION
Level II: It is recommended that chemotherapy be added to the RT in patients with unfavorable LGG to improve their progression free survival.
Topics: Humans; Brain Neoplasms; Evidence-Based Medicine; Glioma; Neoplasm Grading
PubMed: 26530261
DOI: 10.1007/s11060-015-1931-x -
The Cochrane Database of Systematic... Jun 2015In most people with low-grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In most people with low-grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal timing of radiotherapy is controversial. It is unclear whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs.
OBJECTIVES
To assess the effects of early postoperative radiotherapy versus radiotherapy delayed until tumour progression for low-grade intracranial gliomas in people who had initial biopsy or surgical resection.
SEARCH METHODS
We searched up to September 2014 the following electronic databases: the Cochrane Register of Controlled Trials (CENTRAL, Issue 8, 2014), MEDLINE (1948 to Aug week 3, 2014), and EMBASE (1980 to Aug week 3, 2014) to identify trials for inclusion in this Cochrane review.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared early versus delayed radiotherapy following biopsy or surgical resection for the treatment of people with newly diagnosed intracranial LGG (astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthoastrocytoma, or ganglioglioma). Radiotherapy may include conformal external beam radiotherapy (EBRT) with linear accelerator or cobalt-60 sources, intensity-modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS).
DATA COLLECTION AND ANALYSIS
Three review authors independently assessed the trials for inclusion and risk of bias, and extracted study data. We resolved any differences between review authors by discussion. Adverse effects were also extracted from the study report. We performed meta-analyses using a random-effects model with inverse variance weighting.
MAIN RESULTS
We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy is associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but does not significantly improve overall survival (OS). The median progression-free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P value < 0.0001; 311 participants; 1 trail; low quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P value = 0.872; 311 participants; 1 trail; low quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P value = 0.0329, respectively).
AUTHORS' CONCLUSIONS
Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who undergo early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remains unclear whether there are differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated.
Topics: Biopsy; Brain Neoplasms; Disease Progression; Disease-Free Survival; Glioma; Humans; Postoperative Care; Radiotherapy; Seizures; Time Factors; Watchful Waiting
PubMed: 26118544
DOI: 10.1002/14651858.CD009229.pub2