Congress of neurological surgeons systematic review and evidence-based clinical practice parameter guidelines for the treatment of adults with newly diagnosed glioblastoma: Introduction and Methods.

PURPOSE: This is an update of the evidence-based guideline for management of newly diagnosed glioblastomas sponsored by the American Association of Neurological Surgeons (AANS) and Congress of Neurological Surgeons (CNS) initially published in 2008. The objective is to update evidence-based management of newly diagnosed glioblastomas over all commonly used diagnostic and treatment modalities in regularly encountered clinical situations. METHODS: A multidisciplinary writing group was assembled to create documents related to imaging, cytoreductive surgery, neuropathology, radiation therapy, chemotherapy and emerging developments. Questions from the prior set of guidelines, and new and modified questions were used to guide a search of the scientific literature since the last guideline search was completed in June 2005. Citations were screened, classified and used as evidence to create recommendations addressing the questions in a manner that was directly linked to this evidence. RESULTS: The sixteen writers produced 34 questions resulting in eight Level I recommendations, eleven Level II recommendations, and 27 Level II recommendations across all the topics. In some instances, insufficient data was available to answer all or part of a question and this is stated and explained. CONCLUSIONS: This series of guidelines is based upon relevant evidence in the literature related to the management of newly diagnosed glioblastomas. They set a benchmark for the management of this disease while highlighting key areas of weakness in our knowledge and suggest directions for future basic and clinical research to improve evidence quality and recommendation strength.

The role of neuropathology in the management of newly diagnosed glioblastoma: a systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: These recommendations apply to adult patients with newly diagnosed or suspected glioblastoma (GBM) QUESTION : For adult patients with newly diagnosed GBM does testing for Isocitrate Dehydrogenase 1 or 2 (IDH 1/2) mutations afford benefit beyond standard histopathology in providing accurate classification and outcome prognostication? Level III IDH 1/2 mutational status by immunohistochemistry (IHC) and/or sequencing is suggested for classification and prognostic information. Level III Non-canonical IDH 1/2 mutations are very rare in patients aged 55 or older and universal testing of variant mutations by sequence analysis is not suggested for this age range. QUESTION: For adult patients with lower grade infiltrating astrocytomas (WHO grades II and III) can the IDH-wildtype status designation supersede histopathology to predict prognosis and biologic relevance to eventual behavior as a GBM? Level III The designation of infiltrating astrocytomas (WHO grades II and III) as IDH-wildtype is not suggested as sufficient for a higher grade designation alone. Level III It is suggested that IDH-wildtype WHO grades II and III astrocytomas be tested for molecular-genetic alterations typical of IDH-wildtype GBM such as EGFR amplification, gain of chromosome 7/loss of chromosome 10 and TERT-p mutation to substantiate prediction of behavior similar to IDH-wildtype glioblastoma. Level III It is suggested that a diagnosis of diffuse astrocytic glioma, IDH-wildtype, with molecular features of GBM, WHO grade IV be rendered for infiltrating astrocytomas that lack histologic criteria of GBM but harbors molecular-genetic alterations of IDH-wildtype glioblastoma. QUESTION: For adult patients with newly diagnosed infiltrating glioma arising in the midline does testing for H3-K27M mutations provide information beyond that gained by histopathology for accurate classification and outcome prognostication? Level III It is suggested that infiltrating gliomas arising in midline anatomic locations be tested for the H3-K27M mutation as they tend to exhibit WHO grade IV behavior even if they lack histologic criteria for glioblastoma.

The role of radiation therapy in treatment of adults with newly diagnosed glioblastoma multiforme: a systematic review and evidence-based clinical practice guideline update.

TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. QUESTION 1 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is the addition of radiation therapy (RT) more beneficial than management without RT in improving survival? RECOMMENDATIONS: Level I: Radiation therapy (RT) is recommended for the treatment of newly diagnosed malignant glioblastoma in adults. QUESTION 2 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is the RT regimen of 60 Gy given in 2 Gy daily fractions more beneficial than alternative regimens in providing survival benefit while minimizing toxicity? RECOMMENDATIONS: Level I: Treatment schemes should include dosage of up to 60 Gy given in 2 Gy daily fractions that includes the enhancing area. QUESTION 3 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is a tailored target volume superior to regional RT for reduction of radiation-induced toxicity while maintaining efficacy? RECOMMENDATION: Level II: It is recommended that radiation therapy planning include 1-2 cm margin around the radiographically T1 weighted contrast-enhancing tumor volume or the T2 weighted abnormality on MRI. Level III: Recalculation of the radiation volume during RT treatment may be necessary to reduce the radiated volume of normal brain since the volume of surgical defect will change during the long period of RT. QUESTION 4 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, does the addition of RT of the subventricular zone to standard tumor volume treatment improve tumor control and overall survival? RECOMMENDATION: No recommendation can be formulated as there is contradictory evidence in favor of and against intentional radiation of the subventricular zone (SVZ) QUESTION 5 : In elderly (age > 65 years) and/or frail patients with newly diagnosed glioblastoma, does the addition of RT to surgical intervention improve disease control and overall survival? RECOMMENDATION: Level I: Radiation therapy is recommended for treatment of elderly and frail patients with newly diagnosed glioblastoma to improve overall survival. QUESTION 6 : In elderly (age > 65 years) and/or frail patients with newly diagnosed glioblastoma, does modification of RT dose and fractionation scheme from standard regimens decrease toxicity and improve disease control and survival? RECOMMENDATION: Level II: Short RT treatment schemes are recommended in frail and elderly patients as compared to conventional 60 Gy given in 2 daily fractions because overall survival is not different while RT risk profile is better for the short RT scheme. Level II: The 40.05 Gy dose given in 15 fractions or 25 Gy dose given in 5 fractions or 34 Gy dose given in 10 fractions should be considered as appropriate doses for Short RT treatments in elderly and/or frail patients. QUESTION 7 : In adult patients with newly diagnosed glioblastoma is there advantage to delaying the initiation of RT instead of starting it 2 weeks after surgical intervention in decreasing radiation-induced toxicity and improving disease control and survival? RECOMMENDATION: Level III: It is suggested that RT for patients with newly diagnosed GBM starts within 6 weeks of surgical intervention as compared to later times. There is insufficient evidence to recommend the optimal specific post-operative day within the 6 weeks interval to start RT for adult patients with newly diagnosed glioblastoma that have undergone surgical resection. QUESTION 8 : In adult patients with newly diagnosed supratentorial glioblastoma is Image-Modulated RT (IMRT) or similar techniques as effective as standard regional RT in providing tumor control and improve survival? RECOMMENDATION: Level III: There is no evidence that IMRT is a better RT delivering modality when compared to conventional RT in improving overall survival in adult patients with newly diagnosed glioblastoma. Hence, IMRT should not be preferred over the Conventional RT delivery modality. QUESTION 9 : In adult patients with newly diagnosed glioblastoma does the use of radiosensitizers with RT improve the efficacy of RT as determined by disease control and overall survival? RECOMMENDATION: Level III: Iododeoxyuridine is not recommended to be used as radiosensitizer during RT treatment for patients with newly diagnosed GBM QUESTION 10 : In adult patients with newly diagnosed glioblastoma is the use of Ultrafractionated RT superior to standard fractionation regimens in improving disease control and survival? RECOMMENDATION: There is insufficient evidence to formulate a recommendation regarding the use of ultrafractionated RT schemes and patient population that could benefit from it. QUESTION 11 : In patients with poor prognosis with newly diagnosed glioblastoma is hypofractionated RT indicated instead of a standard fractionation regimen as measured by extent of toxicity, disease control and survival? RECOMMENDATION: Level I: Hypofractionated RT schemes may be used for patients with poor prognosis and limited survival without compromising response. There is insufficient evidence in the literature for us to be able to recommend the optimal hypofractionated RT scheme that will confer longest overall survival and/or confer the same overall survival with less toxicities and shorter treatment time. QUESTION 12 : In adult patients with newly diagnosed glioblastoma is the addition of brachytherapy to standard fractionated RT indicated to improve disease control and survival? RECOMMENDATION: Level I: Brachytherapy as a boost to external beam RT has not been shown to be beneficial and is not recommended in the routine management of patients with newly diagnosed GBM. QUESTION 13 : In elderly patients (> 65 year old) with newly diagnosed glioblastoma under what circumstances is accelerated hyperfractionated RT indicated instead of a standard fractionation regimen as measured by extent of toxicity, disease control and survival? RECOMMENDATION: Level III: Accelerated Hyperfractionated RT with a total RT dose of 45 Gy or 48 Gy has been shown to shorten the treatment time without detriment in survival when compared to conventional external beam RT and should be considered as an option for treatment of elderly patients with newly diagnosed GBM. QUESTION 14 : In adult patients with newly diagnosed glioblastoma is the addition of Stereotactic Radiosurgery (SRS) boost to conventional standard fractionated RT indicated to improve disease control and survival? RECOMMENDATION: Level I: Stereotactic Radiosurgery boost to external beam RT has not been shown to be beneficial and is not recommended in patients undergoing routine management of newly diagnosed malignant glioma.

Cytoreductive surgery in the management of newly diagnosed glioblastoma in adults: a systematic review and evidence-based clinical practice guideline update.

TARGET POPULATION: These recommendations apply to adults with newly diagnosed or suspected glioblastoma. QUESTION: What is the effect of extent of surgical resection on patient outcome in the initial management of adult patients with suspected newly diagnosed glioblastoma? RECOMMENDATION: Level II: Maximal cytoreductive surgery is recommended in adult patients with suspected newly diagnosed supratentorial glioblastoma with gross total resection defined as removal of contrast enhancing tumor. Level III: Biopsy, subtotal resection, or gross total resection is suggested depending on medical comorbidities, functional status, and location of tumor if maximal resection may cause significant neurologic deficit. QUESTION: What is the role of cytoreductive surgery in adults with newly diagnosed bi-frontal "butterfly" glioblastoma? RECOMMENDATION: Level III: Resection of newly diagnosed bi-frontal "butterfly" glioblastoma is suggested to improve overall survival over biopsy alone. QUESTION: What is the goal of cytoreductive surgery in elderly adult patients with newly diagnosed glioblastoma? RECOMMENDATION: Level III: Elderly patients (> 65 years) show survival benefit with gross total resection and it is suggested they undergo cytoreductive surgery. QUESTION: What is the role of advanced intraoperative guidance techniques in cytoreductive surgery in adults with newly diagnosed glioblastoma? RECOMMENDATION: Level III: The use of intraoperative guidance adjuncts such as intraoperative MRI (iMRI) or 5-aminolevulinic acid (5-ALA) are suggested to maximize extent of resection in newly diagnosed glioblastoma. There is insufficient evidence to make a suggestion on the use of fluorescein, indocyanine green, or intraoperative ultrasound.

The role of imaging for the management of newly diagnosed glioblastoma in adults: a systematic review and evidence-based clinical practice guideline update.

TARGET POPULATION: These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven glioblastoma (GBM). QUESTION: What are the optimal imaging techniques to be used in the management of a suspected glioblastoma (GBM), specifically: which imaging sequences are critical for most accurately identifying or diagnosing a GBM and distinguishing this tumor from other tumor types? RECOMMENDATIONS: Critical Imaging for the Identification and Diagnosis of Glioblastoma Level II: In patients with a suspected GBM, it is recommended that the minimum magnetic resonance imaging (MRI) exam should be an anatomic exam with both T2 weighted, FLAIR and pre- and post-gadolinium contrast enhanced T1 weighted imaging. The addition of diffusion and perfusion weighted MR imaging can assist in the assessment of suspected GBM for the purposes of distinguishing GBM from other tumor types. Computed tomography (CT) can provide additional information regarding calcification or hemorrhage and also can be useful for subjects who are unable to undergo MR imaging. 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 imaging) to anatomic imaging Level II: One blinded prospective study and a significant number of case series support the addition of diffusion and perfusion weighted MR imaging in the assessment of suspected GBM, for the purposes of distinguishing GBM from other tumor types (e.g., primary CNS lymphoma or metastases). Level III: It is suggested that magnetic resonance spectroscopy (MRS) and nuclear medicine imaging (PET 18F-FDG and 11C-MET) be used to provide additional support for the diagnosis of GBM.

Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: a meta-analysis.

Carmustine wafers (CW; Gliadel(®) wafers) are approved to treat newly-diagnosed high-grade glioma (HGG) and recurrent glioblastoma. Widespread use has been limited for several reasons, including concern that their use may preclude enrollment in subsequent clinical trials due to uncertainty about confounding of results and potential toxicities. This meta-analysis estimated survival following treatment with CW for HGG. A literature search identified relevant studies. Overall survival (OS), median survival, and adverse events (AEs) were summarized. Analysis of variance evaluated effects of treatment (CW vs non-CW) and diagnosis (new vs recurrent) on median survival. The analysis included 62 publications, which reported data for 60 studies (CW: n = 3,162; non-CW: n = 1,736). For newly-diagnosed HGG, 1-year OS was 67 % with CW and 48 % without; 2-year OS was 26 and 15 %, respectively; median survival was 16.4 ± 21.6 months and 13.1 ± 29.9 months, respectively. For recurrent HGG, 1-year OS was 37 % with CW and 34 % without; 2-year OS was 15 and 12 %, respectively; median survival was 9.7 ± 20.9 months and 8.6 ± 22.6 months, respectively. Effects of treatment (longer median survival with CW than without; P = 0.043) and diagnosis (longer median survival for newly-diagnosed HGG than recurrent; P < 0.001) on median survival were significant, with no significant treatment-by-diagnosis interaction (P = 0.620). The most common AE associated with wafer removal was surgical site infection (SSI); the most common AEs for repeat surgery were mass effect, SSI, hydrocephalus, cysts in resection cavity, acute hematoma, wound healing complications, and brain necrosis. These data may be useful in the context of utilizing CW in HGG management, and in designing future clinical trials to allow CW-treated patients to participate in experimental protocols.

The role of initial chemotherapy for the treatment of adults with diffuse low grade glioma : A systematic review and evidence-based clinical practice guideline.

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.

The role of radiotherapy in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

QUESTIONS: (1) What is the optimal role of external beam radiotherapy in the management of adult patients with newly diagnosed low-grade glioma (LGG) in terms of improving outcome (i.e., survival, complications, seizure control or other reported outcomes of interest)? (2) Which radiation strategies (dose, timing, fractionation, stereotactic radiation, brachytherapy, chemotherapy) improve outcomes compared to standard external beam radiation therapy in the initial management of low grade gliomas in adults? (3) Do specific factors (e.g., age, volume, extent of resection, genetic subtype) identify subgroups with better outcomes following radiation therapy than the general population of adults with newly diagnosed low-grade gliomas? TARGET POPULATION: These recommendations apply to adults with newly diagnosed diffuse LGG. RECOMMENDATIONS: OUTCOMES IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level I Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong progression free survival, irrespective of extent of resection. Level II Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults as an equivalent alternative to observation in preserving cognitive function, irrespective of extent of resection. Level III Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults to improve seizure control in patients with epilepsy and subtotal resection. Level III Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong overall survival in patients with subtotal resection. Level III Consideration of the risk of radiation induced morbidity, including cognitive decline, imaging abnormalities, metabolic dysfunction and malignant transformation, is recommended when the delivery of radiotherapy is selected in the management of newly diagnosed low-grade glioma in adults. STRATEGIES OF RADIOTHERAPY IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA: Level I Lower dose radiotherapy is recommended as an equivalent alternative to higher dose immediate postoperative radiotherapy (45-50.4 vs. 59.4-64.8 Gy) in the management of newly diagnosed low-grade glioma in adults with reduced toxicity. Level III Delaying radiotherapy until recurrence or progression is recommended as an equivalent alternative to immediate postoperative radiotherapy in the management of newly diagnosed low-grade glioma in adults but may result in shorter time to progression. Level III The addition of chemotherapy to radiotherapy is not recommended over whole brain radiotherapy alone in the management of low-grade glioma, as it provides no additional survival benefit. Level III Limited-field radiotherapy is recommended over whole brain radiotherapy in the management of low-grade glioma. Level III Either stereotactic radiosurgery or brachytherapy are recommended as acceptable alternatives to external radiotherapy in selected patients. PROGNOSTIC FACTORS IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level II It is recommended that age greater than 40 years, astrocytic pathology, diameter greater than 6 cm, tumor crossing the midline and preoperative neurological deficit be considered as negative prognostic indicators when predicting overall survival in adult low grade glioma patients treated with radiotherapy. Level II It is recommended that smaller tumor size, extent of surgical resection and higher mini-mental status exam be considered as positive prognostic indicators when predicting overall survival and progression free survival in patients in adult low grade glioma patients treated with radiotherapy. Level III It is recommended that seizures at presentation, presence of oligodendroglial histological component and 1p19q deletion (along with additional relevant factors-see Table 1) be considered as positive prognostic indicators when predicting response to radiotherapy in adults with low grade gliomas. Level III It is recommended that increasing age, decreasing performance status, decreasing cognition, presence of astrocytic histological component (along with additional relevant factors (see Tables 1, 2) be considered as negative prognostic indicators when predicting response to radiotherapy.

The role of biopsy in the management of patients with presumed diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

QUESTION: What is the optimal role of biopsy in the initial management of presumptive low-grade glioma in adults? TARGET POPULATION: Adult patients with imaging suggestive of a low-grade glioma. LEVEL III: Stereotactic biopsy is recommended when definitive surgical resection is limited by lesions that are deep-seated, not resectable, and/or located within eloquent cortex, or in patients unable to undergo craniotomy due to medical co-morbidities to obtain the critical tissue diagnosis needed for targeted treatment planning for patients with low-grade gliomas. QUESTION: What is the best technique for brain biopsy? TARGET POPULATION: Adult patients with imaging suggestive of a low-grade glioma. LEVEL III: Frameless and frame-based stereotactic brain biopsy for low-grade gliomas are recommended based on clinical circumstances as they provide similar diagnostic yield, diagnostic accuracy, morbidity, and mortality. It is recommended the surgeon consider advanced imaging techniques (e.g., perfusion, spectroscopy, metabolic studies) to target specific regions of interest to potentially improve diagnostic accuracy.

The role of emerging therapy in the management of patients with diffuse low grade glioma.

QUESTION: What is the role of immunotherapy/tumor vaccines in the treatment of low grade gliomas? TARGET POPULATION: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. RECOMMENDATIONS: There is no evidence to support a recommendation in regards to the efficacy of immunotherapy or tumor vaccines for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess immunotherapies and tumor vaccines for low grade gliomas. QUESTION: What is the role of nutrition in the treatment of low grade gliomas? TARGET POPULATION: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. RECOMMENDATIONS: There was no evidence to support a recommendation in regard to the efficacy of nutritional therapy for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the efficacy of nutrition for this target population. QUESTION: Is there a role for alternative or targeted therapies in the treatment of low grade gliomas? TARGET POPULATION: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. RECOMMENDATION: There was no evidence to support a recommendation in regard to the efficacy of targeted or alternative agents for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess alternative and targeted therapies for this target population.

The role of imaging in the management of adults with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

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.

The role of surgery in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

QUESTION: Should patients with imaging suggestive of low grade glioma (LGG) undergo observation versus treatment involving a surgical procedure? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: Surgical resection is recommended over observation to improve overall survival for patients with diffuse low-grade glioma (Level III) although observation has no negative impact on cognitive performance and quality of life (Level II). QUESTION: What is the impact of extent of resection on progression free survival (PFS) or overall survival (OS) in LGG patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: IMPACT OF EXTENT OF RESECTION ON PFS: LEVEL II: It is recommended that GTR or STR be accomplished instead of biopsy alone when safe and feasible so as to decrease the frequency of tumor progression recognizing that the rate of progression after GTR is fairly high. LEVEL III: Greater extent of resection can improve OS in LGG patients. QUESTION: What tools are available to increase extent of resection in LGG patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: INTRAOPERATIVE MRI DURING SURGERY: LEVEL III: The use of intraoperative MRI should be considered as a method of increasing the extent of resection of LGGs. QUESTION: What is the impact of surgical resection on seizure control and accuracy of pathology in low grade glioma patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: SURGICAL RESECTION AND SEIZURE CONTROL: LEVEL III: After taking into account the patient's clinical status and tumor location, gross total resection is recommended for patients with diffuse LGG as a way to achieve more favorable seizure control. LEVEL III: Taking into account the patient's clinical status and tumor location, surgical resection should be carried out to maximize the chance of accurate diagnosis. QUESTION: What tools can improve the safety of surgery for LGGs in eloquent locations? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: PREOPERATIVE IMAGING: LEVEL III: It is recommended that preoperative functional MRI and diffusion tensor imaging be utilized in the appropriate clinical setting to improve functional outcome after surgery for LGG. LEVEL III: Intraoperative mapping is recommended for patients with diffuse LGGs in eloquent locations compared to patients with non-eloquently located diffuse LGGs as a way of preserving function.

The role of neuropathology in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

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.

Management of patients with recurrence of diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

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.

The role of neuropathology in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline.

QUESTION: 1. What are the most important diagnostic considerations in reporting progressive glioblastoma? TARGET POPULATION: These recommendations apply to adults with progressive glioblastoma LEVEL III: For patients who undergo biopsy or neurosurgical resection at the time of radiologic or clinical progression, it is recommended that the pathologist report the presence and extent of progressive neoplasm as well as the presence and extent of necrosis within the pathologic material examined. Furthermore, to ensure the proper interpretation of progressive glioblastoma, it is recommended that the pathologist take into account the patient's previous diagnosis and treatment, as well as the current clinical and neuroimaging features that have led to a second biopsy or resection. QUESTION: 2. What techniques and ancillary studies are most useful in separating malignant progression from treatment effect? TARGET POPULATION: These recommendations apply to adults with progressive glioblastoma LEVEL III: In the setting of prior radiation and chemotherapy, it is recommended to adhere to strict histologic criteria for microvascular proliferation and necrosis in order to establish a diagnosis of a glioblastoma. Immunohistochemistry and genetic studies are selectively recommended for distinguishing neoplastic cells from atypical reactive cells in progressive glioblastoma.

The role of cytoreductive surgery in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline.

QUESTION: Should patients with previously diagnosed malignant glioma who are suspected of experiencing progression of the neoplasm process undergo repeat open surgical resection? TARGET POPULATION: These recommendations apply to adults with previously diagnosed malignant glioma who are suspected of experiencing progression of the neoplastic process and are amenable to surgical resection. RECOMMENDATIONS LEVEL II: Repeat cytoreductive surgery is recommended in symptomatic patients with locally recurrent or progressive malignant glioma. The median survival in these patient diagnosed with glioblastoma is expected to range from 6 to 17 months following a second procedure. It is recommended that the following preoperative factors be considered when evaluating a patient for repeat operation: location of recurrence in eloquent/critical brain regions, Karnofsky Performance Status and tumor volume.

The role of radiotherapy in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline.

QUESTION: Can re-irradiation (by using conventional radiotherapy, fractionated radiosurgery, or single fraction radiosurgery) be used in patients with progressive glioblastoma multiforme after the first adjuvant combined multimodality treatment with radiation and chemotherapy? TARGET POPULATION: These recommendations apply to adult patients with progressive glioblastoma after first line combined multimodality treatment with chemotherapy and radiation. RECOMMENDATIONS LEVEL III: When the target tumor is amenable for additional radiation, re-irradiation is recommended as it provides improved local tumor control, as measured by best imaging response. Such re-irradiation can take the form of conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery. LEVEL III: Re-irradiation is recommended in order to maintain or improve a patient's neurological status and quality of life prior to any further tumor progression.

The role of targeted therapies in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline.

QUESTION: What is the influence of targeted medical therapies on disease control and survival in the adult patient with progressive glioblastoma? TARGETED POPULATION: This recommendation applies to adult patients with progressive glioblastoma RECOMMENDATIONS: Level III Treatment with bevacizumab is recommended as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months. Given that there are a large number of therapies are available for progressive glioblastoma that may be applied under selected circumstances dependent on patient characteristics and treating physician judgment, it is strongly recommended that patients with progressive glioblastoma be enrolled in properly designed clinical investigations to provide convincing evidence of therapeutic value.

The role of imaging in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline.

QUESTION: Which imaging techniques most accurately differentiate true tumor progression from pseudo-progression or treatment related changes in patients with previously diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adults with previously diagnosed glioblastoma who are suspected of experiencing progression of the neoplastic process. RECOMMENDATIONS LEVEL II: Magnetic resonance imaging with and without gadolinium enhancement is recommended as the imaging surveillance method to detect the progression of previously diagnosed glioblastoma. LEVEL II: Magnetic resonance spectroscopy is recommended as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma. LEVEL III: The routine use of positron emission tomography to identify progression of glioblastoma is not recommended. LEVEL III: Single-photon emission computed tomography imaging is recommended as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma.

Establishing a Gold Standard for Noninvasive Identification of Painful Lumbar Discs: Prospective Comparison of Magnetic Resonance Spectroscopy vs Low-Pressure Provocation Discography.

PURPOSE: Verifying lumbar disc pain can present a clinical challenge. Low-pressure provocative discography (PD) has served as the gold standard, although it is invasive and often a challenge to interpret. We reported that magnetic resonance spectroscopy (MRS) biomarkers accurately predict PD results in lumbar discs and improved outcomes for patients with surgery at positive MRS levels versus nonsurgery. To further substantiate MRS for diagnosing painful discs, we report a prospective comparison of 2 MRS-derived measures: NOCISCORE (pain) and SI-SCORE (degeneration severity). METHODS: Lumbar MRS and software-based postprocessing (NOCISCAN-LS, Aclarion Inc.) was performed in 44 discs in 14 patients (prospective cohort [PC]). PC data were compared to prior data used to establish the NOCISCORE (training cohort [TC]). The NOCISCORE was converted to an ordinal value (high/intermediate/low; NOCI+/mild/-) and compared against painful (P) versus nonpainful (NP) control diagnosis (PD) for 19 discs where PD was performed in the PC (12 NP; 7 P). Sensitivity, specificity, and positive and negative predictive values were calculated. The SI-SCORE was compared against MRI Pfirrmann Grades for 465 discs in 126 patients (PC plus TC). RESULTS: For the PC, MRS (NOCI+/-) compared to PD (P/NP) with an accuracy of 87% and sensitivity and specificity of 100%. The positive and negative predictive values of MRS were 100%. NOCISCOREs were significantly higher for PD+ versus PD- discs for PC and TC (P < 0.05), and the NOCISCORE distributions for PD+/- group were not statistically different between the PC and TC (P > 0.05). SI-SCORES differed between Pfirrmann Grades 1 and 2 (less degenerated) versus Grades 3 and 4 (more degenerated; P < 0.05), with a progressively decreasing trend with Pfirrmann Grades 1-5. CONCLUSION: These current data provide prospective confirmation of the predictive value of disc MRS for distinguishing painful discs and for assessing the disc structural integrity. CLINICAL RELEVANCE: NOCISCAN is an adoptable, noninvasive, and objectively quantitative test to improve management of low back pain patients.