Management of low-grade glioma: a systematic review and meta-analysis

Abstract Background Optimum management of low-grade gliomas remains controversial, and widespread practice variation exists. This evidence-based meta-analysis evaluates the association of extent of resection, radiation, and chemotherapy with mortality and progression-free survival at 2, 5, and 10 years in patients with low-grade glioma. Methods A quantitative systematic review was performed. Inclusion criteria included controlled trials of newly diagnosed low-grade (World Health Organization Grades I and II) gliomas in adults. Eligible studies were identified, assigned a level of evidence for every endpoint considered, and analyzed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relative risk of mortality and of progression at 2, 5, and 10 years was calculated for patients undergoing resection (gross total, subtotal, or biopsy), radiation, or chemotherapy. Results Gross total resection was significantly associated with decreased mortality and likelihood of progression at all time points compared to subtotal resection. Early radiation was not associated with decreased mortality; however, progression-free survival was better at 5 years compared to patients receiving delayed or no radiation. Chemotherapy was associated with decreased mortality at 5 and 10 years in the high-quality literature. Progression-free survival was better at 5 and 10 years compared to patients who did not receive chemotherapy. In patients with isocitrate dehydrogenase 1 gene (IDH1) R132H mutations receiving chemotherapy, progression-free survival was better at 2 and 5 years than in patients with IDH1 wild-type gliomas. Conclusions Results from this review, the first to quantify differences in outcome associated with surgery, radiation, and chemotherapy in patients with low-grade gliomas, can be used to inform evidence-based management and future clinical trials.

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Association of aggressive resection with survival and progression-free survival in adult low-grade glioma: A systematic review and meta-analysis with numbers needed to treat.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2025 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2025-2025 ◽

Cited By ~ 1

Author(s):

Timothy J Brown ◽

Daniela Annenelie Bota ◽

Elizabeth A. Maher ◽

Dawit Gebremichael Aregawi ◽

Linda M. Liau ◽

...

Keyword(s):

Systematic Review ◽

Prospective Studies ◽

Meta Analysis ◽

Progression Free Survival ◽

Extent Of Resection ◽

The Body ◽

Subtotal Resection ◽

Low Grade ◽

Free Survival ◽

Numbers Needed To Treat

2025 Background: Low-grade gliomas (LGG) account for 17-22% of all primary brain tumors. Optimal surgical management consists of optimum safe resection with the goal of complete resection. We performed a systematic review and meta-analysis to quantify the association of extent of resection with likelihood of survival, expressing our results in numbers needed to treat (NNT). Methods: A systematic review and study-level meta-analysis to determine the association of resection with overall survival and progression-free survival in newly diagnosed, supratentorial LGG in adults was performed by querying PubMed. Data were extracted to compare gross total resection (GTR) to subtotal resection (STR) and STR to biopsy (Bx) to determine relative risks (RR) of death and progression at 2, 5, and 10 years. Data were analyzed using a random effects model. NNT were calculated from significant comparisons and rounded up to the nearest whole number. Quality of evidence was determined by American Academy of Neurology criteria. Results: The systematic review resulted in 283 potential studies. Ultimately 29 studies were included in at least one comparison. There were no high quality (class I and II) or prospective studies discovered in the review. Comparing GTR to STR, RR with 95% confidence intervals (CI) of death at 2, 5, and 10 years, and NNT to avoid one death at 2, 5, and 10 years (GTR vs. STR) were 0.29 [0.17-0.52, p < 0.0001, NNT 17], 0.39 [0.29-0.51, p < 0.00001, NNT 6], and 0.50 [0.35-0.70, p < 0.0001 NNT 4]. RR and NNT for progression (GTR vs. STR) at 2, 5, and 10 years were 0.37 [0.24-0.57, p < 0.0001 NNT 7], 0.50 [0.39-0.64, p < 0.0001 NNT 4], and 0.67 [0.53-0.84, p = 0.0005 NNT 4]. Comparing STR to Bx, RR of death at 2, 5, and 10 years were 0.55 [0.34-0.88, p = 0.01 NNT 10], 0.9 [0.61-1.34], and 0.95 [0.73-1.23]. Conclusions: Increasing resection thresholds appear to be associated with improved overall and progression free survival, but the body of literature consists of low quality studies. Prospective studies are required to explore whether extent of resection matters or whether resectable tumors share a favorable biology associated with better outcome.

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P.033 Biopsy versus subtotal versus gross total resection in patients with low-grade glioma: a systematic review and meta-analysis

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.135 ◽

2018 ◽

Vol 45 (s2) ◽

pp. S24-S24

Author(s):

K Yang ◽

S Nath ◽

A Koziarz ◽

M Sourour ◽

D Catana ◽

...

Keyword(s):

Malignant Transformation ◽

Seizure Control ◽

Meta Analysis ◽

Postoperative Mortality ◽

Progression Free Survival ◽

Low Grade Glioma ◽

Cochrane Library ◽

Low Grade ◽

Free Survival ◽

The Cochrane Library

Background: The role of extent of surgical resection (EOR) on clinical outcomes in patients with low-grade glioma requires further examination. Methods: We systematically searched MEDLINE, Embase, and the Cochrane Library for studies published between January 1, 1990 and January 5, 2018 on predefined patient outcomes regarding different EOR of low-grade glioma. Results: Our literature search yielded 60 studies including 13,289 patients. Pooled estimates of overall survival showed an increase from 3.79 years (95% CI, 2.37–5.22) in the biopsy group to 6.68 years (95% CI, 4.19–9.16) in STR to 10.65 years (95% CI, 6.78–14.52) in GTR. When compared to STR, GTR prolonged progression-free survival by 2.08 years (95% CI, 0.26–3.89; P=0.025). Pooled estimates of seizure control showed an improvement from 47.8% (95% CI, 26.7–69.6) with biopsy to 54.2% (95% CI, 48.7–59.6) with STR to 81.0% (95% CI, 74.6–86.2) with GTR. Compared to STR, GTR delayed malignant transformation (RR, 0.43; 95% CI, 0.20–0.93; P=0.032), without increasing postoperative mortality (RR, 0.38; 95% CI, 0.07–1.97; P=0.250) or morbidity (RR, 1.22; 95% CI, 0.65–2.28; P=0.540). Conclusions: Among patients with low grade gliomas, higher degrees of safe EOR, were associated with longer overall and progression-free survival, better seizure control, and delayed malignant transformation, without increased mortality or morbidity.

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Randomized Trial of Radiation Therapy Plus Procarbazine, Lomustine, and Vincristine Chemotherapy for Supratentorial Adult Low-Grade Glioma: Initial Results of RTOG 9802

Journal of Clinical Oncology ◽

10.1200/jco.2011.35.8598 ◽

2012 ◽

Vol 30 (25) ◽

pp. 3065-3070 ◽

Cited By ~ 194

Author(s):

Edward G. Shaw ◽

Meihua Wang ◽

Stephen W. Coons ◽

David G. Brachman ◽

Jan C. Buckner ◽

...

Keyword(s):

Radiation Therapy ◽

Radiation Therapy Oncology Group ◽

Progression Free Survival ◽

Low Grade Glioma ◽

Subtotal Resection ◽

Low Grade ◽

Eligibility Criteria ◽

Who Grade ◽

Free Survival ◽

Post Hoc

PurposeA prior Radiation Therapy Oncology Group (RTOG) clinical trial in anaplastic oligodendroglioma suggested a progression-free survival benefit for procarbazine, lomustine, and vincristine (PCV) chemotherapy in addition to radiation therapy (RT), as have smaller trials in low-grade glioma (LGG).Patients and MethodsEligibility criteria included supratentorial WHO grade 2 LGG, age 18 to 39 years with subtotal resection/biopsy, or age ≥ 40 years with any extent resection. Patients were randomly assigned to RT alone or RT followed by six cycles of PCV. Survival was compared by using the modified Wilcoxon and log-rank tests.ResultsIn all, 251 patients were accrued from 1998 to 2002. Median overall survival (OS) time and 5-year OS rates for RT versus RT + PCV were 7.5 years versus not reached and 63% versus 72%, respectively (hazard ratio [HR]; 0.72; 95% CI, 0.47 to 1.10; P = .33; log-rank P = .13). Median progression-free survival (PFS) time and 5-year PFS rates for RT versus RT + PCV were 4.4 years versus not reached and 46% versus 63%, respectively (HR, 0.6; 95% CI, 0.41 to 0.86; P = .06; log-rank P = .005). OS and PFS were similar for all patients between years 0 and 2. After 2 years, OS and PFS curves separated significantly, favoring RT + PCV. For 2-year survivors (n = 211), the probability of OS for an additional 5 years was 74% with RT + PCV versus 59% with RT alone (HR, 0.52; 95% CI, 0.30 to 0.90; log-rank P = .02).ConclusionPFS but not OS was improved for adult patients with LGG receiving RT + PCV versus RT alone. On post hoc analysis, for 2-year survivors, the addition of PCV to RT conferred a survival advantage, suggesting a delayed benefit for chemotherapy.

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Radiotherapy versus radiotherapy combined with temozolomide in high-risk low-grade gliomas after surgery:Study protocol for a randomized controlled clinical trial

10.21203/rs.2.509/v2 ◽

2019 ◽

Author(s):

Jingjing Wang ◽

Ying Wang ◽

Yan He ◽

Hui Guan ◽

Ling He ◽

...

Keyword(s):

Radiation Therapy ◽

High Risk ◽

Progression Free Survival ◽

Controlled Clinical Trial ◽

Subtotal Resection ◽

Low Grade ◽

Who Grade ◽

Free Survival ◽

Low Grade Gliomas ◽

Randomized Controlled

Abstract Background It has been reported that radiation therapy followed by PCV chemotherapy (procarbazine, lomustine and vincristine) could improve progression-free survival (PFS) and overall survival (OS) in patients with high-risk WHO grade 2 gliomas after surgery. However, procarbazine is not available in China. In clinical practice, Chinese doctors often use radiotherapy combined with temozolomide to treat these patients, though large-scale prospective studies are lacking. This trial aims to confirm whether RT combined with temozolomide (TMZ) can improve PFS and OS in patients with high-risk low-grade gliomas (LGGs). Methods/design This is a two-group, randomized controlled trial (RCT) enrolling patients who have low-grade (WHO grade 2) gliomas aged 40 years or older without regard to the extent of resection or younger than 40 years old with subtotal resection or biopsy. An estimated 250 patients will be enrolled. Eligible participants will be randomly assigned to receive radiation therapy (RT) alone or RT plus temozolomide chemotherapy in a 1:1 ratio. The same RT will be given to all eligible participants regardless of whether they are randomly assigned to RT group or chemoradiotherapy (CRT) group. While in the CRT group, patients will receive adjuvant TMZ with or without concurrent radiochemotherapy. The primary outcome of this trial is progression-free survival and it will be analyzed by intention-to-treat (ITT). Secondary outcomes include OS, adverse events and cognitive function (CF). Discussion The objective of our research is to assess the effect of radiotherapy coupled with temozolomide in high-risk LGGs after surgery, compared with RT alone. Different histological types and molecular subtypes will be examined and subgroup analysis will be conducted based on them. Our data can provide evidence for postoperative adjuvant therapy in Chinese high-risk LGGs.

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Does the routine use of intraoperative MRI prolong progression free survival in low-grade glioma surgery? A retrospective study

Innovative Neurosurgery ◽

10.1515/ins-2015-0003 ◽

2015 ◽

Vol 3 (3-4) ◽

Cited By ~ 1

Author(s):

Andrej Pala ◽

Ralph König ◽

Michal Hlavac ◽

Christian Rainer Wirtz ◽

Jan Coburger

Keyword(s):

Retrospective Study ◽

Prognostic Factor ◽

Cox Regression ◽

Progression Free Survival ◽

Extent Of Resection ◽

Low Grade Glioma ◽

World Health ◽

Low Grade ◽

Free Survival ◽

Historical Group

AbstractAvailable data imply that extent of resection (EOR) improves progression free survival (PFS) in patients harboring a low-grade glioma (LGG). Intraoperative high-field magnetic resonance imaging (iMRI) is an established diagnostic tool that can detect residual tumors in LGG surgery. We conducted a retrospective study to evaluate the extent of resection, clinical outcome and PFS in conventional and iMRI-based LGG resection.A total of 69 patients was assessed. Only World Health Organization (WHO) grade II LGGs were evaluated. Thirty-three patients had surgery using iMRI (2008–2013). Thirty-six patients underwent surgery before introduction of iMRI at our center (2000–2008). Demographic data, extent of resection (EOR), complication rate, overall time of surgery and progression free survival were evaluated.The majority of patients were treated for a diffuse astrocytoma in both cohorts (iMRI: 46.9%, historical (hist.): 61.1%). Extent of resection was a positive prognostic factor for longer PFS according to Cox regression multivariate analysis controlled by eloquent location, tumor recurrence and histological subtype [P<0.001, hazard ratio (HR) 0.247]. Additionally, the Cox regression showed the advantage and longer PFS of iMRI-assisted resections using the same settings (P=0.038, HR=0.378). Permanent neurological deficits (PND) after surgery were found in 12.5% (n=4) of the iMRI group and in 22.2% (n=8) of the historical group. Duration of surgery was significantly higher in the iMRI group (iMRI: 6.3 h, hist.: 4.3 h, P<0.036). However, there was no significant increase of postoperative surgical complications. Gross total resection (GTR) was achieved in 63.6% (n=21) of iMRI patients and 27.8% (n=10, P<0.0069) in the historical control, respectively. Binary logistic regression showed that iMRI has a significant impact on tumor remnants (P<0.001).In our study we have confirmed EOR to be an important positive prognostic factor for PFS. At our center, compared to a historical group, the routine use of iMRI increases EOR and was associated with a decrease in complications. Due to a selection bias no final conclusion can be drawn as to whether the use of iMRI increases PFS.

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A survival analysis of surgically treated incidental low-grade glioma patients

Scientific Reports ◽

10.1038/s41598-021-88023-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lingcheng Zeng ◽

Qi Mei ◽

Hua Li ◽

Changshu Ke ◽

Jiasheng Yu ◽

...

Keyword(s):

Progression Free Survival ◽

Low Grade Glioma ◽

Low Grade ◽

Total Resection ◽

Surgical Timing ◽

Asymptomatic Group ◽

Free Survival ◽

Symptomatic Group ◽

Significant Difference ◽

Asymptomatic Phase

AbstractTo evaluate the surgical effect on survival in patients with incidental low-grade glioma (LGG) through comparison between asymptomatic and symptomatic patients. The medical records of surgically treated adult cerebral incidental LGG (iLGG) patients in our department between January 2008 and December 2015 were retrospectively reviewed. The survival of patients was calculated starting from the initial imaging diagnosis. Factors related to progression-free survival (PFS), overall survival (OS) and malignant progression-free survival (MPFS) were statistically analyzed. Seventy-five iLGG patients underwent surgery: 49 in the asymptomatic group, who underwent surgery in the asymptomatic period, and 26 in the symptomatic group, who underwent surgery after the tumor had grown and the patients had developed tumor-related symptoms. Significantly more tumors were initially located adjacent to the functional area in the symptomatic group than in the asymptomatic group (P < 0.05), but there was no significant difference in the total resection rate between the two groups. The incidence of postoperative complications (15.4%) and postoperative epilepsy (23.1%) was higher in the symptomatic group than in the asymptomatic group (4.1% and 10.2%, respectively). Multivariate analysis showed that surgical timing, namely, surgery performed before or after symptom occurrence, had no significant effect on PFS, OS or MPFS, while total resection significantly prolonged PFS, OS and MPFS, and the pathology of oligodendroglioma was positively correlated with PFS and OS (P < 0.05). Surgical timing for iLGGs should facilitate total resection. If total resection can be achieved, even after symptom occurrence, patients can achieve comparable survival benefits to those treated with surgery in the asymptomatic phase.

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P04.16 TP53 mutations in codon 273 is predictive of overall survival in astrocytoma patients

Neuro-Oncology ◽

10.1093/neuonc/noz126.111 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii32-iii32

Author(s):

H Noor ◽

R Rapkins ◽

K McDonald

Keyword(s):

Overall Survival ◽

Tp53 Mutation ◽

Progression Free Survival ◽

Low Grade Glioma ◽

Low Grade ◽

Wild Type ◽

Mutation Status ◽

Free Survival ◽

Tp53 Mutations ◽

Fresh Frozen

Abstract BACKGROUND Tumour Protein 53 (TP53) is a tumour suppressor gene that is mutated in at least 50% of human malignancies. The prevalence of TP53 mutation is much higher in astrocytomas with reports of up to 75% TP53 mutant cases. Rare cases of TP53 mutation also exist in oligodendroglial tumours (10–13%). P53 pathway is therefore an important factor in low-grade glioma tumorigenesis. Although the prognostic impact of TP53 mutations has been studied previously, no concrete concordance were reached between the studies. In this study, we investigated the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. MATERIAL AND METHODS A cohort of 65 matched primary and recurrent fresh frozen tumours were sequenced to identify hotspot exons of TP53 mutation. Exons 1 to 10 were sequenced and pathogenic mutations were mostly predominant between Exons 4 and 8. The cohort was further expanded with 78 low grade glioma fresh frozen tissues and hotspot exons were sequenced. Selecting only the primary tumour from 65 matched tumours, a total of 50 Astrocytoma cases and 51 oligodendroglioma cases were analysed for prognostic effects of TP53. Only pathogenic TP53 mutations confirmed through COSMIC and NCBI databases were included in the over survival and progression-free survival analysis. RESULTS 62% (31/50) of astrocytomas and 16% (8/51) of oligodendrogliomas harboured pathogenic TP53 mutations. Pathogenic hotspot mutations in codon 273 (c.817 C>T and c.818 G>A) was prevalent in astrocytoma with 58% (18/31) of tumours with these mutations. TP53 mutation status was maintained between primary and recurrent tumours in 93% of cases. In astrocytoma, overall survival of TP53 mutant patients was longer compared to TP53 wild-type patients (p<0.01) but was not significant after adjusting for age, gender, grade and IDH1 mutation status. In contrast, astrocytoma patients with specific TP53 mutation in codon 273 showed significantly better survival compared to other TP53 mutant and TP53 wild-type patients combined (p<0.01) in our multivariate analysis. Time to first recurrence (progression-free survival) of TP53 mutant patients was significantly longer than TP53 wild-type patients (p<0.01) after adjustments were made, while TP53 mutation in codon 273 was not prognostic for progression-free survival. In oligodendroglioma patients, TP53 mutations did not significantly affect overall survival and progression-free survival. CONCLUSION In agreement with others, TP53 mutation is more prevalent in Astrocytoma and mutations in codon 273 are significantly associated with longer survival.

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Low-grade astrocytoma: surgical outcomes in eloquent versus non-eloquent brain areas

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2012005000017 ◽

2013 ◽

Vol 71 (1) ◽

pp. 31-34 ◽

Cited By ~ 7

Author(s):

André de Macedo Bianco ◽

Flavio Key Miura ◽

Carlos Clara ◽

Jose Reynaldo W. Almeida ◽

Clemar Correa da Silva ◽

...

Keyword(s):

Overall Survival ◽

Tumor Resection ◽

Progression Free Survival ◽

Subtotal Resection ◽

Low Grade ◽

Brain Areas ◽

Free Survival ◽

Eloquent Areas ◽

Eloquent Area ◽

Extent Of Surgical Resection

A retrospective study of 81 patients with low-grade astrocytoma (LGA) comparing the efficacy of aggressive versus less aggressive surgery in eloquent and non-eloquent brain areas was conducted. Extent of surgical resection was analyzed to assess overall survival (OS) and progression- free survival (PFS). Degree of tumor resection was classified as gross total resection (GTR), subtotal resection (STR) or biopsy. GTR, STR and biopsy in patients with tumors in non-eloquent areas were performed in 31, 48 and 21% subjects, whereas in patients with tumors in eloquent areas resections were 22.5, 35 and 42.5%. Overall survival was 4.7 and 1.9 years in patients with tumors in non-eloquent brain areas submitted to GTR/STR and biopsy (p=0.013), whereas overall survival among patients with tumors in eloquent area was 4.5 and 2.1 years (p=0.33). Improved outcome for adult patients with LGA is predicted by more aggressive surgery in both eloquent and non-eloquent brain areas.

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Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas

Neurosurgical FOCUS ◽

10.3171/foc.1997.2.3.1 ◽

1997 ◽

Vol 2 (3) ◽

pp. E1

Author(s):

Roger J. Packer ◽

Joanne Ater ◽

Jeffrey Allen ◽

Peter Phillips ◽

Russell Geyer ◽

...

Keyword(s):

Objective Response ◽

Survival Rates ◽

Progression Free Survival ◽

Response To Treatment ◽

Low Grade ◽

Significant Prognostic Factor ◽

Newly Diagnosed ◽

Free Survival ◽

Low Grade Gliomas ◽

Response To Chemotherapy

The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided. There has been increased interest in the use of chemotherapy for young children, but little information concerning the long-term efficacy of such treatment. Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed, progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy. The patients were followed for a median of 30 months from diagnosis, with 31 patients followed for more than 3 years. Fifty-eight children had diencephalic tumors, 12 had brainstem gliomas, and three had diffuse leptomeningeal gliomas. Forty-four (56%) of 78 patients showed an objective response to treatment. Progression-free survival rates were 75 ± 6% at 2 years and 68 ± 7% at 3 years. There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year, progression-free survival 79 ± 11% vs. 75 ± 6%, respectively). The histological subtype of the tumor, its location, and its maximum response to chemotherapy did not have an impact on the duration of disease control. The only significant prognostic factor was age: children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 ± 7% compared with a rate of 39 ± 21% in older children (p < 0.01). Treatment with carboplatin and vincristine is effective, especially in younger children, in controlling newly diagnosed progressive low-grade gliomas.

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