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Neuropathology and Applied Neurobiology Jun 2022Codeletion of chromosomal arms 1p and 19q, in conjunction with a mutation in the isocitrate dehydrogenase 1 or 2 gene, is the molecular diagnostic criterion for... (Meta-Analysis)
Meta-Analysis Review
Codeletion of chromosomal arms 1p and 19q, in conjunction with a mutation in the isocitrate dehydrogenase 1 or 2 gene, is the molecular diagnostic criterion for oligodendroglioma, IDH mutant and 1p/19q codeleted. 1p/19q codeletion is a diagnostic marker and allows prognostication and prediction of the best drug response within IDH-mutant tumours. We performed a Cochrane review and simple economic analysis to establish the most sensitive, specific and cost-effective techniques for determining 1p/19q codeletion status. Fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) test methods were considered as reference standard. Most techniques (FISH, chromogenic in situ hybridisation [CISH], PCR, real-time PCR, multiplex ligation-dependent probe amplification [MLPA], single nucleotide polymorphism [SNP] array, comparative genomic hybridisation [CGH], array CGH, next-generation sequencing [NGS], mass spectrometry and NanoString) showed good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma, irrespective of whether FISH or PCR-based LOH was used as the reference standard. Both NGS and SNP array had a high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. Our findings suggest that G banding is not a suitable test for 1p/19q analysis. Within these limits, considering cost per diagnosis and using FISH as a reference, MLPA was marginally more cost-effective than other tests, although these economic analyses were limited by the range of available parameters, time horizon and data from multiple healthcare organisations.
Topics: Brain Neoplasms; Chromosome Aberrations; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; Oligodendroglioma
PubMed: 34958131
DOI: 10.1111/nan.12790 -
World Journal of Transplantation Jun 2022Patients with a history of primary brain tumors can be eligible for organ donation under extended criteria. The risk assessment of tumor transmission organ transplant...
BACKGROUND
Patients with a history of primary brain tumors can be eligible for organ donation under extended criteria. The risk assessment of tumor transmission organ transplant in primary brain tumors is primarily based on the assessment of tumor histotype and grade. Previous surgeries, chemo-/radiotherapy, and ventriculo-peritoneal shunt placement can lead to a disruption of the blood-brain barrier, concurring to an increase in the transmission risk.
AIM
To investigate the role of tumor transmission risk factors in donors with oligodendrogliomas and astrocytomas.
METHODS
We searched PubMed and EMBASE databases for studies reporting extraneural spreading of oligodendrogliomas and astrocytomas and extracted clinical-pathological data on the primary tumor histotype and grade, the elapsed time from the diagnosis to the onset of metastases, sites and number of metastases, prior surgeries, prior radiotherapy and/or chemotherapy, ventriculo-atrial or ventriculo-peritoneal shunt placement, and the presence of isocitrate dehydrogenase 1/2 mutation and 1p/19q codeletion. Statistical analysis was performed using R software. Statistical correlation between chemotherapy or radiotherapy and the presence of multiple extra-central nervous system metastases was analyzed using and Fischer exact test. The Kaplan-Meier method was used to evaluate the presence of a correlation between the metastasis-free time and: (1) Localization of metastases; (2) The occurrence of intracranial recurrences; and (3) The occurrence of multiple metastases.
RESULTS
Data on a total of 157 patients were retrieved. The time from the initial diagnosis to metastatic spread ranged from 0 to 325 mo in patients with oligodendrogliomas and 0 to 267 mo in those with astrocytomas. Respectively, 19% and 39% of patients with oligodendroglioma and astrocytoma did not receive any adjuvant therapy. The most frequent metastatic sites were bone, bone marrow, and lymph nodes. The lungs and the liver were the most commonly involved visceral sites. There was no significant correlation between the occurrence of multiple metastases and the administration of adjuvant chemo-/radiotherapy. Patients who developed intracranial recurrences/metastases had a significantly longer extraneural metastasis-free time compared to those who developed extraneural metastases in the absence of any intra- central nervous system spread.
CONCLUSION
A long follow-up time does not exclude the presence of extraneural metastases. Therefore, targeted imaging of bones and cervical lymph nodes may improve safety in the management of these donors.
PubMed: 35979537
DOI: 10.5500/wjt.v12.i6.131 -
The Cochrane Database of Systematic... Jan 2018Gliomas are the most common primary brain tumour. They are graded using the WHO classification system, with Grade II-IV astrocytomas, oligodendrogliomas and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Gliomas are the most common primary brain tumour. They are graded using the WHO classification system, with Grade II-IV astrocytomas, oligodendrogliomas and oligoastrocytomas. Low-grade gliomas (LGGs) are WHO Grade II infiltrative brain tumours that typically appear solid and non-enhancing on magnetic resonance imaging (MRI) scans. People with LGG often have little or no neurologic deficit, so may opt for a watch-and-wait-approach over surgical resection, radiotherapy or both, as surgery can result in early neurologic disability. Occasionally, high-grade gliomas (HGGs, WHO Grade III and IV) may have the same MRI appearance as LGGs. Taking a watch-and-wait approach could be detrimental for the patient if the tumour progresses quickly. Advanced imaging techniques are increasingly used in clinical practice to predict the grade of the tumour and to aid clinical decision of when to intervene surgically. One such advanced imaging technique is magnetic resonance (MR) perfusion, which detects abnormal haemodynamic changes related to increased angiogenesis and vascular permeability, or "leakiness" that occur with aggressive tumour histology. These are reflected by changes in cerebral blood volume (CBV) expressed as rCBV (ratio of tumoural CBV to normal appearing white matter CBV) and permeability, measured by K.
OBJECTIVES
To determine the diagnostic test accuracy of MR perfusion for identifying patients with primary solid and non-enhancing LGGs (WHO Grade II) at first presentation in children and adults. In performing the quantitative analysis for this review, patients with LGGs were considered disease positive while patients with HGGs were considered disease negative.To determine what clinical features and methodological features affect the accuracy of MR perfusion.
SEARCH METHODS
Our search strategy used two concepts: (1) glioma and the various histologies of interest, and (2) MR perfusion. We used structured search strategies appropriate for each database searched, which included: MEDLINE (Ovid SP), Embase (Ovid SP), and Web of Science Core Collection (Science Citation Index Expanded and Conference Proceedings Citation Index). The most recent search for this review was run on 9 November 2016.We also identified 'grey literature' from online records of conference proceedings from the American College of Radiology, European Society of Radiology, American Society of Neuroradiology and European Society of Neuroradiology in the last 20 years.
SELECTION CRITERIA
The titles and abstracts from the search results were screened to obtain full-text articles for inclusion or exclusion. We contacted authors to clarify or obtain missing/unpublished data.We included cross-sectional studies that performed dynamic susceptibility (DSC) or dynamic contrast-enhanced (DCE) MR perfusion or both of untreated LGGs and HGGs, and where rCBV and/or K values were reported. We selected participants with solid and non-enhancing gliomas who underwent MR perfusion within two months prior to histological confirmation. We excluded studies on participants who received radiation or chemotherapy before MR perfusion, or those without histologic confirmation.
DATA COLLECTION AND ANALYSIS
Two review authors extracted information on study characteristics and data, and assessed the methodological quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We present a summary of the study characteristics and QUADAS-2 results, and rate studies as good quality when they have low risk of bias in the domains of reference standard of tissue diagnosis and flow and timing between MR perfusion and tissue diagnosis.In the quantitative analysis, LGGs were considered disease positive, while HGGs were disease negative. The sensitivity refers to the proportion of LGGs detected by MR perfusion, and specificity as the proportion of detected HGGs. We constructed two-by-two tables with true positives and false negatives as the number of correctly and incorrectly diagnosed LGG, respectively, while true negatives and false positives are the number of correctly and incorrectly diagnosed HGG, respectively.Meta-analysis was performed on studies with two-by-two tables, with further sensitivity analysis using good quality studies. Limited data precluded regression analysis to explore heterogeneity but subgroup analysis was performed on tumour histology groups.
MAIN RESULTS
Seven studies with small sample sizes (4 to 48) met our inclusion criteria. These were mostly conducted in university hospitals and mostly recruited adult patients. All studies performed DSC MR perfusion and described heterogeneous acquisition and post-processing methods. Only one study performed DCE MR perfusion, precluding quantitative analysis.Using patient-level data allowed selection of individual participants relevant to the review, with generally low risks of bias for the participant selection, reference standard and flow and timing domains. Most studies did not use a pre-specified threshold, which was considered a significant source of bias, however this did not affect quantitative analysis as we adopted a common rCBV threshold of 1.75 for the review. Concerns regarding applicability were low.From published and unpublished data, 115 participants were selected and included in the meta-analysis. Average rCBV (range) of 83 LGGs and 32 HGGs were 1.29 (0.01 to 5.10) and 1.89 (0.30 to 6.51), respectively. Using the widely accepted rCBV threshold of <1.75 to differentiate LGG from HGG, the summary sensitivity/specificity estimates were 0.83 (95% CI 0.66 to 0.93)/0.48 (95% CI 0.09 to 0.90). Sensitivity analysis using five good quality studies yielded sensitivity/specificity of 0.80 (95% CI 0.61 to 0.91)/0.67 (95% CI 0.07 to 0.98). Subgroup analysis for tumour histology showed sensitivity/specificity of 0.92 (95% CI 0.55 to 0.99)/0.42 (95% CI 0.02 to 0.95) in astrocytomas (6 studies, 55 participants) and 0.77 (95% CI 0.46 to 0.93)/0.53 (95% CI 0.14 to 0.88) in oligodendrogliomas+oligoastrocytomas (6 studies, 56 participants). Data were too sparse to investigate any differences across subgroups.
AUTHORS' CONCLUSIONS
The limited available evidence precludes reliable estimation of the performance of DSC MR perfusion-derived rCBV for the identification of grade in untreated solid and non-enhancing LGG from that of HGG. Pooled data yielded a wide range of estimates for both sensitivity (range 66% to 93% for detection of LGGs) and specificity (range 9% to 90% for detection of HGGs). Other clinical and methodological features affecting accuracy of the technique could not be determined from the limited data. A larger sample size of both LGG and HGG, preferably using a standardised scanning approach and with an updated reference standard incorporating molecular profiles, is required for a definite conclusion.
Topics: Adult; Astrocytoma; Brain Neoplasms; Child; Cross-Sectional Studies; Glioma; Humans; Magnetic Resonance Imaging; Oligodendroglioma; Sensitivity and Specificity
PubMed: 29357120
DOI: 10.1002/14651858.CD011551.pub2 -
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 -
Cancer Imaging : the Official... Nov 2022Advances in molecular diagnostics accomplished the discovery of two malignant glioma entities harboring alterations in the H3 histone: diffuse midline glioma, H3... (Review)
Review
BACKGROUND
Advances in molecular diagnostics accomplished the discovery of two malignant glioma entities harboring alterations in the H3 histone: diffuse midline glioma, H3 K27-altered and diffuse hemispheric glioma, H3 G34-mutant. Radiogenomics research, which aims to correlate tumor imaging features with genotypes, has not comprehensively examined histone-altered gliomas (HAG). The aim of this research was to synthesize the current published data on imaging features associated with HAG.
METHODS
A systematic search was performed in March 2022 using PubMed and the Cochrane Library, identifying studies on the imaging features associated with H3 K27-altered and/or H3 G34-mutant gliomas.
RESULTS
Forty-seven studies fulfilled the inclusion criteria, the majority on H3 K27-altered gliomas. Just under half (21/47) were case reports or short series, the remainder being diagnostic accuracy studies. Despite heterogeneous methodology, some themes emerged. In particular, enhancement of H3 K27M-altered gliomas is variable and can be less than expected given their highly malignant behavior. Low apparent diffusion coefficient values have been suggested as a biomarker of H3 K27-alteration, but high values do not exclude this genotype. Promising correlations between high relative cerebral blood volume values and H3 K27-alteration require further validation. Limited data on H3 G34-mutant gliomas suggest some morphologic overlap with 1p/19q-codeleted oligodendrogliomas.
CONCLUSIONS
The existing data are limited, especially for H3 G34-mutant gliomas and artificial intelligence techniques. Current evidence indicates that imaging-based predictions of HAG are insufficient to replace histological assessment. In particular, H3 K27-altered gliomas should be considered when occurring in typical midline locations irrespective of enhancement characteristics.
Topics: Humans; Artificial Intelligence; Brain Neoplasms; Glioma; Histones; Mutation
PubMed: 36397143
DOI: 10.1186/s40644-022-00500-3 -
The Cochrane Database of Systematic... May 2020This is an updated version of the original Cochrane Review published in Issue 8, 2016. High grade glioma (HGG) is a rapidly growing brain tumour in the supporting cells... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is an updated version of the original Cochrane Review published in Issue 8, 2016. High grade glioma (HGG) is a rapidly growing brain tumour in the supporting cells of the nervous system, with several subtypes such as glioblastoma (grade IV astrocytoma), anaplastic (grade III) astrocytoma and anaplastic (grade III) oligodendroglioma. Studies have investigated the best strategy to give radiation to people with HGG. Conventional fractionated radiotherapy involves giving a daily radiation dose (called a fraction) of 180 cGy to 200 cGy. Hypofractionated radiotherapy uses higher daily doses, which reduces the overall number of fractions and treatment time. Hyperfractionated radiotherapy which uses a lower daily dose with a greater number of fractions and multiple fractions per day to deliver a total dose at least equivalent to external beam daily conventionally fractionated radiotherapy in the same time frame. The aim is to reduce the potential for late toxicity. Accelerated radiotherapy (dose escalation) refers to the delivery of multiple fractions per day using daily doses of radiation consistent with external beam daily conventionally fractionated radiotherapy doses. The aim is to reduce the overall treatment time; typically, two or three fractions per day may be delivered with a six to eight hour gap between fractions.
OBJECTIVES
To assess the effects of postoperative external beam radiation dose escalation in adults with HGG.
SEARCH METHODS
We searched CENTRAL, MEDLINE Ovid and Embase Ovid to August 2019 for relevant randomised phase III trials.
SELECTION CRITERIA
We included adults with a pathological diagnosis of HGG randomised to the following external beam radiation regimens: daily conventionally fractionated radiotherapy versus no radiotherapy; hypofractionated radiotherapy versus daily conventionally fractionated radiotherapy; hyperfractionated radiotherapy versus daily conventionally fractionated radiotherapy or accelerated radiotherapy versus daily conventionally fractionated radiotherapy.
DATA COLLECTION AND ANALYSIS
The primary outcomes were overall survival and adverse effects. The secondary outcomes were progression free survival and quality of life. We used the standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach.
MAIN RESULTS
Since the last version of this review, we identified no new relevant trials for inclusion. We included 11 randomised controlled trials (RCTs) with 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for people with HGG receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 favouring postoperative radiotherapy (95% confidence interval (CI) 1.58 to 2.55; P < 0.00001; moderate-certainty evidence). Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17; P = 0.63; very low-certainty evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one participant in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in the subset of two trials (293 participants) which included participants aged 60 years and older with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46; P = 0.21; high-certainty evidence). There were two trials which compared hyperfractionated radiotherapy versus conventional radiation and one trial which compared accelerated radiotherapy versus conventional radiation. However, the results could not be pooled. The conventionally fractionated radiotherapy regimens were 4500 cGy to 6000 cGy given in 180 cGy to 200 cGy daily fractions, over five to six weeks. All trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher. The risk of selection bias was generally low among these RCTs. The number of participants lost to follow-up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life.
AUTHORS' CONCLUSIONS
Postoperative conventional daily radiotherapy probably improves survival for adults with good performance status and HGG compared to no postoperative radiotherapy. Hypofractionated radiotherapy has similar efficacy for survival compared to conventional radiotherapy, particularly for individuals aged 60 years and older with glioblastoma. There are insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy). There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These HGG individuals with poor prognosis have generally been excluded from randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these people with poor prognosis. Since the last version of this review, we found no new relevant studies. The search identified three new trials, but all were excluded as none had a conventionally fractionated radiotherapy arm.
Topics: Adult; Age Factors; Aged; Brain Neoplasms; Cranial Irradiation; Disease-Free Survival; Dose Fractionation, Radiation; Glioma; Humans; Middle Aged; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis
PubMed: 32437039
DOI: 10.1002/14651858.CD011475.pub3 -
The Cochrane Database of Systematic... Mar 2022Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q codeletion, is a mutation that can occur in... (Review)
Review
BACKGROUND
Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q codeletion, is a mutation that can occur in gliomas. It occurs in a type of glioma known as oligodendroglioma and its higher grade counterpart known as anaplastic oligodendroglioma. Detection of 1p/19q codeletion in gliomas is important because, together with another mutation in an enzyme known as isocitrate dehydrogenase, it is needed to make the diagnosis of an oligodendroglioma. Presence of 1p/19q codeletion also informs patient prognosis and prediction of the best drug treatment. The main two tests in use are fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) assays (also known as PCR-based short tandem repeat or microsatellite analysis). Many other tests are available. None of the tests is perfect, although PCR-based LOH is expected to have very high sensitivity.
OBJECTIVES
To estimate the sensitivity and specificity and cost-effectiveness of different deoxyribonucleic acid (DNA)-based techniques for determining 1p/19q codeletion status in glioma.
SEARCH METHODS
We searched MEDLINE, Embase and BIOSIS up to July 2019. There were no restrictions based on language or date of publication. We sought economic evaluation studies from the results of this search and using the National Health Service Economic Evaluation Database.
SELECTION CRITERIA
We included cross-sectional studies in adults with glioma or any subtype of glioma, presenting raw data or cross-tabulations of two or more DNA-based tests for 1p/19q codeletion. We also sought economic evaluations of these tests.
DATA COLLECTION AND ANALYSIS
We followed procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened titles/abstracts/full texts, performed data extraction, and undertook applicability and risk of bias assessments using QUADAS-2. Meta-analyses used the hierarchical summary ROC model to estimate and compare test accuracy. We used FISH and PCR-based LOH as alternate reference standards to examine how tests compared with those in common use, and conducted a latent class analysis comparing FISH and PCR-based LOH. We constructed an economic model to evaluate cost-effectiveness.
MAIN RESULTS
We included 53 studies examining: PCR-based LOH, FISH, single nucleotide polymorphism (SNP) array, next-generation sequencing (NGS), comparative genomic hybridisation (CGH), array comparative genomic hybridisation (aCGH), multiplex-ligation-dependent probe amplification (MLPA), real-time PCR, chromogenic in situ hybridisation (CISH), mass spectrometry (MS), restriction fragment length polymorphism (RFLP) analysis, G-banding, methylation array and NanoString. Risk of bias was low for only one study; most gave us concerns about how patients were selected or about missing data. We had applicability concerns about many of the studies because only patients with specific subtypes of glioma were included. 1520 participants contributed to analyses using FISH as the reference, 1304 participants to analyses involving PCR-based LOH as the reference and 262 participants to analyses of comparisons between methods from studies not including FISH or PCR-based LOH. Most evidence was available for comparison of FISH with PCR-based LOH (15 studies, 915 participants): PCR-based LOH detected 94% of FISH-determined codeletions (95% credible interval (CrI) 83% to 98%) and FISH detected 91% of codeletions determined by PCR-based LOH (CrI 78% to 97%). Of tumours determined not to have a deletion by FISH, 94% (CrI 87% to 98%) had a deletion detected by PCR-based LOH, and of those determined not to have a deletion by PCR-based LOH, 96% (CrI 90% to 99%) had a deletion detected by FISH. The latent class analysis suggested that PCR-based LOH may be slightly more accurate than FISH. Most other techniques appeared to have high sensitivity (i.e. produced few false-negative results) for detection of 1p/19q codeletion when either FISH or PCR-based LOH was considered as the reference standard, although there was limited evidence. There was some indication of differences in specificity (false-positive rate) with some techniques. Both NGS and SNP array had high specificity when considered against FISH as the reference standard (NGS: 6 studies, 243 participants; SNP: 6 studies, 111 participants), although we rated certainty in the evidence as low or very low. NGS and SNP array also had high specificity when PCR-based LOH was considered the reference standard, although with much more uncertainty as these results were based on fewer studies (just one study with 49 participants for NGS and two studies with 33 participants for SNP array). G-banding had low sensitivity and specificity when PCR-based LOH was the reference standard. Although MS had very high sensitivity and specificity when both FISH and PCR-based LOH were considered the reference standard, these results were based on only one study with a small number of participants. Real-time PCR also showed high specificity with FISH as a reference standard, although there were only two studies including 40 participants. We found no relevant economic evaluations. Our economic model using FISH as the reference standard suggested that the resource-optimising test depends on which measure of diagnostic accuracy is most important. With FISH as the reference standard, MLPA is likely to be cost-effective if society was willing to pay GBP 1000 or less for a true positive detected. However, as the value placed on a true positive increased, CISH was most cost-effective. Findings differed when the outcome measure changed to either true negative detected or correct diagnosis. When PCR-based LOH was used as the reference standard, MLPA was likely to be cost-effective for all measures of diagnostic accuracy at lower threshold values for willingness to pay. However, as the threshold values increased, none of the tests were clearly more likely to be considered cost-effective.
AUTHORS' CONCLUSIONS
In our review, most techniques (except G-banding) appeared to have good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma against both FISH and PCR-based LOH as a reference standard. However, we judged the certainty of the evidence low or very low for all the tests. There are possible differences in specificity, with both NGS and SNP array having high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. The economic analysis should be interpreted with caution due to the small number of studies.
Topics: Brain Neoplasms; Chromosomes, Human, Pair 1; Cost-Benefit Analysis; Cross-Sectional Studies; DNA; Diagnostic Tests, Routine; Glioma; Humans; Oligodendroglioma; State Medicine
PubMed: 35233774
DOI: 10.1002/14651858.CD013387.pub2 -
The Cochrane Database of Systematic... Jan 2020This is an update of the review originally published in 2011 and first updated in 2015. In most people with low-grade gliomas (LGG), the primary treatment regimen... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is an update of the review originally published in 2011 and first updated in 2015. 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
Original searches were run up to September 2014. An updated literature search from September 2014 through November 2019 was performed on the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 11), MEDLINE via Ovid (September 2014 to November week 2 2019), and Embase via Ovid (September 2014 to 2019 week 46) to identify trials for inclusion in this Cochrane review update.
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 was associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but did 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 < 0.0001; 311 participants; 1 trial; 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 = 0.872; 311 participants; 1 trial; 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 = 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 underwent 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 remained unclear whether there were differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated.
Topics: Brain Neoplasms; Disease-Free Survival; Glioma; Humans; Postoperative Care; Progression-Free Survival; Radiosurgery; Radiotherapy; Randomized Controlled Trials as Topic; Time Factors; Watchful Waiting
PubMed: 31958162
DOI: 10.1002/14651858.CD009229.pub3