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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.
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.
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.
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).
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.
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).
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.
Low grade gliomas are brain tumours that predominantly affect young adults. They grow at slower rates and are typically associated with a favourable prognosis compared with high grade gliomas. One of the most common presenting symptoms of people with LGG are seizures. Although, there are no definitive guidelines on the management of LGGs, most people with LGGs are treated with a combination of surgery followed by radiotherapy. However, it is unclear whether to use radiotherapy in the early postoperative period, or to delay until the disease progresses.
We aimed to compare the timing of radiotherapy from early (the postoperative period) or whether it should be delayed until the disease (tumour) re-occurs.
From the literature searches in September 2014 we included one randomised controlled trial, involving 311 participants, that looked at early or delayed radiotherapy given at the time of disease progression in people with LGG. This study was well designed and reported useful data on survival, but did not include other clinically important information, such as functional independent survival (functional, or neurological impairment, or both) and quality of life. Therefore, we felt that the trial was of unclear quality. People who received early (soon after surgery) radiotherapy had a longer time until their disease progressed than people who only had radiotherapy once the disease had progressed. However, the people that were initially observed had similar survival to the people who had early radiotherapy. Quality of life measures such as memory, executive function, and cognitive deterioration differences were not evaluated in either group. The findings did not suggest that people who received early radiotherapy lived longer than those had delayed radiotherapy. However, people who had early radiotherapy had better control over their seizures than those who had delayed radiotherapy. The toxic effects of radiotherapy were rated as minimal in both groups using a grading system which measured severity and included skin reactions, ear inflammation, mild headache, nausea, and vomiting.
Based on the current evidence, the results should be interpreted with caution. It is unclear whether or not early radiotherapy is better than delayed radiotherapy because survival was the same in both groups. People who had early radiotherapy experienced longer periods of tumour remission compared with patients who had delayed radiotherapy. However, it is unclear if these people suffered increased rates of cognitive impairment, neuroendocrine dysfunction, or radiation necrosis compared with people who had delayed radiotherapy. Toxic effects of radiation were minimal in both groups and there were no cases of second malignancies.
|Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas|
|Patient or population: People with supratentorial and histologically proven low-grade astrocytoma (including incompletely resected grade I pilocytic astrocytomas); WHO performance status 0 to 2 or Karnofski performance of 60 or more; age between 16 and 65 years; no other significant systemic diseases or malignancies interfering with follow-up; not pregnant. Note: People with completely resected small grade I tumours (pilocytic astrocytoma), optic nerve glioma, brainstem glioma, and third ventricular gliomas were ineligible|
Settings: Between March 1986 and September 1997, eligible participants from the inpatient or outpatient settings from 24 institutions across Europe randomly allocated to intervention or control group
Intervention: Early radiotherapy
Comparison: Delayed radiotherapy at the time of recurrence
|Outcomes||Illustrative comparative risks||Relative effect (95% CI)||No of participants (trials)||Quality of the evidence (GRADE)||Comments|
|Assumed risk||Corresponding risk|
Median 7.8 years follow-up
|See comment||See comment||HR 0.97 (0.71 to 1.33)||311 (1 trial)||1|
|Due to the way HRs are calculated, the assumed and corresponding risks were not estimated|
Median 7.8 years follow-up
|See comment||See comment||HR 0.59 (0.45 to 0.77)||311 (1 trial)||1|
|Due to the way HRs are calculated, the assumed and corresponding risks were not estimated|
CI: confidence interval; HR: hazard ratio.
|GRADE Working Group grades of evidence|
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
Low-grade gliomas (LGG) comprise a group of uncommon, progressive, and slow-growing central nervous system (CNS) tumours that affect approximately 3000 and 9000 people per year in the USA and Europe, respectively, and account for 20% of all gliomas (Ostrom 2014; RARECARE 2011). The incidence of LGG peaks in adulthood, with increased prevalence among whites and men (Ostrom 2014). Compared to the quick pace of tumour progression in people with high-grade glioma, those with LGG typically live with the disease for between five to 20 years. Mean overall survival (OS) ranges from three to six years, four to seven years, and nine to 12 years for three common types of LGG (astrocytoma, mixed oligoastrocytoma, and oligodendroglioma, respectively) (Shaw 1997; Ohgaki 2005; Jaeckle 2011). Median progression-free survival (PFS) for people with LGG who were treated in the post-temozolomide era is 22 months (Quinn 2003). In 45% to 74% of cases, LGG subsequently transforms into higher grade glioma (Jaeckle 2011). Determining the optimal management of people with LGG given their relatively long survival has been a carefully studied topic that as yet remains controversial.
Most people with LGG (approximately 80%) present with seizures (Chang 2008a). Other presentations include personality changes, headache, nausea, and lethargy (DeAngelis 2001). Neurological symptoms largely reflect the location and size of the tumor. LGG commonly occupies frontal or temporal lobes, particularly the supplemental motor area and insula (Duffau 2004). Gliomas have a predilection for growing along white matter tracts into adjacent territories and the contralateral hemisphere. Diagnosis suggested by computerised tomography (CT) or magnetic resonance imaging (MRI), typically as a non-enhancing lesion with little mass effect or vasogenic edema, is confirmed by microscopic analysis of a surgical tissue sample. Pathology establishes two key characteristics: the grade and subtype. LGG include grade 1 and 2 gliomas as defined by the World Health Organization (WHO) classification scheme (Louis 2007). WHO grade 1 tumours, such as pilocytic astrocytomas, are amenable to surgical cure by gross total resection (GTR). In unfortunate cases, involvement of eloquent cortex or key vascular structures may limit the ability to obtain a GTR. WHO grade 2 tumours are not readily cured surgically; these include diffuse astrocytoma, oligodendroglioma, mixed oligoastrocytoma, xanthoastrocytoma, astroblastoma, and ganglioglioma. WHO grade 2 and incompletely resected WHO grade I tumours are often grouped together in clinical trials, as clinical course is protracted and multi-modality therapies are usually required.
Initial management is based on symptomatology. Since most present with seizures, anti-epileptic drugs (AEDs) are often employed for early seizure control (Soffietti 2010), but about half of these people are refractory to AEDs (Chang 2008a). For tumours displaying vasogenic edema (increased fluid in the extracellular space of the brain) on MRI, steroids are often given. In rarer cases, the tumour may cause obstructive hydrocephalus (abnormal increase in the intracranial volume of cerebrospinal fluid resulting from obstruction of cerebrospinal fluid pathways in the ventricular system or subarachnoid space) or increased intracranial pressure necessitating decompressive or drainage maneuvers. Once these initial measures are taken, the patient is then considered for further management based on prognostic factors such as the patient’s age, symptoms, mental and performance status, location and size of tumour, involvement of eloquent cortex, contrast enhancement on MRI, and histologic/genetic aberrations of the tumour (Scerrati 1996; Lote 1997; Pignatti 2002; Yeh 2005; Schiff 2007; Chang 2008b; Daniels 2011).
Further management involves surgery, radiotherapy, chemotherapy, or a combination of these modalities. Surgery is first-line therapy whose chief role is to provide tissue to confirm the diagnosis. In addition, a goal of achieving more extensive resection (over biopsy alone) is often favoured because, in retrospective analyses, it is associated with prolonged survival (van Veelen 1998; Keles 2001; Claus 2005; McGirt 2008; Sanai 2008; Smith 2008; Schomas 2009), greater seizure control (Chang 2008a), and reduced risk of transformation to a higher grade (Smith 2008, Chaichana 2010). The next most common step in management is radiotherapy: either early radiotherapy (within a few weeks of surgery) or delayed radiotherapy (at time of clinical or imaging progression). Controversy exists on its optimal timing (Chan 2010). Radiation induces apoptosis of mitotically active tumour cells (programmed cell death of actively dividing cancer cells), but also damages normal surrounding brain tissue. Radiation causes edema from breakdown of the blood-brain barrier, reactive gliosis (a non-specific change of glial cells in response to damage to the CNS), and a general pro-inflammatory state (Kim 2008). Early adverse effects of radiation include headache, dizziness, ear inflammation, nausea, vomiting, seizure, altered level of consciousness, alopecia, dermatitis, urinary incontinence, and personality change (CTCAE 2009). Late clinical consequences of brain irradiation include leukoencephalopathy, neurocognitive decline, reduced quality of life (QoL), and tissue necrosis that may mimic tumour progression (Surmaaho 2001; Douw 2009). The toxic effects of radiotherapy must be carefully weighed against the benefits for tumour control, including an improvement of seizures (Rudà 2013).
Promising alternative therapeutic modalities include stereotactic radiosurgery (SRS) and chemotherapy. SRS can produce long-term control with an acceptable toxicity profile (Plathow 2003; Combs 2005; Heppner 2005; Wang 2006), and is generally reserved for inoperable tumours in close proximity to critical structures. Similarly, chemotherapy has potential either as a concurrent treatment or substitute for radiotherapy and can also improve seizure control (Rudà 2012). Studies have focused primarily on a three-drug regimen of procarbazine, lomustine, and vincristine (PCV) or single agent temozolomide. Ongoing randomised controlled trials (RCTs) are evaluating whether temozolomide can substitute for radiotherapy (EORTC-22033), or whether concurrent temozolomide and radiotherapy is superior to radiotherapy alone for postoperative tumour control (ECOG-E3F05; RTOG-0424). While standard use of these alternative modalities await trial completion, the current primary effective treatment regimen remains a combination of surgery followed by radiotherapy.
The most common approach to people with LGG includes surgery (biopsy or resection) followed by either early (within a few weeks) or delayed (at the time of clinical progression) radiotherapy. Options for radiotherapeutic delivery exist, which include conformal EBRT, IMRT, and SRS. Each uses dedicated CT or MRI to guide dosimetry and planning, but vary in the technique used to specifically irradiate the tumour while minimizing exposure of normal brain tissue. Sources for high-energy photons include cobalt-60 or a linear accelerator, with typical dosage in the 45 to 60 Gy range, delivered in 1.8 to 2.0 Gy fractions over a four to eight week period. Standard radiation treatment fields target the tumour bed with a small (usually 2 cm) margin. Radiation produces double-stranded DNA breaks and reactive oxygen species in the target tissue, resulting in damage to cycling cells of the tumour but also to normal brain tissue caught in the irradiated field.
The diffusely infiltrative nature of LGG makes even GTRs unlikely to be curative. Early radiotherapy is employed to arrest or kill any residual tumour cells, which may prolong time to tumour recurrence and increase survival. However, early radiotherapy will lead to earlier onset of late adverse effects of radiation, including neurocognitive decline and reduced QoL. In contrast, a strategy of delayed radiotherapy administered at time of tumour recurrence delays radiation exposure and its late adverse effects, but may allow tumour recurrence to occur more quickly.
A fundamental question in the management in LGG has been whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs. Reasons why LGG has been difficult to study in large clinical trials include: (1) the diagnosis is uncommon requiring multi-institution participation and longer enrolment times; and (2) people with LGG have long survival times requiring extensive follow-up. Therefore, consolidating data from available trials through systematic review may provide sufficient power to generate new insights into this uncommon and controversial disease. In addition, in light of new treatment modalities becoming available on an ongoing basis, summarizing the currently available literature will be important in the design of future clinical trials for people with LGG.
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.
We included people who met the following criteria:
We excluded people documented as meeting any of the following criteria at time of trial entry:
We limited interventions to the comparison of early postoperative radiotherapy versus radiotherapy delayed until tumour progression following biopsy or surgical resection in LGG management. Radiotherapy may include conformal EBRT with linear accelerator or cobalt-60 sources, IMRT, or SRS. In cases where glioma progression occurs following postoperative early or delayed radiotherapy, rescue therapy may involve a combination of repeat surgery, repeat radiotherapy, or chemotherapy and these cases were recorded.
We searched up to September 2014 the following electronic databases: the Cochrane Register of Controlled Trials (CENTRAL, Issue 8, 2014) (Appendix 3), MEDLINE (1948 to Aug week 3, 2014) (Appendix 4), and EMBASE (1980 to Aug week 3, 2014) (Appendix 5). All relevant articles were identified on PubMed and we carried out a further search for newly published articles using the ‘related articles’ feature.
We searched the MetaRegister of Controlled Trails (MRCT), Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for ongoing trials. We agreed a priori that if ongoing trials which had not been published were identified through these searches, we would contact the principal investigators to request any relevant data. We approached the major co-operative trial groups active in this area in a similar manner.
Conference proceedings and abstracts were searched through ZE-TOC (http://zetoc.mimas.ac.uk).
We searched for theses and dissertations through WorldCat (http://firstsearch.oclc.org).
We checked the reference lists of included studies, key textbooks, and previous systematic reviews by hand searching. Journal and conference materials over the past year were handsearched in the following sources:
We contacted the authors of relevant trials and experts at major hospitals performing clinical trials to identify further data which may or may not have been published.
We sought papers in all languages and performed translations if necessary.
We downloaded all titles and abstracts retrieved by electronic searching to the reference management database Endnote (ENDNOTE 2014). We removed duplicates and three review authors (AV, JMS, CP) independently examined the remaining references. The review authors were not blinded to the author(s) or affiliations of the studies. We excluded studies which clearly did not meet the inclusion criteria and obtained copies of the full text of potentially relevant references. Three review authors (AV, JMS, CP) independently assessed the eligibility of retrieved papers. We resolved disagreements by discussion between all review authors, and documented the reasons for exclusion of studies.
We extracted data on outcomes as follows:
Where possible, all data extracted were those relevant to an intention-to-treat (ITT) analysis, in which participants are analysed in groups to which they are assigned.
We noted the time points at which outcomes were collected and reported.
Three review authors (AV, JMS, CP) extracted data independently onto a data extraction form specially designed for this Cochrane review. We resolved any differences between review authors by discussion.
Was the allocation sequence adequately generated?
Was allocation adequately concealed?
We restricted the assessment of blinding to blinding of outcome assessors, since it was not possible to blind participants and treatment providers to the different interventions.
Was knowledge of the allocated interventions adequately prevented during the trial?
Was similar care provided to participants in treatment and control groups other than the intervention of interest?
We recorded the proportion of participants whose outcomes were not reported at the end of the trial.
Were incomplete outcome data adequately addressed?
Were reports of the study free of suggestion of selective outcome reporting?
Was the study apparently free of other problems that could put it at a high risk of bias?
Three review authors (AV, JMS, CP) independently applied the ‘Risk of bias’ tool and we resolved differences by discussion. We presented results in both a ‘Risk of bias’ graph and a ‘Risk of bias’ summary. We interpreted results of meta-analyses in light of the findings with respect to risk of bias.
We used the following measures of the effect of treatment:
Three review authors (AV, JMS, CP) reviewed unit of analysis issues according to Higgins 2011a and we resolved differences by discussion. These included reports where:
We did not impute missing outcome data.
We assessed heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage heterogeneity between studies which cannot be ascribed to sampling variation (Higgins 2003), and by a formal statistical test of the significance of the heterogeneity (Deeks 2001). We investigated and reported possible reasons for heterogeneity In studies demonstrating evidence of substantial heterogeneity.
Three review authors (AV, JMS, CP) reviewed and recorded reporting biases.
If sufficient, clinically similar studies were available, we pooled the results in meta-analyses.
We used fixed-effect models with inverse variance weighting for all meta-analyses (DerSimonian 1986). A random-effects model was originally stated in the protocol; however, given that our meta-analysis only included one study we opted to use a fixed-effect computational model to report a more descriptive analysis of the included study (Borenstein 2009).
We analysed outcome measures including OS, PFS, SAP, FIS, steroid requirement, seizure frequency, QoL, and adverse effects of radiotherapy after stratifying by the following clinical characteristics (if data was available): age, histologic subtype, tumour size and location, extent of resection, performance score, approach of radiotherapy used (conformal EBRT, IMRT, SRS), types of rescue therapy (repeat resection, repeat radiotherapy, chemotherapy), genetic aberrations (p53 status, 1p/19q status), and date of trial. We considered the following clinical factors during interpretation of any heterogeneity: age, tumour size, histologic subtype, definition used for ‘tumour recurrence’ and PFS, and length of follow-up.
Two review authors (AV, CP) determined the requirement for sensitivity analysis and we resolved differences through discussion, according to Higgins 2011a. Sensitivity analysis for trial eligibility and analysis would be required if the search produced multiple trials with high risk of bias. This serves to assess whether or not conclusions would have differed if eligibility was restricted to trials without high risk of bias for the outcome concerned.
We identified 1281 references in MEDLINE including Cancer-Lit, 1683 in EMBASE and 539 in CENTRAL, giving a total of 3503 references. We did not find any additional studies from unpublished and grey literature, reference lists, or correspondence. There were 2333 unique references after we removed duplicates. Of these, we excluded 2323 after screening by title/abstract. We retrieved ten full text articles, eight of which were excluded as they did not meet the intervention criteria. From the full text screening of the remaining two it was noted that Karim 2002 was the antecedent of the latest prospective RCT trial by van den Bent 2005. Since van den Bent 2005 refers to the long term efficacy of the primary trial by Karim 2002, it will henceforth be referred to as Karim 2002: van den Bent 2005. We analysed the data from Karim 2002: van den Bent 2005, as this trial met our inclusion criteria and provided the most salient results to address our original question. We described Karim 2002: van den Bent 2005 in the Characteristics of included studies section. The original trial by Karim 2002 is the earlier European Organisation for Research and Treatment of Cancer (EORTC) study of the van den Bent 2005 cohort that provided an interim analysis comparing early radiotherapy with delayed radiotherapy. The interim analysis provides minimal clinical significance compared with the long-term results generated by van den Bent 2005. Please see Figure 1 for the PRISMA study flow diagram.
One RCT met our inclusion criteria. Karim 2002: van den Bent 2005 is a prospective, multi-centre RCT that presents the long-term results of a 1986 EORTC trial (Karim 2002) that compared early radiotherapy with delayed radiotherapy for people with LGGs. Participants from 24 participating institutions across Europe were randomly assigned to either early postoperative radiotherapy of 54 Gy in fractions of 1.8 Gy per week for six weeks or deferred radiotherapy until the time of progression (control group). Eligible participants had to have a histologically-confirmed diagnosis of low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytoma, or incompletely resected pilocytic astrocytoma, with a WHO performance status of zero to two, or KPS of at least 60. In this trial 154 people were assigned early radiotherapy and 157 people served as controls. There were 63 (41%) females in the early radiotherapy group and 52 (33%) in the control group. The median age of people who had early radiotherapy was 36.5 years, while those who had delayed radiotherapy had a median age of 41 years. The early radiotherapy group (5.3 years) had a statistically significantly higher median PFS compared with the control group (3.4 years) (P value < 0.0001), and there was a 20% improvement in five-year PFS due to early radiotherapy (35% versus 55%). However, OS was similar between the two groups; the median survival in the early radiotherapy group was 7.4 years compared with 7.2 years in the control group (P value = 0.872). The early radiotherapy group experienced slightly better performance status, as seizures were better controlled in this group. The trial authors did not assess people’s QoL nor long-term physical or cognitive changes. The median follow-up time for all participants was 93 months. At the time of relapse, no further treatment at progression was given or documented for 13 (11.5%) participants in the control group and 32 (34%) participants in the early radiotherapy group. Salvage radiotherapy was given to 73 (65%) of participants in the control group and four (4%) of participants in the irradiated group. Chemotherapy was given to 18 (16%) participants in the control group and 35 (37%) participants who had early radiotherapy at the time of recurrence.
Of the 2333 unique references identified, we excluded 2323 as they did not meet the pre-specified participant and outcome criteria. Eight studies were excluded as they did not meet the intervention criteria; please see the Characteristics of excluded studies section for the reasons for exclusion of these studies.
The sole trial we evaluated, Karim 2002: van den Bent 2005, had an overall high risk of bias. We classified three out of seven criteria used to assess risk of bias as having unclear risk of bias, while the other four criteria had low risk of bias. Please see Figure 2 for the ‘Risk of bias’ graph and Figure 3 for the ‘Risk of bias’ summary.
Karim 2002: van den Bent 2005 successfully randomised by stratification as various patient traits were distributed equally among both groups of participants, and “at baseline the treatment and control groups were not different with regard to sex, age, WHO performance status, MRC neurological function status, extent of surgery, histology, maximum diameter of the tumour, or whether the tumour crossed the midline”. However, there was no statement of effort to conceal allocation. Since this was an unblinded trial it is conceivable that post-intervention management could affect survival and PFS.
Participants in the early radiotherapy and delayed radiotherapy groups could not be blinded to the results of the random allocation due to the study design. The study authors did not blind outcome assessment since the trial indicated that the “corresponding author had full access to all the data”; however, it is unclear if treatment assignment was concealed from the investigators or those responsible for outcome assessment.
Of the 311 participants randomised to either early or delayed radiotherapy in Karim 2002: van den Bent 2005, eight (2.6%) were ineligible for analysis due to incomplete data before entry to the trial, performance status > two or older than 65 years of age, and missing follow-up data. Most patient characteristic variables (sex, age in years, WHO performance status, MRC-NFS, extent of resection, histology, diameter, and tumour crossing the midline) had missing information, but these proportions are balanced across both groups. Despite random assignment to the control group, three participants received early radiotherapy (total dose of 50 to 54 Gy). This missing data is unlikely to influence the true effect of radiotherapy timing on outcomes for people with LGGs.
We reported all of Karim 2002: van den Bent 2005’s pre-specified (primary) outcomes that were of interest in this Cochrane review in the pre-specified way. This included overall and PFS, as well as the neurological signs and symptoms at one year in participants who were progression-free at two years.
Karim 2002: van den Bent 2005 randomised participants to treatments at the EORTC Data Center or the MRC Cancer Trials Office by use of a minimisation technique and stratification according to treatment institute, histology (astrocytoma versus oligodendroglioma or oligoastrocytoma), and extent of resection (biopsy versus partial, subtotal, or total). Karim 2002: van den Bent 2005 had missing baseline characteristics in both groups of participants, which may potentially predispose the trial to selection bias. However, there was a balance in the distribution of missing baseline characteristics between both groups, minimizing the likelihood that selection bias would affect one group over the other.
This trial also has the potential for intervention, or exposure, bias since the trial authors evaluated performance status based only upon tumour progression. The study authors conceded that “because the patients in the control group (those who received delayed radiotherapy) progressed earlier, there might be a bias in favour of the control group”. However, they limited this possibility by performing an post-hoc analysis on participants’ neurological signs and symptoms at one year only in participants who were progression-free at two years. This prevented any patient with an undetected progression at the one-year mark to bias the analysis.
The difference in median OS between the group who received early radiotherapy and the group who received delayed radiotherapy was not statistically significant (7.2 versus 7.4 years, respectively, log-rank P value = 0.873; HR 0.97, 95% CI 0.71 to 1.33; Figure 4).
People who were randomised to early radiotherapy demonstrated statistically significantly longer PFS than people randomised to delayed radiotherapy (5.3 versus 3.4 years, respectively, long-rank P value < 0.0001; HR 0.59, 95% CI 0.45 to 0.77; Figure 5).
SAP was 3.4 years for the delayed radiotherapy group versus 1.0 years for the early radiotherapy group (log-rank P value < 0.0001).
One of the inclusion criteria of this trial required participants to have a WHO performance status of zero to two, or KPS of ≥ 60, and the trial authors documented WHO performance status and MRC-NFS baseline characteristics in most participants at the time of randomisation. However, Karim 2002: van den Bent 2005 did not report FIS outcomes in the form of WHO performance status, KPS, or MRC-NFS. Instead, they investigated whether participants free from tumour progression had any neurological signs and symptoms by performing a post-hoc analysis of participants’ clinical examination at one year. They found “no differences between the two groups for cognitive deficit, focal deficit, performance status, and headache (data not shown)”.
Karim 2002: van den Bent 2005 did not calculate DSS.
Karim 2002: van den Bent 2005 did not assess steroid requirements.
At baseline there were no differences between early and delayed radiotherapy groups in seizure control (P value = 0.8701). However, at one year follow-up 26 of 102 (25%) participants who were irradiated had seizures compared with 29 of 71 (41%) participants who had not been irradiated (P value = 0.0329).
Karim 2002: van den Bent 2005 evaluated tumour progression by comparing follow-up CT scans with the baseline scan; however, the investigators did not utilize the RANO response criteria for LGG. Among the 311 participants, 217 (70%) had progressed and 156 (50%) had died after follow-up or a median time of 7.8 years.
Among the 156 participants that died, 142 participants (91%) died from a progressive brain tumour, 12 participants (8%) died from unrelated causes, and no information on the cause of death was available for two participants (1%).
Karim 2002: van den Bent 2005 did not assess QoL.
Adverse events were not classified according to CTCAE 2009. The trial authors indicated that “toxic effects were modest in general, and mainly consisted of skin reactions, otitis, mild headache, nausea, and vomiting. Irradiation was interrupted in six patients because of acute reactions”. The trial did not report rates of cognitive impairment or rates of possible radiotherapy-induced leucoencephalopathy. Their findings do not support the speculation that early radiotherapy might induce malignant transformation of LGG, as there was no difference in progression to a high-grade tumour upon disease recurrence between both groups (statistical data not provided).
The large, multi-institutional, prospective RCT of Karim 2002: van den Bent 2005 demonstrated 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 improve OS. The median PFS was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (HR 0.59, 95% confidence interval (CI) 0.45 to 0.77; P value < 0.0001). However, the median OS did not show a statistically significant difference between the groups. The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median OS of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P value = 0.872).
The trial authors used stratified randomisation to equally distribute clinical prognostic factors, such as age, tumour size, functional status, and extent of resection, among both treatment groups. After a median follow-up time of 7.8 years (93 months), approximately 70% of participants had progressed and 50% had died. Adverse effects were minimal; they mainly consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Participants in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed radiotherapy group at one year follow-up (25% versus 41%, P value = 0.0329, respectively). Using an ITT analysis, 55% of participants irradiated early did not show any evidence of tumour progression at five years, compared with 35% of participants who had delayed radiotherapy. Also at five years, 68% of participants in the early radiotherapy group were alive compared with 66% of participants in the delayed radiotherapy group. They provided rescue therapy to 65% of the participants randomised to delayed radiotherapy and 4% of the participants randomised to early radiotherapy. This led to a median SAP of 3.4 years for participants with delayed radiotherapy and one year for the participants with early radiotherapy. The results from Karim 2002: van den Bent 2005 indicate that the timing of radiotherapy is less important for prolonging survival provided it is given at some point during the treatment course and optimal rescue therapy can be readily provided for participants who undergo delayed radiotherapy. Notably, Karim 2002: van den Bent 2005 did not investigate what type of long term QoL their participants experienced. Therefore, it is not known whether improved time to progression is associated with long-term cognitive or neurological deterioration in participants with LGGs.
The optimal treatment of LGG remains controversial, and current guidelines on the management of people with an alleged LGG are not based on established clinical evidence. We aimed to evaluate the fundamental question of whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs. Our search yielded one large, multi-institutional trial by Karim 2002: van den Bent 2005 that sought to elucidate the optimal timing of radiotherapy in people with LGG who have good pre-treatment functional status. This trial showed that early radiotherapy significantly improves PFS compared with observation and delayed radiotherapy until disease progression. However, there was no difference in OS between these two groups, mainly because most people who received delayed radiotherapy were also given some form of rescue therapy. The trial also analysed symptom burden in people who had no evidence of progression and showed that early radiotherapy improves seizure control better than delayed radiotherapy. However, the trial authors assessed tumour control using CT scan instead of MRI, and imaging methods were not guided by specific imaging parameters and endpoints. Furthermore, the trial authors did not adequately report adverse effects of radiotherapy and they did not evaluate people’s postoperative functional status. The greatest limitation of this trial, however, is the lack of data on people’s QoL and cognitive function. Cognitive deterioration may eventually occur from deleterious effects of early radiotherapy or disease progression in people who opt for delayed radiotherapy. This trial affirms the efficacy of radiotherapy in the treatment of LGG, but the optimal time to give radiation therapy still remains unclear because the effect of early versus delayed radiotherapy on neurocognitive deterioration is not known.
One large multi-institutional RCT, Karim 2002: van den Bent 2005, forms the basis of our systematic review and its conclusions. Overall, we determined this trial had a high risk of bias after careful evaluation of the criteria we used to assess risk of bias. Given this risk of bias, the results and conclusions of this Cochrane review must be interpreted in the context of this uncertainty. See Figure 2 for the ‘Risk of bias’ graph and Figure 3 for the ‘Risk of bias’ summary. The lack of allocation concealment, blinding of participants and blinding of outcome assessment introduces various types of biases that may conceivably skew the true effects of early versus delayed postoperative radiation therapy on survival and PFS. For these reasons, we attributed a low GRADE quality of evidence for the OS and PFS outcome parameters reported in Karim 2002: van den Bent 2005.
This large trial showed an increase in PFS after early radiotherapy versus delayed radiotherapy. Since most patients randomised to delayed radiotherapy received some form of rescue therapy at the time of disease progression, there was no significant difference in median OS between the two cohorts. The primary endpoints of this trial were PFS and OS, but the trial authors also assessed SAP, neurological symptoms at one year in people who had not shown evidence of disease progression, seizure frequency, and cause of death. Local tumour control was also included but was not assessed using the RANO response criteria for LGG. Adverse effects were briefly mentioned but they were not quantified or classified according to CTCAE 2009 standards. Other clinically important outcomes such as FIS, DSS, steroid requirement, and QoL were not evaluated. Hence, our systematic review’s internal validity is limited since all of the results and conclusions are based on this single large RCT (Karim 2002: van den Bent 2005).
We performed a comprehensive search, including a thorough search of the grey literature. We screened all identified studies and three review authors independently extracted data. We restricted the included studies to RCTs as these provide the strongest level of evidence available. Hence, we have attempted to reduce bias in the review process. However, the greatest threat to the validity of the review is likely to be the possibility of publication bias, i.e. studies that did not find the treatment to have been effective may not have been published.
EORTC 22845 by Karim 2002: van den Bent 2005 is the only trial that investigated the role of radiation timing on survival for people with LGG.
There are two randomised trials that investigated different radiation doses in the management of LGGs: Karim 1996 (EORTC 22844) and Shaw 2002 (NCCTG). These trials provided class I evidence showing no advantage for higher versus lower radiation doses.
Radiation therapy has been shown to improve seizure control in people with LGG. A retrospective study by Warnke 1997 reported a seizure control rate of 79% using stereotactic interstitial radiosurgery at six months for LGG people with medically refractory seizures. Conventional radiation can also reduce seizure frequency in people with LGG and medically refractory seizures (Rogers 1993).
One of the strongest arguments for delaying or withholding radiotherapy in people with LGG is the risk of radiotherapy-induced leucoencephalopathy, which can result in cognitive dysfunction. Douw 2009 evaluated the cognitive status of 65 people with LGG who had neuropsychological follow-up at a mean of 12 years and were free of tumour progression. People who received radiation therapy performed worse in measures of executive functioning, attentional functioning, and information processing speed compared with people who did not receive radiation therapy. However, it is uncertain whether early radiotherapy can postpone neurological deterioration.
Given the high risk of bias in the included trial, 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 OS 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 were differences in memory, executive function, or cognitive function between the two groups since QoL measures were not evaluated.
Future trials need to include a rigorous comparison of the QoL, cognitive performance, and functional status of people undergoing early versus delayed radiotherapy for LGG. These trials ideally would have long-term follow-up data to effectively monitor for significant neurocognitive side effects of intracranial radiotherapy in people with LGG.
SOURCES OF SUPPORT
Fellowship to ASV
Research support to ASV
Research support to ASV
We thank Clare Jess (Managing Editor) and Jane Hayes (Information Manager) of the Cochrane Gynaecological Cancer Group for their enthusiasm, support, and guidance.
The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group.
The views and opinions expressed therein are those of the review authors and do not necessarily reflect those of the NIHR, NHS, or the Department of Health.
The RANO criteria (Wen 2010):
Note that T2 and FLAIR refer to sequences obtained with standard MRI scans.
The MRC-NFS is scored from one to five (MRC 1983):
The WHO-PS is scored from 0 to four (Zubrod 1960):
mp=title, original title, abstract, name of substance word, subject heading word, unique identifier
|Outcome or subgroup title||No. of studies||No. of participants||Statistical method||Effect size|
|1 Overall survival||1||311||Hazard Ratio (Fixed, 95% CI)||0.97 [0.71, 1.33]|
|2 Progression-free survival||1||311||Hazard Ratio (Fixed, 95% CI)||0.59 [0.45, 0.77]|
CONTRIBUTIONS OF AUTHORSCP had the original idea for the protocol (New Reference) and helped review initial protocol drafts. AV wrote the protocol and search strategy. JMS reviewed the updated search, performed data extraction, and wrote the Results and Discussion sections.
DECLARATIONS OF INTEREST
J Manuel Sarmiento - none known.
Andrew S Venteicher - none known.
Chirag G Patil - none known.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
* Indicates the major publication for the study