Early versus delayed radiotherapy for the treatment of low‐grade gliomas
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare early versus delayed radiotherapy in patients that undergo initial biopsy or surgical resection for LGG.
Background
Description of the condition
Low‐grade gliomas (LGG) comprise a group of progressive, slow‐growing central nervous system (CNS) tumors that affect approximately 3000 and 9000 new patients in the USA and Europe, respectively, accounting for 20% of all gliomas (CBTRUS 2011; RARECARE 2011). Incidence of LGG peaks in adulthood, with increased prevalence among whites and in males (CBTRUS 2011). Compared to the quick pace of tumor progression in patients with high‐grade glioma, those with LGG typically live with the disease for 5 to 20 years. Mean survival ranges from 3 to 6 years, 4 to 7 years, and 9 to 12 years for three common types of LGG (astrocytoma, mixed oligoastrocytoma, and oligodendroglioma, respectively) (Shaw 1997; Ohgaki 2005; Jaeckle 2010). In 45 to 74% of cases, LGG subsequently transforms into higher grade glioma (Jaeckle 2010). Determining the optimal management of patients with LGG given their relatively long survival has been a carefully studied topic that as yet remains controversial.
The majority of patients with LGG (approximately 80%) present with seizures (Chang 2008a). Other presentations include personality changes, headache, nausea, and lethargy (DeAngelis 2001). Neurologic 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 CT or 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 tumors, 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 tumors are not readily cured surgically; these include diffuse astrocytoma, oligodendroglioma, mixed oligoastrocytoma, xanthroastrocytoma, astroblastoma, and ganglioglioma. WHO grade 2 and incompletely resected WHO grade I tumors are often grouped together in clinical studies, as clinical course is protracted and multi‐modality therapies are usually required.
Initial management is based on symptomatology. Since a majority present with seizures, anti‐epileptic drugs (AEDs) are often employed for early seizure control (Soffietti 2010), however about half of these patients are refractory to AEDs alone (Chang 2008a). For tumors displaying vasogenic edema on MRI, steroids are often given. In rarer cases, the tumor may cause obstructive hydrocephalus 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 tumor, involvement of eloquent cortex, contrast enhancement on MRI, and histologic/genetic aberrations of the tumor (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 favored 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 tumor recurrence). Controversy exists on its optimal timing (Chan 2010). Radiation induces apoptosis of mitotically active tumor cells, but also damages normal surrounding brain tissue. Radiation causes edema from breakdown of the blood‐brain barrier, reactive gliosis, and a general pro‐inflammatory state (Kim 2008). Late clinical consequences of brain irradiation include leukoencephalopathy, neurocognitive decline, reduced quality of life (QoL), and tissue necrosis that may mimic tumor progression (Surma‐aho 2001). The side effects of radiotherapy must be carefully weighed against the benefits for tumor control.
Promising alternative therapeutic modalities include stereotactic radiosurgery (SRS) and chemotherapy. SRS can produce long‐term control with acceptable toxicity profile (Plathow 2003; Combs 2005; Heppner 2005; Wang 2006), and is generally reserved for inoperable tumors in close proximity to critical structures. Similarly, chemotherapy has potential either as a concurrent treatment or substitute for radiotherapy. Studies have focused primarily on a three‐drug regimen of procarbazine, lomustine, and vincristine (PCV) or single agent temozolomide. Ongoing randomized 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 post‐operative tumor 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.
Description of the intervention
The most common approach to patients with LGG includes surgery (biopsy or resection) followed by either early or delayed radiotherapy. Options for radiotherapeutic delivery exist, which include conformal external beam radiotherapy (EBRT), intensity‐modulated radiotherapy (IMRT), and stereotactic radiosurgery (SRS). Each uses dedicated CT or MRI to guide dosimetry and planning, but vary in technique used to specifically irradiate the tumor 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 4 to 8 week period. Standard radiation treatment fields target the tumor 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 tumor but also to normal brain tissue caught in the irradiated field.
How the intervention might work
The diffusely infiltrative nature of LGG makes even GTRs unlikely to be curative. Early radiotherapy is employed to arrest or kill any residual tumor cells, which may prolong time to tumor 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 tumor recurrence delays radiation exposure and its late adverse effects, but may allow tumor recurrence to occur more quickly.
Why it is important to do this review
A fundamental question in the management in LGG has been whether to use radiotherapy in the early post‐operative period, or whether radiotherapy should be delayed until tumor progression occurs. Reasons why LGG has been difficult to study in large clinical studies include (1) the diagnosis is uncommon requiring multi‐institution participation and longer enrollment times, and (2) patients with LGG have long survival times requiring extensive follow‐up. Therefore, consolidating data from available studies through systematic review may provide sufficient power to generate new insights in this uncommon and controversial disease. In addition, in light of new treatment modalities becoming available on an ongoing basis, summarizing the literature as it currently stands will be important in the design of future clinical trials for patients with LGG.
Objectives
To compare early versus delayed radiotherapy in patients that undergo initial biopsy or surgical resection for LGG.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs)
Types of participants
Patients meeting the following criteria will be included:
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Any age
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Intracranial LGG
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Histological types: astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthroastrocytoma, or ganglioglioma. This must be determined based on pathology review.
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Grade: WHO grade 2 or incompletely resected WHO grade 1. This must be determined based on pathology review.
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Patients will have undergone surgery, including: biopsy, partial resection (PR; less than 50%), subtotal resection (STR; 50 to 89%) or gross total resection (GTR; greater than 90%). This will be determined by either intra‐operative judgement or by radiologic evaluation by the patient's primary neurosurgical team.
Patients documented as meeting any of the following criteria at time of study entry will be excluded:
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Patient had received previous cranial radiation
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Patient had undergone craniotomy other than for biopsy or resection for the LGG
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Patient had received previous chemotherapy
Types of interventions
Interventions are limited to the comparison of early versus delayed radiotherapy following biopsy or surgical resection in the management of LGG. Radiotherapy may include conformal EBRT with linear accelerator or cobalt‐60 sources, intensity‐modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS). In cases where glioma progression occurs following post‐operative early or delayed radiotherapy, salvage therapy may involve a combination of repeat surgery, repeat radiotherapy, or chemotherapy and will be recorded.
Types of outcome measures
Primary outcomes
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Overall survival (OS), defined as survival until death from all causes from time of randomization.
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Progression‐free survival (PFS), defined as survival until evidence of tumor recurrence is documented by CT or MRI scan
Note, recurrence will be defined according to RANO criteria if data are available (see 'Local tumor control' in Secondary outcomes and Appendix 1)
Secondary outcomes
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Functionally independent survival (FIS), defined as (1) a Karnofsky Performance Scale (KPS) score of >= 70%, or (2) Medical Research Council neurologic functional status (MRC‐NFS) score of 1 to 2, or (3) WHO Performance Scale (WHO‐PS) score of 0 to 2. These scales classify patients according to functional and/or neurological impairment (see Appendix 2)
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Disease‐specific survival (DSS), defined by survival until death due to neurological cause from time of randomization
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Steroid requirement, rated as worsened, unchanged, or improved
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Seizure frequency, rated as increased, unchanged, or decreased
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Local tumor control, rated by CT or MRI compared with baseline scan; based on RANO response criteria for LGG (van den Bent 2011) (see Appendix 1):
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Cause of death
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QoL, as measured using a scale validated through reporting of norms in a peer‐reviewed publication such as QLQ‐C30 (Aaronson 1993), QLQ‐BN20 (Taphoorn 2010), FACT‐G or FACT‐Br (Weitzner 1995), or MDASI‐BT (Armstrong 2006)
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Adverse events caused by radiotherapy, which cannot be attributed to the tumor, as graded per the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Adverse events are graded on up to a five point scale outlined below. See CTCAE v4.0 for specific grading of each adverse event:
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Adverse events will include: headache (graded 1 to 3), dizziness (graded 1 to 3), otitis / ear inflammation (graded 1 to 5), nausea (graded 1 to 3), depressed level of consciousness (graded 1 to 5), seizure (graded 1 to 5), personality change (graded 1 to 5), CNS necrosis (graded 1 to 5), CNS symptoms not otherwise specified (graded 1 to 5), alopecia (graded 1 to 2), dermatitis (graded 1 to 5), urinary incontinence (graded 1 to 3)
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Grade 1: 'mild' defined as asymptomatic or mild symptoms with no intervention necessary
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Grade 2: 'moderate' defined as requiring only minimal, local, or non‐invasive intervention
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Grade 3: 'severe' defined as disabling but not immediately life threatening requiring hospitalization
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Grade 4: 'life‐threatening' and requiring urgent intervention
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Grade 5: 'death' related to adverse event
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Search methods for identification of studies
Electronic searches
The following electronic databases will be searched: the Cochrane Register of Controlled Trials (CENTRAL, Current Issue), MEDLINE (1950 to date), EMBASE (1980 to date). The MEDLINE search strategy is listed in Appendix 3. All relevant articles will be identified on PubMed and using the 'related articles' feature a further search will be carried out for newly published articles.
Searching other resources
Unpublished and Grey literature
Metaregister, Physicians Data Query, www.controlled‐trials.com/rct, www.clinicaltrials.gov and www.cancer.gov/clinicaltrials will be searched for ongoing trials. If ongoing trials which have not been published are identified through these searches, the principal investigators will be contacted to request any relevant data. The major co‐operative trial groups active in this area will likewise be approached.
Conference proceedings and abstracts will be searched through ZETOC (http://zetoc.mimas.ac.uk).
Theses and dissertations will be searched through WorldCat (http://firstsearch.oclc.org).
Hand searching
The reference lists of included studies, key textbooks, and previous systematic reviews will be checked through hand searching. Journal and conference materials over the past year will be hand searched in the following sources:
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British Journal of Cancer
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Neurosurgery
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Annual Meeting of the American Society for Radiation Oncology (ASTRO)
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Annual Meeting of the American Association for Neurological Surgeons (AANS)
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Annual Meeting of European Society of Medical Oncology (ESMO)
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Annual Meeting of the American Society of Clinical Oncology (ASCO)
Correspondence
Authors of relevant trials and experts at major hospitals performing clinical trials will be contacted to identify further data which may or may not have been published.
Language
Papers in all languages will be sought and translations carried out if necessary.
Data collection and analysis
Selection of studies
All titles and abstracts retrieved by electronic searching will be downloaded to the reference management database Endnote, duplicates removed and the remaining references will be examined by two review authors (AV, CP) independently. The review authors will not be blinded to the author or affiliations of the studies. Those studies which clearly do not meet the inclusion criteria will be excluded and copies of the full text of potentially relevant references will be obtained. The eligibility of retrieved papers will be assessed independently by two review authors (AV, CP). Disagreements will be resolved by discussion between the two review authors. Reasons for exclusion will be documented.
Data extraction and management
For included trials, data will be abstracted as recommended in Chapter 7 of Higgins 2009. This includes data on the following:
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Author, year of publication and journal citation (including language)
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Country
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Setting
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Inclusion and exclusion criteria
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Study design, methodology
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Study population
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total number enrolled
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patient characteristics
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age
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sex
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co‐morbidities
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previous treatment
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neurological performance
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Tumor details at diagnosis
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size of tumor
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location of tumor
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tumor histology
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Intervention details
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details of surgery
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extent of biopsy/resection
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details of radiotherapy
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type
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dose
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fractions
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duration
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Risk of bias in study (Assessment of risk of bias in included studies)
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Duration of follow‐up
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Outcomes, which will include OS, PFS, FIS, local tumour control, cause of death, steroid requirement, seizure frequency, and adverse events (Types of outcome measures)
Data on outcomes will be extracted as below
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For time to event (e.g. OS, PFS, DSS and local tumour control rates) data, we will extract the log of the hazard ratio [log(HR)] and its standard error from trial reports; if these are not reported, we will attempt to estimate them from other reported statistics using the methods of Parmar 1998.
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For dichotomous outcomes (e.g. adverse events or deaths if it is not possible to use a HR), we will extract the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate a risk ratio (RR).
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For continuous outcomes (e.g. QoL measures), we will extract the final value and standard deviation (SD) of the outcome of interest and the number of patients assessed at endpoint in each treatment arm at the end of follow‐up, in order to estimate the mean difference (if trials measured outcomes on the same scale) or standardised mean differences (if trials measured outcomes on different scales) between treatment arms and its standard error.
Where possible, all data extracted will be those relevant to an intention‐to‐treat (ITT) analysis, in which participants are analysed in groups to which they are assigned.
The time points at which outcomes were collected and reported will be noted.
Data will be abstracted independently by two review authors (AV, CP) onto a data abstraction form specially designed for the review. Differences between review authors will be resolved by discussion.
Assessment of risk of bias in included studies
Risk of bias in included RCTs will be assessed using the following questions and criteria (see Chapter 8 of Higgins 2009):
Sequence generation
Was the allocation sequence adequately generated?
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Yes (low risk of bias), e.g. a computer‐generated random sequence or a table of random numbers
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No (high risk of bias), e.g. date of birth, clinic id‐number or surname
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Unclear (uncertain risk of bias), e.g. not reported
Allocation concealment
Was allocation adequately concealed?
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Yes (low risk of bias), e.g. where the allocation sequence could not be foretold
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No (high risk of bias), e.g. allocation sequence could be foretold by patients, investigators or treatment providers
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Unclear (uncertain risk of bias), e.g. not reported
Blinding
Assessment of blinding will be restricted to blinding of outcome assessors, since it would not be possible to blind participants and treatment providers to the different interventions.
Was knowledge of the allocated interventions adequately prevented during the study?
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Yes (low risk of bias)
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No (high risk of bias)
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Unclear (uncertain risk of bias)
Performance Bias
Was similar care provided to patients in treatment and control groups other than the intervention of interest?
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Yes (low risk of bias), e.g. both groups were followed on similar schedules of neurologic exam and brain imaging
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No (high risk of bias), e.g. each group was followed according to different schedules
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Unclear (uncertain risk of bias), e.g. not reported
Incomplete reporting of outcome data
We will record the proportion of participants whose outcomes were not reported at the end of the study.
Were incomplete outcome data adequately addressed?
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Yes (low risk of bias), if fewer than 20% of patients were lost to follow‐up and reasons for loss to follow‐up were similar in both treatment arms
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No (high risk of bias), if more than 20% of patients were lost to follow‐up or reasons for loss to follow‐up differed between treatment arms
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Unclear (uncertain risk of bias) if loss to follow‐up was not reported
Selective reporting of outcomes
Are reports of the study free of suggestion of selective outcome reporting?
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Yes (low risk of bias), e.g., if review reported all outcomes specified in the protocol
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No (high risk of bias), otherwise
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Unclear (uncertain risk of bias), if insufficient information available.
Other potential threats to validity
Was the study apparently free of other problems that could put it at a high risk of bias?
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Yes (low risk of bias)
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No (high risk of bias)
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Unclear (uncertain risk of bias)
The risk of bias tool will be applied independently by two review authors (AV, CP) and differences will be resolved by discussion. Results will be presented in both a risk of bias graph and a risk of bias summary. Results of meta‐analyses will be interpreted in light of the findings with respect to risk of bias.
Measures of treatment effect
We will use the following measures of the effect of treatment:
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For time to event data, we used the HR, where possible.
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For dichotomous outcomes, we used the RR.
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For continuous outcomes (e.g. QoL measures), we will use the mean difference between treatment arms.
Unit of analysis issues
Unit of analysis issues will be reviewed by two authors (AV, CP) according to Higgins 2009 and differences will be resolved by discussion. These included reports where:
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Groups of individuals were randomized together to the same intervention (i.e. cluster‐randomized trials);
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Individuals undergo more than one intervention (e.g. in a cross‐over trial, or simultaneous treatment of multiple sites on each individual); or
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There are multiple observations for the same outcome (e.g. repeated measurements, recurring events, measurements on different body parts).
Dealing with missing data
We will not impute missing outcome data. For the primary outcome, if data were missing or only imputed data were reported, we will contact trial authors to request data on the outcomes among participants who were assessed.
Assessment of heterogeneity
Heterogeneity between studies will be assessed by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), and by a formal statistical test of the significance of the heterogeneity (Deeks 2001). If there is evidence of substantial heterogeneity, the possible reasons for this will be investigated and reported.
Assessment of reporting biases
Reporting biases will be reviewed and recorded by two review authors (AV, CP).
Data synthesis
If sufficient, clinically similar studies are available, the results will be pooled in meta‐analyses.
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For time‐to‐event data, HRs will be pooled using the generic inverse variance facility of RevMan 5.
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For dichotomous outcomes, the RR will be calculated for each study and then pooled.
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For continuous outcomes, the mean differences between the treatment arms at the end of follow‐up will be pooled if all trials measured the outcome on the same scale, otherwise standardized mean differences will be pooled.
Random effects models with inverse variance weighting will be used for all meta‐analyses (DerSimonian 1986).
Subgroup analysis and investigation of heterogeneity
Outcome measures including OS, PFS, FIS, steroid requirement, seizure frequency, QoL, and adverse effects of radiotherapy will be analyzed after stratifying by (if data are available): age, histologic subtype, tumor size and location, extent of resection, performance score, approach of radiotherapy used (conformal EBRT, IMRT, SRS), types of salvage therapy (repeat resection, repeat radiotherapy, chemotherapy), genetic aberrations (p53 status, 1p / 19q status), date of trial.
Factors such as age, tumor size, histologic subtype, definition used for 'tumor recurrence' and PFS, and length of follow‐up will be considered in interpretation of any heterogeneity.
Sensitivity analysis
Determination of whether sensitivity analysis will be required will be determined by two review authors (AV, CP) and differences resolved through discussion according to Higgins 2009.
