Description of the condition
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 (Surma-aho 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.
Description of the intervention
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.
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 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.
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 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.