Description of the condition
Intracerebral tumours (tumours that arise within the brain) attract significant research interest due to their poor prognosis. These tumours are graded on a scale from I to IV as defined by the World Health Organisation (WHO) classification of tumors of the central nervous system (CNS), which is based on a malignancy scale and proliferative potential of the tumour (Kleihues 1993; Louis 2007), i.e. how fast they grow and how likely they are to spread.
When intracerebral tumours develop from the supporting tissue of the brain (glial cells), they are known as gliomas. Gliomas may be of different grades of severity, ranging from very slow growing grade 1 tumours to more aggressive grade 3 (anaplastic) or grade 4 (glioblastoma) tumours. Grade 1 and grade 2 tumours are known as low-grade gliomas (LGGs) whereas grade 3 and 4 - the most aggressive and infiltrating types - are known as high-grade gliomas (HGGs), or malignant gliomas. Malignant or HGGs are perceived as incurable, with a median survival following surgical resection alone of approximately three months (Davis 1998). They are characterised by the presence of necrosis, are highly proliferative and invasive, and infiltrate without definite boundary. Common clinical symptoms include a mixture of headache, focal neurological deficits, epileptic seizures, altered mental state and gait dysfunction (Bredel 1997; Croteau 2001; Reddy 2003; Grant 2004; Rooney 2011).
There are three main types of HGGs, which are named according to the cell types they resemble:
ependymomas, which develop from ependymal cells which line the cavities in the brain;
oligodendrogliomas, that arise from oligodendrocytes, which produce fatty coverings to insulate the nerves and are usually found in the temporal or frontal lobes; and
astrocytomas, developing from star-shaped cells, astrocytes, which perform a variety of functions relating to supporting the biochemical composition of the fluid which acts as a nutrient to neurons and endothelial cells that forms the blood brain barrier and formation of the brain's framework.
The majority of HGGs are anaplastic oligodendrocytomas (AO) and astrocytomas (glioblastoma multiforme (GBM), anaplastic astrocytoma (AA)).
Each year, there are 6 to 8 new cases of glioma per 100,000 population and for GBM approximately 3 to 4 per 100,000 in the USA (Christensen 2011); 8 per 100,000 in the UK (Counsell 1996); and 200 cases per year in Norway (Storstein 2011). The peak age of onset is between 50 and 60 years. Epidemiological surveys show that survival rates at 2, 3, 4 and 5 years after diagnosis are 27.3%, 16.7%,12.9% and 6.1%, respectively ( Stupp 2005; Storstein 2011).
Description of the intervention
Up to now, there is no treatment approach to cure gliomas. Currently, the recommended treatment option is surgery (biopsy or resection) followed by radiation therapy alone or in combination with chemotherapy (Desjardins 2005; Stupp 2005). Conventional chemotherapeutic agents are given intravenously or orally at relatively high dosage. Some practitioners have hypothesised that the unsatisfactory outcomes and frequent systemic adverse effects associated with these agents could be avoided by the use of intra-arterial chemotherapy (the administration of chemotherapeutic drugs by injection into the artery supplying the tumour) (Emerich 2000; Neyns 2010).
Research has shown that intra-arterial chemotherapy was able to deliver localised and elevated concentration of chemotherapeutic agents within the tumour site, and thus lower systemic exposure (Shapiro 1992; Hiesiger 1995; Imbesi 2006). However, the risk of local adverse effects from carotid artery infusion of chemotherapy, such as optic nerve neuropathy, local pain in the carotid distribution, and focal encephalopathy, remains unknown.
How the intervention might work
The major arteries supplying the front of the brain are the carotid arteries, while the back of the brain is supplied by the vertebral arteries and basilar arteries. There are two carotid arteries, one on each side of the neck. If a tumour is confined to one side of the front part of the brain, the tumour's blood supply generally comes from only one of the carotid arteries. Chemotherapy drugs given into the carotid artery (intra-arterial chemotherapy) can be given at a lower dose than would be required if they were given by oral route or into the vein. The concentration of chemotherapy reaching the glioma will be the same or possibly higher than if it were given by oral or intravenous routes (Basso 2002; Newton 2005). As a result, the side effect profile of intra-arterial chemotherapy is different, with more common local side effects due to local damage to the artery or to the organs supplied by that carotid artery on that side of the brain or the eye on the same side. In some cases it is possible to deliver the chemotherapy beyond the level at which the artery to the eye leaves the carotid artery (supra carotid injection) in an attempt to minimise toxicity to the eye. The side effects must be balanced against the toxicity of other chemotherapy routes, which include bone marrow disturbances, and lung or neurological effects from temozolomide, nitrosourea, procarbazine, vincristine or platinum drugs, and which tend to be related to the total dose given.
Why it is important to do this review
There is uncertainty about the role of intra-arterial chemotherapy in treating HGG and if this route of administration is superior to conventional routes in terms of patients' tolerance and adverse effects.We feel that a systematic review to answer these clinical questions is warranted. A previous review observed there was no survival advantage of intra-arterial chemotherapy over intravenous drug delivery. The incidence of serious neurotoxicity was reduced, but the risk of acute complications still contraindicated wider use outside the setting of a clinical trial (Basso 2002).
We aim to determine if intra-arterial chemotherapy is better than conventional treatments and to establish if increased local drug concentration can translate into a clinical advantage, or increases local eye and central nervous system complications.