Cerebral gliomas are the most common primary intrinsic brain tumours.
Gliomas are locally invasive and, even after apparently successful macroscopic resection, they recur at the same site in 95% of cases. They rarely spread outwith the central nervous system (<1%), although it has been estimated that CSF spread occurs in up to 5% of cases.
For practical purposes they can be divided into:
- low-grade gliomas (WHO or Dumas-Duport grade 1 and 2);
- high-grade gliomas (WHO or Dumas-Duport grade 3 and 4).
Classification of cerebral gliomas
1 Astrocytic tumours
- Diffuse astrocytoma
- Anaplastic (malignant) astrocytoma
- Pilocytic astrocytoma
- Pleomorphic xanthoastrocytoma
- Subependymal giant cell astrocytoma
2 Oligodendroglial tumours
- Anaplastic (malignant) oligodendroglioma
3 Ependymal tumours
- Anaplastic (malignant) ependymoma
- Myxopapillary ependymoma
4 Mixed gliomas
- Anaplastic (malignant) oligoastrocytoma
5 Choroid plexus tumours
- Choroid plexus papilloma
- Choroid plexus carcinoma
6 Neuroepithelial tumours
- Polar spongioblastoma
- Gliomatosis cerebri
It is not certain whether the type of surgery performed (biopsy versus resection) has any survival benefit other than in patients who are on the verge of coning or who have hydrocephalus (Devaux et al. 1993; Kreth et al. 1993).
There is a place for a randomized controlled trial of biopsy versus resection in patients with glioblastoma multiforme. If biopsy is done, this should be by stereotactic technique rather than freehand, because of the higher complication rate associated with the latter. The goal of resective neurosurgery should be as complete resection as possible along its macroscopic boundaries. If achieved without complications, this provides reliable histological diagnosis, potentially improves the patient's neurological status, and may make the tumour more sensitive for additional therapies (e.g. chemotherapy) (Salcman 1987; Shapiro et al. 1989).
The degree of tumour removal in most studies has been determined by the intraoperative perception of the neurosurgeon. With the increasing availability of neuro-imaging, it has become clear that the surgeon's opinion at the time of operation of what represents a total resection bears little resemblance to the postoperative MRI appearances. Postoperative enhancement on CT scan performed before the fifth postoperative day reflects residual tumour (Jeffries et al. 1981; Cairncross et al. 1985).
Examination of serial postoperative MRI scans has demonstrated that postoperative imaging during days 1–3 after resection of a high-grade glioma avoids artefacts due to postoperative enhancement, and the delineation of tumour was vastly superior to postoperative CT (Albert et al. 1994).
MRI studies have suggested that postoperative residual tumour was a more important prognostic variable than age or performance status, and the incidence of tumour recurrence is directly related to the volume of residual tumour after initial resection (Albert et al. 1994; Berger 1995). However, these results must be interpreted with caution since the selection of patients for aggressive resection based on tumour location and demarcation from surrounding normal tissue may introduce selection bias.
Malignant glioma is one of the most aggressive tumours in humans. It rarely spreads outwith the central nervous system, is highly radioresistant, and has a predilection to locoregional recurrence. Each of these three factors has led to particular approaches to primary treatment and management of ‘recurrence’. There is good randomized controlled evidence from the early 1970s and 1980s that radiation therapy improves survival in patients with high-grade gliomas (Walker et al. 1978, 1980).
Radiation therapy increases the median survival from 4 to 5 months to about 9 months. A randomized controlled trial has demonstrated that 60 Gy (in 30 fractions over 6 weeks) was superior to 45 Gy (in 20 fractions over 4 weeks) and resulted in a prolongation of survival by 3 months in the group treated with 60 Gy. (Bleehen and Stenning 1991).
The current standard practice is to give 60 Gy in 30 fractions over 6 weeks. Radiation therapy is usually directed at the area of the enhancing tumour plus at least a 2 cm margin of peritumoural oedema. Focal radiation (40 Gy in 20 fractions) over 4 weeks to the tumour and peritumoural oedema is usually followed by a further 20 Gy boost to the enhancing tumour and 1–2 cm margin over 2 weeks. The wide margins are because tumour cells can be found 2 cm (or more) from the apparent radiological boundary of the tumour, in areas that simply look ‘oedematous’ on CT or MRI, and most studies demonstrate that relapse occurs within 2 cm of the enhancing rim of the tumour in 80 per cent of cases (Halperin et al. 1989; Wallner et al. 1989).
Boosting the radiation dose to the centre of the tumour is now standard practice in most centres. Dose escalation of radiation, using conformal-beam therapy or stereotactic radiation, aims to treat the centre of the tumour maximally and spare normal tissue outwith the 2 cm margin, to reduce long-term morbidity from radiation damage. Whether either of these approaches will extend survival remains to be seen.
The effect of radiation is greater in the young (under 60 years). In the over-60 age group the effect of radiation therapy remains controversial.
Numerous chemotherapy agents (nitrosoureas, procarbazine, platinum derivatives, etc.) have been shown to reduce tumour size in about one-third of patients in phase II studies (Mahaley 1991). The beneficial effect of chemotherapy has to be balanced with potentially serious side-effects. The risk–benefit ratio will depend on individual patient factors. It may be helpful to re-examine the current evidence of the effectiveness of chemotherapy in the form of answering some questions.
Is the imaging response to chemotherapy related to time to progression or survival? Although one might reasonably think that magnitude of response would be related to duration of response or survival, this has only been demonstrated in patients with anaplastic oligodendroglioma who have achieved a greater than 90 per cent imaging response (Cairncross and Eisenhauer 1995). Magnitude of tumour response has not been demonstrated to be related to duration of response or survival in high-grade glioma (Grant et al. 1997). It has been estimated that therapy must be effective in more than 70 per cent of patients before one would see a significant effect on survival. Imaging may show little change, although there is a profound clinical change.
Response must take into account clinical, imaging, and steroid information. In addition, some patients appear to respond quickly to chemotherapy on imaging but then progress rapidly despite chemotherapy (presumably as a result of acquired resistance).
Other patients respond slowly to chemotherapy, but have more prolonged responses despite discontinuation of chemotherapy (Grant et al. 1997). In patients who do respond to chemotherapy, speed of response is not associated with duration of response. However, in one study where serial measures of tumour volume following chemotherapy were taken, the likelihood of achieving a response was associated with the size of tumour in glioblastoma multiforme, with only small-volume tumours having a response. Tumour volume did not seem to influence the likelihood of achieving an imaging response in patients with anaplastic astrocytoma (Grant et al. 1999).