Guidance on the use of temozolomide for the treatment of recurrent malignant glioma (brain cancer)

There has been only 1 randomised controlled trial (RCT) of 225 patients involving temozolomide versus procarbazine alone in patients with recurrent glioblastoma multiforme (GBM). There are no trials of temozolomide in anaplastic astrocytoma (AA). All patients in the GBM trial had received radiotherapy and two‑thirds had also received first‑line nitrosourea‑based chemotherapy. Patients were required to have a histologically proven supratentorial GBM or gliosarcoma at first relapse, recurrence or progression (as assessed by imaging), Karnofsky performance status of 70 or more and a projected life expectancy of 12 weeks or more at entry.

Progression‑free survival in the RCT at 6 months was 21% for those on temozolomide, compared with 8% for those on procarbazine (a statistically significant difference, p=0.008). The 6‑month survival was 60% for temozolomide and 44% for procarbazine (also a significant difference, p=0.019), however the median survival advantage of 6 weeks in favour of temozolomide was not statistically significant.

Procarbazine alone is rarely if ever used in first line therapy in the UK and a more appropriate control arm for the UK might have been PCV (procarbazine with lomustine and vincristine) or lomustine alone. As this comparison has not been carried out, there is no direct evidence that temozolomide is more effective than a current UK standard treatment.

Six preliminary or phase 2 single‑group studies each with over 40 patients, and several smaller such studies have been undertaken. The main results are that about 5% of GBM patients show a partial response to temozolomide (aggregate tumour volume halved) and for some 30% to 40% the disease exhibited no progression for a period of time. In other forms of malignant glioma about 10% show a complete response to temozolomide (disappearance of all enhancing tumours in neuroimaging), a further 25% a partial response and about 30% exhibit a period of no progression.

Importantly for an incurable condition such as GBM, the quality of life for patients on temozolomide improves significantly prior to the onset of further disease progression, though it deteriorates rapidly thereafter. A similar trend is apparent following recurrence of other malignant gliomas but the evidence is less robust.

There is insufficient evidence to assess the clinical effectiveness of temozolomide as first‑line chemotherapy. Therefore, its cost‑effectiveness in this indication has not been considered any further.

Where first‑line chemotherapy with PCV has failed, temozolomide should be compared with the only alternative, which is best supportive care. However, the only data compares the benefits of temozolomide with those of procarbazine alone. Costs per cycle of temozolomide are estimated to be £1,488 including hospital costs and medications for side effects.

Estimating cost per quality adjusted life year (QALY) is difficult because the extension of median survival time is not statistically significant, and the quality of life data are limited. The main benefit of temozolomide is that a proportion of patients benefit from a longer progression free survival time. Therefore the most useful measure of cost‑effectiveness is cost per progression free week. Costs will continue to accrue if patients remain progression free, because further cycles of the drug will be given until progression occurs.

For glioblastoma multiforme (GBM), the median estimate of progression‑free survival, using temozolomide was 12.4 weeks, and using procarbazine, 8.3 weeks (a difference of 4.1 weeks, p=0.006). The incremental cost of temozolomide against procarbazine was £4,044, giving an incremental cost per progression‑free week of £1,000. The cost per progression‑free week for temozolomide against placebo (assuming the placebo would have no cost and no effect) would have been £400.

For anaplastic astrocytoma (AA), the figures are more uncertain than for GBM, as there is no RCT on which to base estimates, only single group studies. On the basis that for temozolomide the median estimate of progression free survival is 11 weeks in AA, and that none of this is a placebo effect, the cost per progression‑free week would be £410.

For GBM, the costs per life year gained are as follows. For an estimated gain in median progression free survival of 4.1 weeks associated with a gain in total survival of 6 weeks, and for no incremental gain in utility due to an improved quality of life, the incremental cost per life year gained of temozolomide against procarbazine for GBM is estimated to be £35,000. The cost per life year gained of temozolomide for GBM against PCV is not known.

For AA, assuming an estimated gain in progression free survival of 11 weeks and in total overall survival of 12 weeks, with no incremental gain in utility due to an improved quality of life, and assuming no placebo effect, the cost per life‑year gained of temozolomide is estimated to be £35,000. The cost per life‑year gained of temozolomide for AA against PCV is not known.

Whilst the indirect and informal costs of malignant glioma may be substantial, the change in these costs when temozolomide is introduced is unlikely to be large. Therefore the costs per unit of benefit will not alter to any extent from those reported above when these costs are included in the calculations.