David Signorini

Primary lymphoma of central nervous system in immunocompetent patients in south-east Scotland

1 O’Sullivan MG, Whittle IR, Gregor A, Ironside JW. Increasing incidence of CNS primary lymphoma in south-east Scotland. Lancet 1991; 338: 895–96. 2 Rosenthal M, Green MD. Cerebral lymphoma. In: Kaye A, Laws ER, eds. Brain tumours. Edinburgh: Churchill-Livingstone, 1995: 841-72. 3 Viswanathan R, Ironside J, Bell JE, et al. Stereotactic brain biopsy in AIDS patients: does it contribute to patient management? Br J Neurosurg 1994; 8: 307–11. Primary lymphoma of central nervous system in immunocompetent patients in south-east Scotland

Application of the MRC brain tumour prognostic index to patients with malignant glioma not managed in randomised control trial

OBJECTIVES The MRC brain tumour prognostic index, which uses clinical variables to place patients in different outcome categories, has not been evaluated on a cohort outside a randomised controlled trial. The aims of this study were to (a) determine in a large cohort of patients, derived solely from one centre and not in a clinical trial, whether the MRC prognostic index stratified patients for outcome; (b) compare actual outcomes with those obtained in the original studies; and (c) examine whether neuropathological diagnosis was an independent prognostic variable. METHODS The MRC prognostic index was calculated for 236 patients with either glioblastoma or anaplastic astrocytoma managed at a dedicated neuro-oncology clinic in Edinburgh between 1989 and 1995. RESULTS For this mixed population of malignant glioma the median survival was 8.6 months. Two year survival was 72.2% for patients with an MRC index score of 1–10; 36.3% for those with an index score of 11–15; 25.1% for those scoring 16–20; 20.4% with those scoring 21–25; 4.8% with those scoring 26–33; and 0% for those scoring 34–38. Exclusion of 79 patients who would not have been eligible for the MRC studies from which the index was derived, because they were either too old or did not receive radiotherapy, still resulted in a similar pattern of stratification but with significantly improved median survival times for the lowest two categories. Multivariate analysis of prognostic variables in the Edinburgh cohort showed that patients with anaplastic astrocytoma did significantly better than those with glioblastoma (p<0.001). CONCLUSIONS Although there were some differences in median survival times between the patients in the original MRC studies and the Edinburgh cohort in similar prognostic categories and a tendency to improved two year survivorship in the Edinburgh cohort these differences have arisen because (a) the Edinburgh cohort was accrued about 10 years later than the MRC cohorts and thus had optimal radiotherapy; and (b) many Edinburgh patients were included in experimental and other chemotherapy studies on relapse. This study has shown that even outside the setting of a prospective controlled trial and with relaxed inclusion criteria the Medical Research Council (MRC) prognostic index is a robust predictor of outcome in patients with malignant glioma. Survival clearly declines as the prognostic index increases. Moreover, the prognostic model can be substantially improved by the addition of histology data, although there is some evidence that this will require complex modelling procedures.

Significant change in tests of neurological impairment in patients with brain tumours

There is a need for valid objective tests of neurological improvement or deterioration to more accurately define response or progression in phase II studies of malignant glioma. The Edinburgh Functional Impairment Tests (EFIT) incorporate objective measures of upper and lower limb function, memory and a rating scale for dysphasia. We examined the intra-observer repeatability of the (EFIT) 24 hours apart in 55 patients with brain tumors and stable neurological disease and the inter-rater repeatability in 33 patients in the peri-operative period (54 dual assessments).Intra-observer studies of the four subtests, failed to demonstrate any learning effect and showed close agreement. Inter-rater studies were affected by a treatment effect (steroids) and identified slight inter-rater bias for the ten meter walk. Altman-Bland plots showed that the level of agreement was less good in patients with more severe impairment. Correction for the severity of handicap was possible using a simple formulae: (timed tests: [rater 1 − rater 2]/[rater 1 + rater 2], Williams Delayed Recall Test [WDRT] (rater 1 − 2/81). Using this correction, all intra- and inter-rater variance of patients tested within 12 hours were < 0.2.A change of ≥ 0.2 for the timed tests and WDRT, and a change in dysphasia score of ≥ 2, represent a significant change in impairment using the EFIT. The EFIT should be a useful addition in phase II studies where objectively recording response or time to progression is important.

Families of trials: the answers to all our questions?

Many of the important clinical decisions we make on a daily basis in stroke medicine are not supported by adequate evidence. This leads to variations in practice. If practice influences outcome, this must be regarded as unacceptable since it implies that many patients are receiving sub-optimal treatment. Where the advantages of certain treatment policies over others are only moderate, large randomised clinical trials provide the most reliable evidence of effectiveness. However, only a tiny proportion of patients with stroke are randomised in trials. Instead, the majority are exposed to treatments allocated haphazardly, rather than randomly, which serves only to delay the emergence of evidence concerning the relative merits of alternative treatment approaches. We suggest that we might increase the proportion of patients who contribute to advancing our knowledge by developing ‘families’ of trials. A ‘family’ would comprise a series of randomised trials into which patients with stroke may be enrolled either simultaneously or sequentially into one or more of the trials which would share common systems for randomisation and follow-up. Such a system would facilitate large, simple, randomised trials, reduce research costs, increase the generalisability of trial results and allow clinicians and patients to contribute to advancing our knowledge whenever they are uncertain about the best treatment. In this article, we discuss the advantages of this approach, some of the problems and their potential solutions.