Robert Grant

Rates of inclusion of teenagers and young adults in England into National Cancer Research Network clinical trials: Report from the National Cancer Research Institute (NCRI) Teenage and Young Adult Clinical Studies Development Group

Poor inclusion rates into clinical trials for teenagers and young adults (TYA; aged 13–24 years) have been assumed but not systematically investigated in England. We analysed accrual rates (AR) from 1 April 2005 up to 31 March 2007 to National Cancer Research Network (NCRN) Phase III trials for the commonest tumour types occurring in TYA and children: leukaemia, lymphoma, brain and central nervous system, bone sarcomas and male germ cell tumours. AR for 2005–2007 were 43.2% for patients aged 10–14 years, 25.2% for patients aged 15–19 years, and 13.1% for patients aged 20–24 years in the tumour types analysed. Compared with accrual from 1 April 2005 to 31 March 2006, AR between 1 April 2006 and 31 March 2007 increased for those aged 10–14 and 15–19 years, but fell for those aged 20–24 years. AR varied considerably among cancer types. Despite four trials being available, patients over 16 years with central nervous system tumours were not recruited. Rates of participation in clinical trials in England from 2005 to 2007 were much lower for TYA older than 15 years compared with children and younger teenagers. The variations in open trials, trial age eligibility criteria and extent of trial activation in treatment centres in part explain this observation. Other possible influences, such as difficulties associated with the consent of TYA require further evaluation. Closer dialogue between those involved in planning and running trials for children and for adults is necessary to improve trial availability and recruitment. Further research is required to identify trends in trial availability and accrual for those tumours constituting the remaining 26% of TYA cancers.

Recording neurological impairment in clinical trials of glioma

SummaryThe criteria for clinical response to treatment in cerebral glioma remain poorly defined, but could be made more objective if simple measures of neurological impairments were included in the definitions. We assessed the utility of simple fast previously validated tests of limb impairment (Timed nine hole peg test and 10 meter walk), memory (Williams delayed recall test) and language (Boston Aphasia Severity Rating Scale) in fifty patients with primary brain tumours to see if they could act as a surrogate for neurological impairment. The tests were compared with established measures of physical disability (Barthel Disability Index [BDI]) and handicap.Timed tests of hand function and gait were sensitive to minor impairments and were abnormal in patients with physical disability on BDI. Timed tests correlated well with handicap (rank correlation 0.734). Short term memory was impaired more commonly with tumours involving the left hemisphere (p < 0.01). Dysphasia limited testing of memory in 8%. Depression was associated with problems in limb function (p < 0.01), memory (p < 0.001), language (p < 0.001), BDI (p < 0.001) and handicap (p < 0.001). The number of abnormal fast tests also correlated with the severity of handicap (rank correlation 0.786) indicating that memory impairment and aphasia contribute to handicap and should be assessed. Median time to complete all assessments was 7 minutes 20 seconds.Utilization of these simple tests will add sensitivity and objectivity to evaluation of neurological response in clinical trials and can be performed quickly by non medical staff.

Incidence studies of primary and secondary intracranial tumors : A systematic review of their methodology and results

We reviewed the incidence studies of intracranial tumors to compare their methodology and identify whether there was evidence of true differences in incidence by time, place, age, or sex. Studies were identified from Medline (1966–95), bibliographies of relevant articles, and personal knowledge. For each study, various methodological details were recorded, along with the age-standardized incidence of all primary tumors and the crude and age/sex-specific incidences of different types of intracranial tumor. Methodological factors which significantly influenced the reported incidence were identified and the results of different studies were compared and combined in a meta-analysis if appropriate. Twenty studies (over 20,000 primary tumors) were included. Higher incidences of primary tumors were found in studies that: used many methods to identify cases (odds ratio [OR] 1.92); included a high percentage of asymptomatic patients (OR 2.03); did not require histologic confirmation of the diagnosis (OR 1.69). Studies from the 1980s reported higher incidences than in previous decades (OR 1.51), probably because of improved methodology. Comparable studies from the 1980s gave widely different incidence rates for all primary tumors (7.1–18.6 per 100,000 per year). In all studies, the incidence of neuroepithelial and meningeal tumors increased dramatically with age. Neuroepithelial tumors were 40% more common in men, whilst meningeal and cranial nerve tumors were about 80% and 40% more common in women, respectively. Further incidence studies are required to establish geographical and secular variations in the incidence of primary intracranial tumors but these must use comparable methodologies. Provisional guidelines for future studies are given.

Glutathione S-transferases and cytochrome P450 detoxifying enzyme distribution in human cerebral glioma

Malignant astrocytomas are frequently resistant to cytotoxic chemotherapy. A possible mechanism of chemoresistance is drug inactivation within malignant astrocytes by detoxifying enzymes (glutathione transferases (GST) and cytochrome P450s). The aim of this study was to assess whether there was differential expression of these detoxifying enzymes in the central nervous system and any relationship to histological grade (WHO) of the tumours.Immunostaining was performed in 30 consecutive glioma samples, using class specific polyclonal antibodies to subtypes of GST (pi, alpha, mu) and to human cytochrome P450 reductase.GST immunostaining was evident in astrocytes and endothelium but not neurones or oligodendrocytes in normal brain. Immunostaining for GST increased in intensity from well differentiated tumours to glioblastoma. Staining was least evident in surrounding normal brain, strong in reactive astrocytes and astrocytic tumour cells and very intense in gemistocytic and giant tumour cells. Small anaplastic tumour cells had very little GST staining. Where endothelial proliferation was evident, GST staining in endothelial cells was increased. Pi was always the predominant subclass, although GST alpha and mu were also expressed in some tumours. Cytochrome P450 reductase immunostaining was present in normal neurones and malignant astrocytes.Gemistocytic astrocytic tumour cells stained intensely. Further work is necessary to see if there is any correlation between immunostaining intensity survival or response to chemotherapy.

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.

Imaging response to chemotherapy with RMP-7 and carboplatin in malignant glioma: size matters but speed does not

AbstractIntroduction In recurrent malignant glioma, early imaging response to two courses of chemotherapy is generally considered to be predictive of good survival. We studied the relationships between initial tumour volume and speed of imaging response to chemotherapy in malignant glioma. Methods In 43 chemotherapy naïve patients, 26 glioblastoma multiforme (GBM) + 17 anaplastic astrocytoma (AA), median age 45 years, MRI responses to intravenous cereport and carboplatin were assessed at baseline, then at 2 monthly intervals. Patients were classified as fast responders if they had reached a partial response (PR) after two courses, and slow responders if PR was achieved after three or more courses of chemotherapy. Results PR occurred in four patients with GBM (15%) and nine patients with AA (53%). Likelihood of response was related to initial tumour enhancing volume in GBM but not in AA. PR occurred in four of five GBM patients (80%) with initial volume <15,000 mm3 and none of the 21 cases with an initial volume >15,000 mm3. In patients achieving a PR, there was no association between speed or duration of response and eventual survival. Fast responders with AA were significantly older than slow responders (p = 0.033). Conclusions Initial enhancing volume of GBMs may be an important predictor of imaging response. This has implications where response rates of phase II studies are reported and in stratification for phase III trials. Further work is necessary to confirm these findings with other types of chemotherapy and examine the relationship between proliferation markers and speed of response.

LEVETIRACETAM IS INDEPENDENTLY ASSOCIATED WITH FATIGUE IN ADULT GLIOMA OUTPATIENTS

Aims To identify the frequency and severity of fatigue in adults with cerebral glioma, and its association with anti-epileptic drugs (AED). Methods Cross-sectional study. Stable glioma patients attending Edinburgh Neuro-Oncology clinic completed a fatigue Visual Analogue Scale (range 0-100mm, “high” >=60 mm). AED type and dose were recorded. Results One hundred and sixty six patients were enrolled (61% males; mean age 49 yrs; 70% high-grade glioma). Among all patients, 43% reported high fatigue (95% CI 35–50%). Sixty eight percent were taking AEDs (58% of which were non enzyme inducing). Levetiracetam (LEV) was the most common AED. LEV monotherapy correlated with higher fatigue levels (mean=57 mm, SD 5.2, 95% CI 46–67 mm), compared with other AEDs (mean=43 mm, SD 3.9, 95% CI 35–50 mm, ANCOVA p=0.04). Patients taking LEV had poorer Karnofsky Performance Scores (KPS, Mann–Whitney p=0.03). The effect of LEV on fatigue was independent of KPS (LR p<0.0001, R2= 27.7, OR 2.7 [1.1–6.2]). Conclusions Glioma patients on levetiracetam therapy are more fatigued than patients on other or no anti-epileptic therapy. Changes to AED medications may benefit patients with troublesome fatigue.

Use of different outcome measures in randomised studies of malignant glioma can significantly alter the interpretation of time to progression: Reanalysis of the MRC BR2 study

The Medical Research Council (MRC) BR2 study [1] is a randomised trial of two doses of cranial radiation for patients with malignant glioma. We reanalysed data to examine the effect of using change in ranked scales of neurological status (MRC Neurological Status Scale) and performance (World Health Organisation Scale: WHO) to determine progression rather than clinicians impression.Four hundred and seventy four patients were studied. Where clinicians recorded no progression, ranked scales frequently documented progression (MRC 13%; WHO 13%). Where clinicians recorded progression, ranked scales frequently did not alter (MRC 33%; WHO 30%) or occasionally improved (MRC 5%; WHO 3%). When analysing time to progression based on a variety of measures, the estimated difference between treatments was most extreme (hazard ratio 0.81, logrank p=0.04) when change in WHO status was used, and least extreme when change in MRC neurological status was used (hazard ratio 0.99, p=0.94).This study highlights how different outcome measures can significantly alter the interpretation of randomised studies.