Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials

BACKGROUND Trials on the effect of systemic chemotherapy on survival and recurrence in adults with high-grade glioma have had inconclusive results. We undertook a systematic review and meta-analysis to assess the effects of such treatment on survival and recurrence. METHODS We did a systematic review and meta-analysis using updated data on individual patients from all available randomised trials that compared radiotherapy alone with radiotherapy plus chemotherapy. Data for 3004 patients from 12 randomised controlled trials were included (11 published and one unpublished). FINDINGS Overall, the results showed significant prolongation of survival associated with chemotherapy, with a hazard ratio of 0.85 (95% CI 0.78-0.91, p<0.0001) or a 15% relative decrease in the risk of death. This effect is equivalent to an absolute increase in 1-year survival of 6% (95% CI 3-9) from 40% to 46% and a 2-month increase in median survival time (1-3). There was no evidence that the effect of chemotherapy differed in any group of patients defined by age, sex, histology, performance status, or extent of resection. INTERPRETATION This small but clear improvement in survival from chemotherapy encourages further study of drug treatment of these tumours.

[1]  K. Dickersin,et al.  Systematic Reviews: Identifying relevant studies for systematic reviews , 1994 .

[2]  Jensen,et al.  Combined modality treatment of operated astrocytomas grade 3–4. A prospective and randomized study of misonidazole and radiotherapy with two different radiation schedules and subsequent CCNU chemotherapy , 1984 .

[3]  E L Kaplan NON-PARAMETRIC ESTIMATION FROM INCOMPLETE OBSERVATION , 1958 .

[4]  T. Fleming,et al.  Dianhydrogalactitol and radiation therapy. Treatment of supratentorial glioma. , 1979, JAMA.

[5]  K. Dickersin The existence of publication bias and risk factors for its occurrence. , 1990, JAMA.

[6]  G. Bonadonna,et al.  Controlled study with BCNU vs. CCNU as adjuvant chemotherapy following surgery plus radiotherapy for glioblastoma multiforme. , 1979, Cancer clinical trials.

[7]  D P Byar,et al.  Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. , 1980, The New England journal of medicine.

[8]  K. Takakura,et al.  Effects of ACNU and radiotherapy on malignant glioma. , 1986, Journal of neurosurgery.

[9]  D P Byar,et al.  Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. , 1983, Cancer treatment reports.

[10]  T. Trojanowski,et al.  Postoperative radiotherapy and radiotherapy combined with CCNU chemotherapy for treatment of brain gliomas , 1988, Journal of Neuro-Oncology.

[11]  M. Brock,et al.  Long-term survival and recurrence-free interval in combined surgical, radio- and chemotherapy of malignant brain gliomas , 1985, Clinical Neurology and Neurosurgery.

[12]  W. Taylor,et al.  Controlled study of CCNU and radiation therapy in malignant astrocytoma. , 1976, Journal of neurosurgery.

[13]  M. Clarke,et al.  Identifying relevant studies for systematic reviews , 1995, BMJ.

[14]  L. Stewart,et al.  Practical methodology of meta-analyses (overviews) using updated individual patient data. Cochrane Working Group. , 1995, Statistics in medicine.

[15]  D. Schoenfeld,et al.  Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas . A joint radiation therapy oncology group and eastern cooperative oncology group study , 1983, Cancer.

[16]  N. Bleehen,et al.  An overview of published results from randomized studies of nitrosoureas in primary high grade malignant glioma. , 1987, British Journal of Cancer.

[17]  P. Band,et al.  Radiotherapy and CCNU in the treatment of high-grade supratentorial astrocytomas. , 1976, Journal of neurosurgery.

[18]  A. Riccio,et al.  CCNU‐chemotherapy of hemispheric supratentorial glioblastoma multiforme , 1980, Cancer.

[19]  Garrett Mj,et al.  A comparison of radiotherapy alone with radiotherapy and CCNU in cerebral glioma. , 1978 .

[20]  T. Trojanowski,et al.  Postoperative radiotherapy and radiotherapy combined with CCNU chemotherapy for treatment of brain gliomas. , 1988, Journal of neuro-oncology.

[21]  R. Peto,et al.  Beta blockade during and after myocardial infarction: an overview of the randomized trials. , 1985, Progress in cardiovascular diseases.

[22]  E. Alexander,et al.  Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. , 1978, Journal of neurosurgery.

[23]  D. Áfra,et al.  Combined radiotherapy and chemotherapy with dibromodulcitol and CCNU in the postoperative treatment of malignant gliomas. , 1983, Journal of neurosurgery.

[24]  L. Freedman,et al.  A comparison of radiotherapy alone with radiotherapy and CCNU in cerebral glioma. , 1978, Clinical oncology.

[25]  M. Parmar,et al.  Meta-analysis of the literature or of individual patient data: is there a difference? , 1993, The Lancet.

[26]  R. Hatlevoll,et al.  Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: A prospective multicenter trial of the scandinavian glioblastoma study group , 1981, Cancer.

[27]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[28]  P. Graham Meta‐analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults , 1993, Cancer.

[29]  E. Housepian,et al.  Adjuvant nitrosourea therapy for glioblastoma. , 1976, Archives of neurology.

[30]  N. Bleehen,et al.  A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. , 1991, British Journal of Cancer.

[31]  R. J. Hayes,et al.  Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. , 1995, JAMA.

[32]  D. Áfra,et al.  Adjuvant therapy with dibromodulcitol and BCNU increases survival of adults with malignant gliomas , 1994, Neurology.

[33]  M. Clarke,et al.  Systematic reviews using individual patient data: a map for the minefields? , 1998, Annals of oncology : official journal of the European Society for Medical Oncology.