Treatment of recurrent high grade astrocytoma; results of a systematic review of 1415 patients

Objective: The optimum treatment strategy for recurrent high grade glioma (anaplastic astrocytoma and glioblastoma multiforme) remains undefined. The objective of this report is to present a systematic analysis of the published clinical trial literature on the therapy of this disease. Methods: A study protocol was prospectively developed outlining the objectives and methods of the analysis such as; literature search strategy, eligibility criteria for published trials to be included, key data elements to be extracted, and a plan for statistical analysis. Variables of interest were, those describing key features of the study such as publication date and geographic location of repelling institution, characteristics of study population including functional status, details of patient treatment, treatment sequencing and data on clinical outcomes of interest, i.e. time to tumor progression and overall survival. Data were analyzed using SAS version 6.11. Summary statistics were calculated for the primary outcome variables. Data on recognized prognositic variables were recorded in order to adjust the analysis for these parameters. Results: A total of 40 trials (36 non-randomized controlled trials; nRCTs and 4 randomized controlled trials:RCTs) were included in the analysis. Thirty-two of the eligible trials were chemotherapy trials while 7 were radiation therapy trials. One surgical trial met eligibility criteria. A total of 47 treatment arms were analysed which included 1415 patients. Five chemotherapy groups were studied, i.e. interferons nitrosoureas, platinums platinums+nitrosoureas and others. The nitrosoureas were found to significantly extend time to tumor progression compared to all other drugs (26.9 weeks). The nitrosoureas and platinums appear to be the most active agents with regard to overall survival (over 32.0 weeks) as compared with the other drug categories. Patients treated with both a nitrosourea and a platinum compound showed the longest overall survival (40.0 weeks) although this was not significantly different from these drugs used as single agents. Average median survival for patients treated with radiation therapy was 44.7 weeks although selection bias makes these data difficult to compare with those derived from studies of chemotherapy. No definite conclusions can be made regarding surgical therapy in this setting due to limited data. Conclusions: The nitrosoureas and platinums, either as single agents or as combination chemotherapy, appear to be the most active agents in this disease although few, well designed chemotherapy trials are available for analysis. Due to the limitations of the available data on radiation therapy and surgery, as outlined in this report, additional well designed clinical trials are needed to define the appropriate role for these modalities in the treatment of recurrent high grade glioma.