External beam radiation dose escalation for high grade glioma

Background The incidence of high grade glioma (HGG) is approximately 5 per 100,000 person-years in Europe and North America. Objectives To assess the effects of postoperative external beam radiation dose escalation in adults with HGG. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE (1977 to October 2015) and Embase (1980 to end October 2015) for relevant randomised phase III trials. Selection criteria We included adults with a pathological diagnosis of HGG randomised to the following external beam radiation regimens. 1. Daily conventionally fractionated radiation therapy versus no radiation therapy. 2. Hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy. 3. Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy. 4. Accelerated radiation therapy versus daily conventionally fractionated radiation therapy. Data collection and analysis The primary outcomes were overall survival and adverse effects. The secondary outcomes were progression-free survival and quality of life. We used the standard methodological procedures expected by Cochrane. We used the GRADE approach, as outlined by Cochrane, to interpret the overall quality of the evidence from included studies. Main results We included 11 randomised controlled trials (RCTs) with a total of 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for HGG participants receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 (95% confidence interval (CI) 1.58 to 2.55, P < 0.00001), moderate GRADE quality evidence favouring postoperative radiotherapy. Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data. Overall survival was similar between hypofractionated versus conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17, P = 0.63), very low GRADE quality evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one patient in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data. Overall survival was also similar between hypofractionated versus conventional radiotherapy in the subset of two trials (293 participants) which included 60 years and older participants with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46, P = 0.21), high GRADE quality evidence. There were two trials which compared hyperfractionated radiation therapy versus conventional radiation and one trial which compared accelerated radiation therapy versus conventional radiation. However, the results could not be pooled. The conventionally fractionated radiation therapy regimens were 4500 to 6000 cGy given in 180 to 200 cGy daily fractions, over 5 to 6 weeks. All these trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher. The risk of selection bias was generally low among these randomized trials. The number of participants lost to follow-up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life. Authors' conclusions Postoperative conventional daily radiotherapy improves survival for adults with good performance status and HGG as compared to no postoperative radiotherapy. Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, particularly for individuals aged 60 and older with glioblastoma. There is insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy). There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These poor prognosis HGG individuals have generally been excluded from the randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these poor prognosis patients.