UC Irvine

Abstract Introduction: Low-grade gliomas (LGG, WHO grade I-II) account for 16.9-22% of all primary brain tumors. Management of these tumors consists of surgery, sometimes followed by radiation and/or chemotherapy. A rigorous, quantitative evaluation of the literature investigating the management of LGG has never been published. Methods: We conducted an exhaustive, PRISMA-compliant systematic review of the literature from January 1966 to September 2016 comparing the association of chemotherapy, radiation, or extent of resection with survival and progression-free survival at 2, 5, and 10 years in LGG. Included studies were graded for quality using AAN criteria. Pre-specified data were extracted and summary statistics were calculated using the inverse variance method and random effects model. Results: Five studies (n=567) report on LGG patients treated with chemotherapy. The relative risk (RR) and 95% confidence intervals [95% CI] for death (chemotherapy vs. no chemotherapy) at 2, 5, and 10 years was 1.34 [0.85-2.12], 0.83 [0.64-1.09], and 0.77 [0.58-1.03]. RR for progression at 2, 5, and 10 years was 0.92 [0.64-1.33], 0.69 [0.55-0.87, p=0.001], and 0.58 [0.39-0.87, p=0.008]. A sensitivity analysis of OS including only class I and II studies showed a RR of death (chemotherapy vs. no chemotherapy) at 2, 5, and 10 years of 1.23 [0.72-2.08], 0.78 [0.58-1.05, p=0.1], and 0.69 [0.56-0.86, p=0.0006]. Among only IDH1-mutated patients, the RR of progression with chemotherapy compared to control at 2, 5, and 10 years was 0.48 [0.06-4.1], 0.27 [0.08-0.84, p=0.02], and 0.21 [0.03-1.59]. Ten studies (n=1918) provide data regarding the effect of post-operative radiation vs. delayed or no radiation. RR and 95% CI for death at 2, 5, and 10 years was 0.92 [0.53-1.58], 0.93 [0.60-1.43], and 0.99 [0.69-1.41]. RR for progression at 2, 5, and 10 years was 0.66 [0.51-0.86, p=0.002], 0.73 [0.61-0.88, p=0.0008], and 0.74 [0.60-0.91, p=0.005]. Twenty-three studies (n=3891) compare gross total resection (GTR) vs. subtotal resection (STR) in LGG. RR and 95% CI of death at 2, 5, and 10 years (GTR vs. STR) was 0.29 [0.17-0.52, p<0.0001], 0.39 [0.29-0.51, p<0.00001], and 0.50 [0.35-0.70, p<0.0001]. RR of progression (GTR vs. SR) at 2, 5, and 10 years was 0.37 [0.24-0.57, p<0.0001], 0.50 [0.39-0.64, p<0.0001], and 0.67 [0.53-0.84, p=0.0005]. Relevant prognostic factors were also analyzed. For all three treatment subsets combined, only 6 studies provided class I or II evidence, and then only for the OS endpoint. Conclusions: This analysis, the largest systematic review and only quantitative systematic review performed on these questions, suggests that early post-operative radiation and chemotherapy may improve PFS in patients with LGG. Chemotherapy may also improve OS. GTR (compared with STR) is associated with substantially improved OS and PFS. Due to the lack of high quality prospective trials, additional rigorous studies are needed.