Evaluation of Symptomatic Versus Asymptomatic Recurrences in Patients with Glioblastoma Multiforme (GBM)

Glioblastoma multiforme (GBM) is a nearly uniformly fatal brain tumor with a median recurrence rate of 8 months and survival of 14 months after multimodality treatment. We sought to evaluate outcomes based on the presence or absence of symptoms at the time of recurrence. We retrospectively analyzed 60 patients with GBM treated from 2007-2014 at our institution. All patients received radiation therapy with concurrent temozolomide. All patients had a documented symptomatic or radiographic recurrence. Symptomatic recurrence was defined as development of new or recurring symptoms prior to evidence of radiographic recurrence; those in this group had follow-up imaging confirming recurrence. Radiographic recurrence was defined as unequivocal evidence of recurrence on MRI; these individuals did not have symptoms at the time of recurrence. All cases were reviewed and confirmed as recurrences at multidisciplinary tumor board review. Overall survival (OS) was defined as time from the completion of initial radiation therapy to death, while post-relapse survival was defined as the time from recurrence to death. Median age for the symptomatic and radiographic group was 58 and 57 years respectively. The symptomatic group consisted of more male patients (63%) compared to the radiographic cohort (50%). Recursive partitioning analysis (RPA) classes were similar between both groups. MGMT and IDH-1 status were unknown in the majority of patients. Median tumor size (greatest diameter) was larger in the symptomatic group, 46 mm vs 40 mm. The median time to recurrence was 9.5 mos (range 3-49 mo). Forty relapses (66.7%) were symptomatic; 20 (33.3%) were radiographic. Median OS for the symptomatic and radiographic cohort were 15.5 mo and 20 mo respectively, a relative difference of 4.5 mo (p = 0.090). Post-relapse survival was 3 months in patients who recurred symptomatically and 10 mo for those that recurred by imaging (p= 0.005). Among the radiographic recurrence cohort, those who later went on to develop symptoms also had a median survival from symptom onset of 3 mos, equivalent to the symptomatic recurrence group. OS is worse in GBM patients who present with symptoms at the time of recurrence. The development of clinical symptoms is also significantly predictive of post-relapse survival, though a component of this may be due to lead time bias. While median OS only trended toward significance between cohorts, this difference in survival between symptomatic and asymptomatic recurrences is relatively large and should be validated in larger patient cohorts. If this difference is confirmed, we would suggest that future studies evaluating treatment options in the recurrent setting may need to stratify patients based on presence of symptoms at the time of enrollment.