Demographics
Fifty-six patients with full data sets were included in the analysis out of 69 records of potentially suitable study enrollees. Their demographic, clinical, and volumetric characteristics are summarized in Table 1. The median follow-up duration was 21.5 months after diagnosis and 12 months after the Gliadel® surgery. The mean ± SE age at Gliadel® surgery was 51.8 ± 1.8 (range 19-77) years, with a slight male predominance (62.5%). The preoperative KPS was available for 40 patients, 39 of whom had KPS>70. Twenty patients were treated with steroids before undergoing the Gliadel® surgery, consisting of a mean daily dose of 6.5 ± 1.2 mg of dexamethasone. Thirty-six patients (64.3%) had a left-sided tumor. The most common cause for admission for surgery was radiological recurrence without any associated neurologic symptoms (n=22, 39.3%). Among symptomatic patients at the time of Gliadel® surgery, headache and speech deficits (17.8% and 16.1%, respectively) were the most common. Some patients had more than one symptom at presentation.
The mean time between the first surgery and the Gliadel® surgery was 14 ± 2.1 months. Four patients (7.1%) underwent Gliadel® implantation during the third resection (i.e., the second recurrence). The mean extent of tumor resection (EOR) was 93.9% ± 0.9%, calculated among the 33 patients who had available immediate postoperative imaging. Forty-two patients had IDH mutation status, of whom five had a mutation. MGMT methylation status was available for only three patients and that parameter was therefore not included in the final analysis. Twenty patients (35.7%) had at least one postoperative complication. The most common complications were neurological deterioration and deep surgical infections (17.9% each).
Adjuvant salvage therapies were given to patients at the discretion of a neuro-oncologist, with 39 patients (69.6%) receiving them. They were comprised of bevacizumab (n = 36, 64.3%), radiotherapy (n = 14, 25%), temozolomide (n = 10, 17.9%), and other chemotherapeutical agents (n = 10, 17.9%). Some patients received more than one adjuvant treatment. The use of adjuvant therapies did not correlate significantly with survival (p=0.54).
The mean interval between postoperative imaging tests was 58 ±2 days. Fifty patients (89.3%) had three imaging tests postoperatively, six had two imaging tests postoperatively. All imaging tests were analyzed volumetrically as described above. The median OS of the entire cohort was 22 ± 4 months. The median survival after the resection with Gliadel® (GS) was 12 ± 3.8 months.
Clinical Characteristics and Survival
In the univariate analysis (Table 2), age was the only clinical parameter significantly associated with survival, with a median survival from implantation of Gliadel® (GS) of 10 months in patients ≥60 years of age compared to 13 months in patients <60 years of age (p=.04). There was a trend toward significance for IDH status and KPS ≥70 at last follow-up (p=.13 and .06, respectively).
Dynamics of Volumetric Measurements and Survival
Increasing volumes of postoperative FA, TB, and RC all correlated negatively with Gliadel® survival in a univariate analysis (Table 2). Patients with increasing volume of FA over time had a median GS of 10 months compared to 14 months for patients whose FA volume was decreasing (hazard ratio [HR]=1.9, p=.03). Likewise, patients with increasing TB volume over time had a median GS of 11 months compared to 27 months for patients with decreasing TB volume (HR=3.1, p=.003). Similarly, RC volume trends correlated with survival. GS of 6 months was seen in patients whose RC volume increased, compared to 13 months for those whose RC volume decreased (HR=3.8, p=.0002). Kaplan-Meier survival plots of these analyses are presented in Figure 2.
In an all-inclusive multivariate analysis (Table 2), FA no longer predicted survival. However, both an increased TB and RC significantly correlated with worse survival (HR=7.9, p=.003; HR=84, p=.002, respectively). Goodness-of-fit for the model was estimated at a concordance of 79%. In a stepwise multivariate analysis, the only parameter associated with survival was the volume of TB, with an HR of 7.3 and Wald's p-value set at 3∙10-7 (95% confidence interval 3.4-15.7). Goodness-of-fit for the stepwise model was estimated at a concordance of 73% (Table 2).
Temporary FLAIR Reactivity Effect on Survival
Gliadel® may induce a considerable amount of peritumoral edema16,19, which may represent anti-tumor inflammatory activity in a selected group of patients20,21. Accordingly, we analyzed a subgroup of patients who had a temporary surge of peritumoral edema, presenting as increase in FA with subsequent decrease of FA in follow-up imaging. The beginning of this period was set at postoperative day 21 in order to allow for postoperative changes and for direct toxicity of BCNU to resolve5. Accordingly, the end of this period was set to 8 weeks to fit the known stabilization of MRI findings after Gliadel® implantation, at two months postoperatively17. In order to define a significant and reliable degree of change of the FLAIR abnormalities, we set a threshold of 20%. This is double the published intra-observer reliability for contrast enhanced T1 images25, and stems from the fact that FLAIR changes are less well defined than enhanced T1 images. Patients who had >20% increase of FA volume between 3-8 weeks post-surgery with subsequent resolution or >20% decrease in FA were considered as having a "Reactive FLAIR".
Six of the 56 patients (10.7%) belonged to this group, while the rest of the cohort served as control (thus defined "Non-reactive FLAIR"). Table 3 summarizes the basic characteristics of these two groups, the groups being homogeneous. The median survival after Gliadel® surgery for patients who had a reactive FLAIR was 36 months compared to 12 months for the non-reactive FLAIR group (p=.003) (Figure 3).