Location-Dependent Patient Outcome and Recurrence Patterns in IDH1-Wildtype Glioblastoma

Abstract

Recent studies suggest that glioblastomas (GBMs) contacting the subventricular zone (SVZ) as the main adult neurogenic niche confer a dismal prognosis but disregard the unique molecular and prognostic phenotype associated with isocitrate dehydrogenase 1 (IDH1) mutations. We therefore examined location-dependent prognostic factors, growth, and recurrence patterns in a consecutive cohort of 285 IDH1-wildtype GBMs. Based on pre-operative contrast-enhanced MRI, patients were allotted to four location-dependent groups with (SVZ+; groups I, II) and without (SVZ-; groups III, IV) SVZ involvement or with (cortex+; groups I, III) and without (cortex-; groups II, IV) cortical involvement and compared for demographic, treatment, imaging, and survival data at first diagnosis and recurrence. SVZ involvement was associated with lower Karnofsky performance score (p < 0.001), lower frequency of complete resections at first diagnosis (p < 0.0001), and lower non-surgical treatment intensity at recurrence (p < 0.001). Multivariate survival analysis employing a Cox proportional hazards model identified SVZ involvement as an independent prognosticator of inferior overall survival (p < 0.001) and survival after relapse (p = 0.041). In contrast, multifocal growth at first diagnosis (p = 0.031) and recurrence (p < 0.001), as well as distant recurrences (p < 0.0001), was more frequent in cortex+ GBMs. These findings offer the prospect for location-tailored prognostication and treatment based on factors assessable on pre-operative MRI.

Keywords: Glioblastoma; distant recurrence; isocitrate dehydrogenase 1 (IDH1)-wildtype; multifocal growth; subventricular zone; survival.

Figure 1

As exemplified in (A), 285 IDH1-wt GBM patients were allocated to four different location groups based on the CEL’s contact to the SVZ and/or the cortex on pre-operative MRI. Groups were further pooled into GBMs with (SVZ+) and without (SVZ−) SVZ involvement or with (cortex+) and without (cortex−) cortical involvement. (B) At 1st diagnosis, most GBMs were allocated to groups III (37%) and I (34%). (C) SVZ involvement increased from 1st diagnosis to recurrence, as depicted for “pure” SVZ (group II) and “pure” cortical (group III) GBMs. Group III tumors now recurred as SVZ+ GBM in 38.5% of cases while only 11% of group II tumors shed their SVZ contact and recurred as SVZ− GBM. (D) No predilection was found for each of the four groups regarding location of recurrent tumor. Most group I and III GBMs recurred at the same location, while recurrences of group IV GBMs were distributed throughout all groups.

Figure 2

Multifocal growth and distant recurrences were hallmarks of cortical IDH1-wt GBMs. At 1st diagnosis (n = 285), multifocal FLAIR lesions were significantly increased in cortex+ vs. cortex− (A) and group III vs. group II GBMs (B), but not in SVZ+ vs. SVZ− GBMs. At recurrence (n = 187), multifocal CELs were significantly enhanced in cortex+ (C) and group III GBMs (D). Local and distant recurrence patterns differed markedly within location-specific groups. Distant tumor growth remote from the initial resection site was significantly more frequent in GBMs with cortical involvement ((E) cortex+ vs. cortex−; (F) group II vs. group III).

Figure 3

Kaplan-Meier plots depicting the negative prognostic impact of SVZ involvement in 285 IDH1-wt GBM patients; numbers at risk are given. OS and survival after relapse, but not PFS differed significantly when comparing all location groups (A,B), SVZ+ vs. SVZ− GBMs (C,D) and group II vs. group III GBMs (n = 155) (E,F). Shortest median OS and survival after relapse were observed in group I (10 and 5 months) and group II (8 and 6 months) patients. For comparison of survival after relapse in group II vs. group III GBMs, SVZ involvement at recurrence (SVZ+/− rec) was valued.

Figure 4

When analyzing IDH1-wt GBM patients with intensified adjuvant treatment (i.e., completion of concomitant radio-chemotherapy and ≥ 3 cycles of TMZ-based chemotherapy) only (n = 79), absence of radiographic SVZ involvement conferred a non-significant, but meaningful prolongation of OS (24 vs. 18 months; A) and PFS (9 vs. 6 months; B) that also compared favorable to the outcomes of the most recent “historic control” derived from a multicenter trial on tumor-treating fields in newly diagnosed GBM [36] (OS = 16 months; PFS = 4 months; data not shown). (C,D) Kaplan-Meier plots depicting the prognostic significance of SVZ involvement in 285 IDH1-wt GBM patients on OS (C) and PFS (D) when stratified for EOR. Noteworthy, the negative prognostic impact of SVZ involvement can be, in part, resolved by GTR since OS and PFS were comparable in patients undergoing GTR regardless of SVZ involvement (OS: SVZ+GBM 15.5 months vs. SVZ−GBM = 16.5 months; PFS: SVZ+GBM 6.5 months vs. SVZ−GBM 6 months). A tabular overview of numbers at risk is given below each Kaplan-Meier plot.