Interactive Effects of Molecular, Therapeutic, and Patient Factors on Outcome of Diffuse Low-Grade Glioma

Abstract

Purpose: In patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with different levels of EOR is not feasible.

Methods: In a 20-year retrospective cohort of 392 patients with IDH-mutant grade 2 glioma, we analyzed the combined effects of volumetric EOR and molecular and clinical factors on overall survival (OS) and progression-free survival by recursive partitioning analysis. The OS results were validated in two external cohorts (n = 365). Propensity score analysis of the combined cohorts (n = 757) was used to mimic a randomized clinical trial with varying levels of EOR.

Results: Recursive partitioning analysis identified three survival risk groups. Median OS was shortest in two subsets of patients with astrocytoma: those with postoperative tumor volume (TV) > 4.6 mL and those with preoperative TV > 43.1 mL and postoperative TV ≤ 4.6 mL. Intermediate OS was seen in patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL in addition to oligodendroglioma patients with either preoperative TV > 43.1 mL and residual TV ≤ 4.6 mL or postoperative residual volume > 4.6 mL. Longest OS was seen in astrocytoma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL who received no chemotherapy and oligodendroglioma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL. EOR ≥ 75% improved survival outcomes, as shown by propensity score analysis.

Conclusion: Across both subtypes of LGG, EOR beginning at 75% improves OS while beginning at 80% improves progression-free survival. Nonetheless, maximal resection with preservation of neurological function remains the treatment goal. Our findings have implications for surgical strategies for LGGs, particularly oligodendroglioma.

FIG 1.

(A) World map indicating multicenter–multinational study cohorts. (B) Kaplan-Meier curves for OS and PFS across development and external validation cohorts. OS was similar across all three sites, but PFS differed across the sites. BWH, Brigham and Women's Hospital, Boston, MA; OS, overall survival; PFS, progression-free survival; St Olav, St Olavs University Hospital, Trondheim, Norway; UCSF, University of California, San Francisco, CA.

FIG 2.

OS outcomes for development cohort and external validation. (A) RPA for the development cohort identified three risk groups on the basis of postoperative TV, preoperative TV, LGG subtype, and chemotherapy. Groups are denoted by number. Group 1 had the worst survival and consisted of the astrocytoma patients with residual tumor > 4.6 mL or astrocytoma patients with preoperative TV > 43.1 mL and residual tumor ≤ 4.6 mL. Group 2 had intermediate survival and consisted of a combination of two subgroups: (1) oligodendroglioma patients with residual tumor > 4.6 mL or oligodendroglioma patients with preoperative TV > 43.1 mL and residual tumor ≤ 4.6 mL and (2) patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and residual tumor ≤ 4.6 mL. Group 3 had the best survival and consisted of the combination of two subgroups: (1) oligodendroglioma patients with preoperative TV ≤ 43.1 mL and residual tumor ≤ 4.6 mL and (2) patients with astrocytoma who had no chemotherapy with preoperative TV ≤ 43.1 mL and residual tumor ≤ 4.6 mL. (A) Overall Survival RPA Tree (UCSF). (B) Kaplan-Meier curves for OS (UCSF) by the three risk groups delineated in (A) for all patients (overall) in the development cohort, patients with astrocytoma, and patients with oligodendroglioma, respectively. (C) Kaplan-Meier curves for OS (BWH and St Olav) by the three risk groups delineated in (A) for all patients in the external validation, patients with astrocytoma, and patients with oligodendroglioma, respectively. Hazard ratios and CIs for Figure 2 are included in the Data Supplement. BWH, Brigham and Women's Hospital; LGG, low-grade glioma; NA, not available; OS, overall survival; RPA, recursive partitioning analysis; St Olav, St Olavs University Hospital; TV, tumor volume; UCSF, University of California, San Francisco.

FIG 3.

GTR and GTR+ in the development cohort. (A) Schematic of GTR, GTR+ (resection beyond the imaging-defined tumor margin), and GTR– (resection ≤ 100%). (B) Kaplan-Meier curves for all OS UCSF patients stratified by GTR status. OS was longer in patients with GTR+ (P < .001 by Tarone-Ware test). (C) Kaplan-Meier curves stratified by GTR status in UCSF patients with astrocytoma (P < .001 by Tarone-Ware test). (D) Kaplan-Meier curves stratified by GTR status in UCSF patients with oligodendroglioma (P = .11 by Tarone-Ware test). GTR, gross total resection; NA, not available; OS, overall survival; UCSF, University of California, San Francisco.

FIG 4.

RPA of PFS and MTFS and corresponding Kaplan-Meier survival curves. (A) RPA identified three PFS risk groups on the basis of postoperative TV and LGG subtype. Group 1 patients (n = 29) had the worst PFS and included those patients with astrocytoma and residual tumor > 32.7 mL. Group 2 patients (n = 218) had better PFS and included the astrocytoma patients with residual tumor between 1.2 and 32.7 mL. Group 3 patients (n = 510) had the best PFS and included a combination of two subgroups: (1) all patients with oligodendroglioma and (2) astrocytoma patients with residual tumor ≤ 1.2 mL. (B) Kaplan-Meier curves for the three PFS risk groups identified in (A) (P < .001 by log-rank test). (C) RPA identified three MTFS risk groups on the basis of postoperative TV, LGG subtype, age at diagnosis, and preoperative TV. Group 1 patients (n = 143) were patients with astrocytoma age younger than 43 years with preoperative TV > 31.2 mL and residual TV > 0.14 mL and had the poorest MTFS. Group 2 patients (n = 275) had better MTFS and was the combination of three subgroups: (1) oligodendroglioma patients with residual TV > 9.75 mL, (2) patients with astrocytoma age older than 43 years with residual TV > 0.14 mL, and (3) patients with astrocytoma age younger than 43 years with preoperative TV ≤ 31.2 mL and residual TV > 0.14 mL. Group 3 patients (n = 339) had the best MTFS and included both (1) the astrocytoma patients with residual TV ≤ 0.14 mL and (2) oligodendroglioma patients with residual TV ≤ 9.75 mL. (D) Kaplan-Meier curves for the three MTFS risk groups identified in (C; P < .0001 by log-rank test). (E) Forest plot of HRs determined by propensity score analysis (UCSF + BWH + St Olavs). (F) The interactive effects of molecular (tumor), therapeutic, and patient factors indicates that EOR ≥ 75% confers a survival benefit. BWH, Brigham Women’s Hospital; EOR, extent of resection; HR, hazard ratio; LGG, low-grade glioma; OS, overall survival; MTFS, malignant transformation–free survival; NA, not available; PFS, progression-free survival; RPA, recursive partitioning analysis; St Olavs, St Olavs University Hospital; TV, tumor volume; UCSF, University of California, San Francisco.