Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma

Abstract

Importance: Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non-contrast-enhanced (NCE) disease is poorly understood.

Objective: To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery.

Design, setting, and participants: This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019.

Main outcomes and measures: Overall survival.

Results: Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients with IDH-wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients with IDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients with IDH-wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients with IDH-wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients with IDH-wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase.

Conclusions and relevance: This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless of IDH status, and among patients with IDH-wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma.

Figure 1.. Data Flow Diagram for the UCSF Development Cohort

IDH indicates isocitrate dehydrogenase gene 1 or 2; MGMT, promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase.

Figure 2.. Recursive Partitioning Analysis (RPA) for Post-2005/IDH-Known Subset

Includes 434 patients. Four risk groups were determined by RPA based on adjuvant temozolomide treatment after surgery, isocitrate dehydrogenase gene 1 or 2 (IDH) status, age at diagnosis, and residual non–contrast-enhancing (NCE) tumor after surgery. Groups are denoted by numbers 1 through 4. Group 4 is the combination of 2 subgroups: temozolomide-treated patients with IDH-mutant tumors and temozolomide-treated patients aged 65 years or younger with IDH–wild-type tumors with no greater than 5.4 mL of NCE residual tumor.

Figure 3.. Kaplan-Meier Curves for Overall Survival for 4 Risk Groups

Groups are described in Figure 2. A, Includes patients in the post-2005 isocitrate dehydrogenase gene 1 or 2 status (IDH)-known (n = 434). For group 1, median overall survival was 3.6 (95% CI, 2.6-5.4) months (univariable hazard ratio [HR], 3.31 [95% CI, 2.31-4.74]; P < .001); group 2, 12.4 (95% CI, 11.4-14.0) months (univariable HR, 1.45 [95% CI, 1.15-1.83]; P = .001); group 3, 16.5 (95% CI, 14.7-18.3) months (univariable HR, 1 [reference]); and group 4, 37.3 (95% CI, 31.6-70.7) months (univariable HR, 0.36 [95% CI, 0.25-0.51]; P < .001). B, Includes groups 1 to 3 (gray) and the 2 subgroups in group 4. Group 4A represents the temozolomide-treated patients with IDH–wild-type tumors who were younger than 65 years and with no more than 5.4 mL of non–contrast-enhancing residual tumor (median overall survival, 31.7 [95% CI, 22.2-43.9] months); group 4B, the temozolomide-treated patients with IDH-mutant tumors (median overall survival, 78.4 [95% CI, 35.1-not applicable] months). C, Includes Mayo Clinic (n = 107) and Ohio Brain Tumor Study (n = 99) patients with glioblastoma. Median overall survival for group 1 was 3.8 (95% CI, 2.4-4.6) months (univariable HR, 6.17 [95% CI, 4.08-9.33]; P < .001); group 2, 12.8 (95% CI, 10.9-14.6) months (univariable HR, 1.58 [95% CI, 1.11-2.25]; P = .01); group 3, 17.5 (95% CI, 15.3-22.5) months (univariable HR, 1 [reference]); and group 4, 32.4 (95% CI, 21.7-not applicable) months (univariable HR, 0.54 [95% CI, 0.31-0.94]; P = .03).

Figure 4.. Proposed Surgical Strategy for Newly Diagnosed Glioblastoma

Strategy consists of maximal resection of the contrast-enhanced (CE) tumors for all patients with the additional maximum resection of the non–contrast-enhanced (NCE) tumors for patients younger than 65 years, when safely feasible.