This study presents the largest patient cohort analysis on IDH-mutant, 1p19q-codeleted ODG WHO grade 2 conducted by a single institution to date, providing a comprehensive analysis of long-term outcomes and prognostic factors for survival. As detailed in Table 3, the observed median PFS of 6.8 years and median OS of 18.4 years in our cohort are consistent with the favorable prognosis associated with this molecular subtype, consistent with previous studies [6, 14-17]. Notably, these results are better compared to the 24.7 months of median PFS, and 50.8 months of median OS reported in our recent study involving 95 patients with anaplastic ODG at our institution [18]. Our previous research showing the impact of the EOR on the prognosis of anaplastic ODG is consistent with findings from other studies [18-20]. However, the influence of EOR on survival in WHO grade 2 ODG remains a subject of debate.
Our findings distinctly highlight a survival advantage for patients undergoing GTR over those receiving STR or biopsy. Numerous studies have concluded that a more extensive EOR significantly impacts survival, even when considering the molecular characteristic of 1p/19q co-deletion [6, 19, 21-23]. Specifically, in a recent study by Kavouridis et al. on volumetric assessment of EOR, it was determined that a postoperative residual volume greater than 8 cm³ significantly associated with unfavorable PFS and OS [6]. In contrast to studies indicating that the EOR influences survival outcomes, according to the findings studied by Carstam et al., it was reported that initial surgical strategies do not affect survival outcomes. However, this study identifies limitations in accurately evaluating the EOR due to the characteristics of a multicenter study, as well as the absence of postoperative MRIs in the initial study participants [17]. Additionally, a recent study reported that while the EOR impacts PFS, it does not affect OS [16]. In this study, it is reported that 19% of patients received adjuvant CTx within 6 months after surgery, and 35.7% received RTx. When including the percentages of patients who received CTx and RTx up until the point of disease progression, the totals increase to 63.5% and 71.4%, respectively. This suggests that ODG may be more sensitive to adjuvant treatment compared to other subtypes of glioma, potentially diminishing the influence of EOR on overall survival [24]. In our patient cohort, 72.5% underwent watchful observation without additional treatment after surgery, which likely allowed for a more accurate assessment of the role of the EOR.
While ongoing discussions persist regarding the impact of early postoperative treatment on OS in patients with WHO grade 2 ODG [15, 16, 25], recent comprehensive clinical studies have demonstrated that adding PCV CTx to RTx not only improves PFS but also extends OS in patients at high risk [7, 10]. In our study, paradoxically, patients who received RTx or CTx after undergoing STR or biopsy exhibited no differences in PFS and OS compared to those who were simply observed after surgery. Although the current policy at our institution is to administer PCV CTx after RTx in high-risk groups based on the RTOG risk criteria, in many patients included in this study, RTx or CTx was selectively performed in patients with a poor prognosis based on radiological findings. In particular, the PCV CTx was restricted to a few cases primarily due to concerns about adverse effects, such as neutropenia, highlighting a significant limitation of our study.
Our multivariate analysis revealed that contrast enhancement on preoperative MRI as an unfavorable prognostic factor for both PFS and OS. Previous studies have reported contrast enhancement in 25 to 56% of patients with lower grade ODG [14, 17, 26-28], a range comparable to the 31.2% observed in our study. Several studies have also identified contrast enhancement on MRI scans as a potential prognostic factor in IDH-mutant gliomas [14, 26, 29]. In contrast, some studies have reported no correlation between contrast enhancement and PFS or OS [16, 17]. A comparative study on IDH mutation status reveals that the presence of contrast enhancement in diffuse IDH wild-type gliomas had no significant impact on survival, whereas its presence is associated with a poorer prognosis in IDH-mutant gliomas [26]. Although often considered an indicator of aggressive tumor behavior, contrast enhancement may also reflect regions of anaplasia not sampled during biopsy. Ensuring accurate biopsy interpretation is crucial to avoid underestimating disease severity and to guide appropriate treatment strategies. To prevent the underestimation of focal enhancing tumors, using 5-aminolevulinic acid (5-ALA) guided tissue sampling can be advantageous. This technique enhances the precision of biopsy sampling by making tumor cell visibility under fluorescence, thereby improving diagnostic accuracy [30].
Seizures represent the most common symptom in patients with LGGs. In glioblastoma, seizures occur in approximately 40–60% of cases, whereas in oligodendroglioma, the incidence rises to 70–90%, with seizures often being the initial symptom in about 60% of cases [31]. In our study, seizures were the initial symptom in approximately 63% of the cases. Previous studies have confirmed that experiencing a single seizure before surgery is a positive survival indicator for patients with LGG. Conversely, relapsing seizures or an escalation in epileptic activity is predictive of anaplastic transformation [14, 29, 31, 32]. Our multivariate analysis identified the presence of seizures at presentation as a favorable prognostic factor for OS, which may be attributed to an earlier diagnosis and potentially less aggressive tumor behavior in these patients.
Strengths and Limitations
While our study contributes valuable insights into the long-term outcomes and prognostic factors for patients with this rare tumor subtype, it is crucial to acknowledge the inherent limitations associated with a retrospective, single-institution study design. One notable challenge in our study was the heterogeneity in managing patients with ODG WHO grade 2, particularly a significant number of patients were observed without adjuvant treatment. In the context of well-established standard treatments like PCV CTx and the recently FDA approved IDH mutant inhibitor ‘Vorasidenib’ through Phase III trials [33], understanding the impact of the EOR on the disease prognosis becomes increasingly challenging. Against this backdrop, we believe our cohort presents a valuable opportunity to explore how EOR alone influences the outcome of ODG WHO grade 2. Following the introduction of IDH mutant inhibitors, future research should focus on optimizing the EOR to preserve functional outcomes and determining the optimal timing for surgical intervention. Advancements in molecular profiling and imaging techniques promise to deepen our understanding of the biological characteristics of these tumors, potentially leading to more precisely tailored and effective management approaches.