In this cohort of molecularly characterized recurrent lower-grade glioma, repeat resection at 1st recurrence was associated with prolonged PFS-2 (median 7.75 years) and low rates of neurological (2%) and surgical (4%) complications. Particularly, GTR prolonged PFS-2 compared to any incomplete resection or non-surgical treatment.

At 1st diagnosis, the prognostic benefit of maximized resections is established, although interpretation must consider evolving diagnostic criteria for lower-grade gliomas. Recently, Hervey-Jumper et al. analyzed the combined effects of TVs, molecular factors and adjuvant treatment on outcome in IDHmut astrocytoma and oligodendroglioma WHO grade 2 [8]. Across both subtypes, EOR ≥75% improved OS, while EOR ≥80% improved PFS.

At recurrence, the evidence supporting reoperation is sparse. The AANS/CNS guidelines for recurrent glioma WHO grade 2 concluded that data were insufficient to recommend repeat resection for improving outcome [17]. Ramakrishna et al. reported on 52 WHO grade 2 glioma patients undergoing reoperation [14]. Median OS (12.95 years) was prolonged in patients without residual FLAIR tumor after 1st or 2nd resection. Malignant transformation to WHO grade 3 or 4 (22 patients) and residual tumor after reoperation were associated with shorter PFS-2. Spitaels et al. reported on 35 WHO grade 2 glioma patients, of whom 25 underwent repeat resection [15]. Malignant transformation was noted in 6 cases. PFS-2 was significantly prolonged in patients with adjuvant treatment after repeat resection or non-surgical treatment compared to watchful waiting. However, volumetric EOR and molecular status including IDH were not investigated in both studies. Shofty et al. observed prolonged OS (11.2 vs. 5.5 years) and delayed malignant transformation in reoperated IDHmut patients (n = 50) compared to non-surgical patients (n = 22) [16].

In our cohort, GTR at reoperation was significantly associated with prolonged PFS-2, consistent with Ramakrishna et al. [14], compared to any incomplete resection or non-surgical treatment. Notably, patients with GTR had smaller preoperative FLAIR TVs in non-eloquent areas, making them ideal candidates for maximal safe resections. In newly diagnosed IDHmut glioma, preoperative TVs correlate with resectability and survival [8, 23]. Notably, our study included patients independent of surgical intent, yielding a wide range of preoperative TVs (1.59–230.4 cm3), RTVs (0 to 157.4 cm3) and EOR (20.46% to 100%). Hence, a prognostic resection threshold could not be defined, beyond the observed survival benefit of GTR. Interestingly, GTR was associated with improved PFS-2 in both tumor subtypes, consistent with observations in newly diagnosed IDHmut gliomas [10]. Larger cohorts with uniform resection goals are needed to clarify whether a (subtype-dependent) resection threshold exists.

Irrespective of EOR, re-resection at 1st recurrence was associated with prolonged PFS-2 (HR = 0.560; p = 0.029) in multivariable-adjusted analysis and showed a trend towards improved SAR. PFS-2 was almost doubled compared to non-surgical treatment (93 vs. 51 months; p = 0.019). Despite including WHO grade 3 tumors, outcomes of our surgical cohort (median OS 25 years, PFS-2 7.75 years) compare favorably to other studies, likely due to strict inclusion of IDHmut patients [14, 16]. To our knowledge, this is the largest series of lower-grade gliomas comprehensively analyzing the prognostic relevance of reoperation versus non-surgical treatment. Despite different proportions of EOR categories and adjuvant treatment at 1st diagnosis, treatment groups were balanced for most confounders at recurrence, including functional status, glioma subtype and WHO grade, and imbalances (sex, localization) were incorporated in the multivariable model. Lead-time bias was mitigated by adjusting for the interval between recurrence imaging and treatment start. Nevertheless, given the long observation period and the retrospective study design, treatment decisions, particularly regarding re-resection, were not standardized and inherently introduce selection bias. Tumor volume, an established prognostic factor, was not assessed in non-surgical cases, raising the possibility that tumor size influenced treatment selection. Treatment heterogeneity, influenced by changing therapeutic paradigms, represents another source of bias. Yet, similar proportions of patients were treated across pre-specified eras, starting treatment at 1st recurrence mostly between 2011 and 2021, often guided by multidisciplinary tumor board recommendations.

This study investigated whether resection at 1st recurrence was associated with improved survival. Notably, 18 patients (18.4%) of the non-surgical cohort underwent repeat resection at a later timepoint, and patients ever undergoing re-resection (n = 68) showed a trend towards prolonged SAR. However, the primary objective was to evaluate the effect of re-resection at the earliest possible recurrence. Because treatment burden increases with each additional recurrence, prolonging PFS-2 becomes an important therapeutic goal.

In multivariable analysis, symptomatic recurrence predicted poor outcome, irrespective of treatment group. This emphasizes the need to define the optimal timing of re-interventions, particularly reoperation, balancing the individual functional neuroplasticity against continuous tumor growth and invasion of eloquent areas [24]. In newly diagnosed IDHmut glioma, early surgery is beneficial [9, 25]. Given the influence of preoperative TVs on resectability, early repeat resection, ideally before symptom onset, should be considered in recurrent glioma as well.

Beyond outcome, reoperation enables assessment of malignant transformation. In our surgical cohort, this was observed in 10%, lower than previously reported for WHO grade 2 gliomas (19–74% [24]), likely reflecting exclusion of astrocytoma with CDKN2A/B homozygous deletion [2, 19]. In the non-surgical cohort, malignant transformation was not assessed, since neither re-biopsy nor advanced molecular imaging was routinely performed. Nonetheless, the clinical relevance is limited because recurrence usually leads to treatment irrespective of WHO grade [3].

Eloquent location was noted in similar proportions of surgical (30%) and non-surgical (36.7%) patients, with comparable functional status (KPS, NANO, symptomatic recurrence). Making use of surgical adjuncts (iMRI 94%; awake surgery 16%; IONM 12%) also in patients with incomplete resections, the rate of permanent neurological deficits after reoperation was low (2%), consistent with prior studies (0–8.5% [24]). Accordingly, functional status (KPS, NANO) remained stable at a high level at 7 days and 3 months after surgery. This aligns with previous reports that multiple surgeries can be safely performed under function-based resection guidance [26,27,28,29]. Surgical complications requiring revision were rare (4%), reflecting the generally low treatment intensity in lower-grade glioma as a predisposing factor. Thus, repeat resection was associated with prolonged PFS-2 at acceptable risk, supporting its role in the multimodal treatment of recurrent lower-grade glioma.

Strengths of this study include the long follow-up (median 11.7 years), molecular characterization according to WHO 2016 or 2021, exclusion of WHO grade 4 tumors and astrocytomas with homozygous CDKN2A/B deletion and volumetric assessment of EOR. Limitations include the moderate sample size of the surgical cohort, which precluded the identification of prognostic resection thresholds, lack of volumetric data in non-surgical cases, and the retrospective design, with treatment decisions based on the neuropathological diagnosis and treatment options available at the time of treatment, spanning three decades. Furthermore, the number of events - particularly for SAR and in surgical patients - was limited, making data maturation an important constraint. Because lower-grade glioma patients experience long-term survival, randomized trials comparing surgical vs. non-surgical treatment at recurrence seem neither feasible nor justifiable, given the emerging evidence favoring re-resection.