Objective: Maximal safe resection is the first treatment in diffuse low-grade glioma (DLGG). Due to frequent tumor recurrence, a second surgery has already been reported, with favorable results. This study assesses the feasibility and functional and oncological outcomes of a third surgery in recurrent DLGG.

Methods: Patients with DLGG who underwent a third functional-based resection using awake mapping were consecutively selected. They were classified into group 1 in cases of slow tumor regrowth or group 2 if a radiological enhancement occurred during follow-up. All data regarding clinicoradiological features, histomolecular results, oncological treatment, and survival were collected.

Results: Thirty-one patients were included, with a median age of 32 years. There were 20 astrocytomas and 11 oligodendrogliomas in these patients. Twenty-one patients had medical oncological treatment before the third surgery, consisting of chemotherapy in 19 cases and radiotherapy in 8 cases. No neurological deficit persisted after the third resection except mild missing words in 1 patient, with 84.6% of the patients returning to work. The median follow-up duration was 13.1 ± 3.4 years since diagnosis, and 3.1 ± 2.9 years since the third surgery. The survival rates at 7 and 10 years were 100% and 89.7%, respectively, with an estimated median overall survival of 17.8 years since diagnosis. A comparison between the groups showed that the Karnofsky Performance Scale score dropped below 80 earlier in group 2 (14.3 vs 17.1 years, p = 0.01). Median residual tumor volume at the third surgery was smaller (2.8 vs 14.4 cm3, p = 0.003) with a greater extent of resection (89% vs 70%, p = 0.003) in group 1.

Conclusions: This is the first consecutive series showing evidence that, in select patients with progressive DLGG, a third functional-based surgery can be achieved using awake mapping with low neurological risk and a high rate of total resection, especially when reoperation is performed before malignant transformation.