Both AC and surgery under GA are viable options to treat left hemispheric glioblastoma in eloquent regions of the brain. To the best of our knowledge, this is the largest study to compare the feasibility, postoperative functional outcomes, progression free survival and overall survival of GA and AC for single hemisphere, single pathology glioblastoma in eloquent regions of the brain.
Despite advances in functional MRI and neuronavigation techniques that allow for anatomic localization of brain function under general anesthesia, real-time feedback regarding the patient’s neurological status remains a distinct advantage of the AC procedure.18 Brain mapping during removal of intra-axial tumors enables surgeons to reduce the risk of morbidity.19,20 AC is a practical and effective standard surgical approach for supratentorial intrinsic eloquent area lesions, and it is an excellent alternative to craniotomy under GA because it allows for brain mapping and avoids the risks associated with GA.21 Our results showed that compared to surgery under GA, AC for glioblastoma resulted in a higher frequency of radiographic total resection of enhanced tumors, better KPS within 3 months after surgery, and also better PFS and OS.
Extent of Resection
At least STR was achieved in more than 90% of the glioblastoma patients in the AC group. However, comparisons of the EOR between different studies is difficult because this highly depends on localization, tumor burden, and functional reorganization.22 Many studies have reported resection rates and the merits of AC. Gupta et al.23 reported that complete resection was achieved in 47.6% of patients who underwent AC, and also that complete/gross total tumor excision was achieved in a greater number of patients who underwent GA (63%) than AC (47%). In addition, Meyer et al.24 reported that GTR was achieved in 52% of their patients who underwent AC. However, these studies included either different pathologies or varying grades of glioma.
In the present study, only glioblastoma patients were included, and all of the lesions were in left hemispheric eloquent regions. The average EOR was 94.9%, and 83.3% of the patients achieved GTR in the AC group which was a very convincing result showing that AC can improve the tumor resection rate (Table 3). Furthermore, we also compared the EOR between the GA and AC groups according to the tumor location, and the results were interesting but not surprising. The mean EOR was significantly lower in the GA group (80.08%) for tumors located within the language cortex compared to the AC group (93.9%) (p<0.001). This finding is compatible with the study of Sawaya et al.,17 in which tumor functional grade was the most important variable for determining the risk of a new neurological deficit after surgery. To preserve neurological function, tumors in eloquent brain areas can only be biopsied or partially resected, whereas lesions in non-eloquent brain regions can be more aggressively resected. Thus, when evaluating associations between survival and surgical treatment, it is important to take the tumor location into account. We hypothesize that one of the main causes of this difference may be because language function is very complex and hard to monitor using only cortical and subcortical stimulation during surgery. The most accurate and direct method to monitor language is to interact with the patient. Second, since the language region could not be accurately identified from the information provided from neurophysical monitoring in the GA group, the surgeon would perform relatively conservative tumor resection to prevent the occurrence of new neurological deficits.
Progression-free Survival and Overall Survival
There were significant differences in both PFS and OS between the AC and GA groups in this study. To the best of our knowledge, these two major outcomes are fully dependent on the EOR. The mean OS was 25.5 months in the overall cohort, and 30 months and 24.7 months in the patients with GTR and STR, respectively. These results are similar to those of Bloch et al.25, who reported OS ranging from 18.4 months to 20.4 months depending on the EOR. In their study, only 48.6% of the patients achieved GTR initially and the remaining patients achieved STR (51.4%), which is lower than in our study (Table 3).
The optimal EOR in any patient depends on the tumor size and location, the patient’s general and neurological status, and the experience of the surgeon. Lacroix et al.26 reported that the EOR in patients with glioblastoma began to be associated with a survival advantage at 89% of the tumor volume. In addition, aggressive resection of 98% or more of the tumor volume was a significant independent predictor of patient survival. In the field of neuro-oncology, many large retrospective cohort studies have also demonstrated enhanced survival with increased EOR in patients with newly diagnosed GBM, and mathematical modeling of retrospective data suggests incremental improvements in survival with EORs ranging from 78% to 98%.27 In this study, the mean EOR in both groups (GA vs. AC, 90.2% vs. 94.9, respectively) also reached 89%, the threshold of survival advantage.
Some previous studies have reported that age is the most important prognostic factor associated with OS in glioblastoma patients,28,29,30 and other studies have suggested that female glioblastoma patients have a better OS.31 However, in the present study, neither age nor gender was a significant prognostic factor for OS in multivariate analysis (p=0.074 and 0.08, respectively) (Table 6).
With regards to KPS, some studies have suggested that with the current clinical armamentarium, glioblastoma patients with a preoperative KPS <60 are unlikely to survive >5 years.32 In this study, we demonstrated that preoperative KPS was an independent predictive factor of OS (Table 6).
Postoperative Characteristics
In this study, there was no difference in the distribution of preoperative KPS between the AC and GA groups, however there were differences after surgery (Table 7). The proportion of patients with a postoperative KPS >80 increased from 70.8% to 85.4%. This result indicates that AC may not only preserve a patient’s neurological functional activities, but also that intact neurological function can further improve a patient’s general performance status for daily activities.
Our results also showed that the immediate postoperative neurological function in the AC group was significantly better than that in the GA group. Furthermore, in the first few days (within 3-7 days), the KPS in the AC group was even better. It has been shown that mild to moderate postoperative neurological deficits secondary to aggressive tumor debulking in an AC can quickly recover over several days.24,33,34 This clinical finding is compatible with the concept of “brain plasticity” proposed by Duffau.35
Limitations
First, selection bias and a lack of randomization are limitations of this retrospective study. Second, due to the inclusion criteria, the number of case numbers was not large. Third, the prognosis of GBM is influenced by molecular markers including IDH1 and MGMT, however we lacked information on these markers. Fourth, patients undergoing AC require both the ability to and willingness to participate in the operation, and this may be a source of selection bias. A well-designed prospective validation study with independent cohorts is needed to verify our results.