Our patients experienced median OS of 24 months and 2-year and 5-year OS of 48% and 18%, respectively, with ≥ grade 2 acute hematological toxicity of 6%. These results are exceptional, compared to data from major trials [1–7, 40–41] (Supplementary Tables 2, 3) and are attributed to improvements in several areas.
Imaging
Neurosurgeons require high-resolution MRI sequences to plan the surgical approach, and intraoperative guidance to determine the progress of ongoing resection. This is important for maximizing the EOR, while limiting damage to adjoining neural structures. Apart from basic MRI sequences like T1w, T1w-CE, T2-weighted and T2-FLAIR, additional sequences such as gradient-echo, diffusion-weighted, dynamic susceptibility contrast, dynamic contrast enhancement and advanced MRI modalities like MRS, DTI, PWI, functional MRI, tractography and Positron Emission Tomography help individualize surgical decision-making and allow more aggressive resections [42]. They also aid in precisely defining tumour areas during RT-planning, differentiating true progression from pseudo-progression on follow-up, and providing radiomic markers to predict outcomes [43]. In most earlier trials [1–7], the imaging-modalities used were CT-scan or MRI with basic sequences only, and the EOR was often subjective, according to the surgeon’s judgement alone. In addition, non-utilization of pre-RT MRI for planning and relatively crude response-evaluation criteria could have resulted both in suboptimal target-delineation and missing early signs of progression. The SPECTRO-GLIO trial [40–41] used multiparametric MRI to full potential, and expectedly, its control arm employing the standard Stupp protocol has reported survival outcomes comparable to our study.
Surgery
ALA-dye [44], a photosensitive substance that emits red fluorescence after being metabolized, is used to identify tumor areas during GBM surgery. In awake craniotomy, cortical and subcortical eloquent regions are mapped using electrodes to monitor the functional status of the patient. Neuronavigational systems provide precise spatial information regarding the tip of the dissecting instrument in relation to critical brain structures [45]. Intraoperative MRI allows the neurosurgeon to check the adequacy of resection in real-time. Routine use of these advanced surgical aids is a possible reason for the improvement in safety and EOR in our study.
Histopathology
In the Stupp trial [1], 92% patients had GBM, and the rest had lower-grade gliomas. The diagnosis was based on histopathology alone, and MGMT-methylation status was available for only 37% patients. The IDH-mutation status was not a criterion for defining GBM at that time. Our data consisted entirely of GBM patients, and baseline MGMT-methylation and IDH-mutation status were available for 47.2% and 29% patients, respectively. However, majority were MGMT-methylated (62.7%) and IDH-mutant (59%). This contrasts with data from other trials [1–2, 4–6], where MGMT-unmethylated and IDH-wild tumours predominated. Interestingly, the median OS for MGMT-methylated and unmethylated tumours (26 months versus 22 months), and that for IDH-mutant and wild tumours (18 months versus 26 months) were not statistically different in our analysis (Table 4). The paradoxically better survival of IDH-wild tumours could be related to a longer duration of TMZ use in them.
Radiation
The past two decades have witnessed tremendous technological advancements in Radiation Oncology. The Stupp trial [1] used 3D-conformal Radiation Therapy (3DCRT), whereas subsequent trials [3, 5–6] used 3DCRT or IMRT. Navarria [18] analyzed 341 GBM patients treated with 3DCRT or VMAT, and demonstrated that VMAT plans were not only dosimetrically superior, but patients treated with that technique enjoyed better OS as well. This finding is consistent with the outcomes observed in our study. Secondly, objective assessment of residual disease using pre-RT MRI resulted in fewer (26.2%) resections being labelled as complete resection in our study, compared to 39–54% in earlier trials [1–2, 4–6]. However, we included the residual disease within the high-dose radiation volume in all cases. We agree that our target-volumes are marginally larger, which conflicts with contemporary margin-reduction strategies [46], yet the incidence of toxicity in our study was comparable to standard trials [1]. Recent radiobiological studies also allowed us less conservative dose-prescriptions, thus improving the target-coverage. For example, a maximum-dose of 60 Gy for brainstem-core and 64 Gy for brainstem-surface, as supported by modern guidelines [25, 46] would be considered toxic in the Stupp era, where respecting conservative OAR constraints could have resulted in compromised PTV-coverage.
Temozolomide
In our study, 90.3% patients completed the concurrent RT + TMZ phase. This agrees with the 87–93% reported in previous trials [1, 5–6]. While extension of TMZ beyond 6 cycles was not permissible in the Stupp trial [1], the same was allowed in the Gilbert [3] and TTF trials [5–6], as in our study. Our rates of completion of median three adjuvant TMZ cycles, and of ≥ 6 cycles by 36.4% patients agree with previous trials [1–3]. A peculiar feature of our study was the extensive use of low-dose metronomic-TMZ as salvage treatment at progression, with non-TMZ-based regimens being used in < 10% of the cases. Favourable outcomes have been reported with this approach [33–34], and our data add to the evidence in this matter.
Salvage treatment
The Stupp trial [1] used salvage re-surgery in 24%, salvage chemotherapy in 54%, salvage TMZ in 25%, and re-irradiation in just 5% patients. While the rates of surgery and chemotherapy were comparable in our study, salvage re-irradiation was used in 30.8% patients. This demonstrates the benefit of using advanced RT-techniques like VMAT for effective OAR sparing, thus allowing a safe second course of radiation. All three treatment-modalities were used in 12.4%. Best supportive care alone was employed in 30.8%, implying that salvage treatment was utilized in 69.2%. This agrees with data by Gilbert [3] and Chinot [4], who reported the use of salvage treatment in 79.1% and 69.3% patients, respectively. Our effective salvage strategies could be responsible for the median OS2 being 9 months, compared to 6.2 months in the Stupp trial [1] and 7.8 months in the DCvax trial [7].
Factors affecting outcomes
In contrast to literature, none of the patient- or tumour-related factors such as age group, KPS, EOR, MGMT-methylation status, and IDH-mutation status, were significantly associated with PFS or OS in our study. However, treatment-related factors such as RT-dose ≥ 54 Gy and ≥ 4 adjuvant TMZ cycles were significantly associated with PFS. This, along with the significant association of 1-year controlled disease status with OS, underlines the impact of initial treatment in bringing about a survival benefit. The significant association of OS with surgery-use at progression and systemic therapy-use at progression shows that effective salvage treatment plays an equally important role. These findings indicate that modern treatment techniques can overcome the impact of patient- and tumour-related factors in improving GBM outcomes. However, our study was limited by retrospective data analysis, partly telephonic follow-up, and lack of quality-of-life data. Although telephonic follow-up could accurately collect data on the timelines of progression and survival, this was not true for late toxicity, which is likely to be under-reported.
Future Directions
Advances in brain-mapping techniques such as Raman spectroscopy and optical coherence tomography, provide a biochemical signature of tissues and help in differentiating tumour from normal tissue intraoperatively, thus improving EOR [47]. Use of newer imaging-modalities and artificial intelligence-based tools [48–49] to improve and expedite RT target-delineation and outcome prediction is gaining momentum. Newer treatment-modalities such as immunotherapy, including immune checkpoint inhibitors, chimeric antigen receptor-T (CAR-T) cell therapy, vaccine therapy, dendritic cell therapy, and oncolytic virotherapy, appear promising [50]. As new molecular markers become available, the scope for developing and testing newer targeted molecules is only going to increase, making the treatment paradigm for GBM more complex, yet interesting.