Gamma knife radiosurgery for recurrent gliomas

In recent years, GKRS has become increasingly more popular as a salvage treatment modality for patients diagnosed with recurrent gliomas. The goal of GKRS for recurrent glioma patients is to improve survival rates with minimal burden for these patients. One can argue about what type of treatment is best for patients with recurrent glioma. This is dependent on several factors, such as patient’s age, comorbidity, Karnofski-Index, histopathological diagnosis and available treatment modalities. In our center, a difference is made between low grade and high grade tumors. Patients with recurrent low grade tumors are more suitable to undergo reoperation because these tumors are less responsive to radiosurgery. However, this is dependent on location and tumor volume. Patients with recurrence in eloquent locations and/or with small tumor volume are less suitable to undergo reoperation and are more suitable candidates to undergo minimal invasive treatment such as GKRS. In case of high grade tumors, patients with recurrence have limited survival [12‐14] and are more eligible for GKRS. Moreover, high grade tumors have a better radio-surgical response in comparison to low grade tumors. Finally, for patients with glioma the quality of life (QoL) is an increasingly important recognized factor. Not only do these patients suffer from general symptoms associated with cancer, such as fatigue, anxiety, and depression, but also from seizures, cognitive deficits, and focal neurological deficits. Therefore, treatments leading to deterioration of QoL are less favorable for these patients, giving their short lifespan, making GKRS an excellent treatment modality for maintaining QoL and extending survival time.

Determining radiological progression is known to be difficult for gliomas, especially after different treatment modalities have been applied. Until recently, clear definitions of progression and pseudo-progression have been lacking, which makes comparison between different studies on treating recurrent glioma bothersome. For this, the RANO (Response Assessment in Neuro-Oncology) criteria have been proposed to score radiological (pseudo-) progression more uniformally. However, these RANO criteria have not specifically been designed for patients treated with GKRS. Therefore, we have introduced the Tilburg radiological classification for scoring TC after GKRS. The primary goal of this classification is to allow us to compare our own treatment results more objectively. Furthermore, this classification could form the basis for uniform radiological criteria scoring radio-surgical response.

In our study, TC was achieved in 37% of all tumors; 50% in LGGs and 27% in HGGs. A recent study showed a 53.8% TC for LGGs after GKRS [15], which is comparable to our study. For HGGs, the TC is within range of other studies which reported TC of 18.8%–75.6% [16‐19]. LP occurred in 46% of all tumors treated with GKRS. This might indicate a dose problem, meaning that a higher dose is needed to obtain a higher local TC. Another important subject is target definition which led to marginal progression in 9% of all tumors in our study. Koga et al. were the first to address these two problems [19]. They compared two groups, conventional SRS (20 Gy applied to the margin of each gadolinium-enhanced lesion) versus extended field SRS (margin was extended up to 0.5–1 cm). TC in the conventional group was 47%. By extending the margin of the clinical target volume the TC increased to 93% (P = 0.0035). However, there was no significant difference (P = 0.83) in survival time between the two groups. A higher incidence of radiation necrosis was seen in the extended SRS group (29% vs. 6.5%). The goal of extending the irradiation field is to include as many tumor cells invading the surrounding tissue as possible. A limitation of this method is that it is not applicable to large lesions. Extending the margin in a large target results in a large prescribed isodose volume and might cause uncontrollable radiation induced adverse events. In case of GKRS as salvage treatment, the goal is prolonged survival with minimal burden. Therefore we do not find it useful to irradiate more than the enhanced lesion because of the higher incidence of radiation necrosis and uncontrolled radiation induced adverse events. Gliomas are highly vascular tumors and have a tendency to infiltrate extensive areas of the brain. The real tumor may therefore be much larger than what is seen on MRI, making a 0.5–1 cm margin still insufficient. This is another reason to only irradiate the enhanced lesion for both high and low grade gliomas.

The median PFS and OS for all patients were 10.5 and 34.4 months, respectively. Median PFS was 50.1 months and 5.7 months for low and high grade tumors respectively. Median OS was 86.6 months and 12.8 months for low and high grade tumors respectively. This is comparable to other studies about GKRS for recurrent HGG who showed a median OS ranging from 13 to 14 months [18, 20‐22].

Other studies in which radiosurgery was performed using a linear accelerator (LINAC) for the treatment of recurrent HGG showed comparable median OS ranging from 8.5 to 11 months [23‐25]. As could be expected, there was a highly significant increase in both PFS and OS according to tumor grade (i.e. the lower the tumor grade, the better the outcome), reflecting the natural behaviour of these tumors and sensitivity to treatment. Of clinical interest, in recurrent GBM patients median OS was 10.4 months. This shows that GKRS can meaningfully lengthen survival in these patients with a 1 day hospitalization, maintenance of QoL and minimal burden. For patients with a limited life span, these advantages should make one consider GKRS as a treatment option in recurrent glioma patients, as opposed to systemic treatment modalities that might hamper QoL (and might increase the number of hospital visits needed for therapy).

It is important to note that there were no serious adverse events and that the therapy was well tolerated. In general, only mild adverse events were noticed and GKRS was well tolerated.

In the Netherlands, the first line of therapy for HGG is surgical resection followed by chemo-radiation [26]. In case of recurrence, several options do exist: repeat surgery, RT, chemotherapy, experimental therapy or a combination of these treatment modalities, all depending on the clinical state of the patient. We are one of only two centers in the Netherlands who have access to GKRS. In case of recurrent glioma we can use high single dose radiation for small (multiple) lesions without causing damage to surrounding brain tissue, which already has been exposed to radiation. This is a clear advantage over conventional RT. Therefore, our recommendation is to use GKRS if possible in small recurrent glioma since one can give a higher dose radiation in an already irradiated brain compared to conventional RT, minimizing the possible risk of side-effects.

We use triple dose gadolinium for the planning MRI-scan in combination with a small slice thickness of 1.5 mm. This allows for detection of very small recurrence lesions. This is another advantage of using GKRS, because we can treat lesions in a very early stage of recurrence.