Evaluation of Treatment Response, Side Effects, and Prognostic Factors in AVM Patients Treated with Stereotactic Radiosurgery using Filter-Free Energies on LINAC

SRS prevents bleeding by obliterating the vessels. According to some sources, the time to vascular obliteration may take up to 1 year, while in others this duration is shown as 3-5 years.[,] In our study, the median time to complete obliteration was calculated to be 11.5 (3-31) months. This was considered shorter compared to other studies in the literature.

Some of the current linear accelerators have the capacity to treat with both flattening filtered and flattening filter free photons. FFF photons used in stereotactic radiotherapy provide a better protection for the organs at risk by providing a sudden dose fall-off. They have 2?4 times higher dose rate than filtered beams which reduces the beam-on time significantly. Dosimetric results of treatment plans using FFF have been shown to be similar or better than those with FF beams.[] A study by Mamballikalam et al.,[8] which applied SRS to very small (≤1 cc) and small (≤3 cc) lesions in brain with different techniques, established that the dosimetric properties (dose conformity, heterogeneity, dose falloff characteristics, organs at risk doses) of FF and FFF beams as a function of application technique showed a minimal variation. The only difference observed was that FFF provides slightly more monitor units than FF beams for volumes up to 2 cc with rapidarc technique, but the situation was reversed for 3 cc target volume. In conclusion, this study demonstrated that FF and FFF beam models and different irradiation techniques for SRS in small tumor volumes may be equivalent. The only possible advantage of FFF was stated to be the short treatment times due to high dose rates. However, Nakano et al.[] showed that the increased time of dose delivery in photon irradiations reduced the relative biological effectiveness. Therefore, it was concluded that FFF beams could be used for effective radiotherapy with shorter dose delivery times. In addition, it should be kept in mind that the delivery time is shorter in treatment plans using FFF, which can be important for reducing the device density and errors caused by patient movements.[] All patients in our study were treated with FFF and had similar treatment success compared to treatments using FF in the literature.

A review published by Yahya et al.[] concluded that while treatments with GK systems provide a better Conformity Index (CI) and GI, LINAC-based SRS can achieve better dose homogeneity in the target and better protection of critical organs. GI in this study was reported to have a median of 4.3 (2.0-9.9). In our study, median GI was calculated to be 4.41 (2.82-8.97) with LINAC-based FFF, which is similar to values achieved with GK. In a study by Orio et al.,[] the median CI for GK treatments was reported to be 1.1; while in our study with LINACbased FFF, the median CI was calculated to be 1.01.

According to a study which used only LINAC based radiosurgery and had a median follow up of 15.6 years, it was deducted that the positive treatment outcomes are associated with a target volume of <4 cm³ and a marginal dose greater than 12 Gy.[] Ding et al.[] showed in one of their studies that ≥20 Gy margin dose provided better control. Our study has a median follow-up of 20 (5-81) months. Median GTV was 4.20 cc (0.70-22.70), median PTV was 7.30 cc (1.20-37.60) and median treatment dose was 20 Gy (15-20). In contrast to the literature, GTV or the applied dose did not show a significant relationship with the treatment outcome (p=0.11 and p=0.39 respectively). That result may be due to the small number of patients, 20 Gy being administered to 68% (13/19) of the patients and the relatively short follow-up period.

In a study conducted by Esteves et al., which includes patients who were treated with a 6 MV linear accelerator, they reported a 72% occlusion rate, which is similar to some other studies (Colombo et al. 75%; Betti et al. 66%; Souhami et al. 43% in a year; Lunsford et al.[-] 80% with GK). This study mostly comprised of patients with surgically inaccessible lesions, contraindications for surgery and failed total obliteration after embolization. The authors reported that the widest diameter, volume of the malformation and applied dose did not affect the time of the obliteration.[] Twelve of the patients in our study received SRS after embolization, while seven of them did not receive any treatment before SRS. Nine patients were treated with 6X-FFF and ten of them were treated with 10X-FFF energy. All six patients who reached a 3 year follow-up had achieved complete obliteration. The patients were evaluated radiologically at 6, 12, 24 months. The obliteration rates were 6/18 (33%), 6/14 (43%), and 8/13 (62%), respectively. These results are similar to the literature.

Orio et al.[] did not find a statistically significant difference in the AVM obliteration rates between radiosurgery performed with GK and LINAC. They reported high obliteration rates in both groups at 3-4 years after treatment. They also noted that the rates of treatment-related toxicity were similar in both groups. Multivariate analyses indicated that the most significant predictor of chronic toxicity was previous SRS. Unlike previous studies, treatment volume was not found to be a statistically significant risk factor for chronic toxicity. This may be due to the use of more tightly restricted dose limits based on the previous studies. They stated that the similar toxicity rates of two treatment modalities may be due to differences in patient groups and treatment parameters. The biggest difference between two groups was found to be the median applied dose. It should be noted that lower median treatment doses were applied with LINAC due to a lack of sufficient clinical experience, particularly before 2002. The median treatment dose was 16 Gy for LINAC and 20 Gy for GK. In our study which consisted of patients treated in a single fraction with LINAC using FFF, median treatment dose was 20 Gy (15-20 Gy). These results suggest that with the advances in LINAC technology, similar results can be achieved with treatments applied at equivalent doses to those used in GK.

A meta-analysis based on data from 51 studies, classified the complications associated with radiotherapy as radiological, symptomatic and permanent. These side effects were reported as 35.5%, 9.2% and 3.8% respectively in patients treated with radiotherapy with AVM diagnosis. The incidence of these complications was 33.9% in GK based SRS and 43.5% in LINAC based SRS. Symptomatic radiation related complications were as follows: hemiparesis (48.9%), headache (16.3%), seizures (12.1%), sensory loss (7.1%), and ataxia (3.5%). Permanent complications included hemiparesis (52.9%), visual field loss (28.6%), diplopia (12.9%), seizures (5.7%), and ataxia and sensory loss (4.3%). It was noted that fewer radiological anomalies were seen during follow-up in ruptured AVMs.[]

In a study examining radiation induced changes following GK radiosurgery, acute side effects after SRS appeared as peri-nidal hyperintensity that could be visualized in T2-weighted or FLAIR MR within the first 2 years after treatment. The breakdown of the bloodbrain barrier following endothelial damage and subsequent development of demyelination is the suggested pathophysiological mechanism of radiation induced damage. The average time for the onset of acute side effects is 13 months. According to the authorities, 83% of changes in MR disappear spontaneously within an average of 22 months. While the frequency of observed acute side effects in MR is 30%, symptoms can develop in 10% of patients. Acute side effects can be permanent in 3% of patients. Corticosteroids or antiepileptics are used for the treatment of the symptoms. The hospitalization rate is very low.[] AVM localization, nidus size, margin dose, and brain volume receiving a dose over 12 Gy can predict the symptom presence. Symptomatic damage is more common in deep localizations (thalamus, basal ganglia and brainstem).[] In our study, brain edema developed in eight patients (42%) and intracranial hemorrhage developed in three patients (16%) after the treatment. In patients with brain edema, corticosteroids were prescribed and symptoms regressed in all of them. No grade 3 or higher side effects were observed in the acute period.

Late onset side effects are rarely seen. Persistent brain edema, radiation necrosis and cystic vascular formation are some of the late onset side effects that typically appear 5 years or later after the treatment. The incidence of late onset side effects is around 2-6% and depends on the follow-up duration.[] Delayed cyst formation has been associated with larger AVM volumes, higher radiation doses, complete obliteration, and lobar localization.[] It can be treated with drainage, shunt placement or resection when it causes symptoms. Radiation necrosis can be visualized as edema and mass effect on MRI. Resection can be applied if it causes symptoms and is located in a "non-eloquent" area. Secondary tumors related to radiation can also be seen as late side effects, but their frequency is unknown. It has been established that the risk of secondary malignities is lower in single fraction than fractionated treatments.[] In our study, grade 3 or more serious side effects were observed in three patients (16%). In the 11^th, 27^th, and 30^th months, these three patients showed signs of brain necrosis. The patient who experienced necrosis in the 30^th month did not respond to medical treatment, and surgical excision was performed. PTV in this patient's treatment plan was 30.60 cc. V8, V10, and V12 of the brain volume are 7.71%, 5.72%, and 4.59%, respectively. The patient who developed necrosis in the 27th month was treated with high-dose methylprednisolone and then was monitored closely. PTV in the treatment plan of this patient is 5.20 cc. V8, V10, and V12 of the brain volume are measured as 2.76%, 1.83%, and 1.32%, respectively. In the treatment plan of the patient who developed radiation necrosis in the 10th month after treatment, it was observed that the PTV was 31.20 cc. V8, V10, and V12 of the brain volume are 10.93%, 7.41%, and 5.54%, respectively. The clinical symptoms of this patient improved after 5 months of steroid use. No permanent neurological damage was observed in our patient group but longer follow-up periods are needed. Two studies conducted with LINAC-based devices showed a median V12 value of 4.5 cc[] and 5.97 cc, respectively. In the first study, radiation necrosis rate was found to be 20% but there was no relationship with the irradiated volume (p=0.21). In the second study, it was observed that one patient developed radiation-induced necrosis and the V12 value for this patient was 18.5 cc.[] In our study, the V12 values of our patients who developed radiation necrosis at 11^th, 27^th, and 30^th months after treatment were measured as 75.34 cc; 17.53 cc; and 63.22 cc, respectively. These values are higher than those reported in other studies in the literature.