Surgical resection has been the treatment of choice for symptomatic meningiomas^1,20,24). Complete resection is often curative for benign meningiomas and the progression-free survival of approximately 95% at 5 years and 90% at 10 years has been reported^22,23). However, meningiomas that envelop critical neural or vascular structures cannot be completely resected due to post-resective neurological deterioration. Over the past two decades, radiosurgery has been conducted as an adjuvant or alternative procedure to resective surgery¹⁾. Gamma knife radiosurgery (GKRS) can be considered for a tumor that is not suitable for resection because GKRS has shown effective local tumor control rates and acceptable complication rates comparable to those achieved with surgical resections^13,14,21). However, radiation-induced complications, such as aggravation of pre-existing peritumoral edema (PTE) have also been reported to cause neurological deterioration²⁾. Radiation-induced intratumoral necrosis (RIN) is one of the signs of treatment response after radiosurgery, however, it can exacerbate the mass effect especially when the tumor is located adjacent to critical structures or the cerebrospinal fluid pathway until the tumor starts to shrink by RIN. Until now, relatively little has been published regarding RIN or PTE after GKRS in patients with intracranial meningiomas. Therefore, we aimed to study the incidence, clinical significance, and relevant factors of RIN and PTE during the early period after GKRS for intracranial meningiomas.

The median clinical follow-up duration was 19.9 months (range, 3.7-35.1). Sixty-four meningiomas were assessed by at least one follow-up imaging with a mean imaging follow-up duration of 12.9 months (range, 5.4-33.4).

Stereotactic radiosurgery offers a relatively non-invasive and effective method in the management for intracranial tumors, including meningiomas¹⁴⁾. Metellus et al.¹⁵⁾ compared GKRS and conventional radiotherapy for primary and residual meningiomas. They concluded that both conventional radiotherapy and GKRS were safe and efficient, but GKRS provided a better radiological response, and was more compatible with most patients than conventional radiotherapy. Hsieh et al.¹⁰⁾ compared the treatment results of meningioma between GKRS and linear accelerator-based radiosurgery. They reported that the mean complication rate was 15.2% (range, 8.3-23.6) in the GKRS treated group treated, and 25.9% (range, 17.0-34.9) in those treated using a linear accelerator. Therefore, GKRS can be said to provide more beneficial effects in terms of radiation-induced complications. Radiation-induced imaging changes can be the signs showing treatment response after GKRS, but these changes can also exacerbate patients' symptoms or neurological signs by increasing the mass effect. These unwanted effects can prompt additional treatments, such as steroid administration or decompressive surgery, especially in benign tumors. Therefore, some researchers have studied radiation-induced imaging changes after stereotactic radiosurgery for benign intracranial tumors and relevant factors. Chang et al.³⁾ reported that patients treated with GKRS for meningiomas experienced peritumorous imaging changes at a rate of 23.6%. In their series, tumor location, maximal dose, and margin dose were related to the occurrence of imaging changes after GKRS in univariate analysis. However, only tumor location (convexity, parasagittal and falx cerebri) remained significant in multivariate analysis. Other studies have reported regarding the significance of tumor location and the location of the non-skull base meningiomas seemed to encounter more adverse radiation effects compared to the skull base lesions^{4,5,12,16,19)}. However, there was no correlation between tumor location and adverse radiation effects in our study.

Among the imaging changes that can lead to clinical deterioration after GKRS, PTE has been the most frequently studied. Cai et al.²⁾ reported that worsened pre-existing PTE, or new PTE occurred in about 25% of patients who underwent GKRS for intracranial meningiomas. Tumor-brain contact interface area was a strong predictor for the occurrence of new PTE in their series. Kollová et al.¹³⁾ analyzed 400 meningiomas and found that tumors with edema before GKRS, tumor volume >10.0 cc, tumors treated with a maximum dose >30 Gy and margin dose >16 Gy were significantly related to post-GKRS edema (aggravation or new development). We thought that RIN may lead to neurological deterioration because RIN can result in transient tumor volume increase, especially when meningiomas are located adjacent to the critical structures, such as the cerebrospinal fluid pathway. In our series, a target volume >4.5 cc and maximum dose >25 Gy were significantly related to the development of RIN, but there was no significant increase of tumor volume itself in the 21 meningiomas that developed RIN after GKRS. However, RIN was significantly related to new development or aggravation of PTE in both univariate and multivariate analyses. The median interval to the development of RIN (6.5±0.4 months) was a little shorter compared to that of PTE (7.0±0.7 months). These results may suggest that RIN can be a warning sign of the development or aggravation of PTE.

Besides RIN, maximum dose >24 Gy was also a significant factor related to new development or aggravation of PTE in our study. Flickinger et al.⁶⁾ reported on the possible relations between marginal dose and complications occurring after GKRS of meningiomas. They reported that the actuarial rates of any symptomatic post-radiosurgical sequelae (at 10 years) were 5.3±2.3% in the median marginal dose 14 Gy (range, 8.9-20) and 22.9±9.3% in the median marginal dose 17 Gy (range, 10-20). In addition, they insisted that complications correlated with the volume of tissue receiving ≥12 Gy. However, marginal dose was not significantly related to new development or aggravation of PTE in our study. This result may be caused by the lowered prescription dose from October 2009 after having patients experience severe PTE after GKRS. Although prescription dose is a fixed value, maximum dose can be varied. Hur et al.¹¹⁾ reported on the difference of the maximum dose ranges from 0.7-7% by matrix size and target volume. Their results are coherent with our results which showed that maximum dose was significantly related to new development or aggravation of PTE, instead of marginal dose. Among 64 lesions, 11 lesions were treated with marginal dose of 12 Gy showed the range of maximum dose from 23.6-24.3 Gy (mean, 24.1) in our study.

In our series, target volume >4.5 cc and maximum dose >25 Gy were significant factors for the development of RIN after GKRS for intracranial meningiomas. RIN and maximum dose >24 Gy were significantly related to new development or aggravation of PTE, and RIN preceded new development or aggravation of PTE. Therefore, we suggest that close observation is required for meningiomas treated with a maximum dose >24 Gy and showing RIN after GKRS, because accompanying PTE may deteriorate neurological conditions when they are located adjacent to critical structures or the cerebrospinal fluid pathway.