**8. Treatment outcome**

## **8.1 Gamma Knife vs. LINAC radiosurgery**

Gamma Knife Radiosurgery was one of the most popular treatment modalities in centres worldwide. Professor Douglas Kondziolka in Pittsburgh had an early study on 946 patients between September 1987 and December 2004. The actuarial tumor control rates was 93% at 5 years and 10 years for benign types, and 83 +/−7% in 5 years and 72+/−10% for atypical and malignant types. Adverse radiation effect ranged from 5.7 to 16% [21]. Outcome of gamma knife radiosurgery of meningioma in 10 years were reviewed by Lippitz et al. 86 Swedish patients were included between March 1991 and May 2001. Totally 130 tumors were treated in 115 treatment sessions. Local tumor control was achieved in 87.8% with recurrence adjacent but outside the initial radiation field was found in 15.1% of patients. A significant lower rate of in-field local recurrences was seen in meningiomas treated with a prescription dose of >13.4 Gy (7.1% vs. 24%, p=0.02) [13]. Seo et al. had another review on 424 patient after Gamm Knife Radiosurgey from 1998 to 2010. The median tumor volume was 4.35 ml and the median marginal dose was 14 Gy. The actuarial tumor control rates were 91.7% at 5 years and 78.9% at 10 years [22]. Morever, Jang et al. showed overall tumor control rate of 95% with 15% peritumoral oedema in 628 pateints from January 2008 to November 2012, whom had received Gamma Knife Radiosurgery with maximal dosage 27.8 Gy and marginal dosage 13.9 Gy [17].

There are numbers of published papers from centres employing LINAC Radiosurgery in treatment of meningiomas with promising treatment outcome. UCLA group had a review of their early results in using LINAC system in treatment of 161 patients between May 1991 and July 2003. SRS with peripherial dose of 12–22 Gy (mean 15 Gy) was given to 26 lesions and SRT with dose ranged from 23 to 54 Gy (mean 48 Gy) was given to 7 cases. Tumor control rate was 92.3% in SRS group and 100% in SRT group, with 2 patients in SRS group suffered from worsening of neurological deficit [23]. Gallego et al. reported the results in using of LINAC Radiosurgery for treatment of 82 patients with cavernous sinus meningioma from 1992 to 2005. The mean volume of tumor was 17.96 ± 13.67 cm3 . Tumor volume reduced in 74.4% and remained stable in 14.6% [14]. Kaul et al. in Germany had retrospective review of 297 patients with LINAC Radiosurgery. The overall progression free survival was 92.3% at 3 years, 87% at 5 years and 84.1% at 10 years [16].

### **8.2 SRS vs. SRT**

There is always debate on the indications or effectiveness of single fraction therapy in SRS or multiple-fraction therapy in SRT [15]. Huang et al. had a retrospective review of 228 patients with 245 tumors treated with radiosurgery between March 2006 and June 2017 using LINAC radiosurgery using Novalis system. 147 (64.5%) patients were SRS group with total dose of 12–16 Gy in one fraction as treatment protocol and 81 (35.5%) were SRT group with 7 Gy/fraction/day for three consecutive days to 21 Gy as total dose. The actuarial local control rate between two groups was not statistically significant during the total 10-year follow-up period (96.86% vs. 100%, p=0.175, in 2-year, 94.76% vs. 97.56%, p=0.373, in 5-year, 74.4% vs. 91.46%, p=0.204, in 10-year), and with comparable radiation-related side effects [24]. Wegner et al. from Pittsburgh also had a review on 56 patients with either SRS or SRT for meningioma treatment from 2008 to 2017. They concluded that fractionation had improved local control compared with single session (91% vs. 80% at 2 years, p=0.009) with minimal radiation-related toxicity [18].

Hypofractationated therapy by CyberKnife in meningioma treatment was reviewed by French group. Meniai-Merzouki et al. collected 126 patients with 136 meningiomas undergone treatment between December 2008 and June 2016 with median prescription dose of 25 Gy (12–40) in a 5 median fractions (3–10). They showed that the subgroup with more fractions (25–40 Gy in 5–10 fractions) had significant higher progression free survival that the subgroup with less fractions (21–23 Gy in 3 fractions), and only 2% of patients experienced radionecrosis at 24 months [25]. Di Franco et al. reviewed the treatment outcome of stereotactic radiosurgery and fractionated stereotactic radiotherapy with CyberKnife from January 2013 to April 2017. They achieved 100% local control for 28 patients at 12 months, 89% local control for 19 patients at 24 months and 9 patients at 36 months [26]. Smith et al. also reported 100% crude local control rate for large meningiomas with mean treatment volume 14.7 cm3 (range 0.79–64.5 cm3 ) with hypofractionated CyberKnife with dose of 22.5–30 Gy in five fractions [27]. Study of Oermann et al. in 38 patients treated with five-fraction CyberKnife showed similar response rate to SRS but have low peritumoral oedema around 13.2% [28]. Other centres employ fractionation in terms of 1–5 fractions. Bria had treated 73 patients with median volume of 5.54 cm3 . 60 patients had WHO grade I, 11 patients had WHO grade II and 2 patients had WHO grade III. Treatment median dose was 17.5 Gy with median of three fractions. The Actuarial local control at one year was 95% in WHO grade I, 71% in WHO grade II and 0% in WHO grade III. There was no acute significant toxicity and only one late toxicity noticed [29].

Fractionated treatment is also getting its popularity in centers using Gamma knife, particularly after the introduction of the sixth versions of Leksell Gamma Knife System, ICON®. In a retrospective review of 70 patients with large-volume meningiomas (>10 cm3 ) that had undergone gamma knife treatment by Han et al., the single session group having 42 patients with median tumor volume 15.2 cm3 (range 10.3–48.3 cm3 ) and median prescription dose of 12 Gy (range 8–14 Gy) was compared with fractionated group having 28 patients with median tumor volume 21 cm3 (range 10.2–54.73 ) and median prescription dose of 7.5 Gy in 2 fractions (range 5–8 Gy), 6 Gy in 3 fractions (range 5–6.5 Gy) and 4.5 Gy in 4 fractions. The fractionated group had higher progression free survival rate at 5 yars (92.9% vs. 88.1%) with lower complication rate (7.1% vs. 33.3%) compared with patients with single session treatment [30]. Another smaller series by Park et al. showed satisfactory tumor control after fractationated Gamma Knife radiosurgery with functional preservation for large skull base meningiomas in 23 patients with mean volume of tumors of 21.1+/−15.63 cm3 (range 10.09–71.42) [31].

Meta-analysis study by Fatima et al. in 2019 had reviewed a total of 1736 patients from 12 retrospective studies. Treatment modalities included Gamma Knife surgery, linear accelerator and CyberKnife. Results showed SRT group had better radiographic tumor control, progression-free survival at 4–10 years, with significantly lower risk of clinical neurological deterioration during their follow-up (OR 2.07, 95% CI 1.06–4.06, p=0.03) and of immediate symptomatic oedema (OR 4.58, 95% CI 1.67–12.56, p=0.003) [32].

Regarding the radiation-induced oedema after radiosurgery, Milano et al. had reviewed 26 studies from 1998 to 2017. Symptomatic oedema was reported in 5–43% of patients among all oedema in 28–50%. The average time to oedema onset time ranged from around 3 to 9 months. Possible factors correlated with radiationinduced oedema included greater tumor margin and/or maximum dose, greater tumor size and/or volum, non-base of skull location particularly parasagittal, no prior resection for meningioma, and presence of pretreatment oedema [33].
