Patient characteristics
We analyzed the characteristics of 88 patients(table2), the median age was 50.5 (17-80) years. The 88 patients include 56 patients with HGG (WHO Ⅲ & Ⅳ) and 32 patients with LGG (WHO I & II). All patients had histologically confirmed gliomas. Eighty-six patients had undergone at least one operation before GKRS, and 2 patients’ diagnosis of glioma by histopathologic biopsy (both HGG). Fourteen patients (4 cases of LGG and 10 cases of HGG) did not follow-up the specific time of disease progression after gamma knife treatment, but there was a specific time of death. Seventy-three patients had received adjuvant treatment after first surgery, including chemoradiotherapy (41%), EBRT (26%), TMZ (6%), GKRS (10%), and another 15 patients had without any medical treatment. Twenty-nine patients had received multiple GKRS after the recurrence. Univariate analysis demonstrated that prognostic factors associated with OS (Fig.3) and PFS (Fig.4) were primary pathological grade, recurrence time, reoperation, KPS, pathological grade after recurrence and multiple gamma knife treatment; central dose and peripheral dose were correlated with PFS.
Table 2
Univariate analysis of OS and PFS in all patients pre- and post-GKRS
characteristics
|
Number of patients (%)
|
Median PFS (95% CI) P-value
|
Median OS (95% CI) P-value
|
Sex
|
|
0.861
|
0.864
|
Female
|
45(51)
|
4.5(1.7–7.4)
|
10.0(0.0–22.0)
|
Male
|
43(49)
|
5.0(4.3–5.7)
|
12.5(8.0–17.0)
|
Histopathology
|
|
0.008
|
0.001
|
WHO I & II
|
32(36)
|
12.0(3.9–20.1)
|
27.0(0.0–56.0)
|
WHO Ⅲ & Ⅳ
|
56(64)
|
4.5(3.0–6.0)
|
10.0(4.9–15.1)
|
Adjuvant treatment after first surgery
|
|
0.877
|
0.446
|
Chemoradiotherapy
|
36(41)
|
4.0(1.5–6.5)
|
7.5(5.9–9.1)
|
EBRT
|
23(26)
|
6.0(0.8–11.1)
|
14.3(4.6–24.0)
|
TMZ
|
5(6)
|
5.5(4.4–6.6)
|
18.0(11.6–24.4)
|
GKRS
|
9(10)
|
8.0(0.0–18.2)
|
33.5(17.4–50.0)
|
None
|
15(17)
|
4.0(1.4–6.6)
|
12.5(4.4–20.6)
|
Age at GKRS procedure
|
|
0.939
|
0.915
|
≥50 years
|
46(52)
|
5.0(3.5–6.5)
|
17.0(3.6–30.4)
|
<50 years
|
42(48)
|
4.5(2.1–7.0)
|
10.3(7.3–13.3)
|
Recurrence time interval
|
|
0.014
|
0.001
|
≥15 months
|
45(51)
|
6.0(0.9–11.1)
|
24.0(2.2–45.8)
|
<15 months
|
43(49)
|
4.5(3.0–6.0)
|
10.0(4.7–15.3)
|
Reoperation
|
|
0.005
|
0.003
|
Yes
|
23(26)
|
15.3(0.0–51.4)
|
39.0(0.0–97.1)
|
No
|
65(74)
|
4.5(3.7–5.3)
|
11.0(7.0–15.0)
|
KPS
|
|
0.046
|
0.013
|
≥80
|
38(43)
|
7.5(4.9–10.1)
|
28.0(7.3–48.7)
|
<80
|
50(57)
|
4.0(2.6–5.4)
|
9.0(6.5–11.5)
|
Number of targets
|
|
0.097
|
0.479
|
Single
|
51(58)
|
6.0(4.7–7.3)
|
12.5(3.3–21.7)
|
Multiple
|
37(42)
|
4.0(2.8–5.1)
|
10.3(4.4–16.2)
|
Total volume of target
|
|
0.728
|
0.611
|
≥18 cm3
|
41(47)
|
5.0(3.7–6.3)
|
10.5(4.0–17.0)
|
<18 cm3
|
47(53)
|
5.0(3.4–6.6)
|
13.2(3.2–23.2)
|
Maximum dose
|
|
0.042
|
0.145
|
≥25 Gy
|
46(52)
|
6.0(3.0–9.0)
|
18.0(7.6–28.4)
|
<25 Gy
|
42(48)
|
4.0(2.8–5.2)
|
10.0(6.0–14.3)
|
Marginal dose
|
|
0.040
|
0.079
|
≥13 Gy
|
48(55)
|
6.0(3.5–8.5)
|
21.0(11.7–30.3)
|
<13 Gy
|
40(45)
|
3.5(2.1–4.9)
|
9.0(6.2–11.8)
|
Multiple GKRS
|
|
0.036
|
0.022
|
Yes
|
29(33)
|
12.0(3.2–20.8)
|
22.0(9.4–34.6)
|
No
|
59(67)
|
4.0(2.9–5.6)
|
9.0(6.6–11.4)
|
TMZ used post-GKRS
|
|
0.754
|
0.603
|
Yes
|
28(32)
|
4.5(2.7–6.3)
|
11.0(2.9–19.1)
|
No
|
60(68)
|
5.0(3.5–6.5)
|
12.5(7.2–17.8)
|
bevacizumab used post-GKRS
|
|
0.674
|
0.880
|
Yes
|
9(10)
|
6.0(0.9–11.1)
|
17.0(5.7–28.3)
|
No
|
79(90)
|
5.0(3.7–6.3)
|
12.5(7.7–17.3)
|
Abbreviations: LGG (low-grade glioma), HGG (high-grade glioma), WHO (World Health Organization), EBRT (External beam radiotherapy), TMZ (Temozolomide), GKRS (gamma knife radiosurgery), KPS (Karnofsky performance status).
Survival and subgroup analysis
Survival analysis and prognostic factors by PFS and OS was shown in Table 2, Kaplan–Meier survival curves are shown in Fig.5. The median follow-up time was 79.5 months (95% CI: 60.6–98.4). By the end of the study, 65 patients died during the follow-up period. The median OS and PFS for all patients were 12.5 months (95% CI: 7.8–17.1) and 5.0 months (95% CI, 3.8–6.2), respectively. The median OS and the median PFS was 10.0 months (95% CI: 4.9–15.1) and 4.5 months (3.0–6.0) for HGG, respectively. The median OS and the median PFS was 27.0 months (95% CI: 0.0–56.0) and 12.0 months (95% CI: 3.9–20.1) for LGG, respectively.
On multivariate analysis, KPS>80, pathological grade and multiple GKRS significantly affected OS (P =0.005, P =0.001, P =0.032, respectively) and PFS (P =0.038, P =0.012, P =0.021, respectively) (Table 3).
Stratified analysis showed that recurrence time interval (≥ 15 months) was an independent influencing factor of OS and PFS for LGG (P < 0.001, P =0.029) (Table 4). KPS>80 and tumor volume (≥25 cm3) were the influencing factors of OS for HGG (P=0.001, P =0.033). Tumor volume (≥25 cm3) was an independent influencing factor of PFS for HGG (P =0.037) (Table 5).
Table 3
Cox proportional-hazards multivariate models of PFS and OS in all patients
Parameters
|
OS
|
PFS
|
HR (95% CI)
|
P-value
|
HR (95% CI)
|
P-value
|
KPS
|
2.109(1.248–3.564)
|
0.005
|
1.700(1.030–2.803)
|
0.038
|
Pathological grade
|
0.363(0.201–0.655)
|
0.001
|
0.489(0.281–0.853)
|
0.012
|
GKRS times
|
1.757(1.049–2.925)
|
0.032
|
1.858(1.100–3.138)
|
0.021
|
Table 4
Cox proportional-hazards multivariate models of PFS and OS in LGG patients
Parameters
|
OS
|
PFS
|
HR (95% CI)
|
P-value
|
HR (95% CI)
|
P-value
|
KPS
|
0.977(0.388–2.461)
|
0.960
|
0.948(0.385–2.332)
|
0.907
|
GKRS times
|
0.964(0.374–2.486)
|
0.939
|
1.043(0.412–2.584)
|
0.982
|
Recurrence time(15 m)
|
0.081(0.020–0.327)
|
<0.001
|
0.320(0.116–0.889)
|
0.029
|
Table 5
Cox proportional-hazards multivariate models of PFS and OS of HGG patients
Parameters
|
OS
|
PFS
|
HR (95% CI)
|
P-value
|
HR (95% CI)
|
P-value
|
KPS
|
0.275(0.128–0.590)
|
0.001
|
1.647(0.899–3.019)
|
0.107
|
Tumor volume (25 cm3)
|
1.990(1.058–3.743)
|
0.033
|
0.508(0.269–0.959)
|
0.037
|
Adverse reactions:
Seventy-four patients (84%) had no adverse reactions, 9 patients (10.2%) had mild headache (grade I–II), and 4 patients (4.5%) had mild dizziness, which were relieved after symptomatic treatment with mannitol and hormone. Nausea occurred in 3 patients (3.4%), and nausea accompanied with vomiting in 1 (1.1%), which was relieved after antiemetic and brain dehydration treatment. Two patients with fatigue and weakness were relieved after rest. One patient had mild lethargy, which was relieved after three days. No serious adverse reactions occurred. The specific adverse reactions are shown in Table 6.
Table 6
Adverse events after GKRS
Adverse reactions
|
Number of LGG patients (%)
|
Average duration
|
Number of HGG patients (%)
|
Average duration
|
none
|
28(87.5)
|
-
|
46(82.1)
|
-
|
Headache (grade Ⅰ)
|
2(6.3)
|
2d
|
4(7.1)
|
3d
|
Headache (grade Ⅱ)
|
1(3.1)
|
3d
|
2(3.6)
|
5d
|
Dizziness (grade Ⅰ)
|
1(3.1)
|
1d
|
3(5.4)
|
2d
|
Nausea and vomiting
|
1(3.1)
|
2d
|
2(3.6)
|
2d
|
Fatigue (grade Ⅰ)
|
0(0)
|
-
|
2(3.6)
|
3d
|
Somnolence (grade Ⅰ)
|
0(0)
|
-
|
1(1.8)
|
3d
|