Intrathecal methotrexate in combination with systemic chemotherapy in glioblastoma patients with leptomeningeal dissemination: A retrospective analysis

Table 1 Clinical characteristics of the patients at the time of glioblastoma diagnosis

Variable	N (%)
Patient	26 (100)
Age at GBM diagnosis: median (range)	43 (18-61)
Sex
Female	10 (38.5)
Male	16 (61.5)
Location
Infratentorial (cerebellum)	2 (7.7)
Supratentorial	24 (92.3)
Extent of resection of GBM at diagnosis
Gross total	7 (26.9)
Non-gross total	19 (73.1)
Communicating with the ventricle at time of GBM diagnosisa
Yes	18 (69.2)
No	8 (30.8)
Concurrent radiation + TMZ after GBM diagnosis
Yes	26 (100)
No	0 (0)
Adjuvant TMZ cycles for GBM: Median (range)	7 (1-20)
< 7	15 (57.7)
≥ 7	11 (42.3)
Molecular pathology, positive testb
MGMT methylation	5 (19.2)
IDH1 mutation	1 (3.8)
TERT C228T mutation	8 (30.8)

^aThe tumor was within 1 cm of the ventricular system or the ventricular system was open during the operation.

^bPositive test for immunohistochemistry or NextGen sequencing.

GBM: Glioblastoma; TMZ: Temozolomide; IDH: Isocitrate dehydrogenase; LMD: Leptomeningeal dissemination; MGMT: O6-methylguanine-DNA methyltransferase; TERT: Telomerase reverse transcriptase.

Table 2 Patients’ characteristics at the time of the leptomeningeal disease diagnosis

Variable	N (%)
Patient	26 (100)
Time from GBM diagnosis to develop of LMD (months)
Median (range)	9.3 (0.7-41.4)
KPS at LMD diagnosis
≤ 60	12 (46.2)
> 60	14 (53.8)
Common presenting symptoms
Headache	12 (46.2)
None	6 (23.1)
Backache	4 (15.4)
Lower extremity weakness	3 (11.5)
Visual changes	1 (3.8)
MRI positive characteristics
Subarachnoid and ventricular Spinal cord	10 (38.5)16 (61.5)
CSF cytology for malignant cells
Yes	13 (50)
No	13 (50)
The content of total protein in the CSF (mg/fL)a
Median (range)	149.2 (21.6-1600.3)
15-45	2 (7.7)
> 45	21 (80.8)
Ommaya reservoir implant
Yes	20 (76.9)
No	6 (23.1)
Intrathecal injection chemotherapy
MTX	26 (100)
Systemic chemotherapy
TMZ	5 (19.2)
TMZ + DDP	8 (30.8)
vp-16 + CBP	13 (50)
Bevacizumab
Yes	8 (28.6)
No	18 (71.4)
Cycles of intrathecal injection and systemic chemotherapy
Median (range)	4 (1-8)
< 4	13 (50)
≥ 4	13 (50)
Gastrointestinal toxicity (grade)b
1	17 (65.4)
2	7 (26.9)
3	2 (7.7)
Myelotoxicity
< 3	19 (73.1)
3-4	7 (26.9)

^aThree patients CSF protein dates were lost. The tumors were within 1 cm of the ventricular system, or the ventricular system was open during the operation.

^bToxicity was determined by grading standard for toxic and side effects of chemotherapy drugs.

GBM: Glioblastoma; CSF: Cerebral spinal fluid; LMD: Leptomeningeal disease; KPS: Karnofsky performance status; MTX: Methotrexate; DDP: Cisplatin; CBP: Carboplatin; MRI: Magnetic resonance imaging.

Table 3 Univariate Cox regression models from diagnosis of leptomeningeal disease to death according to treatment

Covariate	χ2	P value
Sex	< 0.001	0.99
Extent of resection of GBM at diagnosis	5.236	0.022
Communicating with the ventricle at time of GBM diagnosis	0.08	0.778
MGMT methylation	1.743	0.187
TERT C228T mutation	0.811	0.368
Adjuvant TMZ cycles for GBM	0.153	0.695
Bevacizumab	2.963	0.085
KPS at the time of LMD diagnosis	9.192	0.002
Total protein in the CSF	0.986	0.321
Ommaya reservoir implant	12.701	< 0.001
CSF cytology	3.28	0.07

GBM: Glioblastoma; CSF: Cerebral spinal fluid; LMD: Leptomeningeal disease; KPS: Karnofsky performance status; MTX: Methotrexate; DDP: Cisplatin; CBP: Carboplatin; MRI: Magnetic resonance imaging; TERT: Telomerase reverse transcriptase; MGMT: O6-methylguanine-DNA methyltransferase; TMZ: Temozolomide.

Table 4 Multivariate Cox regression models from diagnosis of leptomeningeal disease to death according to treatment

Covariate	HR (95%CI)	P value
Extent of resection of GBM at diagnosis	0.485 (0.126, 1.871)	0.293
KPS at the time of LMD diagnosis	0.338 (0.122, 0.935)	0.037
Ommaya reservoir implant	0.212 (0.062, 0.729)	0.014

GBM: Glioblastoma; LMD: Leptomeningeal disease; KPS: Karnofsky performance status.