Table 1.
Summary of neurotoxic events in studies using intrathecal liposomal cytarabine#
| Study | No. of patients (age) |
Type of study | Indication | Dose and frequency of liposomal cytarabine |
Total no. of doses |
Route of administr ation |
Measures taken to prevent neurotoxicity |
Concurrent cranial RT or high dose chemotherapy |
Neurotoxicity (≥ Grade III) |
Proportion of patients with≥ grade III neurotoxicity (95% CI) |
Cytologic response (No. of patients) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Kim et al ^ (1993)4 |
12 (6–73 yrs) |
Phase I | Neoplastic meningitis (4 hematologic malignancies, 8 solid tumors) |
12.5–125 mg; Q 2–3 weeks |
47 | IVT: 11 LP: 1 Both: 3 |
NR | Cranial irradiation: 2 |
Encephalopathy: 3 Headache: 2 |
5 of 47 cycles 10.6% (1.8% to 19.5%) |
7 of 9 evaluable patients |
| Chamberl ain et al (1995)3 |
9 (23–67 yrs) |
Phase 1 | Neoplastic meningitis (4 NHL, 1 AML, 3 solid tumors) |
75 mg; Q 2 weeks |
18 | LP | Dexamethasone PO in 15 cycles |
NR | None | 0 of 9 0% (0% to 28%) |
6 of 8 evaluable patients |
| Glantz et al^ (1999)5 |
14 (35–86 yrs) |
Randomized phase II |
Lymphomatous meningitis |
50 mg; Q 2 weeks X 2 months, Q 4 weeks X 8 months |
74 | IVT: 13 LP: 1 |
Dexamethasone PO/IV |
None | Headache: 4 Meningismus: 2 Confusion: 2 Somnolence: 2 |
10 of 74 cycles 13.5% (5.7% to 21.3%) |
10 of 14 |
| Glantz et al (1999)6 |
31 (19–74 yrs) |
Randomized phase II |
Neoplastic meningitis (solid tumors) |
50 mg; Q 2 weeks X 2 months, Q 4 weeks X 8 months |
102 | IVT: 29 LP: 2 |
Dexamethasone PO/IV |
Cranial or spinal irradiation: 4 |
Headache: 4 Altered mental status: 5 Seizures: 1 Sensory/Motor: 1 Drug related meningitis: 3 CNS infection: 3 |
17 of 31 54.8% (37.3% to 72.3%) |
8 of 31 |
| Jaeckle et al^ (2001)12 |
53 (28–74 yrs) |
4 studies (1 randomized, included 11 patients from Glantz et al6, 3 non randomized) |
Neoplastic meningitis (breast cancer) |
50 mg; Q 2 weeks X 2 months, Q 4 weeks X 2 months |
177 | IVT: 42 LP: 8 Both: 3 |
Dexamethasone PO/IV |
Cranial irradiation: 13 |
Headache: 2 Arachnoiditis: 4 |
6 of 177 cycles 3.4% (0.7% to 6%) |
12 of 43 evaluable patients |
| Bomgaar s et al (2004)2 |
18 (4–19 yrs) |
Phase I | Neoplastic meningitis (9 ALL, 1 AML, 8 brain tumors) |
25–50 mg; Q 2 weeks X 1 month, Q 4 weeks X 2 months, Q 8 weeks X 12 months |
78 | IVT: 3 LP: 12 Both: 3 |
Dexamethasone PO/IV |
None | Headache: 3 | 3 of 18 16.6% (0% to 33.9%) |
8 of 14 evaluable patients |
| Sancho et al (2006)13 |
6 (5–50 yrs) |
Retrospective series |
CNS involvement in leukemia |
50 mg; Q 2 weeks (25 mg in 5 yr old) |
29 | LP | Dexamethsaone PO/IV |
NR | None | 0 of 6 0% (0% to 39%) |
2 of 3 evaluable patients |
| Jabbour et al (2007)7 |
31 (>18 yrs) |
Phase II | Newly diagnosed adult ALL |
50 mg Day 2 and 15 of HyperCVAD cycle, Day 10 of MA cycle |
NR | LP | Dexamethsone PO/IV Liposomal cytarabine >7 days after HD cytarabine |
High dose methotrexate and cytarabine: 31 |
Papilledema and blindness: 1 Increased intracranial pressure: 2 Cauda eqina syndrome: 2 |
5 of 31 16.1% (3.2% to 29.1%) |
Prophylactic use 1 combined marrow and CNS relapse |
| Benesch et al (2007)11 |
5 (5–18 yrs) |
Retrospective series |
Neoplastic meningitis (4 leukemia, 1 medulloblastoma |
15–50 mg; Q 2–4 weeks (Single dose in 1 patient) |
33 | LP | Dexamethasone PO/IV |
High dose methotrexate (8 gm/m2): 1 TBI: 1 |
Encephalopathy: 1 Seizures* : 1 |
2 of 5 40% (0% to 82.9%) |
3 of 5 |
| Sancho et al (2007)14 |
10 (18–57 yrs) |
Retrospective series |
AML CNS involvement:6 CNS relapse: 4 |
50 mg; Q 2 or 4 weeks (35 mg in 18 yr old) |
39 | LP | Dexamethasone PO/IV |
High dose cytarabine: 6 |
Headache*: 3 | 3 of 10 30% (1.6% to 58.4%) |
9 of 9 evaluable patients |
| McClune et al (2007)8 |
14 (23–72 yrs) |
Retrospective series |
Newly diagnosed ALL and aggressive lymphomas |
50 mg (25 mg if intraventricular); Q 3 weeks |
40 | IVT: 2 LP: 12 |
Dexamethasone PO/IV Liposomal cytarabine Q3 weeks |
High dose methotrexate and cytarabine: 14 |
Hyponatremia and somnolence*: 1 Headache*: 1 |
2 of 14 14.3% (0% to 32.6%) |
Prophylactic use No CNS relapses |
| Parasole et al (2008)10 |
6 (2–26 yrs) |
Retrospective series |
ALL with CNS relapse |
Q 2 weeks (Q 1 week X 4 in 1 patient) |
33 | LP | Dexamethasone PO/IV Methylprednisone IT (2 patients) Age adjusted dose |
High dose cytarabine (2 gm/m2): 5 |
None | 0/6 0% (0% to 39%) |
6 of 6 |
#
Includes studies ≥ 5 patients, published in English
*
Grade of toxicity not reported
^
Neurotoxic events reported per cycle of intrathecal liposomal cytarabine (not per patient)
IVT: Intraventricular
LP: Lumbar puncture
NR: Not reported
ALL: acute lymphoblastic leukemia
AML: Acute myeloid leukemia
CNS: Central nervous system
RT: Radiation therapy