鞘内注射、脑室Ommaya囊注射的其他抗癌药物

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目前真实世界治疗实践实体瘤软脑膜转移鞘内注射常用甲氨蝶呤、培美曲塞等抗叶酸类化疗药。除此以外，尚有其他多种抗癌药物做过鞘内注射、脑室Ommaya囊注射：
一、依托泊苷
1、《Feasibility of long-term intraventricular therapy with mafosfamide (n = 26) and etoposide (n = 11): experience in 26 children with disseminated malignant brain tumors》
“Etoposide was given at a dose of 0.5 mg x 5 d every 3-6 weeks for a total of 122 courses (1-29/patient).”
“Etoposide did not cause any discomfort. No long-term toxicities attributable to intrathecal therapy as evidenced by magnetic resonance imaging or neurologic evaluation were observed. ”
2、《Durable Response of Leptomeningeal Metastasis of Breast Cancer to Salvage Intrathecal Etoposide After Methotrexate: A Case Report and Literature Review》
Intrathecal etoposide was administered as salvage therapy based on prior clinical trials employing intrathecal etoposide against LM [5,6]. We modified the dosing scheme for intrathecal etoposide to a once-a-week administration schedule instead of consecutive 5 days, with 2 to 5 weeks of rest. For intrathecal administration, a 5-ml vial containing etoposide 100 mg (E.P.S®, Boryung Pharm Co., Ltd, Seoul, Korea) was diluted with normal saline, yielding a final concentration of 0.2 mg per ml. The final solution of 5 ml containing etoposide 1 mg was injected over a 2-min period after draining of 5 ml of CSF from the reservoir for discarding. The treatment was given weekly through an Ommaya reservoir. Corticosteroid (10 mg of dexamethasone) was used for a prophylaxis of chemical arachnoiditis.
3、《Prolonged response of meningeal carcinomatosis from non-small cell lung cancer to salvage intrathecal etoposide subsequent to failure of first-line methotrexate: a case report and literature review》
For intrathecal administration, a 5-ml vial containing 100 mg of etoposide (E.P.S®, Boryung Pharm Co., Ltd., Seoul, Korea) was diluted with normal saline, yielding a final concentration of 0.2 mg per ml. The final solution of 5 mL containing etoposide 1 mg was injected over a 2-minute period after draining of 5 ml of CSF from the reservoir for discarding. The treatment was given weekly through an Ommaya reservoir. Corticosteroid was administered as a prophylaxis of chemical arachnoiditis.
二、拓扑替康
1、《Intrathecal topotecan in adult patients with neoplastic meningitis》
All patients received 0.4 mg of topotecan intrathecally two times per week.
Toxicity was modest. The most common adverse effect reported was fatigue.
2、《Pilot study assessing a seven-day continuous intrathecal topotecan infusion for recurrent or progressive leptomeningeal metastatic cancer》
Study design: Two patients with central nervous system leptomeningeal metastasis were treated with a seven-day continuous infusion of topotecan (0.2 mg/day) administered via continuous intrathecal/intraventricular infusion at a rate of 0.6 mL/h, totaling 1.4 mg/course. CSF and plasma concentrations of topotecan closed lactone (the active metabolite) were quantified at various points during topotecan infusion. Patients were monitored for neurologic and systemic toxicities according to NCI common toxicity criteria.
Results: Both patients tolerated the seven-day continuous topotecan without any significant adverse events. One patient received a second course 21 days after treatment initiation. CSF concentration of topotecan closed lactone ranged from 3.73 to 312 ng/mL (median = 131 ng/mL) and plasma topotecan closed lactone ranged from 0.44 to 1.78 ng/mL (median = 0.92 ng/mL). The median CSF topotecan concentration was greater than the median serum topotecan concentration by a 44-fold magnitude when samples were obtained at the same time point. None of the patients experienced any grade 3 or higher hematological toxicities or signs of arachnoiditis.
3、《Phase 2 clinical trial of intrathecal topotecan in children with refractory leptomeningeal leukemia: a Children's Oncology Group trial (P9962)》
Patients and methods: Patients received age-adjusted IT topotecan (0.4 mg/dose for patients >3 years of age) administered twice weekly (every 3-4 days) for 6 weeks during induction, weekly for 4 weeks during consolidation, and twice monthly for 4 months and then monthly thereafter during maintenance.
Results: Twenty-two patients enrolled in the study, of whom 20 were eligible and assessable for toxicity and 16 were assessable for response. Of 16 patients, 6 (38%) had a complete response, 8 (50%) had stable disease, and 2 (13%) had progressive disease. The median event-free survival time (95% CI) was 3.1 (1.6-10.3) months and the median overall survival time (95% CI) was 18.0 (7.3-38.3) months. Eight patients (40%) experienced grade 3 or 4 adverse events. There were no grade 4 neurological events (Table III). Four patients experienced a total of 6 grade 3 neurological events including an olfactory seizure, a headache, transient grade 3 speech impairment, muscle weakness, motor neuropathy, and ataxia. Headache was the most common grade ≤2 neurologic event and two patients developed grade ≤2 arachnoiditis.
4、《Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis》
Patients and methods: Twenty-three assessable patients received IT topotecan administered by means of either lumbar puncture or an indwelling ventricular access device (Ommaya reservoir). Intrapatient dose escalation from 0.025 mg to 0.2 mg was performed in the first cohort of patients. Subsequent cohorts of patients were treated at fixed dose levels of 0.2 mg, 0.4 mg, or 0.7 mg. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs.
Results: Arachnoiditis, characterized by fever, nausea, vomiting, headache, and back pain, was the dose-limiting toxic effect in two of four patients enrolled at the 0.7 mg dose level. The maximum-tolerated dose (MTD) was 0.4 mg. Six of the 23 assessable patients had evidence of benefit manifested as prolonged disease stabilization or response.
Conclusion: The MTD and recommended phase II dose of IT topotecan in patients who are 3 years or older is 0.4 mg.
三、噻替哌
1、《Survival of breast cancer patients with meningeal carcinomatosis treated by intrathecal thiotepa》
The standard regimen was intrathecal thiotepa (10 mg) and methylprednisolone (40 mg), repeated every other week.
2、《Intrathecal trastuzumab and thiotepa for leptomeningeal spread of breast cancer》
“the i.t. trastuzumab was increased to 50 mg and the i.t. thiotepa to 12 mg every 3 weeks”
四、5-fluoro-2'-deoxyuridine (FdUrd)
《Intracavitary chemotherapy with 5-fluoro-2'-deoxyuridine (FdUrd) in malignant brain tumors》
FdUrd (1-10 microg) was administered every day at least 25 times through an Ommaya device placed in the cyst or closed postoperative cavity reconstructed with a patch of galea aponeurotica.
五、阿糖胞苷
《Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer》
Patients assigned to the experimental group received in addition intrathecal liposomal cytarabine 50 mg every 14 days for 2 months (5 injections) followed by monthly injections of 50 mg until progression, unacceptable toxicity, or for up to 1 year. Oral steroids (5–6 mg equivalent dexamethasone) were recommended for 5 consecutive days from the day of liposomal cytarabine injection to prevent chemical meningitis. In case of severe toxicity, the dose of cytarabine could be reduced to 25 mg. Intrathecal chemotherapy was initiated via the lumbar route, but the intraventricular route was encouraged.
六、曲妥珠
《Phase II study of intrathecal administration of trastuzumab in patients with HER2-positive breast cancer with leptomeningeal metastasis》
IT Trastuzumab (150 mg) was administered weekly by lumbar puncture, through an ventricular device or through an indwelling IT drug delivery device.1 Systemic corticosteroids were introduced at least 3 days before IT treatment (≥20 mg/day prednisolone) and 25 mg of IT hydrocortisone hemisuccinate was administered just before IT trastuzumab.
七、贝伐
《First in-human intrathecal delivery of bevacizumab for leptomeningeal spread from recurrent glioblastoma: rationale for a dose escalation trial》
A 19-year-old female patient presented to Lenox Hill Hospital following thalamic GBM recurrence. She subsequently underwent two infusions of intra-arterial BEV (NCT01269853) and experienced a period of relative disease stability until progression in 2022. One month later, MRI disclosed diffuse enhancement representative of LMS of GBM. The patient subsequently underwent five cycles of IT BEV in mid-2022 (IND 162119). Doses of 25 mg, 37.5 mg, 50 mg, 50 mg, and 37.8 mg were delivered at two-week intervals between doses 1-4. The final 37.8 mg dose was given one day following her fourth dose, given that the patient was to be discharged, traveled several hours to our center, and was tolerating therapy well. Dosage was decreased due to the short interval between the final two treatments. Shortly after IT BEV completion, she received a third dose of IA BEV.
八、O药
《Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results》
The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks.
九、泰欣生
《Nimotuzumab treatment and outcome analysis in patients with leptomeningeal metastasis from nonsmall cell lung cancer》
These twenty patients were treated with weekly IT therapy. Fifteen of them received combination of h-R3 (50 mg/week) and MTX (5–10 mg/week) IT therapy and the other five patients received h-R3 (50 mg/week) IT therapy alone.
十、利妥昔
《Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma》
The protocol planned nine injections of rituximab (10 mg, 25 mg, or 50 mg dose levels) through an Ommaya reservoir over 5 weeks. The safety profile of intraventricular rituximab was defined in 10 patients.
The maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated.
all patients were on a stable or tapering dose of glucocorticoids during pretreatment staging and intrathecal rituximab therapy.
Rituximab was administered once on study week 1 and twice per week thereafter (day 1 and day 4) for 4 weeks for a maximum of nine doses through an Ommaya reservoir. At dose levels 1 and 2, rituximab stock solution (10 mg/mL) was diluted in 0.9% saline to a total volume of 5 mL. At dose level 3, rituximab was directly injected without dilution (5 mL of a 10 mg/mL solution) slowly over a period of 1 to 5 minutes. All patients received acetaminophen, diphenhydramine, and famotidine or cimetidine 30 minutes before intrathecal injection. At least 5 mL of CSF were removed before each intrathecal rituximab injection, after which manual pressure was applied to the skin over the Ommaya device to facilitate delivery into the brain ventricles.
十一、Nk
《Intrathecal CAR-NK cells infusion for isolated CNS relapse after allogeneic stem cell transplantation: case report》
On day 131, we performed IT umbilical cord blood-derived CAR-NK cells (target CD7) infusion (total volume 3 ml, with NK cells count 1.0 × 107). The donor lymphocytes and CAR-NK cells were prepared using a local distributed, standardized, automated system at the cell processing center of Hebei Senlang Biotechnology Company under good manufacturing practice conditions. After IT CAR-NK infusion, he developed high fever, headache, nausea and vomiting. Three days later, he developed a spinal cord transection with incontinence. Physical examination revealed absence of touch and pain sensation below the level of the third lumbar vertebra. Muscle strengths of lower extremities declined to class zero [9]. MRI of brain and spinal cord revealed subacute combined degeneration. Detection of cytokines revealed that interferon-γ, interleukin-6 and interleukin-8 (R&D Systems, Minneapolis, MN, USA) increased in CSF. After IT CAR-NK cells infusion, his limb numbness and movement disorder got worse in a short time, whereas the ptosis and blurred vision improved completely. BM and blood simultaneously remained CR and complete donor chimerism over nine months after IT CAR-NK cells infusion.