Intrathecal Chemotherapy: Focus on Drugs, Dosing, and Preparation

Mandy Gatesman, PharmD BCOP
Clinical Pharmacy Specialist, Hematology & Oncology
Virginia Commonwealth University Health System
Richmond, VA

Intrathecal (IT) administration of chemotherapy by lumbar puncture (LP) or intraventricular injection via Ommaya reservoir is used frequently in prophylaxis and treatment of a central nervous system (CNS) disease in both hematologic and solid tumor malignancies.¹ Nonetheless, there is a paucity of well-designed trials on the optimal dosing and preparation of these agents. Available guidelines primarily address safety aspects of IT chemotherapy dispensing.^2,3 The purpose of this review is to summarize the available literature on medications that can be given by the IT route for treatment of oncologic indications and attempt to address common questions regarding preparation and stability.

Intrathecal Medications for Oncologic Use
Methotrexate: Methotrexate is the most commonly used agent for IT administration. Dosing is based on age in pediatric patients (Table 1 - see PDF); the most common dose used in adults is 10–15 mg per injection. Methotrexate may be diluted to a concentration of 1 mg/ml using an appropriate sterile, preservative-free diluent;⁴ concentrations of up to 2.5 mg/ml also have been reported.⁵ Methotrexate is particularly vulnerable to light degradation, and care should be taken to protect any prepared methotrexate-containing product from light.⁶
For treatment of a CNS disease, IT methotrexate is commonly given twice weekly (every 2–5 days) for 4 weeks, then weekly for an additional 4 weeks; once-monthly maintenance dosing may then be administered.⁷ For prophylaxis of a CNS disease, the frequency of IT methotrexate varies and is usually dictated by the individual chemotherapy protocol.

Cytarabine: Similar to IT methotrexate, cytarabine also is dosed by age in pediatric patients (see Table 1); usual adult dose is 25–100 mg per injection. For treatment of a CNS disease, IT cytarabine may be given on the same schedule as IT methotrexate (twice weekly for 4 weeks, then weekly for 4 weeks, then once per month).7 Cytarabine may be diluted to a concentration of 0.4–20 mg/ml, but concentrations above 10 mg/ml may increase toxicity, perhaps because of the higher pH of the more concentrated product.⁵

A liposomal formulation of cytarabine (DepoCyt^®) prolongs the exposure of cytarabine in the cerebrospinal fluid, thereby allowing for less frequent administration (every 14 days). The dose of IT liposomal cytarabine is 35 mg in pediatrics and 50 mg in adults. Because of the risk of arachnoiditis with IT liposomal cytarabine, oral dexamethasone should be given for 5 days, starting the day of treatment.⁸ Unlike traditional cytarabine, liposomal cytarabine should not be mixed with any other medication in the same syringe (e.g., hydrocortisone). Liposomal cytarabine must be used within 4 hours of withdrawing from the vial.⁸

Cytarabine is commonly given in combination with methotrexate and a steroid as part of “triple IT therapy” (Table 2 - see PDF). For IT therapy consisting of cytarabine, methotrexate, and methylprednisolone, a study by D’Hondt and colleagues demonstrated stability for up to 12 hours when protected from light and stored in refrigeration.⁶ A recent study showed extended stability of cytarabine, methotrexate, and hydrocortisone when protected from light for up to 48 hours at room temperature and up to 5 days under refrigeration.⁹

Rituximab: Rituximab dosing for IT administration was assessed in a phase 1 dose-finding study. The dosing schedule was twice weekly (days 1 and 4) for 4 weeks; the study allowed a maximum of nine IT rituximab injections. The maximum tolerated dose was found to be 25 mg, which was prepared by diluting standard rituximab (10 mg/ml) with preservative-free sodium chloride to a final volume of 5 ml and injected over 1–5 minutes.10 Another phase 1 study investigated the tolerability of IT rituximab in combination with IT methotrexate for CNS lymphoma and confirmed 25 mg as the maximum tolerated dose. Treatment was administered twice weekly (days 1 and 4, +/- 1 day) for 4 weeks with IT rituximab given only on day 1 and IT rituximab followed by IT methotrexate (12 mg) given on day 4.11 Both studies used premedication prior to each IT rituximab dose with acetaminophen, diphenhydramine, and an H2 receptor antagonist. Response rates are reported in 40%–75% of patients with leptomeningeal involvement of lymphoma.^10,11

Trastuzumab: For management of leptomeningeal involvement of HER2+ breast cancer, IT trastuzumab has been employed in a variety of doses (range 4–150 mg) and schedules (every 7–21 days). It also has been used as monotherapy, in combination with systemic therapy, or in combination with other IT treatments (methotrexate, cytarabine, prednisone, thiotepa). Responses were noted in approximately two-thirds of patients.¹² Of note, Herceptin^® is supplied with bacteriostatic water, which contains the preservative benzyl alcohol, for reconstitution and injection. When the medication is prepared for IT administration, a diluent that does not contain preservative (e.g., sterile water for injection) must be used for reconstitution.¹³

Topotecan: IT topotecan has been used to treat primary CNS tumors and leptomeningeal disease in a variety of solid tumors (e.g., ovarian, breast, and lung tumors).^14,15 The usual dose as determined in a phase 1 trial is 0.4 mg twice weekly (every 3–4 days) for 4–6 weeks, then weekly for 4–6 weeks; maintenance therapy can then be administered twice monthly for 4 months, then once monthly thereafter for up to 8 months.^14,16 Each dose may be prepared using preservative-free topotecan diluted with preservative-free sodium chloride to a final volume of 4–10 ml and injected over ~5 minutes.^15,16 Reported responses to IT topotecan in leptomeningeal disease are 21%–33%; responses seem to be higher in primary CNS tumors (~80%).¹⁵

Thiotepa: Thiotepa is less commonly administered via the IT route and has shown limited success, potentially because of its rapid clearance from the CSF.17 When used for treatment of a CNS disease, IT thiotepa has been given as a flat dose of 10 mg or a body-surface-area-based dose of 5–12 mg/m2.^17,18 The schedule also varies from weekly¹⁷ to twice weekly,¹⁸ but thiotepa may be given on the same schedule as IT methotrexate or cytarabine (twice weekly for 4 weeks, then weekly for 4 weeks, then once a month).⁷

Miscellaneous Agents: Etoposide and interferon also have been used for IT administration.¹ Etoposide has been used at a dose of 0.5 mg daily for 5 days, repeated every other week for 8 weeks, with approximately 25% response rates reported in a mixed population of solid tumors and lymphoma.¹⁹ Interferon alfa-2b was studied at a dose of 1 million units three times weekly (given every other day) for 4 weeks, then three times per week every other week for 4 weeks, then three times per week every month for 4 months. Higher responses were noted in patients with hematologic malignancies (chronic myeloid leukemia and non-Hodgkin lymphoma). Arachnoiditis was common (73%) but mostly grade 1; of note, steroids were not used to prevent or treat arachnoiditis because of the concern of compromising interferon efficacy.²⁰ Because of the high risk of neurotoxicity, the National Comprehensive Cancer Network rates interferon alfa-2b as a category 2B option for IT therapy.¹

Intraventricular Versus Intralumbar Administration
Delivery of medications directly into the CSF can occur by either LP or direct administration into the ventricles via a subcutaneous access device such as an Ommaya reservoir. Both have risks and benefits. The risks include patient discomfort and the inconvenience of repeated LPs for the intralumbar route and the risk of infection with placement of an Ommaya reservoir. Regardless of which method is used, drug clearance of most agents, including methotrexate and cytarabine, is directly related to the rate of CSF bulk flow excretion rather than usual mechanisms of drug metabolism.²¹

There is high interpatient variability of ventricular concentration of methotrexate following intralumbar administration.²² If the intralumbar route of administration is chosen, patients should remain in the prone position for at least 1 hour following injection to maximize drug distribution throughout the CSF and into the ventricular space.²³

Intrathecal Chemotherapy Toxicity
Toxicity following IT chemotherapy may include nausea or vomiting, arachnoiditis (headache, back pain, nuchal rigidity, fever), and chronic leukoencephalopathy (confusion, somnolence, ataxia, seizures).⁴ The Children’s Oncology Group recommends removing enough CSF to equal at least 50% of the volume of the administered IT product to decrease the risk of neurotoxicity associated with IT therapy. Liposomal cytarabine may be associated with higher risk of neurotoxicity than standard triple IT therapy.^24,25 Patients previously treated with IT chemotherapy may be at increased risk for neurotoxicity from nelarabine.²⁶ Vinca alkaloids (vincristine, vinblastine, vinorelbine) are fatal if given intrathecally and should be mixed in minibags or labeled appropriately.³

Headache also may occur as a result of the LP procedure itself, presumably because of a leakage of CSF through the puncture site. The headache usually is constant, worsens within 15 minutes of standing, and is relieved within 15 minutes of lying down. Bed rest and analgesics are primary treatments, but if the headache persists for more than 72 hours, alternative treatments may be initiated.²⁷ Caffeine and sodium benzoate significantly improve the symptoms of post-LP headache when given at a dose of 500 mg in 1,000 ml normal saline over 1 hour.²⁸ Gabapentin, hydrocortisone, and theophylline also have demonstrated benefit. Nonpharmacologic interventions may include an epidural blood patch to block the leakage of CSF if the condition is refractory to drug therapy.²⁷

Preparation: Other Considerations
Regardless of which agent is being used, only preservative-free products and diluents should be used for IT administration because of the risk of neurotoxicity with preservatives such as benzyl alcohol. Diluents for reconstitution may include preservative-free 0.9% sodium chloride, lactated Ringer’s solution, or Elliot’s B solution. The volume of the finished product varies significantly but often is in the range of 3–10 ml. Stability often is drug specific, but preparation as close to the time of administration as possible is prudent. 

One question commonly encountered is the use of a filter in preparing IT chemotherapy products. Theoretically, filtration would be used to remove microorganisms such as bacteria and fungus, which would require a ≤0.2-micron filter. United States Pharmacopeia (USP) chapter 797 accepts filtration as a form of sterilization only for high-risk, compounded products. IT products prepared using aseptic technique in an appropriate ISO class 5 environment would be considered low or medium risk; filtration is not specifically addressed for those classifications.²⁹ No data exist regarding the use of filtration specifically for IT products. Larger molecules, such as the monoclonal antibodies (rituximab, trastuzumab) and liposomal cytarabine, should not be filtered because of the large size of the molecule.⁸

References

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