Glass J et al. J Clin Oncol 2016;34:1620–1625
The regimen consists of a single dose of intravenous rituximab 375 mg/m2 followed 3 days later by initiation of high-dose methotrexate 3.5 g/m2 given every 2 weeks for 5 doses (during weeks 1, 3, 5, 7, and 9) and two 5-day courses of temozolomide 100 mg/m2/day (during weeks 4 and 8). Twice-daily whole-brain radiation therapy is given for a total of 30 fractions (during weeks 11, 12, and 13), followed lastly by ten 5-day courses of single-agent temozolomide maintenance, initiated at 150 mg/m2/day with the first course and then escalated to 200 mg/m2/day for remaining courses, repeated every 4 weeks (during weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50)
Premedications for Rituximab:
Acetaminophen 650–1000 mg; administer orally 30–60 minutes before starting rituximab, plus
Diphenhydramine 25–50 mg; administer orally or intravenously 30–60 minutes before starting rituximab
Rituximab 375 mg/m2; administer intravenously in 0.9% sodium chloride (0.9% NS) or 5% dextrose injection (D5W) diluted to a concentration within the range 1–4 mg/mL once, 3 days prior to the first (week 1) dose of methotrexate (total dosage = 375 mg/m2)
Notes on rituximab administration:
Administer initially at a rate of 50 mg/h. If hypersensitivity or infusion reactions do not occur during the first 30 minutes, increase the rate by 50 mg/h every 30 minutes as tolerated to a maximum rate of 400 mg/h
Interrupt rituximab administration for fever, chills, edema, congestion of the head and neck mucosa, hypertension, and other serious adverse events. Resume rituximab administration after adverse events abate
Hydration before, during, and after each methotrexate administration:
Before each methotrexate administration:
5% D5W or 5% dextrose/0.45% sodium chloride injection (D5W/0.45% NS) with 50–100 mEq sodium bicarbonate injection/L; administer intravenously at 100–150 mL/h
Adjust infusion rate to achieve and maintain a urine output ≥100 mL/h for ≥4 hours before starting methotrexate
Adjust sodium bicarbonate content to produce a urine pH within the range ≥7.0 to ≤8.0 before starting methotrexate
During each methotrexate administration:
No additional hydration (see below)
After each methotrexate administration:
D5W or D5W/0.45% NS with 50–100 mEq sodium bicarbonate injection/L; administer intravenously at 100–150 mL/h until serum methotrexate concentration <0.1 μmol/L
Methotrexate 3500 mg/m2 in 500 mL D5W or 0.45% NS injection, with 50–100 mEq sodium bicarbonate per dose; administer intravenously over 4 hours, every 14 days for 5 doses during weeks 1, 3, 5, 7, and 9 (total dosage every 14 days = 3500 mg/m2)
Notes:
Add sodium bicarbonate in amounts sufficient to produce a bicarbonate concentration equivalent to fluid used for the same volume of hydration fluid given over a 4-hour period
No methotrexate dose reduction is necessary for patients with a creatinine clearance ≥50 mL/min
Methotrexate should not be administered if creatinine clearance is <50 mL/min
Avoid nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, sulfonamides, penicillins, probenecid, and proton pump inhibitors during methotrexate therapy
Preservative-free formulations of methotrexate injection should be used for high-dose therapy
Leucovorin calcium 25 mg per dose; administer orally or intravenously in 25–250 mL 0.9% NS or D5W over 15–30 minutes every 6 hours, starting 24 hours after each methotrexate administration began, and continue until serum methotrexate concentration <0.1 μmol/L, repeated every 14 days for 5 courses during weeks 1, 3, 5, 7, and 9
When serum methotrexate concentrations are ≤0.1 μmol/L, discontinue intravenous hydration and intravenous leucovorin, then:
Give leucovorin calcium 25 mg; administer orally every 6 hours for 2 days (8 doses), and
Continue hydration orally with >1500 mL/m2 (>50 fluid ounces/m2) for 3 days after intravenous hydration is discontinued
Temozolomide 100 mg/m2/day; administer orally once daily for 5 consecutive days, on an empty stomach with water at bedtime, every 4 weeks for 2 cycles during weeks 4 and 8 (total dosage/4-week course = 500 mg/m2)
Whole-brain radiation therapy twice daily at 1.2 Gy/fraction for 5 days/week for a total of 30 fractions during weeks 11, 12, and 13 (total dosage = 36 Gy)
Temozolomide; administer orally once daily for 5 consecutive days, on an empty stomach with water at bedtime, every 4 weeks, for 10 cycles during weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50, as follows:
Week 14: administer 150 mg/m2/day (total dosage/4-week course during week 14 = 750 mg/m2)
Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50: administer 200 mg/m2/day (total dosage/4-week course = 1000 mg/m2)
Note: Patients who vomit after taking temozolomide should be instructed to take their next dose at the next regularly scheduled time
Supportive Care
Antiemetic prophylaxis
Emetogenic potential on days with methotrexate or temozolomide is MODERATE
Emetogenic potential on day with rituximab is MINIMIAL
See Chapter 39 for antiemetic recommendations
Hematopoietic growth factor (CSF) prophylaxis
Primary prophylaxis is NOT indicated
See Chapter 43 for more information
Antimicrobial prophylaxis
Risk of fever and neutropenia is LOW
Antimicrobial primary prophylaxis to be considered:
Antibacterial—not indicated; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—not indicated
Antiviral— antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)
See Chapter 47 for more information