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

• Adjust infusion rate to maintain urine output ≥100 mL/h

• Adjust sodium bicarbonate content to maintain urine pH ≥7.0 to ≤8.0

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)

• Note: Patients who vomit after taking temozolomide should be instructed to take their next dose at the next regularly scheduled time

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

This phase 1/2 trial (Radiation Therapy Oncology Group [RTOG] 0227) involved 53 patients with newly diagnosed primary central nervous system lymphoma (PCNSL). Of the enrolled patients, 12 took part in both the phase 1 and phase 2 portions of the trial and the remainder were enrolled in only the phase 2 portion. All patients received the following chemotherapy regimen: rituximab (375 mg/m²) 3 days before the first methotrexate dose, methotrexate (3.5 g/m²) in weeks 1, 3, 5, 7, and 9, and temozolomide in weeks 4 and 8 (the temozolomide dose in the phase 1 portion patients was initially 100 g/m², with dose escalations to 150 and 200 g/m²; in the phase 2 portion patients, temozolomide was administered at the maximum tolerated dose of 100 mg/m²). Each methotrexate dose was preceded by urine alkalinization with intravenous sodium bicarbonate and followed (after 24 hours) by intravenous administration of leucovorin (25 mg every 6 hours) until the patient’s methotrexate level (measured daily) was ≤ 0.1 µmol/L. In weeks 11–13, patients received twice-daily 1.2 Gy fractions of whole-brain radiotherapy (total of 36 Gy). In weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50, patients received temozolomide (200 mg/m² daily, although in week 14 a daily dose of 150 mg/m² was allowed) for 5 days.

1. Prior to rituximab administration: Hepatitis B surface antigen, hepatitis B core antibody (total antibody, or IgG only)

2. Prior to the first dose of methotrexate: 24-hour urine collection for creatinine clearance, serum creatinine

3. Prior to each dose of methotrexate: CBC with differential, platelet count, BUN, serum creatinine, estimated creatinine clearance (Cockroft-Gault method), AST, ALT, total bilirubin, electrolytes, serum bicarbonate, urine output, urine pH, review medication list for potential drug-drug interactions, urine hCG (women of childbearing potential only)

4. Following each dose of methotrexate, until methotrexate concentration is <0.1 µmol/L:

   • ✓Daily: methotrexate concentration (draw first sample 24 hours after start of methotrexate infusion and repeat every 24 hours), CBC with differential, platelet count, BUN, serum creatinine, AST, ALT, total bilirubin, weight, fluid balance

   • ✓At least every 8 hours during methotrexate administration: Urine pH

5. Prior to each course of temozolomide: CBC with differential, platelet count, AST, ALT, total bilirubin, urine hCG (women of childbearing potential only)

6. During first cycle and in any cycle after a dose adjustment, weekly CBC with differential and platelet count to assess dose

7. Response assessment: At the completion of initial rituximab, methotrexate, temozolomide chemotherapy, after completion of radiation therapy, every 2 months during postradiation temozolomide, at completion of temozolomide, every 3 months from the end of treatment until 2 years since the start of treatment, every 6 months for 3 to 5 years