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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

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Leucovorin Rescue Guidelines

Clinical Situation

Serum Methotrexate Concentration

Leucovorin Dosage, Schedule, and Duration

Normal methotrexate elimination

• ≤10 μmol/L at 24 hours, or

• ≤1 μmol/L at 48 hours, or

• ≤0.1 μmol/L at 72 hours

• Give leucovorin calcium 25 mg intravenously every 6 hours until serum methotrexate concentrations are <0.1 μmol/L (<1 × 10−7 mol/L, or <100 nmol/L), then give leucovorin calcium 25 mg orally every 6 hours for 2 days (8 doses)

Delayed/late methotrexate elimination

• ≥10 μmol/L at 24 hours, or

• ≥1 μmol/L at 48 hours, or

• ≥0.1 μmol/L at 72 hours, or

• ≥0.05 μmol/L at 96 hours, or

• ≥100% increase in serum creatinine concentration at 24 hours after methotrexate administration

• Give leucovorin calcium 100 mg/m2 intravenously every 3 hours

• When serum methotrexate concentration results are <0.1 μmol/L, the leucovorin dosage may be decreased to 10 mg/m2 intravenously given every 3 hours until the serum methotrexate concentration is <0.05 μmol/L or undetectable

Consider administration of glucarpidase (if methotrexate concentration is >1 μmol/L in the setting of acute kidney injury)

After methotrexate administration is begun

Methotrexate concentration conversions: 1 μmol/L = 10−6 mol/L = 1000 nmol/L

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

Patient Population Studied

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.

Efficacy (N = 53)

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Efficacy (N = 53)

2-year overall survival

80.8%

Estimated median overall survival

7.5 years

2-year progression-free survival

63.6%

Estimated median progression-free survival

5.4 years

Note: Of the 53 patients initially treated, 45 completed the initial chemotherapy and 42 received the whole-brain radiotherapy. After completion of the initial chemotherapy, 35 patients were assessable for radiographic response. Median follow-up time for eligible living patients was 3.6 years

Therapy Monitoring

  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

Treatment Modifications

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Treatment Modifications

PRERADIATION [Methotrexate, Rituximab, and Temozolomide]

Methotrexate, Rituximab, and Temozolomide—Hematologic Toxicity

ANC <1000/mm3 or platelet count <70,000/mm3 on weeks 4/8 at start of temozolomide but persisting for <2 weeks

Withhold temozolomide until ANC ≥1000/mm3 and platelet count ≥70,000/mm3. Chemotherapy can then be administered at full dose

ANC <1000/mm3 or platelet count <70,000/mm3 on weeks 4/8 at start of temozolomide but persisting for ≥2 weeks

Withhold treatment until ANC ≥1000/mm3 and platelet count >70,000/mm3. Temozolomide can then be administered but at 25% reduced dose. The dose of methotrexate is not reduced for hematologic toxicity

Recurrence of ANC <1000/mm3 or platelet count <70,000/mm3 on weeks 4/8 at start of temozolomide persisting for ≥2 weeks despite a previous dose reduction

Discontinue temozolomide

ANC <1000/mm3 or platelet count <70,000/mm3 at time of methotrexate administration on weeks 1, 3, 5, 7 and 9

Delay administration of methotrexate until ANC ≥1000/mm3 and platelet count >70,000/mm3. The dose of methotrexate is not reduced for hematologic toxicity

ANC <1000/mm3 at any time during treatment

Administer filgrastim if deemed to be of value

Methotrexate, Rituximab, and Temozolomide—Nonhematologic Toxicity

Serum bilirubin >1.2 mg/dL at time of methotrexate administration on weeks 1, 3, 5, 7, and 9

Delay administration of methotrexate until recovery

ALT >450 U/L at time of methotrexate administration on weeks 1, 3, 5, 7, and 9

Mucositis with as yet no evidence of healing at time of methotrexate administration on weeks 1, 3, 5, 7, and 9

≥G2 nephrotoxicity from methotrexate (serum creatinine >1.5× baseline value, or >1.5× laboratory ULN)

Obtain 24-hour urine collection for CrCl prior to the next dose of methotrexate. The CrCl must be >50 mL/min per 1.73 m2 to receive additional methotrexate

Methotrexate, Rituximab, and Temozolomide— Rituximab Infusion-Related Toxicity

Onset of infusion-related events (fevers, chills, rigors, edema, congestion of the head and neck mucosa, hypotension) during rituximab infusion

1. Interrupt rituximab infusion

2. For fever, chills: Give additional dose of acetaminophen 650 mg orally and diphenhydramine 25–50 mg by intravenous push

3. For rigors: Give meperidine 12.5–25 mg by intravenous push ± promethazine 12.5–25 mg by intravenous infusion in at least 10 mL 0.9% NS or D5W over 5–15 minutes. If after 15–20 minutes the response to a single dose is considered inadequate, the dose may be repeated

4. After symptoms resolve, resume rituximab infusion at a minimum of 50% reduction in the rate at which the event occurred. If no further infusion-related events, increase the rate by 50 mg/h every 30 minutes, as tolerated, up to a maximum rate of 400 mg/h

Dyspnea or wheezing, without allergic findings (urticaria, or tongue or laryngeal edema) during rituximab infusion

1. Interrupt rituximab infusion immediately

2. Give hydrocortisone 100 mg by intravenous push (or glucocorticoid equivalent)

3. Give an additional dose of diphenhydramine 25–50 mg by intravenous push and an H2-antagonist (ranitidine 50 mg or famotidine 20 mg) by intravenous push

4. After symptoms resolve, resume rituximab infusion at a minimum of 50% reduction in the rate at which the event occurred. If no further infusion-related events, increase the rate by 50 mg/h every 30 minutes, as tolerated, up to a maximum rate of 400 mg/h

Note: Medications and equipment for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction during rituximab administration (eg, intravenous fluids, epinephrine, antihistamines, glucocorticoids, and oxygen)

POSTRADIATION CHEMOTHERAPY [Temozolomide daily for 5 days every 28 days on weeks 14– 50]

Temozolomide— Hematologic Toxicity

ANC <1000/mm3 or platelet count <70,000/mm3 on day of start of a course of temozolomide but persisting for <2 weeks

Withhold treatment until the ANC ≥1000/mm3 and platelet count >70,000/mm3. Temozolomide can then be administered at full dose

ANC <1000/mm3 or platelet count <70,000/mm3 on day of start of a course of temozolomide but persisting for ≥2 weeks

Withhold treatment until the ANC ≥1000/mm3 and platelet count >70,000/mm3. Temozolomide can then be administered but at 25% reduced dose

Recurrence of ANC <1000/mm3 or platelet count <70,000/mm3 on day of start of a course of temozolomide persisting for ≥2 weeks despite a previous dose reduction

Discontinue chemotherapy

ANC <1000/mm3 at any time during treatment

Administer filgrastim if deemed to be of value

Temozolomide— Nonhematologic Toxicity

G1

Continue treatment and maintain dose in subsequent cycle

G2 (1st occurrence)

Interrupt until resolved to ≤G1; administer 100% of original dose in subsequent cycle

G2 (2nd occurrence)

Interrupt until resolved to ≤G1; administer 75–80% of original dose in subsequent cycle. Note: Once the dose has been reduced, it should not be increased at a later time

G2 (3rd occurrence)

Interrupt until resolved to ≤G1; administer 50% of original dose in subsequent cycle. Note: Once the dose has been reduced, it should not be increased at a later time

G2 (4th occurrence)

Discontinue treatment permanently

G3 (1st occurrence)

Interrupt until resolved to ≤G1; administer 75–80% of original dose in subsequent cycle. Note: Once the dose has been reduced, it should not be increased at a later time

G3 (2nd occurrence)

Interrupt until resolved to ≤G1; administer 50% of original dose in subsequent cycle. Note: Once the dose has been reduced, it should not be increased at a later time

G3 (3rd occurrence)

Discontinue treatment permanently

G4 (1st occurrence)

Discontinue permanently or if physician deems it to be in the patient’s best interest to continue, interrupt until resolved to ≤G1, then resume therapy with doses ≤50% of that at the time G4 toxicity occurred. Note: Once the dose has been reduced, it should not be increased at a later time

Adverse Events (N = 53)

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Adverse Events (N = 53)
 

Chemotherapy-Related Toxicities (prior to start of whole-brain radiotherapy; N = 53)

Toxicities Related to Chemotherapy and Acute Radiotherapy (after start of whole-brain radiotherapy; N = 42)

Grade (%)

Grade 3

Grade 4

Grade 3

Grade 4

Hematologic

17

4

2

12

Metabolic

11

0

2

0

Hepatic

11

0

0

0

Neurologic

9

0

   

Constitutional

6

2

2

0

Gastrointestinal

2

2

5

0

Pain

4

2

0

0

Renal/genitourinary

6

0

0

0

Cardiovascular

4

0

2

0

Ocular

2

0

2

0

Auditory/hearing

0

0

2

0

Coagulation

0

0

2

0

Dermatologic

0

0

2

0

Febrile neutropenia

2

0

0

0

Musculoskeletal

0

0

0

0

According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 2.0

Note: Grade 3 and 4 toxicities defined as being definitely, probably, or possibly related to phase 2 treatment are included. Hematologic toxicities that occurred during radiotherapy were attributed to prior chemotherapy

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