CNS lymphoma

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Untreated

EORTC-BTG Protocol 26952

Regimen

Level of Evidence: Phase II

Induction phase

• Methotrexate (MTX) 1000 mg/m2 IV once on days 1, 10, 20
• Lomustine (Ceenu) 40 mg/m2 PO once on day 1
• Procarbazine (Matulane) 60 mg/m2 PO once per day on days 1 to 7
• Methylprednisolone (Solumedrol) 120 mg/m2 PO/IV every other day from days 1 to 20, and 60 mg/m2 days 20 to 45
• Methotrexate (MTX) 15 mg IT (admixed with cytarabine) once on days 1, 5, 10, 15
• Cytarabine (Cytosar) 40 mg IT (admixed with methotrexate) once on days 1, 5, 10, 15
• Folinic acid (Leucovorin) 25 mg PO every 6 hours for 3 days, initiated 24 hours after IV MTX administrations, and 10 mg PO every 6 hours for 2 days after IT MTX administrations

45 days, those with PR or CR proceed to:

Maintenance phase

• Methotrexate (MTX) 1000 mg/m2 IV once on day 1
• Lomustine (Ceenu) 40 mg/m2 PO once on day 1
• Procarbazine (Matulane) 60 mg/m2 PO once per day on days 1 to 7
• Methotrexate (MTX) 15 mg IT (admixed with cytarabine) once on day 1
• Cytarabine (Cytosar) 40 mg IT (admixed with methotrexate) once on day 1
• Folinic acid (Leucovorin) 25 mg PO every 6 hours for 3 days, initiated 24 hours after IV MTX administration

6-week cycles x 5 cycles

References

1. Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B; European Organization for Research and Treatment of Cancer Brain Tumor Group. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003 Jul 15;21(14):2726-31. link to original article contains verified protocol PubMed

High-Dose Methotrexate

Regimen #1, Batchelor, et al. 2003

Level of Evidence: Phase II

The full dose of 8000 mg/m2 was only given if CrCl was at least 100. For CrCl less than 100, the dose was reduced by the percentage reduction below 100. For example, a CrCl of 50 would mandate a 50% dose reduction.

Induction phase

• Methotrexate (MTX) 8000 mg/m2 IV once over 4 hours on day 1

14-day cycles until CR or a maximum of 8 cycles

Patients achieving CR proceeded to consolidation:

Consolidation

• Methotrexate (MTX) 8000 mg/m2 IV once over 4 hours on day 1

14-day cycles x 2 cycles, then:

Maintenance

• Methotrexate (MTX) 8000 mg/m2 IV once over 4 hours on day 1

28-day cycles x 11 cycles

Regimen #2, Ferreri, et al. 2009

Level of Evidence: Randomized Phase II, >20 per arm

• Methotrexate (MTX) 3500 mg/m2 IV once on day 1: first 500 mg/m2 given over 15 minutes, remaining 3000 mg/m2 given over 3 hours

21-day cycles x 4 cycles, followed within 4 weeks by:

• Whole-brain irradiation 36 Gy (any response) or 40 Gy (stable or progressive disease) plus 9 Gy boost to the tumor bed

Regimen #3, Herrlinger, et al. 2005 (NOA-03)

Level of Evidence: Phase II

This was considered a negative trial by the authors and is included here for historical purposes.

• Methotrexate (MTX) 8000 mg/m2 IV once over 4 hours on day 1

14-day cycles x 6 cycles

Patients intolerant of MTX or not achieving CR after 6 cycles were randomized to WBRT or PCV; see article for details.

References

1. Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003 Mar 15;21(6):1044-9. link to original article contains verified protocol PubMed
2. Herrlinger U, Küker W, Uhl M, Blaicher HP, Karnath HO, Kanz L, Bamberg M, Weller M; Neuro-Oncology Working Group of the German Society. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol. 2005 Jun;57(6):843-7. link to original article contains verified protocol PubMed
3. Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F; International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18. link to original article contains verified protocol PubMed

High-Dose Methotrexate & Cytarabine

Regime, Ferreri, et al. 2009

Level of Evidence: Randomized Phase II, >20 per arm

• Methotrexate (MTX) 3500 mg/m2 IV once on day 1: first 500 mg/m2 given over 15 minutes, remaining 3000 mg/m2 given over 3 hours
• Cytarabine (Cytosar) 2000 mg/m2 IV bid on days 2 & 3

21-day cycles x 4 cycles, followed within 4 weeks by:

• Whole-brain irradiation 36 Gy (any response) or 40 Gy (stable or progressive disease) plus 9 Gy boost to the tumor bed

References

1. Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F; International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18. link to original article contains verified protocol PubMed

MPV

MPV: Methotrexate, Procarbazine, Vincristine

Regimen, DeAngelis, et al. 2002 (RTOG 93-10)

Level of Evidence: Phase II

• Methotrexate (MTX) 2500 mg/m2 IV once over 2 to 3 hours on day 1
• Folinic acid (Leucovorin) 20 mg PO every 6 hours x 12 doses, beginning 24 hours after IV MTX administration
• Vincristine (Oncovin) 1.4 mg/m2 (capped at 2.8 mg) IV on day 1
• Procarbazine (Matulane) 100 mg/m2 PO once per day on days 1 to 7 of odd cycles (1, 3, 5)

• Methotrexate (MTX) 12 mg IT (via Ommaya) once one week after IV MTX administration
• Folinic acid (Leucovorin) 10 mg PO every 6 hours x 8 doses, beginning the evening of IT MTX administration

14-day cycles x 5 cycles, accompanied by:

• Dexamethasone (Decadron) 16 mg PO once per day x 7 days, then 12 mg PO once per day x 7 days, then 8 mg PO once per day x 7 days, then 6 mg PO once per day x 7 days, then 4 mg PO once per day x 7 days, then 2 mg PO once per day x 7 days

Followed by:

• Whole-brain irradiation to 45 Gy in 1.80-Gy fractions or to 36 Gy in 1.20-Gy twice-daily fractions

References

1. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002 Dec 15;20(24):4643-8. link to original article contains verified protocol PubMed

MT-R

MT-R: Methotrexate, Temozolomide, Rituximab

Regimen, Rubenstein, et al. 2013 (CALGB 50202)

Level of Evidence: Phase II

Induction phase

• Methotrexate (MTX) 8000 mg/m2 IV once over 4 hours on day 1
  • Given for a total of 7 doses.
• Folinic acid (Leucovorin) 100 mg/m2 IV every 6 hours, start on day 2, continue until MTX level <0.05
• Rituximab (Rituxan) 375 mg/m2 IV once on day 3
  • Rituximab omitted for T-cell PCNSL and given for a total of 6 doses in all others.
• Temozolomide (Temodar) 150 mg/m2 PO once per day on days 7 to 11 (odd cycles only)

14-day cycles x 8 cycles

Patients achieving CR or CRu were given one additional cycle of methotrexate & temozolomide, followed by consolidation therapy:

Consolidation

• Etoposide (Vepesid) 40 mg/kg IV continuous infusion over 96 hours, days 1 to 4
• Cytarabine (Cytosar) 2 gm/m2 IV Q12H over 2 hours × 8 doses, days 1 to 4

One course

References

1. Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD. Intensive Chemotherapy and Immunotherapy in Patients With Newly Diagnosed Primary CNS Lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013 Sep 1;31(25):3061-8. Epub 2013 Apr 8 link to original article contains verified protocol PubMed

R-MPV

R-MPV: Rituximab, Methotrexate, Procarbazine, Vincristine

Regimen, Shah, et al. 2007

Level of Evidence: Phase II

• Rituximab (Rituxan) 500 mg/m2 IV once over 5 hours on day 1
• Methotrexate (MTX) 3500 mg/m2 IV once over 2 hours on day 2
• Folinic acid (Leucovorin) 20 to 25 mg every 6 hours for at least 72 hours or until serum MTX level < 1e-8 mg/dL, beginning 24 hours after IV MTX administration
• Vincristine (Oncovin) 1.4 mg/m2 (capped at 2.8 mg) IV on day 2
• Procarbazine (Matulane) 100 mg/m2 PO once per day on days 1 to 7 of odd cycles

• Methotrexate (MTX) 12 mg IT (via Ommaya) once sometime between day 5 and 12 (for patients with positive CSF cytology)

14-day cycles x 5 to 7 cycles, followed in 3 to 5 weeks by:

• Complete responders: Whole-brain irradiation to 23.4 Gy in 1.80-Gy fractions
• All others: Whole-brain irradiation to 45 Gy in 1.80-Gy fractions

References

1. Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, LaRocca R, Grant B, DeAngelis LM, Abrey LE. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007 Oct 20;25(30):4730-5. Erratum in: J Clin Oncol. 2008 Jan 10;26(2):340. link to original article contains verified protocol PubMed

Relapsed/refractory

High-dose Methotrexate (MTX) & Ifosfamide

Regimen

Level of Evidence: Retrospective

• Methotrexate (MTX) 4000 mg/m2 IV over 4 hours once on day 1
• Ifosfamide (Ifex) 1500 to 2000 mg/m2 IV over 3 hours once per day on days 3 to 5
• Mesna (Mesnex) for prophylaxis of hemorrhagic cystitis
• Folinic acid (Leucovorin) rescue starting 24 hours after start of methotrexate infusion
• Sodium bicarbonate via IV fluid or PO routes used for urine alkalinization to maintain urine pH of at least 8
• Check methotrexate levels 24, 48, and 72 hours after completion of methotrexate infusion.

Methotrexate (MTX) dose adjusted for creatinine clearances <100 mL/min according to the following formula:

• Dose of methotrexate = (creatinine clearance/100) x 4000 mg/m2; the paper did not specify what method was used for calculating creatinine clearance. Patients with creatinine clearance <50 mL/min were excluded from the study.

up to 8 cycles (reference did not list timing/criteria to be used for next cycle of therapy)

• Example orders for High-dose Methotrexate (MTX) & Ifosfamide in lymphoma

References

1. Fischer L, Korfel A, Kiewe P, Neumann M, Jahnke K, Thiel E. Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma. Ann Hematol. 2009 Feb;88(2):133-9. Epub 2008 Aug 5. link to original article contains verified protocol PubMed