CNS lymphoma

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Last updated on 2024-09-06:43 regimens on this page
64 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==BSH==
*2023: Cwynarski, et al. Management of secondary central nervous system lymphoma EuroPMC
*2018: Fox et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma EuroPMC
==EANO==
*2015: Hoang-Xuan et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology EuroPMC
==EHA/ESMO==
*2024: Ferreri et al. Primary central nervous system lymphomas: EHA-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
==ESH==
*2019: Fox et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma EuroPMC
==ESMO==
*2016: Vitolo et al. Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==GEL/TAMO==
*2016: Peñalver et al. Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO) EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Central Nervous System Cancers.
=CNS prophylaxis, systemic therapy=
==High-dose Cytarabine monotherapy (HiDAC)==
HiDAC: High Dose Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment	Evidence
Holte et al. 2013 (NLG LBC-04)	2004-2008 	Phase 2
Note: IT treatment was not part of prophylaxis, except that Methotrexate (MTX) 15 mg IT was allowed at time of diagnostic LP.
====Preceding treatment====
*Induction R-CHOEP-14 x 8
====Chemotherapy====
*Cytarabine (Ara-C) by the following age-based criteria:
**Younger than 60 years old: 3000 mg/m2 IV twice per day on days 1 & 2 (total dose: 12,000 mg/m2)
**60 to 65 years old: 2000 mg/m2 IV twice per day on days 1 & 2 (total dose: 8000 mg/m2)
21-day course
====Subsequent treatment====
*Induction HD-MTX
===References===
# NLG LBC-04: Holte H, Leppä S, Björkholm M, Fluge O, Jyrkkiö S, Delabie J, Sundström C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fosså A, Ostenstad B, Löfvenberg E, Nordström M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M; Nordic Lymphoma Group. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. Epub 2012 Dec 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01502982
==Methotrexate monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Holte et al. 2013 (NLG LBC-04)	2004-2008 	Phase 2
Note: IT treatment was not part of prophylaxis, except that Methotrexate (MTX) 15 mg IT was allowed at time of diagnostic LP.
====Preceding treatment====
*Induction HiDAC
====Chemotherapy====
*Methotrexate (MTX) 3000 mg/m2 IV continuous infusion over 24 hours, started on day 1
====Supportive therapy====
*Leucovorin (Folinic acid) (dose/frequency not specified) starting at 36 hours
One course
===References===
# NLG LBC-04: Holte H, Leppä S, Björkholm M, Fluge O, Jyrkkiö S, Delabie J, Sundström C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fosså A, Ostenstad B, Löfvenberg E, Nordström M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M; Nordic Lymphoma Group. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. Epub 2012 Dec 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01502982
=CNS treatment, local therapy=
==IT Cytarabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Glantz et al. 1999	1994-1998 	Phase 3 (C)	IT liposomal cytarabine	Lower ORR
====CNS therapy, treatment====
*Cytarabine (Ara-C) 50 mg IT once per day on days 1, 4, 8, 11, 15, 18, 22, 25
4-week course
====Subsequent treatment====
*Glantz et al. 1999, responders: Further therapy was given to responders; see text for details
===References===
# Glantz MJ, LaFollette S, Jaeckle KA, Shapiro W, Swinnen L, Rozental JR, Phuphanich S, Rogers LR, Gutheil JC, Batchelor T, Lyter D, Chamberlain M, Maria BL, Schiffer C, Bashir R, Thomas D, Cowens W, Howell SB. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol. 1999 Oct;17(10):3110-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==IT Cytarabine liposomal monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Glantz et al. 1999	1994-1998 	Phase 3 (E-RT-switch-ic)	IT cytarabine	Higher ORR (secondary endpoint)
Note: this study was not designed to make formal statitiscal comparisons, but the difference in ORR was very large.
====CNS therapy, treatment====
*Cytarabine liposomal (DepoCyt) 50 mg IT once on day 1
14-day cycle for 2 cycles
====Subsequent treatment====
*Glantz et al. 1999, responders: Further therapy was given to responders; see text for details
===References===
# Glantz MJ, LaFollette S, Jaeckle KA, Shapiro W, Swinnen L, Rozental JR, Phuphanich S, Rogers LR, Gutheil JC, Batchelor T, Lyter D, Chamberlain M, Maria BL, Schiffer C, Bashir R, Thomas D, Cowens W, Howell SB. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol. 1999 Oct;17(10):3110-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Upfront therapy, randomized data=
==Cytarabine & Methotrexate (CYM)==
CYM: CYtarabine & Methotrexate
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ferreri et al. 2009 (IELSG20)	2004-2007 	Randomized Phase 2, >20 per arm (E-esc)	High-dose MTX 	Seems to have higher CR rate (primary endpoint)
Ferreri et al. 2016 (IELSG32)	2010-2014 	Randomized Phase 2 (C) 	1. Cytarabine, Methotrexate, Rituximab	Did not meet primary endpoint of CR rate
Ferreri et al. 2016 (IELSG32)	2010-2014 	Randomized Phase 2 (C) 	2. MATRix 	Lower CR rate
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 60 minutes every 12 hours on days 2 & 3
*Methotrexate (MTX) 500 mg/m2 IV over 15 minutes, then 3000 mg/m2 IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m2) 
====Supportive therapy====
*As described in Ferreri et al. 2016:
*Levoleucovorin (Fusilev) 15 mg/m2 IV every 6 hours for 12 doses, beginning 24 hours after the start of methotrexate, with modifications if MTX level is high 48 hours after the end of the infusion; see paper for details
21-day cycle for 4 cycles
====Subsequent treatment====
*IELSG20: Whole brain irradiation consolidation , within 4 weeks
*IELSG32: Whole brain irradiation versus Carmustine & Thiotepa with auto HSCT consolidation
===References===
# IELSG20: 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. 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00210314
# IELSG32: Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gørløv JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01011920
==Cytarabine, Methotrexate, Rituximab==
R-HD-MTX/ARA-C: Rituximab, High-Dose MethoTreXate, ARA-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ferreri et al. 2015 (SCNSL1) 	2006-2013 	Phase 2 	 	
Ferreri et al. 2016 (IELSG32)	2010-2014 	Randomized Phase 2 (E-esc)	1. CYM 	Did not meet primary endpoint of CR rate
Ferreri et al. 2016 (IELSG32)	2010-2014 	Randomized Phase 2 (E-esc)	2. MATRix 	Seems to have lower CR rate
Note: SCNSL1 was intended for secondary CNS lymphoma, whereas IELSG32 was intended for primary CNS lymphoma.
====Preceding treatment====
*SCNSL1: Induction R-CHOP x 1
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 60 minutes every 12 hours on days 2 & 3
*Methotrexate (MTX) 500 mg/m2 IV over 15 minutes, then 3000 mg/m2 IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m2)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days -5 & 0
====CNS therapy====
*SCNSL1: Cytarabine liposomal (DepoCyt)
====Supportive therapy====
*Levoleucovorin (Fusilev) 15 mg/m2 IV every 6 hours for 12 doses, beginning 24 hours after the start of methotrexate, with modifications if MTX level is high 48 hours after the end of the infusion; see paper for details
21-day cycle for 4 cycles
====Subsequent treatment====
*SCNSL1: Intensification phase (see paper for details)
*IELSG32: Whole brain irradiation versus Carmustine & Thiotepa with auto HSCT consolidation
===References===
# SCNSL1: Ferreri AJ, Donadoni G, Cabras MG, Patti C, Mian M, Zambello R, Tarella C, Di Nicola M, D'Arco AM, Doa G, Bruno-Ventre M, Assanelli A, Foppoli M, Citterio G, Fanni A, Mulè A, Caligaris-Cappio F, Ciceri F. High doses of antimetabolites followed by high-dose sequential chemoimmunotherapy and autologous stem-cell transplantation in patients with systemic B-cell lymphoma and secondary CNS involvement: Final results of a multicenter phase II trial. J Clin Oncol. 2015 Nov 20;33(33):3903-10. Epub 2015 Aug 17. link to original article EuroPMC NCT00801216
# IELSG32: Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gørløv JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01011920
==MATRix==
MATRix: Methotrexate, Ara-C (Cytarabine), Thiotepa, Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ferreri et al. 2016 (IELSG32)	2010-2014 	Randomized Phase 2 (E-esc)	1. CYM 	Higher CR rate (primary endpoint)
Ferreri et al. 2016 (IELSG32)	2010-2014 	Randomized Phase 2 (E-esc)	2. Cytarabine, Methotrexate, Rituximab	Seems to have higher CR rate (primary endpoint)
====Chemotherapy====
*Methotrexate (MTX) 500 mg/m2 IV over 15 minutes, then 3000 mg/m2 IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m2) 
*Cytarabine (Ara-C) 2000 mg/m2 IV over 60 minutes every 12 hours on days 2 & 3
*Thiotepa (Thioplex) 30 mg/m2 IV over 30 minutes once on day 4
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days -5 & 0
====Supportive therapy====
*Levoleucovorin (Fusilev) 15 mg/m2 IV every 6 hours for 12 doses, beginning 24 hours after the start of methotrexate, with modifications if MTX level is high 48 hours after the end of the infusion; see paper for details
21-day cycle for 4 cycles
====Subsequent treatment====
*Whole brain irradiation versus Carmustine & Thiotepa with auto HSCT consolidation
===References===
# IELSG32: Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gørløv JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01011920
==MBVP==
MBVP: Methotrexate, BCNU (Carmustine), Vumon (Teniposide), Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Bromberg et al. 2019 (HOVON 105/ALLG NHL 24)	2010-2016 	Phase 3 (C)	R-MBVP 	Did not meet primary endpoint of EFS
====Chemotherapy====
*Methotrexate (MTX) 3000 mg/m2 IV once per day on days 1 & 15
*Carmustine (BCNU) 100 mg/m2 IV once on day 4
*Teniposide (Vumon) 100 mg/m2 IV once per day on days 2 & 3
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
28-day cycle for 2 cycles
====Subsequent treatment====
*HOVON 105/ALLG NHL 24, responders 60 years old or older: HiDAC consolidation
*HOVON 105/ALLG NHL 24, responders younger than 60: HiDAC consolidation, then low-dose WBRT consolidation
 
===References===
# HOVON 105/ALLG NHL 24: Bromberg JEC, Issa S, Bakunina K, Minnema MC, Seute T, Durian M, Cull G, Schouten HC, Stevens WBC, Zijlstra JM, Baars JW, Nijland M, Mason KD, Beeker A, van den Bent MJ, Beijert M, Gonzales M, de Jong D, Doorduijn JK; HOVON; ALLG. Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2019 Feb;20(2):216-228. Epub 2019 Jan 7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC ACTRN12610000908033
## HRQoL analysis: van der Meulen M, Bakunina K, Nijland M, Minnema MC, Cull G, Stevens WBC, Baars JW, Mason KD, Beeker A, Beijert M, Taphoorn MJB, van den Bent MJ, Issa S, Doorduijn JK, Bromberg JEC, Dirven L. Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study. Ann Oncol. 2020 Aug;31(8):1046-1055. Epub 2020 May 3. link to original article EuroPMC
##HRQoL analysis: Bromberg JEC, Issa S, van der Holt B, van der Meulen M, Dirven L, Minnema MC, Seute T, Durian M, Cull G, van der Poel MWM, Stevens WBC, Zijlstra JM, Brandsma D, Nijland M, Mason KD, Beeker A, Abrahamse-Testroote MCJ, van den Bent MJ, de Jong D, Doorduijn JK. Survival, neurocognitive function, and health-related quality of life outcomes after rituximab-methotrexate, BCNU, teniposide, and prednisolone for primary CNS lymphoma: Final results of the HOVON 105/ALLG NHL 24 study. Neuro Oncol. 2024 Apr 5;26(4):724-734. link to original article link to PMC article EuroPMC
==Methotrexate monotherapy==
===Regimen variant #1, 3500 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ferreri et al. 2009 (IELSG20)	2004-2007 	Randomized Phase 2 (C)	CYM; high-dose	Seems to have lower CR rate
====Chemotherapy====
*Methotrexate (MTX) 500 mg/m2 IV over 15 minutes, then 3000 mg/m2 IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m2) 
21-day cycle for 4 cycles
====Subsequent treatment====
*Whole brain irradiation consolidation, within 4 weeks
===Regimen variant #2, 4000 mg/m2===
Study 	Dates of enrollment	Evidence
Thiel et al. 2010 (G-PCNSL-SG-1)	2000-2009 	Non-randomized part of phase 3 RCT
Note: All patients received the same induction regimen; however, the induction regimen was changed after 2006 to high-dose MTX & ifosfamide.
====Chemotherapy====
*Methotrexate (MTX) 4000 mg/m2 IV over 4 hours once on day 1
14-day cycle for 6 cycles
====Subsequent treatment====
*G-PCNSL-SG-1, patients with CR: whole-brain irradiation consolidation versus no further treatment
*G-PCNSL-SG-1, patients with less than CR in the WB-XRT arm: Salvage whole-brain irradiation
*G-PCNSL-SG-1, patients with less than CR in the no-WB-XRT: Salvage HiDAC
===Regimen variant #3, 8000 mg/m2===
Study 	Dates of enrollment	Evidence
Herrlinger et al. 2005 (NOA-03)	1998-05 to 2000-03 	Phase 2
Note: This was considered a negative trial by the authors and is included here for historical purposes.
====Chemotherapy====
*Methotrexate (MTX) 8000 mg/m2 IV over 4 hours once on day 1
14-day cycle for 6 cycles
====Subsequent treatment====
*NOA-03, patients intolerant of MTX or not achieving CR after 6 cycles: Salvage whole-brain irradiation versus PCV; see article for details
===Regimen variant #4, 8000 mg/m2 with renal adjustment===
Study 	Dates of enrollment	Evidence
Batchelor et al. 2003 (NABTT 96-07)	1998-1999 	Phase 2
====Chemotherapy====
*Methotrexate (MTX) by the following renal function-based criteria:
**CrCl 100 mL/min/1.73m2 or more: 8000 mg/m2 IV over 4 hours once on day 1
14-day cycle until CR or a maximum of 8 cycles
====Subsequent treatment====
*NABTT 96-07, patients achieving CR: HD-MTX continuation x 2, then methotrexate maintenance
====Dose and schedule modifications====
*CrCl less than 100 mL/min/1.73m2: Methotrexate dose was reduced by the percentage reduction below 100. For example, a CrCl of 50 mL/min/1.73m2 would mandate a 50% dose reduction to 4000 mg/m2.
===Regimen variant #5, 20-day course===
Study 	Dates of enrollment	Evidence
Montemurro et al. 2007 (OSHO-53)	1999-2004 	Phase 2
====Chemotherapy====
*Methotrexate (MTX) by the following age-based criteria:
**60 years old or younger: 8000 mg/m2 IV over 4 hours once per day on days 1 & 10
**Older than 60 years old: 6000 mg/m2 IV over 4 hours once per day on days 1 & 10
20-day course
====Subsequent treatment====
*OSHO-53, responders (CR or PR): Bu/TT, then autologous HSCT consolidation
===References===
# NABTT 96-07: 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# NOA-03: 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 dosing details in manuscript have been reviewed by our editors EuroPMC content property of HemOnc.org
# OSHO-53: Montemurro M, Kiefer T, Schüler F, Al-Ali HK, Wolf HH, Herbst R, Haas A, Helke K, Theilig A, Lotze C, Hirt C, Niederwieser D, Schwenke M, Krüger WH, Dölken G. Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study. Ann Oncol. 2007 Apr;18(4):665-71. Epub 2006 Dec 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# IELSG20: 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. 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00210314
# G-PCNSL-SG-1: Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol. 2010 Nov;11(11):1036-47. Epub 2010 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00153530
## Update: Korfel A, Thiel E, Martus P, Möhle R, Griesinger F, Rauch M, Röth A, Hertenstein B, Fischer T, Hundsberger T, Mergenthaler HG, Junghanß C, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Roth P, Bamberg M, Pietsch T, Weller M. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology. 2015 Mar 24;84(12):1242-8. Epub 2015 Feb 25. link to original article EuroPMC
=Upfront therapy, non-randomized or retrospective data=
==Lomustine, Methotrexate, Procarbazine==
MCP: Methotrexate, CCNU (Lomustine), Procarbazine
===Regimen===
Study 	Dates of enrollment	Evidence
Illerhaus et al. 2008a	1998-2004 	Phase 2
====Chemotherapy====
*Lomustine (CCNU) 110 mg/m2 PO once on day 1
*Methotrexate (MTX) 3000 mg/m2 IV over 4 hours once per day on days 1, 15, 30
*Procarbazine (Matulane) 60 mg/m2 PO once per day on days 1 to 10
====Supportive therapy====
*Leucovorin (Folinic acid) 15 mg/m2 (route not specified) every 6 hours beginning 24 hours after start of methotrexate infusion, continued until clearance
45-day cycle for up to 3 cycles
===References===
# Illerhaus G, Marks R, Müller F, Ihorst G, Feuerhake F, Deckert M, Ostertag C, Finke J. High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study. Ann Oncol. 2009 Feb;20(2):319-25. Epub 2008 Oct 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Lomustine, Methotrexate, Procarbazine, Methylprednisolone==
===Regimen===
Study 	Dates of enrollment	Evidence
Hoang-Xuan et al. 2003 (EORTC 26952)	1997-1999 	Phase 2
Note: This was the first prospective phase 2 trial evaluating chemotherapy alone in older patients with PCNSL.
====Chemotherapy====
*Methotrexate (MTX) 1000 mg/m2 IV once per day on days 1, 10, 20
*Lomustine (CCNU) 40 mg/m2 PO once on day 1
*Procarbazine (Matulane) 60 mg/m2 PO once per day on days 1 to 7
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) as follows:
**Days 1 to 20: 120 mg/m2 IV or PO every other day 
**Days 20 to 45: 60 mg/m2 IV or PO every other day
====CNS therapy====
*Methotrexate (MTX) 15 mg IT (admixed with cytarabine) once per day on days 1, 5, 10, 15
*Cytarabine (Ara-C) 40 mg IT (admixed with methotrexate) once per day on days 1, 5, 10, 15
====Supportive therapy====
*Leucovorin (Folinic acid) 25 mg PO every 6 hours for 3 days, initiated 24 hours after IV methotrexate administrations, and 10 mg PO every 6 hours for 2 days after IT methotrexate administrations
45-day course
====Subsequent treatment====
*EORTC 26952, patients achieving PR or CR: Lomustine, methotrexate, procarbazine maintenance
===References===
# EORTC 26952: Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B; EORTC 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 Organisation for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003 Jul 15;21(14):2726-31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==MATRix-RICE==
MATRix-RICE: Methotrexate, Ara-C (Cytarabine), Thiotepa, Rituximab, followed by Rituximab, 
===Regimen===
Study 	Dates of enrollment 	Evidence
Ferreri et al. 2021 (MARIETTA)	2015-03-30 to 2018-08-03	Phase 2
====Chemotherapy, MATRix portion (cycles 1 to 3)====
*Methotrexate (MTX) 500 mg/m2 IV over 15 minutes, then 3000 mg/m2 IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m2) 
*Cytarabine (Ara-C) 2000 mg/m2 IV over 60 minutes every 12 hours on days 2 & 3
*Thiotepa (Thioplex) 30 mg/m2 IV over 30 minutes once on day 4
====Targeted therapy, MATRix portion (cycles 1 to 3)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0
====CNS therapy, MATRix portion (cycles 1 to 3)====
*ONE of the following:
**Cytarabine liposomal (DepoCyt) 50 mg IT once on day 5
**Triple therapy with Methotrexate (MTX) 12 mg; Cytarabine (Ara-C) 50 mg; Hydrocortisone (Cortef) 50 mg IT once on day 5
====Targeted therapy, RICE portion (cycles 4 to 6)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy, RICE portion (cycles 4 to 6)====
*Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2
*Carboplatin (Paraplatin) AUC 5 IV over 60 minutes once on day 2
*Etoposide (Vepesid) 100 mg/m2 IV over 60 minutes once per day on days 1 to 3
====CNS therapy, RICE portion (cycles 4 to 6)====
*ONE of the following:
**Cytarabine liposomal (DepoCyt) 50 mg IT once on day 4
**Triple therapy with Methotrexate (MTX) 12 mg; Cytarabine (Ara-C) 50 mg; Hydrocortisone (Cortef) 50 mg IT once on day 4
====Supportive therapy, RICE portion (cycles 4 to 6)====
*Mesna (Mesnex)
21-day cycle for 6 cycles
====Subsequent treatment====
*Carmustine & Thiotepa with auto HSCT consolidation
===References===
# MARIETTA: Ferreri AJM, Doorduijn JK, Re A, Cabras MG, Smith J, Ilariucci F, Luppi M, Calimeri T, Cattaneo C, Khwaja J, Botto B, Cellini C, Nassi L, Linton K, McKay P, Olivieri J, Patti C, Re F, Fanni A, Singh V, Bromberg JEC, Cozens K, Gastaldi E, Bernardi M, Cascavilla N, Davies A, Fox CP, Frezzato M, Osborne W, Liberati AM, Novak U, Zambello R, Zucca E, Cwynarski K; International Extranodal Lymphoma Study Group (IELSG). MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial. Lancet Haematol. 2021 Feb;8(2):e110-e121. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02329080
==Methotrexate-Cytarabine==
===Regimen===
Study 	Dates of enrollment	Evidence
Abrey et al. 2003	Not reported 	Phase 2
Note: Patients proceed to part two 72 hours after 5th dose of MTX or once the 5th dose MTX level has cleared.
====Chemotherapy, first portion (cycles 1 to 5)====
*Methotrexate (MTX) 3500 mg/m2 (maximum dose of 7000 mg) IV over 2 hours once on day 1
====Supportive therapy, first portion (cycles 1 to 5)====
*Leucovorin (Folinic acid) 25 mg PO every 6 hours, beginning 24 hours after start of methotrexate, continued for 12 doses or until serum MTX level less than 100 nmol/L
====Chemotherapy, second portion (cycles 6 & 7)====
*Cytarabine (Ara-C) 3000 mg/m2 IV once per day on days 1 & 2
====Supportive therapy, second portion====
*Filgrastim (Neupogen) as follows:
**Cycle 6: 10 mcg/kg SC once per day, starting on day 4 and continued until stem cell collection complete
**Cycle 7: 5 mcg/kg SC once per day continued for 2 weeks or until ANC greater than 3000/μL
14-day cycle for 5 cycles, then 1-month cycle for 2 cycles (stem cell collection took place between cycles 6 & 7)
====Subsequent treatment====
*BEAM, then autologous hematopoietic stem cell transplant consolidation
===References===
# Abrey LE, Moskowitz CH, Mason WP, Crump M, Stewart D, Forsyth P, Paleologos N, Correa DD, Anderson ND, Caron D, Zelenetz A, Nimer SD, DeAngelis LM. Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis. J Clin Oncol. 2003 Nov 15;21(22):4151-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Methotrexate-Cytarabine & Thiotepa==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Illerhaus et al. 2006	1998-2003 	Phase 2
====Chemotherapy, MTX portion (course 1)====
*Methotrexate (MTX) 8000 mg/m2 IV over 4 hours once per day on days 1, 10, 20
====Supportive therapy, MTX portion (course 1)====
*Leucovorin (Folinic acid) 15 mg/m2 every 6 hours, beginning 24 hours after start of methotrexate, continuing until clearance
Patients with CR, PR, or SD "with clinical improvement" after the 2nd dose of MTX proceeded to:
====Chemotherapy, stem cell mobilization portion (course 2)====
*Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours once per day on days 2 & 3
*Thiotepa (Thioplex) 40 mg/m2 (route not specified) once on day 3
28-day course, then 20-day course
====Subsequent treatment====
*BCNU/TT, then autologous hematopoietic stem cell transplant consolidation
===Protocol variant #2===
Study 	Dates of enrollment	Evidence
Illerhaus et al. 2008	2003-2006 	Pilot, fewer than 20 patients
====Chemotherapy, part 1====
*Methotrexate (MTX) 8000 mg/m2 IV over 4 hours once on day 1
====Supportive therapy====
*Leucovorin (Folinic acid) 15 mg/m2 every 6 hours, beginning 24 hours after start of methotrexate, continuing until clearance
10-day cycle for 2 to 4 cycles, followed by:
====Chemotherapy, part 2====
*Cytarabine (Ara-C) 3000 mg/m2 IV once per day on days 1 & 2
*Thiotepa (Thioplex) 40 mg/m2 (route not specified) once on day 2
21-day cycle for 2 cycles (Stem cells are mobilized and collected after the first cycle)
====Subsequent treatment====
*BCNU/TT, then autologous hematopoietic stem cell transplant consolidation
===References===
# Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, Frickhofen N, Feuerhake F, Volk B, Finke J. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol. 2006 Aug 20;24(24):3865-70. Epub 2006 Jul 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article EuroPMC
# Illerhaus G, Müller F, Feuerhake F, Schäfer AO, Ostertag C, Finke J. High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system. Haematologica. 2008 Jan;93(1):147-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article EuroPMC
==Methotrexate & Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence
Chamberlain et al. 2010	2000-2007 	Phase 2
Note: the bounds as described in the paper do not account for the situation where CrCl = 60 mL/min/1.73m2.
====Chemotherapy====
*Methotrexate (MTX) by the following renal function-based criteria:
**CrCl more than 60 mL/min/1.73m2: 8000 mg/m2 IV over 6 hours once on day 1
**CrCl less than 60 mL/min/1.73m2: 4000 mg/m2 IV over 6 hours once on day 1
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 8
14-day cycle for 4 to 6 cycles
====Subsequent treatment====
*Chamberlain et al. 2010, patients with PR/CR: High-dose methotrexate consolidation
===References===
# Chamberlain MC, Johnston SK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro Oncol. 2010 Jul;12(7):736-44. Epub 2010 Feb 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==MPV==
MPV: Methotrexate, Procarbazine, Vincristine
===Regimen===
Study 	Dates of enrollment 	Evidence
Abrey et al. 2000 	1992-1998 	Non-randomized
DeAngelis et al. 2002 (RTOG 93-10)	1993 to not reported	Phase 2
====Chemotherapy====
*Methotrexate (MTX) 2500 mg/m2 IV over 2 to 3 hours once on day 1
*Procarbazine (Matulane) as follows:
**Cycles 1, 3, 5: 100 mg/m2 PO once per day on days 1 to 7
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2.8 mg) IV once on day 1
====CNS therapy====
*Methotrexate (MTX) 12 mg IT once on day 8 (via Ommaya reservoir)
====Supportive therapy====
*Leucovorin (Folinic acid) as follows:
**Days 2 to 4: 20 mg PO every 6 hours for 12 doses, beginning 24 hours after IV methotrexate administration
**Days 8 & 9: 10 mg PO every 6 hours for 8 doses, beginning on the evening of IT methotrexate administration
*Dexamethasone (Decadron) as follows:
**Cycle 1: 16 mg PO once per day on days 1 to 7, then 12 mg PO once per day on days 8 to 14
**Cycle 2: 8 mg PO once per day on days 1 to 7, then 6 mg PO once per day on days 8 to 14
**Cycle 3: 4 mg PO once per day on days 1 to 7, then 2 mg PO once per day on days 8 to 14
14-day cycle for 5 cycles
====Subsequent treatment====
*Whole-brain irradiation consolidation
===References===
# Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000 Sep;18(17):3144-50. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2006 Oct 1;24(28):4570-4. link to original article EuroPMC
# RTOG 93-10: DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group; SWOG. 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==MT-R==
MT-R: Methotrexate, Temozolomide, Rituximab
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Glass et al. 2016 (RTOG 0227)	Not reported 	Phase 1/2
Note: This is the MTD of this phase 1/2 trial; it appears that only a single dose of rituximab was given.
====Chemotherapy====
*Methotrexate (MTX) 3500 mg/m2 IV once on day 1
*Temozolomide (Temodar) as follows:
**Cycles 2 & 4: 100 mg/m2 PO once per day on days 8 to 12
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once, 3 days prior to first dose of MTX
====Supportive therapy====
*Leucovorin (Folinic acid) 25 mg IV every 6 hours, starting 24 hours after methotrexate, continue until MTX level less than 100 nmol/L 
14-day cycle for 5 cycles
====Subsequent treatment====
*WB-XRT consolidation
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Rubenstein et al. 2013 (CALGB 50202)	2004-2009 	Phase 2
Note: There was a discrepancy between rituximab dosing described in the text of the manuscript and in Figure 1. Based upon other information available in the article, the dosing mentioned in the text is felt to be the correct dosing and is replicated here. The authors have been contacted on November 22, 2024 for clarification. 
====Chemotherapy====
*Methotrexate (MTX) 8000 mg/m2 IV over 4 hours once on day 1
*Temozolomide (Temodar) as follows:
**Cycles 1, 3, 5, 7: 150 mg/m2 PO once per day on days 7 to 11
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycles 1 to 3: 375 mg/m2 IV once per day on days 3 & 10 (see note)
====Supportive therapy====
*Leucovorin (Folinic acid) 100 mg/m2 IV every 6 hours, start on day 2, continue until MTX level less than 50 nmol/L 
14-day cycle for 7 cycles
====Subsequent treatment====
*CALGB 50202, patients achieving CR or CRu: CYVE consolidation
===References===
# CALGB 50202: 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00098774
# RTOG 0227: Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, Bokstein F, Bovi JA, Solhjem MC, Mehta MP. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016 May 10;34(14):1620-5. Epub 2016 Mar 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00068250
==MVBP==
MVBP: Methotrexate, VP16 (Etoposide), BCNU (Carmustine), MethylPrednisolone
===Regimen===
Study 	Dates of enrollment	Evidence
Colombat et al. 2006	1999-2001 	Phase 2
====Chemotherapy====
*Methotrexate (MTX) 3000 mg/m2 IV once per day on days 1 & 15
*Etoposide (Vepesid) 100 mg/m2 IV once on day 2
*Carmustine (BCNU) 100 mg/m2 IV once on day 3
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) 60 mg/m2 (route not specified) once per day on days 1 to 5
====Supportive therapy====
*Leucovorin (Folinic acid) details not specified
2 courses (length not specified), separated by 21 days
====CNS therapy====
*Methotrexate (MTX) 20 mg IT (admixed with cytarabine and methylpredinsolone)
*Cytarabine (Ara-C) 50 mg IT (admixed with methotrexate and methylprednisolone)
*Methylprednisolone (Solumedrol) 40 mg IT (admixed with cytarabine and methotrexate)
6 doses total (timing not specified)
====Subsequent treatment====
*Colombat et al. 2006, responding patients (CR or PR): Cytarabine & Ifosfamide for stem cell mobilization, then BEAM, then autologous hematopoietic stem cell transplant consolidation
*Colombat et al. 2006, non-responders: Salvage CYVE
===References===
# Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Nordic Regimen, older patients==
===Regimen===
Study 	Dates of enrollment	Evidence
Pulczynski et al. 2015 (NLGPCNSL)	2007-2010 	Phase 2
====Eligibility criteria====
*Age 66-75 years
====Targeted therapy, A portion====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 1
====Chemotherapy, A portion====
*Methotrexate (MTX) as follows:
**Cycles 1 & 4: 3000 mg/m2 IV once on day 1
*Ifosfamide (Ifex) as follows:
**Cycle 1: 800 mg/m2 IV once per day on days 2 to 5
====Glucocorticoid therapy, A portion (cycles 1 & 4)====
*Dexamethasone (Decadron) 10 mg/m2/day PO on days 2 to 5
====CNS therapy, A portion (cycles 1 & 4)====
*Cytarabine liposomal (DepoCyt) 50 mg IT once on day 2
====Chemotherapy, B portion (cycles 2 & 5)====
*Methotrexate (MTX) 5000 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 150 mg/m2 IV once per day on days 2 to 6
====Glucocorticoid therapy, B portion (cycles 2 & 5)====
*Dexamethasone (Decadron) 10 mg/m2/day PO on days 2 to 5
====CNS therapy, B portion (cycles 2 & 5)====
*Cytarabine liposomal (DepoCyt) 50 mg IT once on day 2
====Glucocorticoid therapy, C portion (cycles 3 & 6)====
*Dexamethasone (Decadron) 20 mg/m2/day PO on days 3 to 7
====Chemotherapy, C portion (cycles 3 & 6)====
*Cytarabine (Ara-C) 1000 mg/m2 IV every 12 hours on days 1 & 2
*Vindesine (Eldisine) 5 mg IV once on day 1
21-day cycle for 6 cycles (A1, then B1, then C1, then A2, then B2, then C2)
====Subsequent treatment====
*Temozolomide maintenance
===References===
# NLGPCNSL: Pulczynski EJ, Kuittinen O, Erlanson M, Hagberg H, Fosså A, Eriksson M, Nordstrøm M, Østenstad B, Fluge Ø, Leppä S, Fiirgaard B, Bersvendsen H, Fagerli UM; Nordic Lymphoma Group. Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by de-escalating induction and introducing temozolomide maintenance: results from a phase II study by the Nordic Lymphoma Group. Haematologica. 2015 Apr;100(4):534-40. Epub 2014 Dec 5. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01458730
==Nordic Regimen, younger patients==
===Regimen===
Study 	Dates of enrollment	Evidence
Pulczynski et al. 2015 (NLGPCNSL)	2007-2010 	Phase 2
====Eligibility criteria====
*Age: 18 to 65 years
====Targeted therapy, A portion (cycles 1 & 4)====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 1
====Chemotherapy, A portion (cycles 1 & 4)====
*Methotrexate (MTX) 5000 mg/m2 IV once on day 1
*Ifosfamide (Ifex) 800 mg/m2 IV once per day on days 2 to 5
====Glucocorticoid therapy, A portion (cycles 1 & 4)====
*Dexamethasone (Decadron) 10 mg/m2/day PO on days 2 to 5
====CNS therapy, A portion (cycles 1 & 4)====
*Cytarabine liposomal (DepoCyt) 50 mg IT once on day 2
====Chemotherapy, B portion (cycles 2 & 5)====
*Methotrexate (MTX) 5000 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
*Cyclophosphamide (Cytoxan) 200 mg/m2 IV once per day on days 2 to 5
====Glucocorticoid therapy, B portion (cycles 2 & 5)====
*Dexamethasone (Decadron) 10 mg/m2/day PO on days 2 to 5
====CNS therapy, B portion (cycles 2 & 5)====
*Cytarabine liposomal (DepoCyt) 50 mg IT once on day 2
====Glucocorticoid therapy, C portion (cycles 3 & 6)====
*Dexamethasone (Decadron) 20 mg/m2/day PO on days 3 to 7
====Chemotherapy, C portion (cycles 3 & 6)====
*Cytarabine (Ara-C) 1500 mg/m2 IV every 12 hours on days 1 & 2
*Vindesine (Eldisine) 5 mg IV once on day 1
21-day cycle for 6 cycles (A1, then B1, then C1, then A2, then B2, then C2)
===References===
# NLGPCNSL: Pulczynski EJ, Kuittinen O, Erlanson M, Hagberg H, Fosså A, Eriksson M, Nordstrøm M, Østenstad B, Fluge Ø, Leppä S, Fiirgaard B, Bersvendsen H, Fagerli UM; Nordic Lymphoma Group. Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by de-escalating induction and introducing temozolomide maintenance: results from a phase II study by the Nordic Lymphoma Group. Haematologica. 2015 Apr;100(4):534-40. Epub 2014 Dec 5. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01458730
==R-MCP (CCNU)==
R-MCP: Rituximab, Methotrexate, CCNU (Lomustine), Procarbazine
===Regimen===
Study 	Dates of enrollment	Evidence
Fritsch et al. 2011	2005-2009 	Phase 2
Note: this regimen should not be confused with the other R-MCP (rituximab, mitoxantrone, cyclophosphamide, prednisone) used in indolent lymphomas.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV over 90 minutes once per day on days -6, 1, 15, 29
====Chemotherapy====
*Methotrexate (MTX) 3000 mg/m2 IV over 4 hours once per day on days 2, 16, 30
*Lomustine (CCNU) 110 mg/m2 PO once on day 2
*Procarbazine (Matulane) 60 mg/m2 PO once per day on days 2 to 11
====Supportive therapy====
*Leucovorin (Folinic acid) (dose/route not specified) every 6 hours beginning 24 hours after start of MTX infusion, continued for 3 days or until clearance
43-day cycle for up to 3 cycles
===References===
# Fritsch K, Kasenda B, Hader C, Nikkhah G, Prinz M, Haug V, Haug S, Ihorst G, Finke J, Illerhaus G. Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly. Ann Oncol. 2011 Sep;22(9):2080-5. Epub 2011 Feb 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==R-MP==
R-MP: Rituximab, Methotrexate, Procarbazine
===Regimen===
Study 	Dates of enrollment	Evidence
Fritsch et al. 2016 (PRIMAIN)	2009-2013 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV over 90 minutes once per day on days -6, 1, 15, 29
**Cycles 2 & 3: 375 mg/m2 IV over 90 minutes once per day on days 1, 15, 29
====Chemotherapy====
*Methotrexate (MTX) 3000 mg/m2 IV over 4 hours once per day on days 2, 16, 30
*Procarbazine (Matulane) 60 mg/m2 PO once per day on days 2 to 11
42-day cycle for 3 cycles
====Subsequent treatment====
*Procarbazine maintenance
===References===
# PRIMAIN: Fritsch K, Kasenda B, Schorb E, Hau P, Bloehdorn J, Möhle R, Löw S, Binder M, Atta J, Keller U, Wolf HH, Krause SW, Heß G, Naumann R, Sasse S, Hirt C, Lamprecht M, Martens U, Morgner A, Panse J, Frickhofen N, Röth A, Hader C, Deckert M, Fricker H, Ihorst G, Finke J, Illerhaus G. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017 Apr;31(4):846-852. Epub 2016 Nov 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00989352
#PRIMA-CNS: DRKS00024085
==R-MPV==
R-MPV: Rituximab, Methotrexate, Procarbazine, Vincristine
===Regimen===
Study 	Dates of enrollment	Evidence
Shah et al. 2007 (MSK 01-146) 	2002-2005 	Phase 2
Omuro et al. 2015 (MSK 04-129)	2005-2011 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 500 mg/m2 IV over 5 hours once on day 1
====Chemotherapy====
*Methotrexate (MTX) 3500 mg/m2 IV over 2 hours once on day 2
*Procarbazine (Matulane) as follows:
**Odd cycles: 100 mg/m2 PO once per day on days 1 to 7
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2.8 mg) IV once on day 2
====CNS therapy====
*(only described in MSK 01-146)
*Methotrexate (MTX) 12 mg IT (via Ommaya) once sometime between day 5 and 12 (for patients with positive CSF cytology)
====Supportive therapy====
*Leucovorin (Folinic acid) 20 to 25 mg every 6 hours for at least 72 hours or until serum MTX level less than 100 nmol/L, beginning 24 hours after IV methotrexate administration
14-day cycle for 5 to 7 cycles
====Subsequent treatment====
*MSK 01-146: whole-brain irradiation consolidation, in 3 to 5 weeks
*MSK 04-129: Bu/TT/Cy, then autologous hematopoietic stem cell transplant consolidation, after 5 cycles if CR achieved, or after 7 cycles for PR/CR at that time
===References===
# MSK 01-146: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00594815
## Update: Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, Grimm S, Lai RK, Reiner AS, Panageas K, Karimi S, Curry R, Shah G, Abrey LE, DeAngelis LM, Omuro A. Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol. 2013 Nov 1;31(31):3971-9. Epub 2013 Oct 7. link to original article link to PMC article EuroPMC
# MSK 04-129: Omuro A, Correa DD, DeAngelis LM, Moskowitz CH, Matasar MJ, Kaley TJ, Gavrilovic IT, Nolan C, Pentsova E, Grommes CC, Panageas KS, Baser RE, Faivre G, Abrey LE, Sauter CS. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood. 2015 Feb 26;125(9):1403-10. Epub 2015 Jan 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00596154
=Consolidation after upfront therapy=
==BCNU/TT, then auto HSCT==
BCNU/TT: BCNU (Carmustine), ThioTepa
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Illerhaus et al. 2006	1998-2003 	Phase 2
Note that the day count starts from the very beginning of treatment.
====Preceding treatment====
*High-dose methotrexate, then Ara-C & Thiotepa induction
====Subsequent treatment====
*Whole-brain irradiation consolidation
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Illerhaus et al. 2008	2003-2006 	Pilot, fewer than 20 patients
====Preceding treatment====
*High-dose methotrexate, then Ara-C & Thiotepa induction
===References===
# Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, Frickhofen N, Feuerhake F, Volk B, Finke J. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol. 2006 Aug 20;24(24):3865-70. Epub 2006 Jul 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article EuroPMC
# Illerhaus G, Müller F, Feuerhake F, Schäfer AO, Ostertag C, Finke J. High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system. Haematologica. 2008 Jan;93(1):147-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article EuroPMC
# IELSG32: Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gørløv JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01011920
## Update: Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosée P, Binder M, Fabbri A, Torri V, Minacapelli E, Falautano M, Ilariucci F, Ambrosetti A, Roth A, Hemmaway C, Johnson P, Linton KM, Pukrop T, Sønderskov Gørløv J, Balzarotti M, Hess G, Keller U, Stilgenbauer S, Panse J, Tucci A, Orsucci L, Pisani F, Levis A, Krause SW, Schmoll HJ, Hertenstein B, Rummel M, Smith J, Pfreundschuh M, Cabras G, Angrilli F, Ponzoni M, Deckert M, Politi LS, Finke J, Reni M, Cavalli F, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol. 2017 Nov;4(11):e510-e523. Epub 2017 Oct 17. link to original article EuroPMC
==BEAM, then auto HSCT==
BEAM: BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Colombat et al. 2006	1999-2001 	Phase 2
====Preceding treatment====
*MVBP induction x 2
====Subsequent treatment====
*Whole-brain irradiation consolidation
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Abrey et al. 2003	Not reported 	Phase 2
====Preceding treatment====
*Methotrexate, then Cytarabine induction
===References===
# Abrey LE, Moskowitz CH, Mason WP, Crump M, Stewart D, Forsyth P, Paleologos N, Correa DD, Anderson ND, Caron D, Zelenetz A, Nimer SD, DeAngelis LM. Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis. J Clin Oncol. 2003 Nov 15;21(22):4151-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Bu/TT, then auto HSCT==
Bu/TT: Busulfan, ThioTepa
===Regimen===
Study 	Dates of enrollment	Evidence
Montemurro et al. 2007 (OSHO-53)	1999-2004 	Phase 2
====Preceding treatment====
*High-dose methotrexate induction x 2
===References===
# OSHO-53: Montemurro M, Kiefer T, Schüler F, Al-Ali HK, Wolf HH, Herbst R, Haas A, Helke K, Theilig A, Lotze C, Hirt C, Niederwieser D, Schwenke M, Krüger WH, Dölken G. Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study. Ann Oncol. 2007 Apr;18(4):665-71. Epub 2006 Dec 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Bu/TT/Cy, then auto HSCT==
Bu/TT/Cy: Busulfan, ThioTepa, Cyclophosphamide
TBC: Thiotepa, Busulfan, Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence
Omuro et al. 2015 (MSK 04-129)	2005-2011 	Phase 2
====Preceding treatment====
*R-MPV induction
===References===
# MSK 04-129: Omuro A, Correa DD, DeAngelis LM, Moskowitz CH, Matasar MJ, Kaley TJ, Gavrilovic IT, Nolan C, Pentsova E, Grommes CC, Panageas KS, Baser RE, Faivre G, Abrey LE, Sauter CS. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood. 2015 Feb 26;125(9):1403-10. Epub 2015 Jan 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00596154
==High-dose Cytarabine monotherapy (HiDAC)==
HiDAC: High Dose Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment 	Evidence
Abrey et al. 2000 	1992-1998 	Non-randomized
DeAngelis et al. 2002 (RTOG 93-10)	1993 to not reported	Phase 2
Time interval of cycles is not explicitly described and is derived from Table 1 in DeAngelis et al. 2002.
====Preceding treatment====
*Definitive Whole-brain irradiation x 4500 cGy
====Chemotherapy====
*Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours once per day on days 1 & 2
21-day cycle for 2 cycles
===References===
# Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000 Sep;18(17):3144-50. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2006 Oct 1;24(28):4570-4. link to original article EuroPMC
# RTOG 93-10: DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group; SWOG. 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Cytarabine & Etoposide (CYVE)==
CYVE: CYtarabine & VEpesid (Etoposide)
EA: Etoposide & Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment	Evidence
Rubenstein et al. 2013 (CALGB 50202)	2004-2009 	Phase 2
====Preceding treatment====
*MT-R induction
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 2 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m2)
*Etoposide (Vepesid) 10 mg/kg/day IV continuous infusion over 96 hours, started on day 1 (total dose: 40 mg/kg)
4-day course
===References===
# CALGB 50202: 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00098774
==Lomustine, Methotrexate, Procarbazine==
===Regimen===
Study 	Dates of enrollment	Evidence
Hoang-Xuan et al. 2003 (EORTC 26952)	1997-1999 	Phase 2
====Preceding treatment====
*Lomustine, Methotrexate, Procarbazine, Methylprednisolone induction
====Chemotherapy====
*Methotrexate (MTX) 1000 mg/m2 IV once on day 1
*Lomustine (CCNU) 40 mg/m2 PO once on day 1
*Procarbazine (Matulane) 60 mg/m2 PO once per day on days 1 to 7
====CNS therapy====
*Methotrexate (MTX) 15 mg IT (admixed with cytarabine) once on day 1
*Cytarabine (Ara-C) 40 mg IT (admixed with methotrexate) once on day 1
====Supportive therapy====
*Leucovorin (Folinic acid) 25 mg PO every 6 hours for 3 days, initiated 24 hours after IV methotrexate administration
42-day cycle for 5 cycles
===References===
# Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B; EORTC 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 Organisation for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003 Jul 15;21(14):2726-31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Methotrexate monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Chamberlain et al. 2010	2000-2007 	Phase 2
Note: the bounds as described in the paper do not account for the situation where CrCl = 60 mL/min/1.73m2.
====Preceding treatment====
*High-dose methotrexate & Rituximab induction
====Chemotherapy====
*Methotrexate (MTX) by the following renal function-based criteria:
**CrCl more than 60 mL/min/1.73m2: 8000 mg/m2 IV over 6 hours once on day 1
**CrCl less than 60 mL/min/1.73m2: 4000 mg/m2 IV over 6 hours once on day 1
28-day cycle for 4 cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Batchelor et al. 2003 (NABTT 96-07)	1998-1999 	Phase 2
====Preceding treatment====
*High-dose methotrexate induction
====Chemotherapy====
*Methotrexate (MTX) by the following renal function-based criteria:
**CrCl 100 mL/min/1.73m2 or more: 8000 mg/m2 IV over 4 hours once on day 1
28-day cycle for 11 cycles
====Dose and schedule modifications====
*CrCl less than 100 mL/min/1.73m2: Methotrexate dose was reduced by the percentage reduction below 100. For example, a CrCl of 50 mL/min/1.73m2 would mandate a 50% dose reduction to 4000 mg/m2.
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# Chamberlain MC, Johnston SK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro Oncol. 2010 Jul;12(7):736-44. Epub 2010 Feb 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Procarbazine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Fritsch et al. 2016 (PRIMAIN)	2009-2013 	Phase 2
====Preceding treatment====
*Induction R-MP x 3
====Chemotherapy====
*Procarbazine (Matulane) 100 mg PO once per day on days 1 to 5
28-day cycle for 6 cycles
===References===
# PRIMAIN: Fritsch K, Kasenda B, Schorb E, Hau P, Bloehdorn J, Möhle R, Löw S, Binder M, Atta J, Keller U, Wolf HH, Krause SW, Heß G, Naumann R, Sasse S, Hirt C, Lamprecht M, Martens U, Morgner A, Panse J, Frickhofen N, Röth A, Hader C, Deckert M, Fricker H, Ihorst G, Finke J, Illerhaus G. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017 Apr;31(4):846-852. Epub 2016 Nov 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00989352
==Temozolomide monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Glass et al. 2016 (RTOG 0227)	Not reported 	Phase 1/2
====Preceding treatment====
*WB-XRT consolidation
====Chemotherapy====
*Temozolomide (Temodar) as follows:
**Week 14: 200 mg/m2 PO once per day for 5 days (150 mg/m2 allowed)
**Weeks 18, 22, 26, 30, 34, 38, 42, 46, 50: 200 mg/m2 PO once per day for 5 days
50-week course
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Pulczynski et al. 2015 (NLGPCNSL)	2007-2010 	Phase 2
====Preceding treatment====
*Nordic Regimen for older patients induction
====Chemotherapy====
*Temozolomide (Temodar) 150 mg/m2/day PO on days 1 to 5
28-day cycle for up to 13 cycles (1 year)
===References===
# NLGPCNSL: Pulczynski EJ, Kuittinen O, Erlanson M, Hagberg H, Fosså A, Eriksson M, Nordstrøm M, Østenstad B, Fluge Ø, Leppä S, Fiirgaard B, Bersvendsen H, Fagerli UM; Nordic Lymphoma Group. Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by de-escalating induction and introducing temozolomide maintenance: results from a phase II study by the Nordic Lymphoma Group. Haematologica. 2015 Apr;100(4):534-40. Epub 2014 Dec 5. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01458730
# RTOG 0227: Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, Bokstein F, Bovi JA, Solhjem MC, Mehta MP. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016 May 10;34(14):1620-5. Epub 2016 Mar 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00068250
==Whole brain irradiation==
WBRT: Whole-Brain Radiation Therapy
===Regimen variant #1, 2340 cGy===
Study 	Dates of enrollment	Evidence
Shah et al. 2007 (MSK 01-146)	2002-2005 	Phase 2
====Preceding treatment====
*Induction R-MPV x 5 to 7 cycles, with complete response
====Radiotherapy====
*Whole-brain irradiation to 2340 cGy in 180 cGy fractions
===Regimen variant #2, 3000 cGy===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Colombat et al. 2006 	1999-2001 	Phase 2 	 	
Mishima et al. 2023 (JCOG1114C)	2014-09-20 to 2018-08-24	Phase 3 (C)	Temozolomide & WBRT	Might have longer OS (primary endpoint)OS24: 86.8% vs 71.4%(HR 0.46, 95% CI 0.20-1.05)
====Preceding treatment====
*Colombat et al. 2006: BEAM, then autologous hematopoietic stem cell transplant consolidation, with complete response
*JCOG1114C: HD-MTX induction
====Radiotherapy====
*Whole-brain irradiation to 3000 cGy in 180 cGy fractions
===Regimen variant #3, 3000 cGy + 1000 cGy boost===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Colombat et al. 2006 	1999-2001 	Phase 2 	 	
Mishima et al. 2023 (JCOG1114C)	2014-09-20 to 2018-08-24	Phase 3 (C)	Temozolomide & WBRT	Might have longer OS (primary endpoint)OS24: 86.8% vs 71.4%(HR 0.46, 95% CI 0.20-1.05)
Note: boost was optional in JCOG1114C.
====Preceding treatment====
*Colombat et al. 2006: BEAM, then autologous hematopoietic stem cell transplant consolidation, with partial response
*JCOG1114C: HD-MTX induction
====Radiotherapy====
*Whole-brain irradiation to 3000 cGy in 180 cGy fractions plus 1000 cGy boost to the tumor bed
===Regimen variant #4, 3600 cGy===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Glass et al. 2016 (RTOG 0227)	Not reported 	Phase 1/2 	 	
Ferreri et al. 2016 (IELSG32)	2010-2014 	Randomized Phase 2 (C)	BCNU/TT, then auto HSCT	Did not meet primary endpoint of PFS241
1Reported efficacy for IELSG32 is based on the 2017 update.
====Preceding treatment====
*RTOG 0227: MT-R induction
*IELSG32: CYM versus Cytarabine, MTX, Rituximab versus MATRix induction, with complete response
====Radiotherapy====
*Whole-brain irradiation to 3600 cGy by the following study-specific criteria:
**RTOG 0227: 120 cGy twice per day fractions on weeks 11 to 13
**IELSG32: 180 cGy fractions
====Subsequent treatment====
*RTOG 0227: Temozolomide consolidation
===Regimen variant #5, 3600 cGy + 900 cGy boost===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ferreri et al. 2009 (IELSG20)	2004-2007 	Non-randomized part of phase 2 RCT	 	
Ferreri et al. 2016 (IELSG32)	2010-2014 	Randomized Phase 2 (C) 	BCNU/TT, then auto HSCT	Did not meet primary endpoint of PFS241
1Reported efficacy for IELSG32 is based on the 2017 update.
====Preceding treatment====
*IELSG20: Induction High-dose methotrexate x 4 versus High-dose CYM x 4, with any response
*IELSG32: Induction CYM versus Cytarabine, MTX, Rituximab versus MATRix induction, with partial response
====Radiotherapy====
*Whole-brain irradiation to 3600 cGy in 180 cGy fractions plus 900 cGy boost to the tumor bed
===Regimen variant #6, 4000 cGy + 900 cGy boost===
Study 	Dates of enrollment	Evidence
Ferreri et al. 2009 (IELSG20)	2004-2007 	Non-randomized part of phase 2 RCT
====Preceding treatment====
*Induction High-dose methotrexate x 4 versus High-dose CYM x 4, with stable or progressive disease
====Radiotherapy====
*Whole-brain irradiation to 4000 cGy in 180 cGy fractions plus 900 cGy boost to the tumor bed
===Regimen variant #7, 4500 cGy===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Abrey et al. 2000 	1992-1998 	Non-randomized 	 	
DeAngelis et al. 2002 (RTOG 93-10)	1993 to not reported	Phase 2 	 	
Illerhaus et al. 2006 	1998-2003 	Phase 2 	 	
Thiel et al. 2010 (G-PCNSL-SG-1) 	2000-2009 	Phase 3 (E-esc)	No further treatment	Inconclusive whether non-inferior OS (primary endpoint)
Shah et al. 2007 (MSK 01-146) 	2002-2005 	Phase 2 	 	
Note that the day count in Illerhaus et al. 2006 starts from the very beginning of treatment.
====Preceding treatment====
*Abrey et al. 2000 & RTOG 93-10: Induction MPV x 5
*Illerhaus et al. 2006: BCNU/TT, then autologous hematopoietic stem cell transplant consolidation, with complete response
*MSK 01-146: Induction R-MPV x 5 to 7 cycles, without complete response
*G-PCNSL-SG-1, before 2006: Induction High-dose methotrexate x 6
*G-PCNSL-SG-1, after 2006: Induction High-dose methotrexate & ifosfamide x 6
====Radiotherapy====
*Whole-brain irradiation to 4500 cGy by the following study-specific criteria:
**Illerhaus et al. 2006: 100 cGy fractions, starting on day 90
**G-PCNSL-SG-1: 150 cGy fractions
**Abrey et al. 2000, RTOG 93-10, MSK 01-146: 180 cGy fractions
====Subsequent treatment====
*Abrey et al. 2000 & RTOG 93-10: HiDAC consolidation
===Regimen variant #8, 5000 cGy===
Study 	Dates of enrollment	Evidence
Illerhaus et al. 2006	1998-2003 	Phase 2
Note that the day count starts from the very beginning of treatment.
====Preceding treatment====
*BCNU/TT, then autologous hematopoietic stem cell transplant consolidation, with partial response
====Radiotherapy====
*Whole-brain irradiation to 5000 cGy in 100 cGy fractions, starting on day 90
===References===
# Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000 Sep;18(17):3144-50. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2006 Oct 1;24(28):4570-4. link to original article EuroPMC
# RTOG 93-10: DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group; SWOG. 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, Frickhofen N, Feuerhake F, Volk B, Finke J. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol. 2006 Aug 20;24(24):3865-70. Epub 2006 Jul 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article EuroPMC
# Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00594815
## Update: Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, Grimm S, Lai RK, Reiner AS, Panageas K, Karimi S, Curry R, Shah G, Abrey LE, DeAngelis LM, Omuro A. Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol. 2013 Nov 1;31(31):3971-9. Epub 2013 Oct 7. link to original article link to PMC article EuroPMC
# IELSG20: 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. 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00210314
# G-PCNSL-SG-1: Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol. 2010 Nov;11(11):1036-47. Epub 2010 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00153530
## Update: Korfel A, Thiel E, Martus P, Möhle R, Griesinger F, Rauch M, Röth A, Hertenstein B, Fischer T, Hundsberger T, Mergenthaler HG, Junghanß C, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Roth P, Bamberg M, Pietsch T, Weller M. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology. 2015 Mar 24;84(12):1242-8. Epub 2015 Feb 25. link to original article EuroPMC
# RTOG 0227: Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, Bokstein F, Bovi JA, Solhjem MC, Mehta MP. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016 May 10;34(14):1620-5. Epub 2016 Mar 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00068250
# IELSG32: Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gørløv JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01011920
## Update: Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosée P, Binder M, Fabbri A, Torri V, Minacapelli E, Falautano M, Ilariucci F, Ambrosetti A, Roth A, Hemmaway C, Johnson P, Linton KM, Pukrop T, Sønderskov Gørløv J, Balzarotti M, Hess G, Keller U, Stilgenbauer S, Panse J, Tucci A, Orsucci L, Pisani F, Levis A, Krause SW, Schmoll HJ, Hertenstein B, Rummel M, Smith J, Pfreundschuh M, Cabras G, Angrilli F, Ponzoni M, Deckert M, Politi LS, Finke J, Reni M, Cavalli F, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol. 2017 Nov;4(11):e510-e523. Epub 2017 Oct 17. link to original article EuroPMC
#JCOG1114C: Mishima K, Nishikawa R, Narita Y, Mizusawa J, Sumi M, Koga T, Sasaki N, Kinoshita M, Nagane M, Arakawa Y, Yoshimoto K, Shibahara I, Shinojima N, Asano K, Tsurubuchi T, Sasaki H, Asai A, Sasayama T, Momii Y, Sasaki A, Nakamura S, Kojima M, Tamaru JI, Tsuchiya K, Gomyo M, Abe K, Natsumeda M, Yamasaki F, Katayama H, Fukuda H. Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C. Neuro Oncol. 2023 Apr 6;25(4):687-698. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC jRCTs031180207
=Relapsed or refractory, salvage therapy=
==High-dose Cytarabine monotherapy (HiDAC)==
HiDAC: High Dose Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment	Evidence
Thiel et al. 2010 (G-PCNSL-SG-1)	2000-2009 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*G-PCNSL-SG-1, before 2006: Non-response to High-dose methotrexate induction
*G-PCNSL-SG-1, after 2006: Non-response to Methotrexate & Ifosfamide induction
====Chemotherapy====
*Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1 & 2
21-day cycle for 4 cycles
===References===
# G-PCNSL-SG-1: Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol. 2010 Nov;11(11):1036-47. Epub 2010 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00153530
## Update: Korfel A, Thiel E, Martus P, Möhle R, Griesinger F, Rauch M, Röth A, Hertenstein B, Fischer T, Hundsberger T, Mergenthaler HG, Junghanß C, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Roth P, Bamberg M, Pietsch T, Weller M. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology. 2015 Mar 24;84(12):1242-8. Epub 2015 Feb 25. link to original article EuroPMC
==Cytarabine & Etoposide (CYVE)==
CYVE: CYtarabine, VEpesid (Etoposide)
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Soussain et al. 2001	1992-03 to 1995-03 	Pilot, >20 pts
Soussain et al. 2008	2000-01 to 2005-12 	Phase 2
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours once per day on days 2 to 5
*Cytarabine (Ara-C) 50 mg/m2 IV over 12 hours once per day on days 1 to 5
*Etoposide (Vepesid) 200 mg/m2 IV over 2 hours once per day on days 2 to 5
2 cycles
====Subsequent treatment====
*Soussain et al. 2008, responders: Bu/TT/Cy, then autologous hematopoietic stem cell transplant consolidation
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Colombat et al. 2006	1999-2001 	Phase 2
====Preceding treatment====
*Non-response to MVBP induction x 2
====Chemotherapy====
*Cytarabine (Ara-C) 1000 mg/m2 IV every 12 hours on days 1 & 2
*Etoposide (Vepesid) 150 mg/m2 IV once per day on days 1 & 2
2 cycles (length not specified)
====Subsequent treatment====
*Whole-brain irradiation consolidation
===References===
# Soussain C, Suzan F, Hoang-Xuan K, Cassoux N, Levy V, Azar N, Belanger C, Achour E, Ribrag V, Gerber S, Delattre JY, Leblond V. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol. 2001 Feb 1;19(3):742-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Soussain C, Hoang-Xuan K, Taillandier L, Fourme E, Choquet S, Witz F, Casasnovas O, Dupriez B, Souleau B, Taksin AL, Gisselbrecht C, Jaccard A, Omuro A, Sanson M, Janvier M, Kolb B, Zini JM, Leblond V; Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. J Clin Oncol. 2008 May 20;26(15):2512-8. Epub 2008 Apr 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Ifosfamide & Methotrexate==
*Example orders for High-dose Methotrexate (MTX) & Ifosfamide in lymphoma
===Regimen===
Study 	Dates of enrollment	Evidence
Fischer et al. 2008	2002-07 to 2007-08 	Retrospective
====Chemotherapy====
*Ifosfamide (Ifex) 1500 to 2000 mg/m2 IV over 3 hours once per day on days 3 to 5
*Methotrexate (MTX) 4000 mg/m2 IV over 4 hours once on day 1
====Supportive therapy====
*Mesna (Mesnex) for prophylaxis of hemorrhagic cystitis
*Leucovorin (Folinic acid) rescue starting 24 hours after start of methotrexate infusion
*Sodium bicarbonate IV or PO 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.
Up to 8 cycles (reference did not list timing/criteria to be used for next cycle of therapy)
====Dose and schedule modifications====
*Methotrexate (MTX) dose adjusted for CrCl less than 100 mL/min/1.73m2 according to the following formula:
*Dose of methotrexate = (CrCl/100) x 4000 mg/m2; the paper did not specify what method was used for calculating CrCl. Patients with CrCl less than 50 mL/min/1.73m2 were excluded from the study.
===References===
# Retrospective: 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Whole brain irradiation==
===Regimen variant #1, 3000 cGy===
Study 	Dates of enrollment	Evidence
Colombat et al. 2006	1999-2001 	Phase 2
====Preceding treatment====
*CYVE salvage
====Radiotherapy====
*Whole-brain irradiation to 3000 cGy in 180 cGy fractions plus 1000 cGy boost to the tumor bed
One course
===Regimen variant #2, 3600 cGy===
Study 	Dates of enrollment	Evidence
Nguyen et al. 2005	1994-2003 	Phase 2
Note: The authors do not clearly describe a pre-determined dosing protocol but report that the most common fraction size was 150 cGy.
====Radiotherapy====
*Whole-brain irradiation: median dose 3600 cGy (range 28 to 4500 cGy)
One course
===Regimen variant #3, 3600 cGy + 1000 cGy boost===
Study 	Dates of enrollment	Evidence
Nguyen et al. 2005	1994-2003 	Phase 2
Note: The authors do not clearly describe a pre-determined dosing protocol but report that the most common fraction size was 150 cGy.
====Radiotherapy====
*Whole-brain irradiation: median dose 3600 cGy (range 19.6 to 4000 cGy) + 1000 cGy (range 10 to 2160 cGy)
One course
===Regimen variant #4, 4500 cGy===
Study 	Dates of enrollment	Evidence
Thiel et al. 2010 (G-PCNSL-SG-1)	2000-2009 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*G-PCNSL-SG-1, before 2006: Non-response to high-dose MTX induction x 6 
*G-PCNSL-SG-1, after 2006: Non-response to High-dose methotrexate & ifosfamide induction x 6
====Radiotherapy====
*Whole-brain irradiation to 4500 cGy in 150 cGy fractions
One course
===References===
# Nguyen PL, Chakravarti A, Finkelstein DM, Hochberg FH, Batchelor TT, Loeffler JS. Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol. 2005 Mar 1;23(7):1507-13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 
# Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# G-PCNSL-SG-1: Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol. 2010 Nov;11(11):1036-47. Epub 2010 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00153530
## Update: Korfel A, Thiel E, Martus P, Möhle R, Griesinger F, Rauch M, Röth A, Hertenstein B, Fischer T, Hundsberger T, Mergenthaler HG, Junghanß C, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Roth P, Bamberg M, Pietsch T, Weller M. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology. 2015 Mar 24;84(12):1242-8. Epub 2015 Feb 25. link to original article EuroPMC
=Consolidation after salvage therapy=
==Bu/TT/Cy, then auto HSCT==
Bu/TT/Cy: Busulfan, ThioTepa, Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence
Soussain et al. 2001	1992-03 to 1995-03 	Pilot, >20 pts
Soussain et al. 2008	2000-01 to 2005-12 	Phase 2
====Preceding treatment====
*CYVE salvage x 2
===References===
# Soussain C, Suzan F, Hoang-Xuan K, Cassoux N, Levy V, Azar N, Belanger C, Achour E, Ribrag V, Gerber S, Delattre JY, Leblond V. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol. 2001 Feb 1;19(3):742-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Soussain C, Hoang-Xuan K, Taillandier L, Fourme E, Choquet S, Witz F, Casasnovas O, Dupriez B, Souleau B, Taksin AL, Gisselbrecht C, Jaccard A, Omuro A, Sanson M, Janvier M, Kolb B, Zini JM, Leblond V; Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. J Clin Oncol. 2008 May 20;26(15):2512-8. Epub 2008 Apr 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Relapsed or refractory, subsequent lines of therapy=
==Rituximab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Batchelor et al. 2011 (NABTT-2201)	2004 to not reported	Pilot, fewer than 20 pts
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
7-day cycle for up to 8 cycles
===References===
# NABTT-2201: Batchelor TT, Grossman SA, Mikkelsen T, Ye for, Desideri S, Lesser GJ. Rituximab monotherapy for patients with recurrent primary CNS lymphoma. Neurology. 2011 Mar 8;76(10):929-30. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00072449
==Temozolomide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Reni et al. 2007	2000-2005 	Phase 2
====Chemotherapy====
*Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 5
28-day cycles
===References===
# Reni M, Zaja F, Mason W, Perry J, Mazza E, Spina M, Bordonaro R, Ilariucci F, Faedi M, Corazzelli G, Manno P, Franceschi E, Pace A, Candela M, Abbadessa A, Stelitano C, Latte G, Ferreri AJ. Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer. 2007 Mar 26;96(6):864-7. Epub 2007 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Temsirolimus monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Korfel et al. 2016 (TemPCNSL)	2009-2014 	Phase 2
Note: This is the dose used in stage 2 of this two-stage protocol.
====Targeted therapy====
*Temsirolimus (Torisel) 75 mg IV once per day on days 1, 8, 15, 22
28-day cycles
===References===
# TemPCNSL: Korfel A, Schlegel U, Herrlinger U, Dreyling M, Schmidt C, von Baumgarten L, Pezzutto A, Grobosch T, Kebir S, Thiel E, Martus P, Kiewe P. Phase II trial of temsirolimus for relapsed/refractory primary CNS lymphoma. J Clin Oncol. 2016 May 20;34(15):1757-63. Epub 2016 Mar 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00942747
==Topotecan monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Voloschin et al. 2008	1998-2002 	Phase 2, fewer than 20 pts	ORR: 40%
Fischer et al. 2006 	2000-2004 	Phase 2 	ORR: 33%
====Chemotherapy====
*Topotecan (Hycamtin) 1.5 mg/m2 IV over 30 minutes once per day on days 1 to 5
====Supportive therapy====
*Voloschin et al. 2008: Ondansetron (Zofran) (dose/route not specified), given prior to topotecan
21-day cycle for varying durations: 6 cycles (Fischer et al. 2006); 10 cycles (Voloschin et al. 2008)
===References===
# Fischer L, Thiel E, Klasen HA, Birkmann J, Jahnke K, Martus P, Korfel A. Prospective trial on topotecan salvage therapy in primary CNS lymphoma. Ann Oncol. 2006 Jul;17(7):1141-5. Epub 2006 Apr 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Voloschin AD, Betensky R, Wen PY, Hochberg F, Batchelor T. Topotecan as salvage therapy for relapsed or refractory primary central nervous system lymphoma. J Neurooncol. 2008 Jan;86(2):211-5. Epub 2007 Sep 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Prognosis=
==IELSG Prognostic Scoring System (2003)==
# Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, Calderoni A, Rossi A, Vavassori V, Conconi A, Devizzi L, Berger F, Ponzoni M, Borisch B, Tinguely M, Cerati M, Milani M, Orvieto E, Sanchez J, Chevreau C, Dell'Oro S, Zucca E, Cavalli F. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003 Jan 15;21(2):266-72. link to original article EuroPMC
Category:CNS lymphoma regimens
Category:Disease-specific pages
Category:CNS cancers