Difference between revisions of "CNS lymphoma"

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'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
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<span id="BackToTop"></span>
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<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
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Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
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[[#top|Back to Top]]
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</div>
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{{#lst:Editorial board transclusions|cnsl}}
 +
''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[CNS lymphoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
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|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
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<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
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{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 +
=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==
 +
*'''2018:''' Fox et al. [https://doi.org/10.1111/bjh.15661 Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma] [https://www.ncbi.nlm.nih.gov/pubmed/30467845 PubMed]
 +
 +
==EANO==
 +
*'''2015:''' Hoang-Xuan et al. [https://doi.org/10.1016/s1470-2045(15)00076-5 Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology] [https://www.ncbi.nlm.nih.gov/pubmed/26149884 PubMed]
 +
 +
==ESH==
 +
*'''2019:''' Fox et al. [https://doi.org/10.1111/bjh.15661 Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma] [https://www.ncbi.nlm.nih.gov/pubmed/30467845 PubMed]
 +
 +
==[https://www.esmo.org/ ESMO]==
 +
*'''2016:''' Vitolo et al. [https://doi.org/10.1093/annonc/mdw175 Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/27377716/ PubMed]
 +
==GEL/TAMO==
 +
*'''2016:''' Peñalver et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286932/ Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)] [https://www.ncbi.nlm.nih.gov/pubmed/27846613 PubMed]
  
−
=Untreated, randomized data=
+
==NCCN==
 +
*''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425 NCCN Guidelines - Central Nervous System Cancers].''
  
−
==High-Dose Methotrexate {{#subobject:031ce9|Regimen=1}}==
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=CNS prophylaxis, systemic therapy=
−
{| class="wikitable" style="float:right; margin-left: 5px;"
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==High-dose Cytarabine monotherapy (HiDAC) {{#subobject:75c24e|Regimen=1}}==
 +
HiDAC: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:0258f4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mds621 Holte et al. 2013 (NLG LBC-04)]
 +
|2004-2008
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
''Note: IT treatment was not part of prophylaxis, except that [[Methotrexate (MTX)]] 15 mg IT was allowed at time of diagnostic LP.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Induction [[Diffuse_large_B-cell_lymphoma#R-CHOEP-14|R-CHOEP-14]] x 8
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] by the following age-based criteria:
 +
**Younger than 60 years old: 3000 mg/m<sup>2</sup> IV twice per day on days 1 & 2 (total dose: 12,000 mg/m<sup>2</sup>)
 +
**60 to 65 years old: 2000 mg/m<sup>2</sup> IV twice per day on days 1 & 2 (total dose: 8000 mg/m<sup>2</sup>)
 +
**Older than 65 years old: not defined
 +
'''21-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Induction [[#Methotrexate_monotherapy|HD-MTX]]
 +
</div></div>
 +
===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. [https://doi.org/10.1093/annonc/mds621 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23247661/ PubMed] [https://clinicaltrials.gov/study/NCT01502982 NCT01502982]
 +
==Methotrexate monotherapy {{#subobject:e89965|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:a5d109|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mds621 Holte et al. 2013 (NLG LBC-04)]
 +
|2004-2008
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
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|[[#toc|back to top]]
 
 
|}
 
|}
 +
''Note: IT treatment was not part of prophylaxis, except that [[Methotrexate (MTX)]] 15 mg IT was allowed at time of diagnostic LP.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Induction [[#High-dose_Cytarabine_monotherapy_.28HiDAC.29|HiDAC]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> 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'''
 +
</div></div>
 +
===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. [https://doi.org/10.1093/annonc/mds621 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23247661/ PubMed] [https://clinicaltrials.gov/study/NCT01502982 NCT01502982]
  
−
===Regimen {{#subobject:8ce96f|Variant=1}}===
+
=CNS treatment, local therapy=
−
{| border="1" style="text-align:center;" !align="left"  
+
==IT Cytarabine monotherapy {{#subobject:867516|Regimen=1}}==
−
|'''Study'''
+
<div class="toccolours" style="background-color:#eeeeee">
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
===Regimen {{#subobject:a436da|Variant=1}}===
−
|'''Comparator'''
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.sciencedirect.com/science/article/pii/S0140673609614161 Ferreri et al. 2009]
+
|[https://doi.org/10.1200/jco.1999.17.10.3110 Glantz et al. 1999]
−
|<span
+
|1994-1998
−
style="background:#00CD00;
+
|style="background-color:#1a9851"|Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#IT_Cytarabine_liposomal_monotherapy|IT liposomal cytarabine]]
−
border-color:black;
+
|style="background-color:#d73027"|Inferior ORR
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
 
−
|[[CNS_lymphoma#High-Dose_Methotrexate_.26_Cytarabine|High-dose MTX & Cytarabine]]
 
−
|<span
 
−
style="background:#ff0000;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Seems to have inferior CRR</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Methotrexate (MTX)]] 3500 mg/m2 IV once on day 1: first 500 mg/m2 given over 15 minutes, remaining 3000 mg/m2 given over 3 hours
+
====CNS therapy, treatment====
−
 
+
*[[Cytarabine (Ara-C)]] 50 mg IT once per day on days 1, 4, 8, 11, 15, 18, 22, 25
−
'''21-day cycles x 4 cycles'''
+
'''4-week course'''
−
 
+
</div>
−
''Followed within 4 weeks by [[CNS_lymphoma#Whole_brain_irradiation|whole brain irradiation]].''
+
<div class="toccolours" style="background-color:#cbd5e7">
−
 
+
====Subsequent treatment====
 +
*Glantz et al. 1999, responders: Further therapy was given to responders; see text for details
 +
</div></div>
 
===References===
 
===References===
−
# Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F; International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18. [http://www.sciencedirect.com/science/article/pii/S0140673609614161 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19767089 PubMed]
+
# 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. [https://doi.org/10.1200/jco.1999.17.10.3110 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10506606/ PubMed]
−
 
+
==IT Cytarabine liposomal monotherapy {{#subobject:fbf1d4|Regimen=1}}==
−
==High-Dose Methotrexate & Cytarabine {{#subobject:eef91c|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:c43afb|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1999.17.10.3110 Glantz et al. 1999]
 +
|1994-1998
 +
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ic)
 +
|[[#IT_Cytarabine_monotherapy_2|IT cytarabine]]
 +
|style="background-color:#1a9850"|Superior ORR (secondary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
 +
''Note: this study was not designed to make formal statitiscal comparisons, but the difference in ORR was very large.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====CNS therapy, treatment====
 +
*[[Cytarabine liposomal (DepoCyt)]] 50 mg IT once on day 1
 +
'''14-day cycle for 2 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Glantz et al. 1999, responders: Further therapy was given to responders; see text for details
 +
</div></div>
 +
===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. [https://doi.org/10.1200/jco.1999.17.10.3110 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10506606/ PubMed]
 +
=Upfront therapy, randomized data=
 +
==Cytarabine & Methotrexate (CYM) {{#subobject:eef91c|Regimen=1}}==
 +
CYM: '''<u>CY</u>'''tarabine & '''<u>M</u>'''ethotrexate
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:5ead03|Variant=1}}===
 
===Regimen {{#subobject:5ead03|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
|'''Study'''
+
!style="width: 20%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 20%"|Dates of enrollment
−
|'''Comparator'''
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
|[[Levels_of_Evidence#Efficacy|'''Efficacy''']]
+
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S0140-6736(09)61416-1 Ferreri et al. 2009 (IELSG20)]
 +
|2004-2007
 +
|style="background-color:#1a9851"|Randomized Phase 2, >20 per arm (E-esc)
 +
|[[#Methotrexate_monotherapy_2|High-dose MTX]]
 +
|style="background-color:#91cf60"|Seems to have superior CR rate (primary endpoint)
 +
|-
 +
|rowspan=2|[https://doi.org/10.1016/S2352-3026(16)00036-3 Ferreri et al. 2016 (IELSG32)]
 +
|rowspan=2|2010-2014
 +
|rowspan=2 style="background-color:#1a9851"|Randomized Phase 2 (C)
 +
|1. [[#Cytarabine.2C_Methotrexate.2C_Rituximab|Cytarabine, Methotrexate, Rituximab]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate
 +
|-
 +
|2. [[#MATRix|MATRix]]
 +
|style="background-color:#d73027"|Inferior CR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 60 minutes every 12 hours on days 2 & 3
 +
*[[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV over 15 minutes, then 3000 mg/m<sup>2</sup> IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)
 +
====Supportive therapy====
 +
*As described in Ferreri et al. 2016:
 +
*[[Levoleucovorin (Fusilev)]] 15 mg/m<sup>2</sup> 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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*IELSG20: [[#Whole_brain_irradiation|Whole brain irradiation]] consolidation , within 4 weeks
 +
*IELSG32: [[#Whole_brain_irradiation|Whole brain irradiation]] versus [[#BCNU.2FTT.2C_then_auto_HSCT|Carmustine & Thiotepa with auto HSCT]] consolidation
 +
</div></div>
 +
===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. [https://doi.org/10.1016/S0140-6736(09)61416-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19767089/ PubMed] [https://clinicaltrials.gov/study/NCT00210314 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. [https://doi.org/10.1016/S2352-3026(16)00036-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27132696/ PubMed] [https://clinicaltrials.gov/study/NCT01011920 NCT01011920]
 +
==Cytarabine, Methotrexate, Rituximab {{#subobject:a4671e|Regimen=1}}==
 +
R-HD-MTX/ARA-C: '''<u>R</u>'''ituximab, '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>M</u>'''etho'''<u>T</u>'''re'''<u>X</u>'''ate, '''<u>ARA-C</u>''' (Cytarabine)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:1c6830|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2015.61.1236 Ferreri et al. 2015 (SCNSL1)]
 +
|2006-2013
 +
|style="background-color:#91cf61"|Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[http://www.sciencedirect.com/science/article/pii/S0140673609614161 Ferreri et al. 2009]
+
|rowspan=2|[https://doi.org/10.1016/S2352-3026(16)00036-3 Ferreri et al. 2016 (IELSG32)]
−
|<span
+
|rowspan=2|2010-2014
−
style="background:#00CD00;
+
|rowspan=2 style="background-color:#1a9851"|Randomized Phase 2 (E-esc)
−
padding:3px 6px 3px 6px;
+
|1. [[#Cytarabine_.26_Methotrexate_.28CYM.29|CYM]]
−
border-color:black;
+
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate
−
border-width:2px;
+
|-
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
+
|2. [[#MATRix|MATRix]]
−
|[[CNS_lymphoma#High-Dose_Methotrexate|High-dose MTX]]
+
|style="background-color:#fc8d59"|Seems to have inferior CR rate
−
|<span
 
−
style="background:#00cd00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Seems to have superior CRR</span>
 
 
|-
 
|-
 
|}
 
|}
−
*[[Methotrexate (MTX)]] 3500 mg/m2 IV once on day 1: first 500 mg/m2 given over 15 minutes, remaining 3000 mg/m2 given over 3 hours
+
''Note: SCNSL1 was intended for secondary CNS lymphoma, whereas IELSG32 was intended for primary CNS lymphoma.''
−
*[[Cytarabine (Cytosar)]] 2000 mg/m2 IV bid on days 2 & 3
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
'''21-day cycles x 4 cycles'''
+
*SCNSL1: Induction [[Diffuse_large_B-cell_lymphoma#R-CHOP|R-CHOP]] x 1
−
 
+
</div>
−
''Followed within 4 weeks by [[CNS_lymphoma#Whole_brain_irradiation|whole brain irradiation]].''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 60 minutes every 12 hours on days 2 & 3
 +
*[[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV over 15 minutes, then 3000 mg/m<sup>2</sup> IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)
 +
====Targeted therapy====
 +
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days -5 & 0
 +
====CNS therapy====
 +
*SCNSL1: [[Cytarabine liposomal (DepoCyt)]]
 +
====Supportive therapy====
 +
*[[Levoleucovorin (Fusilev)]] 15 mg/m<sup>2</sup> 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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*SCNSL1: Intensification phase (see paper for details)
 +
*IELSG32: [[#Whole_brain_irradiation|Whole brain irradiation]] versus [[#BCNU.2FTT.2C_then_auto_HSCT|Carmustine & Thiotepa with auto HSCT]] consolidation
 +
</div></div>
 
===References===
 
===References===
−
# Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F; International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18. [http://www.sciencedirect.com/science/article/pii/S0140673609614161 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19767089 PubMed]
+
# '''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. [https://doi.org/10.1200/jco.2015.61.1236 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26282634/ PubMed] [https://clinicaltrials.gov/study/NCT00801216 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. [https://doi.org/10.1016/S2352-3026(16)00036-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27132696/ PubMed] [https://clinicaltrials.gov/study/NCT01011920 NCT01011920]
−
=Untreated, non-randomized or retrospective data=
+
==MATRix {{#subobject:7b7130|Regimen=1}}==
−
 
+
MATRix: '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine), '''<u>T</u>'''hiotepa, '''<u>Ri</u>'''tu'''<u>x</u>'''imab
−
==Ferreri regimen {{#subobject:2e75bb|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:278704|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1016/S2352-3026(16)00036-3 Ferreri et al. 2016 (IELSG32)]
 +
|rowspan=2|2010-2014
 +
|rowspan=2 style="background-color:#1a9851"|Randomized Phase 2 (E-esc)
 +
|1. [[#Cytarabine_.26_Methotrexate_.28CYM.29|CYM]]
 +
|style="background-color:#1a9850"|Superior CR rate (primary endpoint)
 +
|-
 +
|2. [[#Cytarabine.2C_Methotrexate.2C_Rituximab|Cytarabine, Methotrexate, Rituximab]]
 +
|style="background-color:#91cf60"|Seems to have superior CR rate (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:b5ef1c|Variant=1}}===
+
====Chemotherapy====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV over 15 minutes, then 3000 mg/m<sup>2</sup> IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)
−
|'''Study'''
+
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 60 minutes every 12 hours on days 2 & 3
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[Thiotepa (Thioplex)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 4
 +
====Targeted therapy====
 +
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days -5 & 0
 +
====Supportive therapy====
 +
*[[Levoleucovorin (Fusilev)]] 15 mg/m<sup>2</sup> 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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Whole_brain_irradiation|Whole brain irradiation]] versus [[#BCNU.2FTT.2C_then_auto_HSCT|Carmustine & Thiotepa with auto HSCT]] consolidation
 +
</div></div>
 +
===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. [https://doi.org/10.1016/S2352-3026(16)00036-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27132696/ PubMed] [https://clinicaltrials.gov/study/NCT01011920 NCT01011920]
 +
==MBVP {{#subobject:7b8320|Regimen=1}}==
 +
MBVP: '''<u>M</u>'''ethotrexate, '''<u>B</u>'''CNU (Carmustine), '''<u>V</u>'''umon (Teniposide), '''<u>P</u>'''rednisone
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:27aa04|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/33/33/3903.full Ferreri et al. 2015]
+
|[https://doi.org/10.1016/S1470-2045(18)30747-2 Bromberg et al. 2019 (HOVON 105/ALLG NHL 24)]
−
|<span
+
|2010-2016
−
style="background:#EEEE00;
+
|style="background-color:#1a9851"|Phase 3 (C)
−
padding:3px 6px 3px 6px;
+
|[[#R-MBVP_999|R-MBVP]]
−
border-color:black;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
To be completed
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 15
 +
*[[Carmustine (BCNU)]] 100 mg/m<sup>2</sup> IV once on day 4
 +
*[[Teniposide (Vumon)]] 100 mg/m<sup>2</sup> IV once per day on days 2 & 3
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 5
 +
'''28-day cycle for 2 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*HOVON 105/ALLG NHL 24, responders 60 years old or older: [[#High-dose_Cytarabine_monotherapy_.28HiDAC.29_2|HiDAC]] consolidation
 +
*HOVON 105/ALLG NHL 24, responders younger than 60: [[#High-dose_Cytarabine_monotherapy_.28HiDAC.29_2|HiDAC]] consolidation, then [[#Whole_brain_irradiation|low-dose WBRT]] consolidation
 +
 +
</div></div>
 
===References===
 
===References===
−
# 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. [http://jco.ascopubs.org/content/33/33/3903.full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/26282634 PubMed]
+
# '''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. [https://doi.org/10.1016/S1470-2045(18)30747-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30630772/ PubMed] 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. [https://doi.org/10.1016/j.annonc.2020.04.014 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32371123/ PubMed]
−
==High-Dose Methotrexate {{#subobject:178376|Regimen=1}}==
+
==Methotrexate monotherapy {{#subobject:031ce9|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 3500 mg/m<sup>2</sup> {{#subobject:8ce96f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S0140-6736(09)61416-1 Ferreri et al. 2009 (IELSG20)]
 +
|2004-2007
 +
|style="background-color:#1a9851"|Randomized Phase 2 (C)
 +
|[[#Cytarabine_.26_Methotrexate_.28CYM.29|CYM]]; high-dose
 +
|style="background-color:#fc8d59"|Seems to have inferior CR rate
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen #1 {{#subobject:dcc365|Variant=1}}===
+
====Chemotherapy====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV over 15 minutes, then 3000 mg/m<sup>2</sup> IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)
−
|'''Study'''
+
'''21-day cycle for 4 cycles'''
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Whole_brain_irradiation|Whole brain irradiation]] consolidation, within 4 weeks
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 4000 mg/m<sup>2</sup> {{#subobject:dcc365|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.sciencedirect.com/science/article/pii/S1470204510702291 Thiel et al. 2010 (G-PCNSL-SG-1)]
+
|[https://doi.org/10.1016/S1470-2045(10)70229-1 Thiel et al. 2010 (G-PCNSL-SG-1)]
−
|<span
+
|2000-2009
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Non-randomized part of phase 3 RCT
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Nonrandomized</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: All patients received the same induction regimen; however, the induction regimen was changed after 2006 to [[#Ifosfamide_.26_Methotrexate|high-dose MTX & ifosfamide]].''
−
''All patients received the same induction regimen; however, the induction regimen was changed after 2006 to [[CNS_lymphoma#High-Dose_Methotrexate_.26_Ifosfamide|high-dose MTX & ifosfamide]].''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
*[[Methotrexate (MTX)]] 4000 mg/m2 IV once over 4 hours on day 1
+
*[[Methotrexate (MTX)]] 4000 mg/m<sup>2</sup> IV over 4 hours once on day 1
−
 
+
'''14-day cycle for 6 cycles'''
−
'''14-day cycle x 6 cycles'''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e7">
−
''Patients with a complete response were randomized to [[CNS_lymphoma#Whole_brain_irradiation|whole-brain irradiation]] versus no further treatment. Patients with less than a complete response were randomized to salvage whole-brain irradiation versus salvage HiDAC.''
+
====Subsequent treatment====
−
 
+
*G-PCNSL-SG-1, patients with CR: [[#Whole_brain_irradiation|whole-brain irradiation]] consolidation versus [[CNS_lymphoma_-_null_regimens#Observation|no further treatment]]
−
===Regimen #2 {{#subobject:8e0230|Variant=1}}===
+
*G-PCNSL-SG-1, patients with less than CR in the WB-XRT arm: Salvage [[#Whole_brain_irradiation_2|whole-brain irradiation]]
−
{| border="1" style="text-align:center;" !align="left"  
+
*G-PCNSL-SG-1, patients with less than CR in the no-WB-XRT: Salvage [[#High-dose_Cytarabine_monotherapy_.28HiDAC.29_3|HiDAC]]
−
|'''Study'''
+
</div></div><br>
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 8000 mg/m<sup>2</sup> {{#subobject:8e0230|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://onlinelibrary.wiley.com/doi/10.1002/ana.20495/full Herrlinger et al. 2005 (NOA-03)]
+
|[https://doi.org/10.1002/ana.20495 Herrlinger et al. 2005 (NOA-03)]
−
|<span
+
|1998-05 to 2000-03
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: This was considered a negative trial by the authors and is included here for historical purposes.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 hours once on day 1
 +
'''14-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*NOA-03, patients intolerant of MTX or not achieving CR after 6 cycles: Salvage [[#Whole_brain_irradiation_2|whole-brain irradiation]] versus [[#PCV_999|PCV]]; see article for details
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
''This was considered a negative trial by the authors and is included here for historical purposes.''
+
===Regimen variant #4, 8000 mg/m<sup>2</sup> with renal adjustment {{#subobject:567824|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
*[[Methotrexate (MTX)]] 8000 mg/m2 IV once over 4 hours on day 1
+
!style="width: 33%"|Study
−
 
+
!style="width: 33%"|Dates of enrollment
−
'''14-day cycle x 6 cycles'''
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
 
−
''Patients intolerant of MTX or not achieving CR after 6 cycles were randomized to WBRT or PCV; see article for details.''
 
−
 
 
−
===Regimen #3 {{#subobject:567824|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/21/6/1044.long Batchelor et al. 2003]
+
|[https://doi.org/10.1200/jco.2003.03.036 Batchelor et al. 2003 (NABTT 96-07)]
−
|<span
+
|1998-1999
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''The full dose of 8000 mg/m2 was only given if CrCl was at least 100. For CrCl less than 100, the dose was reduced by the percentage reduction below 100. For example, a CrCl of 50 would mandate a 50% dose reduction.''
+
====Chemotherapy====
−
 
+
*[[Methotrexate (MTX)]] by the following renal function-based criteria:
−
====Induction phase====
+
**CrCl 100 mL/min/1.73m<sup>2</sup> or more: 8000 mg/m<sup>2</sup> IV over 4 hours once on day 1
−
*[[Methotrexate (MTX)]] 8000 mg/m2 IV once over 4 hours on day 1
+
**CrCl less than 100 mL/min/1.73m<sup>2</sup>: The dose was reduced by the percentage reduction below 100. For example, a CrCl of 50 mL/min/1.73m<sup>2</sup> would mandate a 50% dose reduction to 4000 mg/m<sup>2</sup>.
−
 
 
 
'''14-day cycle until CR or a maximum of 8 cycles'''
 
'''14-day cycle until CR or a maximum of 8 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*NABTT 96-07, patients achieving CR: [[#Methotrexate_monotherapy_2|HD-MTX]] continuation x 2, then [[#Methotrexate_monotherapy_3|methotrexate]] maintenance
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 20-day course {{#subobject:a12fcc|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdl458 Montemurro et al. 2007 (OSHO-53)]
 +
|1999-2004
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] by the following age-based criteria:
 +
**60 years old or younger: 8000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 & 10
 +
**Older than 60 years old: 6000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 & 10
 +
'''20-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*OSHO-53, responders (CR or PR): [[#Bu.2FTT.2C_then_auto_HSCT|Bu/TT, then autologous HSCT]] consolidation
 +
</div></div>
 +
===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. [https://doi.org/10.1200/jco.2003.03.036 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12637469/ PubMed]
 +
# '''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. [https://doi.org/10.1002/ana.20495 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15929034/ PubMed] content property of [https://hemonc.org 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. [https://doi.org/10.1093/annonc/mdl458 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17185743/ PubMed]
 +
# '''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. [https://doi.org/10.1016/S0140-6736(09)61416-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19767089/ PubMed] [https://clinicaltrials.gov/study/NCT00210314 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. [https://doi.org/10.1016/S1470-2045(10)70229-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20970380/ PubMed] [https://clinicaltrials.gov/study/NCT00153530 NCT00153530]
 +
<!-- ## '''Update: Abstract:''' Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) [https://doi.org/10.1200/jco.2014.32.15_suppl.8527 link to abstract] -->
 +
## '''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. [https://doi.org/10.1212/wnl.0000000000001395 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25716362/ PubMed]
  
−
''Patients achieving CR proceeded to consolidation:''
+
=Upfront therapy, non-randomized or retrospective data=
−
 
+
==Lomustine, Methotrexate, Procarbazine {{#subobject:95c040|Regimen=1}}==
−
====Consolidation====
+
MCP: '''<u>M</u>'''ethotrexate, '''<u>C</u>'''CNU (Lomustine), '''<u>P</u>'''rocarbazine
−
*[[Methotrexate (MTX)]] 8000 mg/m2 IV once over 4 hours on day 1
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen {{#subobject:0caeaa|Variant=1}}===
−
'''14-day cycle x 2 cycles, then:'''
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
 
+
!style="width: 33%"|Study
−
====Maintenance====
+
!style="width: 33%"|Dates of enrollment
−
*[[Methotrexate (MTX)]] 8000 mg/m2 IV once over 4 hours on day 1
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
|-
−
'''28-day cycle x 11 cycles'''
+
|[https://doi.org/10.1093/annonc/mdn628 Illerhaus et al. 2008a]
−
 
+
|1998-2004
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Lomustine (CCNU)]] 110 mg/m<sup>2</sup> PO once on day 1
 +
*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1, 15, 30
 +
*[[Procarbazine (Matulane)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 10
 +
====Supportive therapy====
 +
*[[Leucovorin (Folinic acid)]] 15 mg/m<sup>2</sup> (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'''
 +
</div></div>
 
===References===
 
===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. [http://jco.ascopubs.org/content/21/6/1044.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12637469 PubMed]
+
# 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. [https://doi.org/10.1093/annonc/mdn628 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18953065/ PubMed]
−
# 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. [http://onlinelibrary.wiley.com/doi/10.1002/ana.20495/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15929034 PubMed] content property of [http://hemonc.org HemOnc.org]
+
==Lomustine, Methotrexate, Procarbazine, Methylprednisolone {{#subobject:c81fd|Regimen=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. [http://www.sciencedirect.com/science/article/pii/S1470204510702291 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20970380 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
## '''Update: Abstract:''' Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) [http://meetinglibrary.asco.org/content/129168-144 link to abstract]
+
===Regimen {{#subobject:d3269c|Variant=1}}===
−
## '''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. [http://www.neurology.org/content/84/12/1242.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25716362 PubMed]
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
 
+
!style="width: 33%"|Study
−
==High-Dose Methotrexate -> Cytarabine & Thiotepa {{#subobject:990369|Regimen=1}}==
+
!style="width: 33%"|Dates of enrollment
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2003.11.036 Hoang-Xuan et al. 2003 (EORTC 26952)]
 +
|1997-1999
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: This was the first prospective phase 2 trial evaluating chemotherapy alone in older patients with PCNSL.''
−
===Regimen #1 {{#subobject:e9fd90|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
{| border="1" style="text-align:center;" !align="left"  
+
====Chemotherapy====
−
|'''Study'''
+
*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 10, 20
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[Lomustine (CCNU)]] 40 mg/m<sup>2</sup> PO once on day 1
 +
*[[Procarbazine (Matulane)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 7
 +
====Glucocorticoid therapy====
 +
*[[Methylprednisolone (Solumedrol)]] as follows:
 +
**Days 1 to 20: 120 mg/m<sup>2</sup> IV or PO every other day
 +
**Days 20 to 45: 60 mg/m<sup>2</sup> 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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*EORTC 26952, patients achieving PR or CR: [[#Lomustine.2C_Methotrexate.2C_Procarbazine_2|Lomustine, methotrexate, procarbazine]] maintenance
 +
</div></div>
 +
===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; [[Study_Groups#EORTC|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. [https://doi.org/10.1200/jco.2003.11.036 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860951/ PubMed]
 +
==MATRix-RICE {{#subobject:7b7ri0|Regimen=1}}==
 +
MATRix-RICE: '''<u>M</u>'''ethotrexate, '''<u>A</u>'''ra-C (Cytarabine), '''<u>T</u>'''hiotepa, '''<u>Ri</u>'''tu'''<u>x</u>'''imab, followed by '''<u>R</u>'''ituximab,
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:cxjc04|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/24/24/3865.full Illerhaus et al. 2006]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7844712/ Ferreri et al. 2021 (MARIETTA)]
−
|<span
+
|2015-03-30 to 2018-08-03
−
style="background:#EEEE00;
+
| style="background-color:#91cf61" |Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, MATRix portion (cycles 1 to 3)====
 +
*[[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV over 15 minutes, then 3000 mg/m<sup>2</sup> IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m<sup>2</sup>)
 +
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 60 minutes every 12 hours on days 2 & 3
 +
*[[Thiotepa (Thioplex)]] 30 mg/m<sup>2</sup> IV over 30 minutes once on day 4
 +
====Targeted therapy, MATRix portion (cycles 1 to 3)====
 +
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> 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/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, RICE portion (cycles 4 to 6)====
 +
*[[Ifosfamide (Ifex)]] 5000 mg/m<sup>2</sup> 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/m<sup>2</sup> 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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#BCNU.2FTT.2C_then_auto_HSCT|Carmustine & Thiotepa with auto HSCT]] consolidation
 +
</div></div>
 +
===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. [https://doi.org/10.1016/s2352-3026(20)30366-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7844712/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33513372/ PubMed] [https://clinicaltrials.gov/study/NCT02329080 NCT02329080]
  
−
*[[Methotrexate (MTX)]] 8000 mg/m2 IV over 4 hours once per day on days 1, 10, 20
+
==Methotrexate-Cytarabine {{#subobject:f24bde|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
Supportive medications:
+
===Regimen {{#subobject:1d3fff|Variant=1}}===
−
*[[Folinic acid (Leucovorin)]] 15 mg/m2 every 6 hours, beginning 24 hours after start of [[Methotrexate (MTX)]], continuing until clearance
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
 
+
!style="width: 33%"|Study
−
'''One course'''
+
!style="width: 33%"|Dates of enrollment
−
 
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
''Patients with CR, PR, or SD "with clinical improvement" after the 2nd dose of MTX proceeded to:''
 
−
 
 
−
*[[Cytarabine (Cytosar)]] 3 g/m2 IV over 3 hours once per day on days 30 & 31
 
−
*[[Thiotepa (Thioplex)]] 40 mg/m2 (route not specified) once on day 31
 
−
 
 
−
'''One course'''
 
−
 
 
−
''This was for stem cell mobilization and was followed by [[CNS_lymphoma#Autologous_stem_cell_transplant|autologous stem cell transplant]].''
 
−
 
 
−
===Regimen #2 {{#subobject:92e01d|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
 
|-
 
|-
−
|[http://www.haematologica.org/content/93/1/147.long Illerhaus et al. 2008]
+
|[https://doi.org/10.1200/jco.2003.05.024 Abrey et al. 2003]
−
|<span
+
|NR
−
style="background:#ff0000;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Pilot, <20 patients</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note: Patients proceed to part two 72 hours after 5th dose of MTX or once the 5th dose MTX level has cleared.''
−
*[[Methotrexate (MTX)]] 8000 mg/m2 IV over 4 hours once on day 1
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy, first portion (cycles 1 to 5)====
−
Supportive medications:
+
*[[Methotrexate (MTX)]] 3500 mg/m<sup>2</sup> (maximum dose of 7000 mg) IV over 2 hours once on day 1
−
*[[Folinic acid (Leucovorin)]] 15 mg/m2 every 6 hours, beginning 24 hours after start of [[Methotrexate (MTX)]], continuing until clearance
+
====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
−
'''10-day cycle x 2 to 4 cycles, followed by:'''
+
====Chemotherapy, second portion (cycles 6 & 7)====
−
 
+
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2
−
*[[Cytarabine (Cytosar)]] 3 g/m2 IV once per day on days 1 & 2
+
====Supportive therapy, second portion====
−
*[[Thiotepa (Thioplex)]] 40 mg/m2 (route not specified) once on day 2
+
*[[Filgrastim (Neupogen)]] as follows:
−
 
+
**Cycle 6: 10 mcg/kg SC once per day, starting on day 4 and continued until stem cell collection complete
−
'''21-day cycle x 2 cycles'''
+
**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)'''
−
''Stem cells are mobilized and collected after the first cycle; this part was followed by [[CNS_lymphoma#Autologous_stem_cell_transplant|autologous stem cell transplant]].''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#BEAM.2C_then_auto_HSCT|BEAM, then autologous hematopoietic stem cell transplant]] consolidation
 +
</div></div>
 
===References===
 
===References===
−
<!-- Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005. -->
+
# 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. [https://doi.org/10.1200/jco.2003.05.024 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14615443/ PubMed]
−
# 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. [http://jco.ascopubs.org/content/24/24/3865.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16864853 PubMed]
 
−
# 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. [http://www.haematologica.org/content/93/1/147.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18166803 PubMed]
 
  
−
==High-Dose Methotrexate & Ifosfamide {{#subobject:bdba26|Regimen=1}}==
+
==Methotrexate-Cytarabine & Thiotepa {{#subobject:990369|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:e9fd90|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2006.06.2117 Illerhaus et al. 2006]
 +
|1998-2003
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:7ea29f|Variant=1}}===
+
====Chemotherapy, MTX portion (course 1)====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1, 10, 20
−
|'''Study'''
+
====Supportive therapy, MTX portion (course 1)====
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[Leucovorin (Folinic acid)]] 15 mg/m<sup>2</sup> 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/m<sup>2</sup> IV over 3 hours once per day on days 2 & 3
 +
*[[Thiotepa (Thioplex)]] 40 mg/m<sup>2</sup> (route not specified) once on day 3
 +
'''28-day course, then 20-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#BCNU.2FTT.2C_then_auto_HSCT|BCNU/TT, then autologous hematopoietic stem cell transplant]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Protocol variant #2 {{#subobject:92e01d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.sciencedirect.com/science/article/pii/S1470204510702291 Thiel et al. 2010 (G-PCNSL-SG-1)]
+
|[https://doi.org/10.3324/haematol.11771 Illerhaus et al. 2008]
−
|<span
+
|2003-2006
−
style="background:#EEEE00;
+
|style="background-color:#ffffbe"|Pilot, fewer than 20 patients
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Nonrandomized</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''All patients received the same induction regimen; however, the induction regimen was [[CNS_lymphoma#High-Dose_Methotrexate|high-dose MTX]] until 2006.''
+
====Chemotherapy, part 1====
−
 
+
*[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 hours once on day 1
−
*[[Methotrexate (MTX)]] 4000 mg/m2 IV once over 4 hours on day 1
+
====Supportive therapy====
−
*[[Ifosfamide (Ifex)]] 1500 g/m2 IV over 3 hours once per day on days 3 to 5
+
*[[Leucovorin (Folinic acid)]] 15 mg/m<sup>2</sup> every 6 hours, beginning 24 hours after start of methotrexate, continuing until clearance
−
 
+
'''10-day cycle for 2 to 4 cycles, followed by:'''
−
'''14-day cycle x 6 cycles'''
+
====Chemotherapy, part 2====
−
 
+
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2
−
''Patients with a complete response were randomized to [[CNS_lymphoma#Whole_brain_irradiation|whole-brain irradiation]] versus no further treatment. Patients with less than a complete response were randomized to [[CNS_lymphoma#Whole_brain_irradiation_2|salvage whole-brain irradiation]] versus salvage HiDAC.''
+
*[[Thiotepa (Thioplex)]] 40 mg/m<sup>2</sup> (route not specified) once on day 2
−
 
+
'''21-day cycle for 2 cycles (Stem cells are mobilized and collected after the first cycle)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#BCNU.2FTT.2C_then_auto_HSCT|BCNU/TT, then autologous hematopoietic stem cell transplant]] consolidation
 +
</div></div>
 
===References===
 
===References===
−
# 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. [http://www.sciencedirect.com/science/article/pii/S1470204510702291 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20970380 PubMed]
+
<!-- Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005. -->
−
## '''Update: Abstract:''' Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) [http://meetinglibrary.asco.org/content/129168-144 link to abstract]
+
# 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. [https://doi.org/10.1200/jco.2006.06.2117 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16864853/ PubMed]
−
## '''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. [http://www.neurology.org/content/84/12/1242.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25716362 PubMed]
+
## '''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. [https://doi.org/10.1093/annonc/mds059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22473593/ PubMed]
−
 
+
# 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. [https://doi.org/10.3324/haematol.11771 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18166803/ PubMed]
−
==MPV {{#subobject:245afd|Regimen=1}}==
+
## '''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. [https://doi.org/10.1093/annonc/mds059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22473593/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==Methotrexate & Rituximab {{#subobject:45f333|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:715330|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940660/ Chamberlain et al. 2010]
 +
|2000-2007
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
 +
''Note: the bounds as described in the paper do not account for the situation where CrCl = 60 mL/min/1.73m<sup>2</sup>.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] by the following renal function-based criteria:
 +
**CrCl more than 60 mL/min/1.73m<sup>2</sup>: 8000 mg/m<sup>2</sup> IV over 6 hours once on day 1
 +
**CrCl less than 60 mL/min/1.73m<sup>2</sup>: 4000 mg/m<sup>2</sup> IV over 6 hours once on day 1
 +
====Targeted therapy====
 +
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 8
 +
'''14-day cycle for 4 to 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Chamberlain et al. 2010, patients with PR/CR: [[#Methotrexate_monotherapy_3|High-dose methotrexate]] consolidation
 +
</div></div>
 +
===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. [https://doi.org/10.1093/neuonc/noq011 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940660/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20511181/ PubMed]
 +
==MPV {{#subobject:245afd|Regimen=1}}==
 
MPV: '''<u>M</u>'''ethotrexate, '''<u>P</u>'''rocarbazine, '''<u>V</u>'''incristine
 
MPV: '''<u>M</u>'''ethotrexate, '''<u>P</u>'''rocarbazine, '''<u>V</u>'''incristine
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:2cb0c6|Variant=1}}===
 
===Regimen {{#subobject:2cb0c6|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable" style="width: 60%; text-align:center;"  
−
|'''Study'''
+
!style="width: 33%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2000.18.17.3144 Abrey et al. 2000]
 +
|1992-1998
 +
|style="background-color:#91cf61"|Non-randomized
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/20/24/4643.long DeAngelis et al. 2002 (RTOG 93-10)]
+
|[https://doi.org/10.1200/jco.2002.11.013 DeAngelis et al. 2002 (RTOG 93-10)]
−
|<span
+
|1993-NR
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Methotrexate (MTX)]] 2500 mg/m2 IV once over 2 to 3 hours on day 1
+
====Chemotherapy====
−
*[[Procarbazine (Matulane)]] 100 mg/m2 PO once per day on days 1 to 7 of odd cycles (1, 3, 5)
+
*[[Methotrexate (MTX)]] 2500 mg/m<sup>2</sup> IV over 2 to 3 hours once on day 1
−
*[[Vincristine (Oncovin)]] 1.4 mg/m2 (capped at 2.8 mg) IV on day 1
+
*[[Procarbazine (Matulane)]] as follows:
−
 
+
**Cycles 1, 3, 5: 100 mg/m<sup>2</sup> PO once per day on days 1 to 7
−
Intrathecal component:
+
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2.8 mg) IV once on day 1
−
*[[Methotrexate (MTX)]] 12 mg IT (via Ommaya) once one week after IV [[Methotrexate (MTX)]] administration
+
====CNS therapy====
−
*[[Folinic acid (Leucovorin)]] 10 mg PO every 6 hours x 8 doses, beginning the evening of IT [[Methotrexate (MTX)]] administration
+
*[[Methotrexate (MTX)]] 12 mg IT once on day 8 (via Ommaya reservoir)
−
 
+
====Supportive therapy====
−
Supportive medications:
+
*[[Leucovorin (Folinic acid)]] as follows:
−
*[[Folinic acid (Leucovorin)]] 20 mg PO every 6 hours x 12 doses, beginning 24 hours after IV [[Methotrexate (MTX)]] administration
+
**Days 2 to 4: 20 mg PO every 6 hours for 12 doses, '''beginning 24 hours after IV methotrexate administration'''
−
*[[Dexamethasone (Decadron)]] 16 mg PO once per day x 7 days, then 12 mg PO once per day x 7 days, then 8 mg PO once per day x 7 days, then 6 mg PO once per day x 7 days, then 4 mg PO once per day x 7 days, then 2 mg PO once per day x 7 days (starts with first cycle)
+
**Days 8 & 9: 10 mg PO every 6 hours for 8 doses, '''beginning on the evening of IT methotrexate administration'''
−
 
+
*[[Dexamethasone (Decadron)]] as follows:
−
'''14-day cycles x 5 cycles, followed by:'''
+
**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
−
*Whole-brain irradiation to 45 Gy in 1.80-Gy fractions or to 36 Gy in 1.20-Gy twice-daily fractions
+
**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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Whole_brain_irradiation|Whole-brain irradiation]] consolidation
 +
</div></div>
 
===References===
 
===References===
−
# DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002 Dec 15;20(24):4643-8. [http://jco.ascopubs.org/content/20/24/4643.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12488408 PubMed]
+
# Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000 Sep;18(17):3144-50. [https://doi.org/10.1200/JCO.2000.18.17.3144 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10963643/ PubMed]
−
 
+
## '''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. [https://doi.org/10.1200/JCO.2006.06.6910 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17008697/ PubMed]
 +
# '''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. [https://doi.org/10.1200/jco.2002.11.013 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12488408/ PubMed]
 
==MT-R {{#subobject:cc7d83|Regimen=1}}==
 
==MT-R {{#subobject:cc7d83|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
MT-R: '''<u>M</u>'''ethotrexate, '''<u>T</u>'''emozolomide, '''<u>R</u>'''ituximab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:5cf6d6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872318/ Glass et al. 2016 (RTOG 0227)]
 +
|NR
 +
|style="background-color:#91cf61"|Phase 1/2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
MT-R: '''<u>M</u>'''ethotrexate, '''<u>T</u>'''emozolomide, '''<u>R</u>'''ituximab
+
''Note: This is the MTD of this phase 1/2 trial; it appears that only a single dose of rituximab was given.''
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:5df6e6|Variant=1}}===
+
====Chemotherapy====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[Methotrexate (MTX)]] 3500 mg/m<sup>2</sup> IV once on day 1
−
|'''Study'''
+
*[[Temozolomide (Temodar)]] as follows:
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
**Cycles 2 & 4: 100 mg/m<sup>2</sup> PO once per day on days 8 to 12
 +
====Targeted therapy====
 +
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> 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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Whole_brain_irradiation|WB-XRT]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:5df6e6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/early/2013/06/25/JCO.2012.46.9957.long Rubenstein et al. 2013 (CALGB 50202)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753699/ Rubenstein et al. 2013 (CALGB 50202)]
−
|<span
+
|2004-2009
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
====Induction phase====
+
====Chemotherapy====
−
*[[Methotrexate (MTX)]] 8000 mg/m2 IV once over 4 hours on day 1
+
*[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 hours once on day 1
−
**''Given for a total of 7 doses.''
+
*[[Temozolomide (Temodar)]] as follows:
−
*[[Temozolomide (Temodar)]] 150 mg/m2 PO once per day on days 7 to 11 (odd cycles only)
+
**Cycles 1, 3, 5, 7: 150 mg/m<sup>2</sup> PO once per day on days 7 to 11
−
*[[Rituximab (Rituxan)]] 375 mg/m2 IV once on day 3
+
====Targeted therapy====
−
**''Rituximab omitted for T-cell PCNSL and given for a total of 6 doses in all others.''
+
*[[Rituximab (Rituxan)]] as follows:
−
 
+
**Cycles 1 to 6: 375 mg/m<sup>2</sup> IV once on day 3
−
Supportive medications:
+
====Supportive therapy====
−
*[[Folinic acid (Leucovorin)]] 100 mg/m2 IV every 6 hours, start on day 2, continue until MTX level <0.05
+
*[[Leucovorin (Folinic acid)]] 100 mg/m<sup>2</sup> IV every 6 hours, start on day 2, continue until MTX level less than 50 nmol/L
−
 
+
'''14-day cycle for 7 cycles'''
−
'''14-day cycles x 8 cycles'''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e7">
−
''Patients achieving CR or CRu were given one additional cycle of methotrexate & temozolomide, followed by consolidation therapy:''
+
====Subsequent treatment====
−
 
+
*CALGB 50202, patients achieving CR or CRu: [[#Cytarabine_.26_Etoposide_.28CYVE.29|CYVE]] consolidation
−
====Consolidation====
+
</div></div>
−
*[[Etoposide (Vepesid)]] 40 mg/kg IV continuous infusion over 96 hours, days 1 to 4
 
−
*[[Cytarabine (Cytosar)]] 2 gm/m2 IV Q12H over 2 hours × 8 doses, days 1 to 4
 
−
 
 
−
'''One course'''
 
  
 
===References===
 
===References===
−
# 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 [http://jco.ascopubs.org/content/early/2013/06/25/JCO.2012.46.9957.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23569323 PubMed]
+
# '''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. [https://doi.org/10.1200/jco.2012.46.9957 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753699/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23569323/ PubMed] [https://clinicaltrials.gov/study/NCT00098774 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. [https://doi.org/10.1200/jco.2015.64.8634 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872318/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27022122/ PubMed] [https://clinicaltrials.gov/study/NCT00068250 NCT00068250]
−
==MTX, Lomustine, Procarbazine, Methylprednisolone {{#subobject:c81fd|Regimen=1}}==
+
==MVBP {{#subobject:891647|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
MVBP: '''<u>M</u>'''ethotrexate, '''<u>V</u>'''P16 (Etoposide), '''<u>B</u>'''CNU (Carmustine), Methyl'''<u>P</u>'''rednisolone
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:70497b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[[#toc|back to top]]
+
|[https://doi.org/10.1038/sj.bmt.1705452 Colombat et al. 2006]
−
|}
+
|1999-2001
−
 
+
|style="background-color:#91cf61"|Phase 2
−
===Regimen {{#subobject:d3269c|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
−
|-
 
−
|[http://jco.ascopubs.org/content/21/14/2726.long Hoang-Xuan et al. 2003 (EORTC 26952)]
 
−
|<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
''This was the first prospective phase II trial evaluating chemotherapy alone in older patients with PCNSL.''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
*[[Methotrexate (MTX)]] 1000 mg/m2 IV once per day on days 1, 10, 20
+
*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 15
−
*[[Lomustine (Ceenu)]] 40 mg/m2 PO once on day 1
+
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once on day 2
−
*[[Procarbazine (Matulane)]] 60 mg/m2 PO once per day on days 1 to 7
+
*[[Carmustine (BCNU)]] 100 mg/m<sup>2</sup> IV once on day 3
−
*[[Methylprednisolone (Solumedrol)]] as follows:
+
====Glucocorticoid therapy====
−
**Days 1 to 20: 120 mg/m2 PO/IV every other day  
+
*[[Methylprednisolone (Solumedrol)]] 60 mg/m<sup>2</sup> (route not specified) once per day on days 1 to 5
−
**Days 20 to 45: 60 mg/m2 PO/IV every other day
+
====Supportive therapy====
−
 
+
*[[Leucovorin (Folinic acid)]] details not specified
−
Intrathecal component:
+
'''2 courses (length not specified), separated by 21 days'''
−
*[[Methotrexate (MTX)]] 15 mg IT (admixed with [[Cytarabine (Cytosar)]]) once per day on days 1, 5, 10, 15
+
====CNS therapy====
−
*[[Cytarabine (Cytosar)]] 40 mg IT (admixed with [[Methotrexate (MTX)]]) once per day on days 1, 5, 10, 15
+
*[[Methotrexate (MTX)]] 20 mg IT (admixed with cytarabine and methylpredinsolone)
−
 
+
*[[Cytarabine (Ara-C)]] 50 mg IT (admixed with methotrexate and methylprednisolone)
−
Supportive medications:
+
*[[Methylprednisolone (Solumedrol)]] 40 mg IT (admixed with cytarabine and methotrexate)
−
*[[Folinic acid (Leucovorin)]] 25 mg PO every 6 hours for 3 days, initiated 24 hours after IV [[Methotrexate (MTX)]] administrations, and 10 mg PO every 6 hours for 2 days after IT [[Methotrexate (MTX)]] administrations
+
'''6 doses total (timing not specified)'''
−
 
+
</div>
−
'''45-day course'''
+
<div class="toccolours" style="background-color:#cbd5e7">
−
 
+
====Subsequent treatment====
−
''Patients achieving PR or CR proceeded to [[#MTX.2C_Lomustine.2C_Procarbazine|MTX, lomustine, procarbazine maintenance]].'''
+
*Colombat et al. 2006, responding patients (CR or PR): [[Stem_cell_mobilization_regimens#Cytarabine.2C_Ifosfamide.2C_G-CSF|Cytarabine & Ifosfamide]] for stem cell mobilization, then [[#BEAM.2C_then_auto_HSCT|BEAM, then autologous hematopoietic stem cell transplant]] consolidation
−
 
+
*Colombat et al. 2006, non-responders: Salvage [[#Cytarabine_.26_Etoposide_.28CYVE.29|CYVE]]
 +
</div></div>
 
===References===
 
===References===
−
# Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B; European Organization for Research and Treatment of Cancer Brain Tumor Group. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003 Jul 15;21(14):2726-31. [http://jco.ascopubs.org/content/21/14/2726.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12860951 PubMed]
+
# 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. [https://doi.org/10.1038/sj.bmt.1705452 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16951691/ PubMed]
−
 
 
 
==Nordic Regimen, older patients {{#subobject:1778db|Regimen=1}}==
 
==Nordic Regimen, older patients {{#subobject:1778db|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#toc|back to top]]
 
−
|}
 
−
 
 
 
===Regimen {{#subobject:eb66bd|Variant=1}}===
 
===Regimen {{#subobject:eb66bd|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|'''Study'''
+
!style="width: 33%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.haematologica.org/content/100/4/534.full Pulczynski et al. 2015]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380727/ Pulczynski et al. 2015 (NLGPCNSL)]
−
|<span
+
|2007-2010
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
''This regimen is meant for patients aged 66-75 years.''
+
====Eligibility criteria====
−
 
+
*Age 66-75 years
−
====A cycles====
+
</div>
−
*[[Rituximab (Rituxan)]] 375 mg/m2 IV once on day 1 '''of the 1st A cycle only'''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Methotrexate (MTX)]] 3000 mg/m2 IV once on day 1
+
====Targeted therapy, A portion====
−
*[[Ifosfamide (Ifex)]] 800 mg/m2 IV once per day on days 2 to 5 '''of the 1st A cycle only'''
+
*[[Rituximab (Rituxan)]] as follows:
−
*[[Dexamethasone (Decadron)]] 10 mg/m2/day PO on days 2 to 5
+
**Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, A portion====
 +
*[[Methotrexate (MTX)]] as follows:
 +
**Cycles 1 & 4: 3000 mg/m<sup>2</sup> IV once on day 1
 +
*[[Ifosfamide (Ifex)]] as follows:
 +
**Cycle 1: 800 mg/m<sup>2</sup> IV once per day on days 2 to 5
 +
====Glucocorticoid therapy, A portion (cycles 1 & 4)====
 +
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO on days 2 to 5
 +
====CNS therapy, A portion (cycles 1 & 4)====
 
*[[Cytarabine liposomal (DepoCyt)]] 50 mg IT once on day 2
 
*[[Cytarabine liposomal (DepoCyt)]] 50 mg IT once on day 2
−
 
+
====Chemotherapy, B portion (cycles 2 & 5)====
−
====B cycles====
+
*[[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV once on day 1
−
*[[Methotrexate (MTX)]] 5000 mg/m2 IV once on day 1
+
*[[Cyclophosphamide (Cytoxan)]] 150 mg/m<sup>2</sup> IV once per day on days 2 to 6
−
*[[Dexamethasone (Decadron)]] 10 mg/m2/day PO on days 2 to 5
+
====Glucocorticoid therapy, B portion (cycles 2 & 5)====
 +
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO on days 2 to 5
 +
====CNS therapy, B portion (cycles 2 & 5)====
 
*[[Cytarabine liposomal (DepoCyt)]] 50 mg IT once on day 2
 
*[[Cytarabine liposomal (DepoCyt)]] 50 mg IT once on day 2
−
*[[Cyclophosphamide (Cytoxan)]] 150 mg/m2 IV once per day on days 2 to 6
+
====Glucocorticoid therapy, C portion (cycles 3 & 6)====
−
 
+
*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup>/day PO on days 3 to 7
−
====C cycles====
+
====Chemotherapy, C portion (cycles 3 & 6)====
−
*[[Dexamethasone (Decadron)]] 20 mg/m2/day PO on days 3 to 7
+
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV every 12 hours on days 1 & 2
−
*[[Cytarabine (Cytosar)]] 1000 mg/m2 IV q12h on days 1 & 2
 
 
*[[Vindesine (Eldisine)]] 5 mg IV once on day 1
 
*[[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)'''
−
'''21-day cycle x 6 cycles (A -> B -> C -> A -> B -> C)'''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e7">
−
''Treatment followed by [[CNS_lymphoma#Temozolomide_.28Temodar.29|temozolomide maintenance]].''
+
====Subsequent treatment====
−
 
+
*[[#Temozolomide_monotherapy|Temozolomide]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
# 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. 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. [http://www.haematologica.org/content/100/4/534.full link to original article] '''contains verified protocol [http://www.haematologica.org/content/haematol/suppl/2015/04/01/haematol.2014.108472.DC1/2014.108472.PULCZYNSKI_SUPPL.pdf in supplement]''' [http://www.ncbi.nlm.nih.gov/pubmed/25480497 PubMed]
+
# '''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. [https://doi.org/10.3324/haematol.2014.108472 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380727/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25480497/ PubMed] [https://clinicaltrials.gov/study/NCT01458730 NCT01458730]
−
 
 
 
==Nordic Regimen, younger patients {{#subobject:e571ce|Regimen=1}}==
 
==Nordic Regimen, younger patients {{#subobject:e571ce|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#toc|back to top]]
 
−
|}
 
−
 
 
 
===Regimen {{#subobject:2874b2|Variant=1}}===
 
===Regimen {{#subobject:2874b2|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|'''Study'''
+
!style="width: 33%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.haematologica.org/content/100/4/534.full Pulczynski et al. 2015]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380727/ Pulczynski et al. 2015 (NLGPCNSL)]
−
|<span
+
|2007-2010
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
''This regimen is meant for patients aged 18-65 years.''
+
====Eligibility criteria====
−
 
+
*Age: 18 to 65 years
−
====A cycles====
+
</div>
−
*[[Rituximab (Rituxan)]] 375 mg/m2 IV once on day 1 '''of the 1st A cycle only'''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Methotrexate (MTX)]] 5000 mg/m2 IV once on day 1
+
====Targeted therapy, A portion (cycles 1 & 4)====
−
*[[Ifosfamide (Ifex)]] 800 mg/m2 IV once per day on days 2 to 5
+
*[[Rituximab (Rituxan)]] as follows:
−
*[[Dexamethasone (Decadron)]] 10 mg/m2/day PO on days 2 to 5
+
**Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, A portion (cycles 1 & 4)====
 +
*[[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV once on day 1
 +
*[[Ifosfamide (Ifex)]] 800 mg/m<sup>2</sup> IV once per day on days 2 to 5
 +
====Glucocorticoid therapy, A portion (cycles 1 & 4)====
 +
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO on days 2 to 5
 +
====CNS therapy, A portion (cycles 1 & 4)====
 
*[[Cytarabine liposomal (DepoCyt)]] 50 mg IT once on day 2
 
*[[Cytarabine liposomal (DepoCyt)]] 50 mg IT once on day 2
−
 
+
====Chemotherapy, B portion (cycles 2 & 5)====
−
====B cycles====
+
*[[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV once on day 1
−
*[[Methotrexate (MTX)]] 5000 mg/m2 IV once on day 1
 
−
*[[Dexamethasone (Decadron)]] 10 mg/m2/day PO on days 2 to 5
 
 
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
 
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 200 mg/m<sup>2</sup> IV once per day on days 2 to 5
 +
====Glucocorticoid therapy, B portion (cycles 2 & 5)====
 +
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO on days 2 to 5
 +
====CNS therapy, B portion (cycles 2 & 5)====
 
*[[Cytarabine liposomal (DepoCyt)]] 50 mg IT once on day 2
 
*[[Cytarabine liposomal (DepoCyt)]] 50 mg IT once on day 2
−
*[[Cyclophosphamide (Cytoxan)]] 200 mg/m2 IV once per day on days 2 to 5
+
====Glucocorticoid therapy, C portion (cycles 3 & 6)====
−
 
+
*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup>/day PO on days 3 to 7
−
====C cycles====
+
====Chemotherapy, C portion (cycles 3 & 6)====
−
*[[Dexamethasone (Decadron)]] 20 mg/m2/day PO on days 3 to 7
+
*[[Cytarabine (Ara-C)]] 1500 mg/m<sup>2</sup> IV every 12 hours on days 1 & 2
−
*[[Cytarabine (Cytosar)]] 1500 mg/m2 IV q12h on days 1 & 2
 
 
*[[Vindesine (Eldisine)]] 5 mg IV once on day 1
 
*[[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)'''
 +
</div></div>
 +
===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. [https://doi.org/10.3324/haematol.2014.108472 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380727/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25480497/ PubMed] [https://clinicaltrials.gov/study/NCT01458730 NCT01458730]
  
−
'''21-day cycle x 6 cycles (A -> B -> C -> A -> B -> C)'''
+
==R-MCP (CCNU) {{#subobject:58966e|Regimen=1}}==
−
 
+
R-MCP: '''<u>R</u>'''ituximab, '''<u>M</u>'''ethotrexate, '''<u>C</u>'''CNU (Lomustine), '''<u>P</u>'''rocarbazine
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6b72ea|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdq712 Fritsch et al. 2011]
 +
|2005-2009
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
''Note: this regimen should not be confused with the other R-MCP (rituximab, mitoxantrone, cyclophosphamide, prednisone) used in indolent lymphomas.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV over 90 minutes once per day on days -6, 1, 15, 29
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2, 16, 30
 +
*[[Lomustine (CCNU)]] 110 mg/m<sup>2</sup> PO once on day 2
 +
*[[Procarbazine (Matulane)]] 60 mg/m<sup>2</sup> 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'''
 +
</div></div>
 +
===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. [https://doi.org/10.1093/annonc/mdq712 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21303800/ PubMed]
 +
==R-MP {{#subobject:58b4a9|Regimen=1}}==
 +
R-MP: '''<u>R</u>'''ituximab, '''<u>M</u>'''ethotrexate, '''<u>P</u>'''rocarbazine
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6ea131|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383936/ Fritsch et al. 2016 (PRIMAIN)]
 +
|2009-2013
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Rituximab (Rituxan)]] as follows:
 +
**Cycle 1: 375 mg/m<sup>2</sup> IV over 90 minutes once per day on days -6, 1, 15, 29
 +
**Cycles 2 & 3: 375 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1, 15, 29
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 3000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2, 16, 30
 +
*[[Procarbazine (Matulane)]] 60 mg/m<sup>2</sup> PO once per day on days 2 to 11
 +
'''42-day cycle for 3 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Procarbazine_monotherapy|Procarbazine]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
# 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. 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. [http://www.haematologica.org/content/100/4/534.full link to original article] '''contains verified protocol [http://www.haematologica.org/content/haematol/suppl/2015/04/01/haematol.2014.108472.DC1/2014.108472.PULCZYNSKI_SUPPL.pdf in supplement]''' [http://www.ncbi.nlm.nih.gov/pubmed/25480497 PubMed]
+
# '''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. [https://doi.org/10.1038/leu.2016.334 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383936/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27843136/ PubMed] [https://clinicaltrials.gov/study/NCT00989352 NCT00989352]
 +
#'''PRIMA-CNS:''' DRKS00024085
  
 
==R-MPV {{#subobject:5ca49d|Regimen=1}}==
 
==R-MPV {{#subobject:5ca49d|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
R-MPV: '''<u>R</u>'''ituximab, '''<u>M</u>'''ethotrexate, '''<u>P</u>'''rocarbazine, '''<u>V</u>'''incristine
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:ac140a|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.12.5062 Shah et al. 2007 (MSK 01-146)]
 +
|2002-2005
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342354/ Omuro et al. 2015 (MSK 04-129)]
 +
|2005-2011
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
R-MPV: '''<u>R</u>'''ituximab, '''<u>M</u>'''ethotrexate, '''<u>P</u>'''rocarbazine, '''<u>V</u>'''incristine
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Rituximab (Rituxan)]] 500 mg/m<sup>2</sup> IV over 5 hours once on day 1
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 3500 mg/m<sup>2</sup> IV over 2 hours once on day 2
 +
*[[Procarbazine (Matulane)]] as follows:
 +
**Odd cycles: 100 mg/m<sup>2</sup> PO once per day on days 1 to 7
 +
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*MSK 01-146: [[#Whole_brain_irradiation|whole-brain irradiation]] consolidation, in 3 to 5 weeks
 +
*MSK 04-129: [[#Bu.2FTT.2FCy.2C_then_auto_HSCT|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
 +
</div></div>
 +
===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. [https://doi.org/10.1200/jco.2007.12.5062 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17947720/ PubMed] [https://clinicaltrials.gov/study/NCT00594815 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. [https://doi.org/10.1200/jco.2013.50.4910 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24101038/ PubMed]
 +
# '''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. [https://doi.org/10.1182/blood-2014-10-604561 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342354/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25568347/ PubMed] [https://clinicaltrials.gov/study/NCT00596154 NCT00596154]
  
−
===Regimen {{#subobject:ac140a|Variant=1}}===
+
=Consolidation after upfront therapy=
−
{| border="1" style="text-align:center;" !align="left"  
+
==BCNU/TT, then auto HSCT {{#subobject:a7b7ae|Regimen=1}}==
−
|'''Study'''
+
BCNU/TT: '''<u>BCNU</u>''' (Carmustine), '''<u>T</u>'''hio'''<u>T</u>'''epa
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:81ede7|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/25/30/4730.long Shah et al. 2007]
+
|[https://doi.org/10.1200/jco.2006.06.2117 Illerhaus et al. 2006]
−
|<span
+
|1998-2003
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
−
!colspan="4" align="center"|
+
|}
 +
''Note that the day count starts from the very beginning of treatment.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Methotrexate-Cytarabine_.26_Thiotepa|High-dose methotrexate, then Ara-C & Thiotepa]] induction
 +
</div>
 +
{{#lst:Autologous HSCT|81ede7}}
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Whole_brain_irradiation|Whole-brain irradiation]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:769950|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/125/9/1403 Omuro et al. 2015]
+
|[https://doi.org/10.3324/haematol.11771 Illerhaus et al. 2008]
−
|<span
+
|2003-2006
−
style="background:#EEEE00;
+
|style="background-color:#ffffbe"|Pilot, fewer than 20 patients
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
*[[Rituximab (Rituxan)]] 500 mg/m2 IV once over 5 hours on day 1
+
<div class="toccolours" style="background-color:#cbd5e8">
−
*[[Methotrexate (MTX)]] 3500 mg/m2 IV once over 2 hours on day 2
+
====Preceding treatment====
−
*[[Procarbazine (Matulane)]] 100 mg/m2 PO once per day on days 1 to 7 of odd cycles
+
*[[#Methotrexate-Cytarabine_.26_Thiotepa|High-dose methotrexate, then Ara-C & Thiotepa]] induction
−
*[[Vincristine (Oncovin)]] 1.4 mg/m2 (capped at 2.8 mg) IV once on day 2
+
</div>
−
 
+
{{#lst:Autologous HSCT|769950}}
−
Intrathecal component (only described in the Shah et al. 2007 trial):
+
</div>
−
*[[Methotrexate (MTX)]] 12 mg IT (via Ommaya) once sometime between day 5 and 12 (for patients with positive CSF cytology)
 
−
 
 
−
Supportive medications:
 
−
*[[Folinic acid (Leucovorin)]] 20 to 25 mg every 6 hours for at least 72 hours or until serum MTX level < 1e-8 mg/dL, beginning 24 hours after IV [[Methotrexate (MTX)]] administration
 
−
 
 
−
'''14-day cycle x 5 to 7 cycles'''
 
−
 
 
−
''In Shah et al. 2007, followed in 3 to 5 weeks by [[CNS_lymphoma#Whole_brain_irradiation|whole-brain irradiation]]. In Omuro et al. 2015, patients proceeded to [[CNS_lymphoma#Autologous_stem_cell_transplant|autologous stem cell transplant]], after 5 cycles if CR achieved, or after 7 cycles for PR/CR at that time.''
 
−
 
 
 
===References===
 
===References===
−
# 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. [http://jco.ascopubs.org/content/25/30/4730.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17947720 PubMed]
+
<!-- Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005. -->
−
## '''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. [http://jco.ascopubs.org/content/31/31/3971.full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/24101038 PubMed]
+
# 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. [https://doi.org/10.1200/jco.2006.06.2117 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16864853/ PubMed]
−
# 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 Jan 7. [Epub ahead of print] [http://www.bloodjournal.org/content/125/9/1403 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25568347 PubMed]
+
## '''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. [https://doi.org/10.1093/annonc/mds059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22473593/ PubMed]
 +
# 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. [https://doi.org/10.3324/haematol.11771 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18166803/ PubMed]
 +
## '''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. [https://doi.org/10.1093/annonc/mds059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22473593/ PubMed]
 +
# '''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. [https://doi.org/10.1016/S2352-3026(16)00036-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27132696/ PubMed] [https://clinicaltrials.gov/study/NCT01011920 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. [https://doi.org/10.1016/S2352-3026(17)30174-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29054815/ PubMed]
  
−
=Consolidation and/or maintenance after upfront therapy=
+
==BEAM, then auto HSCT {{#subobject:c9216e|Regimen=1}}==
−
 
+
BEAM: '''<u>B</u>'''iCNU (Carmustine), '''<u>E</u>'''toposide, '''<u>A</u>'''ra-C (Cytarabine), '''<u>M</u>'''elphalan
−
==Autologous stem cell transplant {{#subobject:e04a91|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen variant #1 {{#subobject:bbc83f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1038/sj.bmt.1705452 Colombat et al. 2006]
 +
|1999-2001
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen #1 {{#subobject:df1bb4|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
{| border="1" style="text-align:center;" !align="left"  
+
====Preceding treatment====
−
|'''Study'''
+
*[[#MVBP|MVBP]] induction x 2
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div>
 +
{{#lst:Autologous HSCT|bbc83f}}
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Whole_brain_irradiation|Whole-brain irradiation]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:5bf047|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/125/9/1403 Omuro et al. 2015]
+
|[https://doi.org/10.1200/jco.2003.05.024 Abrey et al. 2003]
−
|<span
+
|NR
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Methotrexate-Cytarabine|Methotrexate, then Cytarabine]] induction
 +
</div>
 +
{{#lst:Autologous HSCT|16f7a3}}
 +
</div>
 +
===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. [https://doi.org/10.1200/jco.2003.05.024 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14615443/ PubMed]
 +
# 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. [https://doi.org/10.1038/sj.bmt.1705452 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16951691/ PubMed]
  
−
''Treatment preceded by [[CNS_lymphoma#R-MPV|R-MPV]].''
+
==Bu/TT, then auto HSCT {{#subobject:e04a91|Regimen=1}}==
−
 
+
Bu/TT: '''<u>Bu</u>'''sulfan, '''<u>T</u>'''hio'''<u>T</u>'''epa
−
*[[Thiotepa (Thioplex)]] 250 mg/m2 IV once per day on days −9, −8, and −7
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Busulfan (Myleran)]] 3.2 mg/kg IV once per day on days −6, −5, and −4
+
===Regimen {{#subobject:df1bb4|Variant=1}}===
−
*[[Cyclophosphamide (Cytoxan)]] 60 mg/kg IV once per day on days −3 and −2
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
 
+
!style="width: 33%"|Study
−
'''Stem cell re-infusion occurs on day 0'''
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdl458 Montemurro et al. 2007 (OSHO-53)]
 +
|1999-2004
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Methotrexate_monotherapy_2|High-dose methotrexate]] induction x 2
 +
</div>
 +
{{#lst:Autologous HSCT|df1bb4}}
 +
</div>
 +
===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. [https://doi.org/10.1093/annonc/mdl458 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17185743/ PubMed]
  
−
===Regimen #2 {{#subobject:81ede7|Variant=1}}===
+
==Bu/TT/Cy, then auto HSCT {{#subobject:e04a91|Regimen=1}}==
−
{| border="1" style="text-align:center;" !align="left"  
+
Bu/TT/Cy: '''<u>Bu</u>'''sulfan, '''<u>T</u>'''hio'''<u>T</u>'''epa, '''<u>Cy</u>'''clophosphamide
−
|'''Study'''
+
<br>TBC: '''<u>T</u>'''hiotepa, '''<u>B</u>'''usulfan, '''<u>C</u>'''yclophosphamide
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:df1bb4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/24/24/3865.full Illerhaus et al. 2006]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342354/ Omuro et al. 2015 (MSK 04-129)]
−
|<span
+
|2005-2011
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#R-MPV|R-MPV]] induction
 +
</div>
 +
{{#lst:Autologous HSCT|df1bb5}}
 +
</div>
 +
===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. [https://doi.org/10.1182/blood-2014-10-604561 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342354/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25568347/ PubMed] [https://clinicaltrials.gov/study/NCT00596154 NCT00596154]
  
−
''Treatment preceded by [[CNS_lymphoma#High-Dose_Methotrexate_-.3E_Cytarabine_.26_Thiotepa|HD-MTX -> Ara-C & Thiotepa]]. Note that the day count starts from the very beginning of treatment.''
+
==High-dose Cytarabine monotherapy (HiDAC) {{#subobject:25959d|Regimen=1}}==
−
 
+
HiDAC: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)
−
*[[Carmustine (BiCNU)]] 400 mg/m2 IV once on day 50
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Thiotepa (Thioplex)]] 5 mg/kg (route not specified) once per day on days 51 & 52
+
===Regimen {{#subobject:4d5aee|Variant=1}}===
−
 
+
{| class="wikitable" style="width: 60%; text-align:center;"  
−
Supportive medications:
+
!style="width: 33%"|Study
−
*[[:Category:Granulocyte_growth_factors|Granulocyte colony-stimulating factor]] starting on day 61, continued until WBC > 1x10^9/L for 3 days
+
!style="width: 33%"|Dates of enrollment
−
*"Standard supportive measures were taken according to institutional guidelines."
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
|-
−
'''Stem cells re-infused on day 56'''
+
|[https://doi.org/10.1200/JCO.2000.18.17.3144 Abrey et al. 2000]
−
 
+
|1992-1998
−
''Followed by [[CNS_lymphoma#Whole_brain_irradiation|whole-brain irradiation]].''
+
|style="background-color:#91cf61"|Non-randomized
−
 
 
−
===Regimen #3 {{#subobject:769950|Variant=1}}===
 
−
{| border="1" style="text-align:center;" !align="left"  
 
−
|'''Study'''
 
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
 
 
|-
 
|-
−
|[http://www.haematologica.org/content/93/1/147.long Illerhaus et al. 2008]
+
|[https://doi.org/10.1200/jco.2002.11.013 DeAngelis et al. 2002 (RTOG 93-10)]
−
|<span
+
|1993-NR
−
style="background:#ff0000;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Pilot, <20 patients</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Time interval of cycles is not explicitly described and is derived from Table 1 in DeAngelis et al. 2002.''
−
''Treatment preceded by [[CNS_lymphoma#High-Dose_Methotrexate_-.3E_Cytarabine_.26_Thiotepa|HD-MTX -> Ara-C & Thiotepa]].''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
*[[Carmustine (BiCNU)]] 400 mg/m2 IV once on day 1
+
*Definitive [[#Whole_brain_irradiation|Whole-brain irradiation]] x 4500 cGy
−
*[[Thiotepa (Thioplex)]] 5 mg/kg (route not specified) BID on days 2 & 3
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
'''Stem cells re-infused on day 7'''
+
====Chemotherapy====
−
 
+
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 & 2
 +
'''21-day cycle for 2 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
<!-- Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005. -->
+
# Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000 Sep;18(17):3144-50. [https://doi.org/10.1200/JCO.2000.18.17.3144 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10963643/ PubMed]
−
# 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. [http://jco.ascopubs.org/content/24/24/3865.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16864853 PubMed]
+
## '''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. [https://doi.org/10.1200/JCO.2006.06.6910 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17008697/ PubMed]
−
# 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. [http://www.haematologica.org/content/93/1/147.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18166803 PubMed]
+
# '''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. [https://doi.org/10.1200/jco.2002.11.013 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12488408/ PubMed]
−
# 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 Jan 7. [Epub ahead of print] [http://www.bloodjournal.org/content/125/9/1403 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25568347 PubMed]
+
==Cytarabine & Etoposide (CYVE) {{#subobject:b2c919|Regimen=1}}==
−
 
+
CYVE: '''<u>CY</u>'''tarabine & '''<u>VE</u>'''pesid (Etoposide)
−
==MTX, Lomustine, Procarbazine {{#subobject:7f4fbe|Regimen=1}}==
+
<br>EA: '''<u>E</u>'''toposide & '''<u>A</u>'''ra-C (Cytarabine)
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:4df5e6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753699/ Rubenstein et al. 2013 (CALGB 50202)]
 +
|2004-2009
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#MT-R|MT-R]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m<sup>2</sup>)
 +
*[[Etoposide (Vepesid)]] 10 mg/kg/day IV continuous infusion over 96 hours, started on day 1 (total dose: 40 mg/kg)
 +
'''4-day course'''
 +
</div></div>
 +
===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. [https://doi.org/10.1200/jco.2012.46.9957 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753699/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23569323/ PubMed] [https://clinicaltrials.gov/study/NCT00098774 NCT00098774]
 +
==Lomustine, Methotrexate, Procarbazine {{#subobject:7f4fbe|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:156623|Variant=1}}===
 
===Regimen {{#subobject:156623|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
|'''Study'''
+
!style="width: 33%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/21/14/2726.long Hoang-Xuan et al. 2003 (EORTC 26952)]
+
|[https://doi.org/10.1200/jco.2003.11.036 Hoang-Xuan et al. 2003 (EORTC 26952)]
−
|<span
+
|1997-1999
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
''Treatment was preceded by [[#MTX.2C_Lomustine.2C_Procarbazine.2C_Methylprednisolone|MTX, lomustine, procarbazine, methylprednisolone induction]].''
+
====Preceding treatment====
−
 
+
*[[#Lomustine.2C_Methotrexate.2C_Procarbazine.2C_Methylprednisolone.2C|Lomustine, Methotrexate, Procarbazine, Methylprednisolone]] induction
−
*[[Methotrexate (MTX)]] 1000 mg/m2 IV once on day 1
+
</div>
−
*[[Lomustine (Ceenu)]] 40 mg/m2 PO once on day 1
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Procarbazine (Matulane)]] 60 mg/m2 PO once per day on days 1 to 7
+
====Chemotherapy====
−
 
+
*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV once on day 1
−
Intrathecal component:
+
*[[Lomustine (CCNU)]] 40 mg/m<sup>2</sup> PO once on day 1
−
*[[Methotrexate (MTX)]] 15 mg IT (admixed with [[Cytarabine (Cytosar)]]) once on day 1
+
*[[Procarbazine (Matulane)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 7
−
*[[Cytarabine (Cytosar)]] 40 mg IT (admixed with [[Methotrexate (MTX)]]) once on day 1
+
====CNS therapy====
−
 
+
*[[Methotrexate (MTX)]] 15 mg IT (admixed with cytarabine) once on day 1
−
Supportive medications:
+
*[[Cytarabine (Ara-C)]] 40 mg IT (admixed with methotrexate) once on day 1
−
*[[Folinic acid (Leucovorin)]] 25 mg PO every 6 hours for 3 days, initiated 24 hours after IV [[Methotrexate (MTX)]] administration
+
====Supportive therapy====
−
 
+
*[[Leucovorin (Folinic acid)]] 25 mg PO every 6 hours for 3 days, initiated 24 hours after IV methotrexate administration
−
'''6-week cycle x 5 cycles'''
+
'''42-day cycle for 5 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B; European Organization for Research and Treatment of Cancer Brain Tumor Group. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003 Jul 15;21(14):2726-31. [http://jco.ascopubs.org/content/21/14/2726.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12860951 PubMed]
+
# Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B; [[Study_Groups#EORTC|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. [https://doi.org/10.1200/jco.2003.11.036 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12860951/ PubMed]
−
 
+
==Methotrexate monotherapy {{#subobject:66ffbb|Regimen=1}}==
−
==Observation {{#subobject:8030ff|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen variant #1 {{#subobject:f64ee1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940660/ Chamberlain et al. 2010]
 +
|2000-2007
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
''Note: the bounds as described in the paper do not account for the situation where CrCl = 60 mL/min/1.73m<sup>2</sup>.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Methotrexate_.26_Rituximab|High-dose methotrexate & Rituximab]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] by the following renal function-based criteria:
 +
**CrCl more than 60 mL/min/1.73m<sup>2</sup>: 8000 mg/m<sup>2</sup> IV over 6 hours once on day 1
 +
**CrCl less than 60 mL/min/1.73m<sup>2</sup>: 4000 mg/m<sup>2</sup> IV over 6 hours once on day 1
 +
'''28-day cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:c0f639|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2003.03.036 Batchelor et al. 2003 (NABTT 96-07)]
 +
|1998-1999
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen {{#subobject:bb069d|Variant=1}}===
+
====Preceding treatment====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[#Methotrexate_monotherapy_2|High-dose methotrexate]] induction
−
|'''Study'''
+
</div>
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#b3e2cd">
−
|'''Comparator'''
+
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] by the following renal function-based criteria:
 +
**CrCl 100 mL/min/1.73m<sup>2</sup> or more: 8000 mg/m<sup>2</sup> IV over 4 hours once on day 1
 +
**CrCl less than 100 mL/min/1.73m<sup>2</sup>: The dose was reduced by the percentage reduction below 100. For example, a CrCl of 50 mL/min/1.73m<sup>2</sup> would mandate a 50% dose reduction to 4000 mg/m<sup>2</sup>.
 +
'''28-day cycle for 11 cycles'''
 +
</div></div>
 +
===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. [https://doi.org/10.1200/jco.2003.03.036 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12637469/ PubMed]
 +
# 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. [https://doi.org/10.1093/neuonc/noq011 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940660/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20511181/ PubMed]
 +
==Procarbazine monotherapy {{#subobject:37e11d|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:13bae4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.sciencedirect.com/science/article/pii/S1470204510702291 Thiel et al. 2010 (G-PCNSL-SG-1)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383936/ Fritsch et al. 2016 (PRIMAIN)]
−
|<span
+
|2009-2013
−
style="background:#00CD00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[CNS_lymphoma#Whole_brain_irradiation|Whole-brain irradiation]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
''Treatment preceded by [[CNS_lymphoma#High-Dose_Methotrexate|high-dose MTX x 6]] before 2006 or [[CNS_lymphoma#High-Dose_Methotrexate_.26_Ifosfamide|high-dose methotrexate & ifosfamide x 6]] after 2006.''
+
====Preceding treatment====
−
 
+
*Induction [[#R-MP|R-MP]] x 3
−
'''No further treatment'''
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Procarbazine (Matulane)]] 100 mg PO once per day on days 1 to 5
 +
'''28-day cycle for 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# 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. [http://www.sciencedirect.com/science/article/pii/S1470204510702291 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20970380 PubMed]
+
# '''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. [https://doi.org/10.1038/leu.2016.334 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383936/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27843136/ PubMed] [https://clinicaltrials.gov/study/NCT00989352 NCT00989352]
−
## '''Update: Abstract:''' Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) [http://meetinglibrary.asco.org/content/129168-144 link to abstract]
+
==Temozolomide monotherapy {{#subobject:5c7608|Regimen=1}}==
−
## '''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. [http://www.neurology.org/content/84/12/1242.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25716362 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #1 {{#subobject:5cf6d6|Variant=1}}===
−
==Temozolomide (Temodar) {{#subobject:5c7608|Regimen=1}}==
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872318/ Glass et al. 2016 (RTOG 0227)]
 +
|NR
 +
|style="background-color:#91cf61"|Phase 1/2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen {{#subobject:084bc7|Variant=1}}===
+
====Preceding treatment====
−
{| border="1" style="text-align:center;" !align="left"  
+
*[[#Whole_brain_irradiation|WB-XRT]] consolidation
−
|'''Study'''
+
</div>
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Temozolomide (Temodar)]] as follows:
 +
**Week 14: 200 mg/m<sup>2</sup> PO once per day for 5 days (150 mg/m<sup>2</sup> allowed)
 +
**Weeks 18, 22, 26, 30, 34, 38, 42, 46, 50: 200 mg/m<sup>2</sup> PO once per day for 5 days
 +
'''50-week course'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:084bc7|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.haematologica.org/content/100/4/534.full Pulczynski et al. 2015]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380727/ Pulczynski et al. 2015 (NLGPCNSL)]
−
|<span
+
|2007-2010
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
''Treatment preceded by the [[CNS_lymphoma#Nordic_Regimen.2C_older_patients|Nordic Regimen for older patients]].''
+
====Preceding treatment====
−
 
+
*[[#Nordic_Regimen.2C_older_patients|Nordic Regimen for older patients]] induction
−
*[[Temozolomide (Temodar)]] 150 mg/m2/day PO on days 1 to 5
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
'''28-day cycles for one year or until relapse/progression'''
+
====Chemotherapy====
−
 
+
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup>/day PO on days 1 to 5
 +
'''28-day cycle for up to 13 cycles (1 year)'''
 +
</div></div>
 
===References===
 
===References===
−
# 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. 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. [http://www.haematologica.org/content/100/4/534.full link to original article] '''contains verified protocol [http://www.haematologica.org/content/haematol/suppl/2015/04/01/haematol.2014.108472.DC1/2014.108472.PULCZYNSKI_SUPPL.pdf in supplement]''' [http://www.ncbi.nlm.nih.gov/pubmed/25480497 PubMed]
+
# '''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. [https://doi.org/10.3324/haematol.2014.108472 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380727/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25480497/ PubMed] [https://clinicaltrials.gov/study/NCT01458730 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. [https://doi.org/10.1200/jco.2015.64.8634 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872318/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27022122/ PubMed] [https://clinicaltrials.gov/study/NCT00068250 NCT00068250]
 
==Whole brain irradiation {{#subobject:6115dc|Regimen=1}}==
 
==Whole brain irradiation {{#subobject:6115dc|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
WBRT: '''<u>W</u>'''hole-'''<u>B</u>'''rain '''<u>R</u>'''adiation '''<u>T</u>'''herapy
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 2340 cGy {{#subobject:a6ae7a|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.12.5062 Shah et al. 2007 (MSK 01-146)]
 +
|2002-2005
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Induction [[#R-MPV|R-MPV]] x 5 to 7 cycles, with complete response
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 2340 cGy in 1.8000 cGy fractions
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 3000 cGy {{#subobject:8ca014|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1038/sj.bmt.1705452 Colombat et al. 2006]
 +
|1999-2001
 +
|style="background-color:#91cf61"|Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076938/ Mishima et al. 2023 (JCOG1114C)]
 +
|2014-09-20 to 2018-08-24
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Temozolomide_.26_RT_999|Temozolomide & WBRT]]
 +
| style="background-color:#d9ef8b" |Might have superior OS<br>OS24: 86.8% vs 71.4%<br>(HR 0.46, 95% CI 0.20-1.05)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen #1 {{#subobject:1475db|Variant=1}}===
+
====Preceding treatment====
−
{| border="1" style="text-align:center;" !align="left"  
+
*Colombat et al. 2006: [[#BEAM.2C_then_auto_HSCT|BEAM, then autologous hematopoietic stem cell transplant]] consolidation, with complete response
−
|'''Study'''
+
*JCOG1114C: [[#Methotrexate_monotherapy_2|HD-MTX]] induction
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
</div>
−
|'''Comparator'''
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 3000 cGy in 1.8000 cGy fractions
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 3000 cGy + 1000 cGy boost {{#subobject:b8264a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1038/sj.bmt.1705452 Colombat et al. 2006]
 +
|1999-2001
 +
|style="background-color:#91cf61"|Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076938/ Mishima et al. 2023 (JCOG1114C)]
 +
|2014-09-20 to 2018-08-24
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Temozolomide_.26_RT_999|Temozolomide & WBRT]]
 +
| style="background-color:#d9ef8b" |Might have superior OS<br>OS24: 86.8% vs 71.4%<br>(HR 0.46, 95% CI 0.20-1.05)
 +
|-
 +
|}
 +
''Note: boost was optional in JCOG1114C.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Colombat et al. 2006: [[#BEAM.2C_then_auto_HSCT|BEAM, then autologous hematopoietic stem cell transplant]] consolidation, with partial response
 +
*JCOG1114C: [[#Methotrexate_monotherapy_2|HD-MTX]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 3000 cGy in 1.8000 cGy fractions plus 1000 cGy boost to the tumor bed
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 3600 cGy {{#subobject:d477fd|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872318/ Glass et al. 2016 (RTOG 0227)]
 +
|NR
 +
|style="background-color:#91cf61"|Phase 1/2
 +
|style="background-color:#d3d3d3"|
 +
|style="background-color:#d3d3d3"|
 +
|-
 +
|[https://doi.org/10.1016/S2352-3026(16)00036-3 Ferreri et al. 2016 (IELSG32)]
 +
|2010-2014
 +
|style="background-color:#1a9851"|Randomized Phase 2 (C)
 +
|[[#BCNU.2FTT.2C_then_auto_HSCT|BCNU/TT, then auto HSCT]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS24<sup>1</sup>
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for IELSG32 is based on the 2017 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*RTOG 0227: [[#MT-R|MT-R]] induction
 +
*IELSG32: [[#Cytarabine_.26_Methotrexate_.28CYM.29|CYM]] versus [[#Cytarabine.2C_Methotrexate.2C_Rituximab|Cytarabine, MTX, Rituximab]] versus [[#MATRix|MATRix]] induction, with complete response
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_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: 1.8000 cGy fractions
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*RTOG 0227: [[#Temozolomide_monotherapy|Temozolomide]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 3600 cGy + 900 cGy boost {{#subobject:d377ed|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S0140-6736(09)61416-1 Ferreri et al. 2009 (IELSG20)]
 +
|2004-2007
 +
|style="background-color:#91cf61"|Non-randomized part of phase 2 RCT
 +
|style="background-color:#d3d3d3"|
 +
|style="background-color:#d3d3d3"|
 
|-
 
|-
−
|[http://www.sciencedirect.com/science/article/pii/S1470204510702291 Thiel et al. 2010 (G-PCNSL-SG-1)]
+
|[https://doi.org/10.1016/S2352-3026(16)00036-3 Ferreri et al. 2016 (IELSG32)]
−
|<span
+
|2010-2014
−
style="background:#00CD00;
+
|style="background-color:#1a9851"|Randomized Phase 2 (C)
−
padding:3px 6px 3px 6px;
+
|[[#BCNU.2FTT.2C_then_auto_HSCT|BCNU/TT, then auto HSCT]]
−
border-color:black;
+
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS24<sup>1</sup>
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
|[[CNS_lymphoma#Observation|No further treatment]]
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''<sup>1</sup>Reported efficacy for IELSG32 is based on the 2017 update.''
−
''Treatment preceded by [[CNS_lymphoma#High-Dose_Methotrexate|high-dose MTX x 6]] before 2006 or [[CNS_lymphoma#High-Dose_Methotrexate_.26_Ifosfamide|high-dose methotrexate & ifosfamide x 6]] after 2006.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
To be completed
+
*IELSG20: Induction [[#Methotrexate_monotherapy_2|High-dose methotrexate]] x 4 versus [[#Cytarabine_.26_Methotrexate_.28CYM.29|High-dose CYM]] x 4, with any response
−
 
+
*IELSG32: Induction [[#Cytarabine_.26_Methotrexate_.28CYM.29|CYM]] versus [[#Cytarabine.2C_Methotrexate.2C_Rituximab|Cytarabine, MTX, Rituximab]] versus [[#MATRix|MATRix]] induction, with partial response
−
===Regimen #2 {{#subobject:d377ed|Variant=1}}===
+
</div>
−
{| border="1" style="text-align:center;" !align="left"  
+
<div class="toccolours" style="background-color:#b3e2cd">
−
|'''Study'''
+
====Radiotherapy====
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 3600 cGy in 1.8000 cGy fractions plus 900 cGy boost to the tumor bed
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #6, 4000 cGy + 900 cGy boost {{#subobject:d662c5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.sciencedirect.com/science/article/pii/S0140673609614161 Ferreri et al. 2009]
+
|[https://doi.org/10.1016/S0140-6736(09)61416-1 Ferreri et al. 2009 (IELSG20)]
−
|<span
+
|2004-2007
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Non-randomized part of phase 2 RCT
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Nonrandomized</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
''Treatment preceded by [[CNS_lymphoma#High-Dose_Methotrexate|high-dose MTX x 4]] versus [[CNS_lymphoma#High-Dose_Methotrexate_.26_Cytarabine|high-dose MTX & cytarabine x4]].''
+
====Preceding treatment====
−
 
+
*Induction [[#Methotrexate_monotherapy_2|High-dose methotrexate]] x 4 versus [[#Cytarabine_.26_Methotrexate_.28CYM.29|High-dose CYM]] x 4, with stable or progressive disease
−
*Any responders: Whole-brain irradiation to 36 Gy plus 9 Gy boost to the tumor bed
+
</div>
−
*Stable or progressive disease: Whole-brain irradiation to 40 Gy plus 9 Gy boost to the tumor bed
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Radiotherapy====
−
===Regimen #3 {{#subobject:a6ae7a|Variant=1}}===
+
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 4000 cGy in 1.8000 cGy fractions plus 900 cGy boost to the tumor bed
−
{| border="1" style="text-align:center;" !align="left"  
+
</div></div><br>
−
|'''Study'''
+
<div class="toccolours" style="background-color:#eeeeee">
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
===Regimen variant #7, 4500 cGy {{#subobject:1475db|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2000.18.17.3144 Abrey et al. 2000]
 +
|1992-1998
 +
|style="background-color:#91cf61"|Non-randomized
 +
|style="background-color:#d3d3d3"|
 +
|style="background-color:#d3d3d3"|
 +
|-
 +
|[https://doi.org/10.1200/jco.2002.11.013 DeAngelis et al. 2002 (RTOG 93-10)]
 +
|1993-NR
 +
|style="background-color:#91cf61"|Phase 2
 +
|style="background-color:#d3d3d3"|
 +
|style="background-color:#d3d3d3"|
 +
|-
 +
|[https://doi.org/10.1200/jco.2006.06.2117 Illerhaus et al. 2006]
 +
|1998-2003
 +
|style="background-color:#91cf61"|Phase 2
 +
|style="background-color:#d3d3d3"|
 +
|style="background-color:#d3d3d3"|
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(10)70229-1 Thiel et al. 2010 (G-PCNSL-SG-1)]
 +
|2000-2009
 +
|style="background-color:#1a9851"|Phase 3 (E-esc)
 +
|[[CNS_lymphoma_-_null_regimens#Observation|No further treatment]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior OS (primary endpoint)
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/25/30/4730.long Shah et al. 2007]
+
|[https://doi.org/10.1200/jco.2007.12.5062 Shah et al. 2007 (MSK 01-146)]
−
|<span
+
|2002-2005
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
+
|style="background-color:#d3d3d3"|
−
border-color:black;
+
|style="background-color:#d3d3d3"|
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note that the day count in Illerhaus et al. 2006 starts from the very beginning of treatment.''
−
''Treatment preceded by [[CNS_lymphoma#R-MPV|R-MPV x 5 to 7 cycles]].''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
*Complete responders: Whole-brain irradiation to 23.4 Gy in 1.80-Gy fractions
+
*Abrey et al. 2000 & RTOG 93-10: Induction [[#MPV|MPV]] x 5
−
*All others: Whole-brain irradiation to 45 Gy in 1.80-Gy fractions
+
*Illerhaus et al. 2006: [[#BCNU.2FTT.2C_then_auto_HSCT|BCNU/TT, then autologous hematopoietic stem cell transplant]] consolidation, with complete response
−
 
+
*MSK 01-146: Induction [[#R-MPV|R-MPV]] x 5 to 7 cycles, without complete response
−
===Regimen #4 {{#subobject:b0e47a|Variant=1}}===
+
*G-PCNSL-SG-1, before 2006: Induction [[#Methotrexate_monotherapy_2|High-dose methotrexate]] x 6
−
{| border="1" style="text-align:center;" !align="left"  
+
*G-PCNSL-SG-1, after 2006: Induction [[#Ifosfamide_.26_Methotrexate|High-dose methotrexate & ifosfamide]] x 6
−
|'''Study'''
+
</div>
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_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: 1.8000 cGy fractions
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Abrey et al. 2000 & RTOG 93-10: [[#High-dose_Cytarabine_monotherapy_.28HiDAC.29_2|HiDAC]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #8, 5000 cGy {{#subobject:b0e47a|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/24/24/3865.full Illerhaus et al. 2006]
+
|[https://doi.org/10.1200/jco.2006.06.2117 Illerhaus et al. 2006]
−
|<span
+
|1998-2003
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Phase 2
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
''Note that the day count starts from the very beginning of treatment.''
−
''Treatment preceded by [[CNS_lymphoma#Autologous_stem_cell_transplant|autologous stem cell transplant]]. Note that the day count starts from the very beginning of treatment.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
*Complete responders: Whole-brain irradiation to 45 Gy in 1-Gy fractions, starting on day 90
+
*[[#BCNU.2FTT.2C_then_auto_HSCT|BCNU/TT, then autologous hematopoietic stem cell transplant]] consolidation, with partial response
−
*Partial responders: Whole-brain irradiation to 50 Gy in 1-Gy fractions, starting on day 90
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 5000 cGy in 100 cGy fractions, starting on day 90
 +
</div></div>
 
===References===
 
===References===
 +
# Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000 Sep;18(17):3144-50. [https://doi.org/10.1200/JCO.2000.18.17.3144 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10963643/ PubMed]
 +
## '''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. [https://doi.org/10.1200/JCO.2006.06.6910 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17008697/ PubMed]
 +
# '''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. [https://doi.org/10.1200/jco.2002.11.013 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12488408/ PubMed]
 
<!-- Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005. -->
 
<!-- Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005. -->
−
# 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. [http://jco.ascopubs.org/content/24/24/3865.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16864853 PubMed]
+
# 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. [https://doi.org/10.1200/jco.2006.06.2117 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16864853/ PubMed]
−
# 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. [http://jco.ascopubs.org/content/25/30/4730.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17947720 PubMed]
+
## '''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. [https://doi.org/10.1093/annonc/mds059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22473593/ PubMed]
−
## '''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. [http://jco.ascopubs.org/content/31/31/3971.full link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/24101038 PubMed]
+
# 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. [https://doi.org/10.1038/sj.bmt.1705452 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16951691/ PubMed]
−
# Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F; International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18. [http://www.sciencedirect.com/science/article/pii/S0140673609614161 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19767089 PubMed]
+
# 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. [https://doi.org/10.1200/jco.2007.12.5062 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17947720/ PubMed] [https://clinicaltrials.gov/study/NCT00594815 NCT00594815]
−
# 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. [http://www.sciencedirect.com/science/article/pii/S1470204510702291 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20970380 PubMed]
+
## '''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. [https://doi.org/10.1200/jco.2013.50.4910 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24101038/ PubMed]
−
## '''Update: Abstract:''' Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) [http://meetinglibrary.asco.org/content/129168-144 link to abstract]
+
# '''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. [https://doi.org/10.1016/S0140-6736(09)61416-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19767089/ PubMed] [https://clinicaltrials.gov/study/NCT00210314 NCT00210314]
−
## '''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. [http://www.neurology.org/content/84/12/1242.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/25716362 PubMed]
+
# '''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. [https://doi.org/10.1016/S1470-2045(10)70229-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20970380/ PubMed] [https://clinicaltrials.gov/study/NCT00153530 NCT00153530]
 +
<!-- ## '''Update: Abstract:''' Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) [https://doi.org/10.1200/jco.2014.32.15_suppl.8527 link to abstract] -->
 +
## '''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. [https://doi.org/10.1212/wnl.0000000000001395 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25716362/ PubMed]
 +
# '''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. [https://doi.org/10.1200/jco.2015.64.8634 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872318/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27022122/ PubMed] [https://clinicaltrials.gov/study/NCT00068250 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. [https://doi.org/10.1016/S2352-3026(16)00036-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27132696/ PubMed] [https://clinicaltrials.gov/study/NCT01011920 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. [https://doi.org/10.1016/S2352-3026(17)30174-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29054815/ PubMed]
 +
#'''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. [https://doi.org/10.1093/neuonc/noac246 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076938/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/36334050/ PubMed] jRCTs031180207
  
−
=Relapsed/refractory=
+
=Relapsed or refractory, salvage therapy=
−
 
+
==High-dose Cytarabine monotherapy (HiDAC) {{#subobject:c36841|Regimen=1}}==
−
==High-dose Methotrexate & Ifosfamide {{#subobject:683c6d|Regimen=1}}==
+
HiDAC: '''<u>Hi</u>'''gh '''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine)
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:9c7334|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(10)70229-1 Thiel et al. 2010 (G-PCNSL-SG-1)]
 +
|2000-2009
 +
|style="background-color:#91cf61"|Non-randomized part of phase 3 RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*G-PCNSL-SG-1, before 2006: Non-response to [[#Methotrexate_monotherapy_2|High-dose methotrexate]] induction
 +
*G-PCNSL-SG-1, after 2006: Non-response to [[#Ifosfamide_.26_Methotrexate|Methotrexate & Ifosfamide]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1 & 2
 +
'''21-day cycle for 4 cycles'''
 +
</div></div>
 +
===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. [https://doi.org/10.1016/S1470-2045(10)70229-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20970380/ PubMed] [https://clinicaltrials.gov/study/NCT00153530 NCT00153530]
 +
<!-- ## '''Update: Abstract:''' Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) [https://doi.org/10.1200/jco.2014.32.15_suppl.8527 link to abstract] -->
 +
## '''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. [https://doi.org/10.1212/wnl.0000000000001395 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25716362/ PubMed]
 +
==Cytarabine & Etoposide (CYVE) {{#subobject:a2d919|Regimen=1}}==
 +
CYVE: '''<u>CY</u>'''tarabine, '''<u>VE</u>'''pesid (Etoposide)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:b4b13a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2001.19.3.742 Soussain et al. 2001]
 +
|1992-1995
 +
|style="background-color:#91cf61"|Pilot, >20 pts
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.13.5533 Soussain et al. 2008]
 +
|2000-2005
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 3 hours once per day on days 2 to 5
 +
*[[Cytarabine (Ara-C)]] 50 mg/m<sup>2</sup> IV over 12 hours once per day on days 1 to 5
 +
*[[Etoposide (Vepesid)]] 200 mg/m<sup>2</sup> IV over 2 hours once per day on days 2 to 5
 +
'''2 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Soussain et al. 2008, responders: [[#Bu.2FTT.2FCy.2C_then_auto_HSCT_2|Bu/TT/Cy, then autologous hematopoietic stem cell transplant]] consolidation
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:921bc8|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1038/sj.bmt.1705452 Colombat et al. 2006]
 +
|1999-2001
 +
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Non-response to [[#MVBP|MVBP]] induction x 2
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV every 12 hours on days 1 & 2
 +
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 & 2
 +
'''2 cycles (length not specified)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Whole_brain_irradiation_2|Whole-brain irradiation]] consolidation
 +
</div></div>
 +
===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. [https://doi.org/10.1200/jco.2001.19.3.742 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11157026/ PubMed]
 +
# 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. [https://doi.org/10.1038/sj.bmt.1705452 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16951691/ PubMed]
 +
# 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. [https://doi.org/10.1200/jco.2007.13.5533 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18413641/ PubMed]
 +
==Ifosfamide & Methotrexate {{#subobject:683c6d|Regimen=1}}==
 +
*[[Example orders for High-dose Methotrexate (MTX) & Ifosfamide in lymphoma]]
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:1c70bc|Variant=1}}===
 
===Regimen {{#subobject:1c70bc|Variant=1}}===
−
{| border="1" style="text-align:center;" !align="left"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
|'''Study'''
+
!style="width: 25%"|Study
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.springerlink.com/content/550r5617ll610848/ Fischer et al. 2008]
+
|[https://doi.org/10.1007/s00277-008-0575-8 Fischer et al. 2008]
−
|<span
+
|style="background-color:#ffffbe"|Retrospective
−
style="background:#ff0000;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Retrospective</span>
 
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Methotrexate (MTX)]] 4000 mg/m2 IV over 4 hours once on day 1
+
====Chemotherapy====
−
*[[Ifosfamide (Ifex)]] 1500 to 2000 mg/m2 IV over 3 hours once per day on days 3 to 5
+
*[[Ifosfamide (Ifex)]] 1500 to 2000 mg/m<sup>2</sup> IV over 3 hours once per day on days 3 to 5
−
 
+
*[[Methotrexate (MTX)]] 4000 mg/m<sup>2</sup> IV over 4 hours once on day 1
−
Supportive medications:
+
====Supportive therapy====
 
*[[Mesna (Mesnex)]] for prophylaxis of hemorrhagic cystitis
 
*[[Mesna (Mesnex)]] for prophylaxis of hemorrhagic cystitis
−
*[[Folinic acid (Leucovorin)]] rescue starting 24 hours after start of [[Methotrexate (MTX)]] infusion
+
*[[Leucovorin (Folinic acid)]] rescue starting 24 hours after start of methotrexate infusion
−
*Sodium bicarbonate via IV fluid or PO routes used for urine alkalinization to maintain urine pH of at least 8
+
*[[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.
 
**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)
−
[[Methotrexate (MTX)]] dose adjusted for creatinine clearances <100 mL/min according to the following formula:
+
</div>
−
*Dose of methotrexate = (creatinine clearance/100) x 4000 mg/m2; the paper did not specify what method was used for calculating creatinine clearance. Patients with creatinine clearance <50 mL/min were excluded from the study.
+
<div class="toccolours" style="background-color:#fff2ae">
−
 
+
====Dose and schedule modifications====
−
'''up to 8 cycles''' (reference did not list timing/criteria to be used for next cycle of therapy)
+
*[[Methotrexate (MTX)]] dose adjusted for CrCl less than 100 mL/min/1.73m<sup>2</sup> according to the following formula:
−
 
+
*Dose of methotrexate = (CrCl/100) x 4000 mg/m<sup>2</sup>; the paper did not specify what method was used for calculating CrCl. Patients with CrCl less than 50 mL/min/1.73m<sup>2</sup> were excluded from the study.
−
*[[Example orders for High-dose Methotrexate (MTX) & Ifosfamide in lymphoma]]
+
</div></div>
−
 
 
 
===References===
 
===References===
−
# 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. [http://www.springerlink.com/content/550r5617ll610848/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18679681 PubMed]
+
# '''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. [https://doi.org/10.1007/s00277-008-0575-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18679681/ PubMed]
  
 
==Whole brain irradiation {{#subobject:49c1e3|Regimen=1}}==
 
==Whole brain irradiation {{#subobject:49c1e3|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 3000 cGy {{#subobject:d82ebe|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1038/sj.bmt.1705452 Colombat et al. 2006]
 +
|1999-2001
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Cytarabine_.26_Etoposide_.28CYVE.29_2|CYVE]] salvage
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 3000 cGy in 180 cGy fractions plus 1000 cGy boost to the tumor bed
 +
'''One course'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 3600 cGy {{#subobject:a2619f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.01.161 Nguyen et al. 2005]
 +
|1994-2003
 +
|style="background-color:#91cf61"|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.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]]: median dose 3600 cGy (range 28 to 4500 cGy)
 +
'''One course'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 3600 cGy + 1000 cGy boost {{#subobject:a2619f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.01.161 Nguyen et al. 2005]
 +
|1994-2003
 +
|style="background-color:#91cf61"|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.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]]: median dose 3600 cGy (range 19.6 to 4000 cGy) + 1000 cGy (range 10 to 2160 cGy)
 +
'''One course'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 4500 cGy {{#subobject:1475db|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(10)70229-1 Thiel et al. 2010 (G-PCNSL-SG-1)]
 +
|2000-2009
 +
|style="background-color:#91cf61"|Non-randomized part of phase 3 RCT
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*G-PCNSL-SG-1, before 2006: Non-response to [[#Methotrexate_monotherapy_2|high-dose MTX]] induction x 6
 +
*G-PCNSL-SG-1, after 2006: Non-response to [[#Ifosfamide_.26_Methotrexate|High-dose methotrexate & ifosfamide]] induction x 6
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] to 4500 cGy in 150 cGy fractions
 +
'''One course'''
 +
</div></div>
 +
===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. [https://doi.org/10.1200/jco.2005.01.161 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15735126/ PubMed]
 +
# 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. [https://doi.org/10.1038/sj.bmt.1705452 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16951691/ PubMed]
 +
# '''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. [https://doi.org/10.1016/S1470-2045(10)70229-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20970380/ PubMed] [https://clinicaltrials.gov/study/NCT00153530 NCT00153530]
 +
<!-- ## '''Update: Abstract:''' Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) [https://doi.org/10.1200/jco.2014.32.15_suppl.8527 link to abstract] -->
 +
## '''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. [https://doi.org/10.1212/wnl.0000000000001395 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25716362/ PubMed]
  
−
===Regimen {{#subobject:a2619f|Variant=1}}===
+
=Consolidation after salvage therapy=
−
{| border="1" style="text-align:center;" !align="left"  
+
==Bu/TT/Cy, then auto HSCT {{#subobject:3f8412|Regimen=1}}==
−
|'''Study'''
+
Bu/TT/Cy: '''<u>Bu</u>'''sulfan, '''<u>T</u>'''hio'''<u>T</u>'''epa, '''<u>Cy</u>'''clophosphamide
−
|[[Levels_of_Evidence#Evidence|'''Evidence''']]
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:ab67a7|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://jco.ascopubs.org/content/23/7/1507.full Nguyen et al. 2005]
+
|[https://doi.org/10.1200/jco.2001.19.3.742 Soussain et al. 2001]
−
|<span
+
|1992-1995
−
style="background:#EEEE00;
+
|style="background-color:#91cf61"|Pilot, >20 pts
−
padding:3px 6px 3px 6px;
+
|-
−
border-color:black;
+
|[https://doi.org/10.1200/jco.2007.13.5533 Soussain et al. 2008]
−
border-width:2px;
+
|2000-2005
−
border-style:solid;">Phase II</span>
+
|style="background-color:#91cf61"|Phase 2
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Cytarabine_.26_Etoposide_.28CYVE.29_2|CYVE]] salvage x 2
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Busulfan (Myleran)]] by the following age-based criteria:
 +
**60 years old or younger: 10 mg/kg PO or 8 mg/kg IV once per day on days -6, -5, and -4
 +
**60 years old or older: 6 mg/kg PO or 4.8 mg/kg IV once per day on days -6, -5, and -4
 +
*[[Thiotepa (Thioplex)]] 250 mg/m<sup>2</sup> IV once per day on days -9, -8, and -7
 +
*[[Cyclophosphamide (Cytoxan)]] 60 mg/kg IV once per day on days -3 & -2
 +
====Supportive therapy====
 +
*[[Clonazepam (Klonopin)]] 2 mg/day IV from the first day of busulfan until completion of busulfan
 +
'''Stem cell re-infusion occurs on day 0'''
 +
</div></div>
  
−
''The authors do not clearly describe a pre-determined dosing protocol but report that the most common fraction size was 1.5 Gy.''
 
−
 
−
*Median dose:
 
−
**Patients not receiving a boost: 36 Gy (range 28 to 45 Gy)
 
−
**Patients receiving a boost: 36 Gy (range 19.6 to 40 Gy) + 10 Gy (range 10 to 21.6 Gy)
 
−
 
 
===References===
 
===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. [http://jco.ascopubs.org/content/23/7/1507.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15735126 PubMed]  
+
# 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. [https://doi.org/10.1200/jco.2001.19.3.742 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11157026/ PubMed]
−
 
+
# 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. [https://doi.org/10.1200/jco.2007.13.5533 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18413641/ PubMed]
−
[[Category:Chemotherapy regimens]]
+
=Relapsed or refractory, subsequent lines of therapy=
−
[[Category:Malignant hematology regimens]]
+
==Rituximab monotherapy {{#subobject:b1f8c5|Regimen=1}}==
−
[[Category:Central nervous system (CNS) regimens]]
+
<div class="toccolours" style="background-color:#eeeeee">
−
[[Category:Lymphoma regimens]]
+
===Regimen {{#subobject:3e2c19|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059144/ Batchelor et al. 2011 (NABTT-2201)]
 +
|2004-NR
 +
|style="background-color:#ffffbe"|Pilot, fewer than 20 pts
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycle for up to 8 cycles'''
 +
</div></div>
 +
===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. [https://doi.org/10.1212/wnl.0b013e31820f2d94 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059144/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21383331/ PubMed] [https://clinicaltrials.gov/study/NCT00072449 NCT00072449]
 +
==Temozolomide monotherapy {{#subobject:be70fc|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:23777b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360092/ Reni et al. 2007]
 +
|2000-2005
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Temozolomide (Temodar)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
 +
'''28-day cycles'''
 +
</div></div>
 +
===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. [https://doi.org/10.1038/sj.bjc.6603660 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360092/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17325700/ PubMed]
 +
==Temsirolimus monotherapy {{#subobject:021ac0|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:0ad4c0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2015.64.9897 Korfel et al. 2016 (TemPCNSL)]
 +
|2009-2014
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
''Note: This is the dose used in stage 2 of this two-stage protocol.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Temsirolimus (Torisel)]] 75 mg IV once per day on days 1, 8, 15, 22
 +
'''28-day cycles'''
 +
</div></div>
 +
===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. [https://doi.org/10.1200/jco.2015.64.9897 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26976424/ PubMed] [https://clinicaltrials.gov/study/NCT00942747 NCT00942747]
 +
==Topotecan monotherapy {{#subobject:f51103|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:26ef01|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1007/s11060-007-9464-6 Voloschin et al. 2008]
 +
|1998-2002
 +
|style="background-color:#ffffbe"|Phase 2, fewer than 20 pts
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdl070 Fischer et al. 2006]
 +
|2000-2004
 +
|style="background-color:#91cf61"|Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Topotecan (Hycamtin)]] 1.5 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 +
====Supportive therapy====
 +
*Voloschin et al. 2008: [[Ondansetron (Zofran)]] (dose/route not specified) prior to topotecan
 +
'''21-day cycle for 6 to 10 cycles'''
 +
</div></div>
 +
===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. [https://doi.org/10.1093/annonc/mdl070 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16603598/ PubMed]
 +
# 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. [https://doi.org/10.1007/s11060-007-9464-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17896078/ PubMed]
 +
=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. [https://doi.org/10.1200/jco.2003.09.139 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12525518/ PubMed]
 +
[[Category:CNS lymphoma regimens]]
 +
[[Category:Disease-specific pages]]
 +
[[Category:CNS cancers]]

Revision as of 17:49, 23 June 2024

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Section editor Section editor
SeemaNagpal.jpg
 Seema Nagpal, MD
Stanford University
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 Tarsheen Sethi, MD, MSCI
Yale University
New Haven, CT, USA
LinkedIn

Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!

42 regimens on this page
60 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

EANO

ESH

ESMO

GEL/TAMO

NCCN

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

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)
    • Older than 65 years old: not defined

21-day course

Subsequent treatment

References

  1. 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 contains dosing details in manuscript PubMed 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

Chemotherapy

Supportive therapy

One course

References

  1. 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 contains dosing details in manuscript PubMed 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 Inferior ORR

CNS therapy, treatment

4-week course

Subsequent treatment

  • Glantz et al. 1999, responders: Further therapy was given to responders; see text for details

References

  1. 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 contains dosing details in manuscript PubMed

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 Superior 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

14-day cycle for 2 cycles

Subsequent treatment

  • Glantz et al. 1999, responders: Further therapy was given to responders; see text for details

References

  1. 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 contains dosing details in manuscript PubMed

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 superior 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
2. MATRix Inferior 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

References

  1. 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 contains dosing details in manuscript PubMed NCT00210314
  2. 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 contains dosing details in manuscript PubMed 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
2. MATRix Seems to have inferior CR rate

Note: SCNSL1 was intended for secondary CNS lymphoma, whereas IELSG32 was intended for primary CNS lymphoma.

Preceding treatment

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

CNS therapy

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

References

  1. 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 PubMed NCT00801216
  2. 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 contains dosing details in manuscript PubMed 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 Superior CR rate (primary endpoint)
2. Cytarabine, Methotrexate, Rituximab Seems to have superior CR rate (primary endpoint)

Chemotherapy

Targeted therapy

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

References

  1. 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 contains dosing details in manuscript PubMed 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

Glucocorticoid therapy

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

  1. 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 contains dosing details in abstract PubMed ACTRN12610000908033
    1. 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 PubMed

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 inferior 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


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

14-day cycle for 6 cycles

Subsequent treatment


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

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
    • CrCl less than 100 mL/min/1.73m2: The 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.

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


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

References

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed content property of HemOnc.org
  3. 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 contains dosing details in manuscript PubMed
  4. 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 contains dosing details in manuscript PubMed NCT00210314
  5. 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 contains dosing details in manuscript PubMed NCT00153530
    1. 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 PubMed

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

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

  1. 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 contains dosing details in manuscript PubMed

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

Glucocorticoid therapy

CNS therapy

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

References

  1. 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 contains dosing details in manuscript PubMed

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)

Targeted therapy, MATRix portion (cycles 1 to 3)

CNS therapy, MATRix portion (cycles 1 to 3)

Targeted therapy, RICE portion (cycles 4 to 6)

Chemotherapy, RICE portion (cycles 4 to 6)

CNS therapy, RICE portion (cycles 4 to 6)

Supportive therapy, RICE portion (cycles 4 to 6)

21-day cycle for 6 cycles

Subsequent treatment

References

  1. 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 contains dosing details in manuscript PubMed NCT02329080

Methotrexate-Cytarabine

Regimen

Study Dates of enrollment Evidence
Abrey et al. 2003 NR 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)

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)

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

References

  1. 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 contains dosing details in manuscript PubMed

Methotrexate-Cytarabine & Thiotepa

Regimen variant #1

Study Dates of enrollment Evidence
Illerhaus et al. 2006 1998-2003 Phase 2

Chemotherapy, MTX portion (course 1)

Supportive therapy, MTX portion (course 1)

Patients with CR, PR, or SD "with clinical improvement" after the 2nd dose of MTX proceeded to:

Chemotherapy, stem cell mobilization portion (course 2)

28-day course, then 20-day course

Subsequent treatment


Protocol variant #2

Study Dates of enrollment Evidence
Illerhaus et al. 2008 2003-2006 Pilot, fewer than 20 patients

Chemotherapy, part 1

Supportive therapy

10-day cycle for 2 to 4 cycles, followed by:

Chemotherapy, part 2

21-day cycle for 2 cycles (Stem cells are mobilized and collected after the first cycle)

Subsequent treatment

References

  1. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed

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

14-day cycle for 4 to 6 cycles

Subsequent treatment

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed

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-NR Phase 2

Chemotherapy

CNS therapy

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

References

  1. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed

MT-R

MT-R: Methotrexate, Temozolomide, Rituximab

Regimen variant #1

Study Dates of enrollment Evidence
Glass et al. 2016 (RTOG 0227) NR 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

Targeted therapy

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


Regimen variant #2

Study Dates of enrollment Evidence
Rubenstein et al. 2013 (CALGB 50202) 2004-2009 Phase 2

Chemotherapy

Targeted therapy

Supportive therapy

14-day cycle for 7 cycles

Subsequent treatment

  • CALGB 50202, patients achieving CR or CRu: CYVE consolidation

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00098774
  2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00068250

MVBP

MVBP: Methotrexate, VP16 (Etoposide), BCNU (Carmustine), MethylPrednisolone

Regimen

Study Dates of enrollment Evidence
Colombat et al. 2006 1999-2001 Phase 2

Chemotherapy

Glucocorticoid therapy

Supportive therapy

2 courses (length not specified), separated by 21 days

CNS therapy

6 doses total (timing not specified)

Subsequent treatment

References

  1. 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 contains dosing details in manuscript PubMed

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

Chemotherapy, A portion

Glucocorticoid therapy, A portion (cycles 1 & 4)

CNS therapy, A portion (cycles 1 & 4)

Chemotherapy, B portion (cycles 2 & 5)

Glucocorticoid therapy, B portion (cycles 2 & 5)

CNS therapy, B portion (cycles 2 & 5)

Glucocorticoid therapy, C portion (cycles 3 & 6)

Chemotherapy, C portion (cycles 3 & 6)

21-day cycle for 6 cycles (A1, then B1, then C1, then A2, then B2, then C2)

Subsequent treatment

References

  1. 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 contains dosing details in supplement link to PMC article PubMed 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)

Chemotherapy, A portion (cycles 1 & 4)

Glucocorticoid therapy, A portion (cycles 1 & 4)

CNS therapy, A portion (cycles 1 & 4)

Chemotherapy, B portion (cycles 2 & 5)

Glucocorticoid therapy, B portion (cycles 2 & 5)

CNS therapy, B portion (cycles 2 & 5)

Glucocorticoid therapy, C portion (cycles 3 & 6)

Chemotherapy, C portion (cycles 3 & 6)

21-day cycle for 6 cycles (A1, then B1, then C1, then A2, then B2, then C2)

References

  1. 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 contains dosing details in supplement link to PMC article PubMed 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

Chemotherapy

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

  1. 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 contains dosing details in manuscript PubMed

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

42-day cycle for 3 cycles

Subsequent treatment

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00989352
  2. 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

Chemotherapy

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

References

  1. 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 contains dosing details in manuscript PubMed NCT00594815
    1. 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 PubMed
  2. 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 contains dosing details in manuscript link to PMC article PubMed 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

Chemotherapy

Supportive therapy

One course

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence
Illerhaus et al. 2008 2003-2006 Pilot, fewer than 20 patients

Preceding treatment

Chemotherapy

Supportive therapy

One course

References

  1. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
  3. 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 contains dosing details in manuscript PubMed NCT01011920
    1. 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 PubMed

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

Chemotherapy

Supportive therapy

One course

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence
Abrey et al. 2003 NR Phase 2

Preceding treatment

Chemotherapy

Supportive therapy

  • Autologous stem cells re-infused on day 0
  • (described in some publications)
  • Filgrastim (Neupogen) by the following weight-based criteria:
    • Less than 70 kg: 300 mcg SC once per day, starting on day +7 after stem cell transplant
    • More than 70 kg (reference did not clarify which dosage to use for patients who are exactly 70 kg): 480 mcg SC once per day, starting on day +7 after stem cell transplant
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day on Monday and Thursdays, until 6 months after BEAM
  • Ciprofloxacin (Cipro) 500 mg PO twice per day while ANC less than 500/μL
  • Antifungal prophylaxis with one of the following:
  • Acyclovir (Zovirax) 400 mg PO three times per day while ANC less than 500/μL

One course

References

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed

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

Chemotherapy

Supportive therapy

One course

References

  1. 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 contains dosing details in manuscript PubMed

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

Chemotherapy

Supportive therapy

One course

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed 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-NR Phase 2

Time interval of cycles is not explicitly described and is derived from Table 1 in DeAngelis et al. 2002.

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed

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

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

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00098774

Lomustine, Methotrexate, Procarbazine

Regimen

Study Dates of enrollment Evidence
Hoang-Xuan et al. 2003 (EORTC 26952) 1997-1999 Phase 2

Preceding treatment

Chemotherapy

CNS therapy

Supportive therapy

42-day cycle for 5 cycles

References

  1. Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B; 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 contains dosing details in manuscript PubMed

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

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

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
    • CrCl less than 100 mL/min/1.73m2: The 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.

28-day cycle for 11 cycles

References

  1. Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003 Mar 15;21(6):1044-9. link to original article contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript link to PMC article PubMed

Procarbazine monotherapy

Regimen

Study Dates of enrollment Evidence
Fritsch et al. 2016 (PRIMAIN) 2009-2013 Phase 2

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00989352

Temozolomide monotherapy

Regimen variant #1

Study Dates of enrollment Evidence
Glass et al. 2016 (RTOG 0227) NR Phase 1/2

Preceding treatment

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

Chemotherapy

28-day cycle for up to 13 cycles (1 year)

References

  1. 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 contains dosing details in supplement link to PMC article PubMed NCT01458730
  2. 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 contains dosing details in manuscript link to PMC article PubMed 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


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 superior OS
OS24: 86.8% vs 71.4%
(HR 0.46, 95% CI 0.20-1.05)

Preceding treatment

Radiotherapy


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 superior OS
OS24: 86.8% vs 71.4%
(HR 0.46, 95% CI 0.20-1.05)

Note: boost was optional in JCOG1114C.

Preceding treatment

Radiotherapy


Regimen variant #4, 3600 cGy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Glass et al. 2016 (RTOG 0227) NR 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

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: 1.8000 cGy fractions

Subsequent treatment


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

Radiotherapy


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

Radiotherapy


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-NR 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

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: 1.8000 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

Radiotherapy

References

  1. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed
  3. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
  4. 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 contains dosing details in manuscript PubMed
  5. Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, LaRocca R, Grant B, DeAngelis LM, Abrey LE. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007 Oct 20;25(30):4730-5. Erratum in: J Clin Oncol. 2008 Jan 10;26(2):340. link to original article contains dosing details in manuscript PubMed NCT00594815
    1. 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 PubMed
  6. 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 contains dosing details in manuscript PubMed NCT00210314
  7. 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 contains dosing details in manuscript PubMed NCT00153530
    1. 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 PubMed
  8. 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 contains dosing details in manuscript link to PMC article PubMed NCT00068250
  9. 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 contains dosing details in manuscript PubMed NCT01011920
    1. 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 PubMed
  10. 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 contains dosing details in manuscript PubMed 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

Chemotherapy

21-day cycle for 4 cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT00153530
    1. 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 PubMed

Cytarabine & Etoposide (CYVE)

CYVE: CYtarabine, VEpesid (Etoposide)

Regimen variant #1

Study Dates of enrollment Evidence
Soussain et al. 2001 1992-1995 Pilot, >20 pts
Soussain et al. 2008 2000-2005 Phase 2

Chemotherapy

2 cycles

Subsequent treatment


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

2 cycles (length not specified)

Subsequent treatment

References

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed
  3. 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 contains dosing details in manuscript PubMed

Ifosfamide & Methotrexate

Regimen

Study Evidence
Fischer et al. 2008 Retrospective

Chemotherapy

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

  1. 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 contains dosing details in manuscript PubMed

Whole brain irradiation

Regimen variant #1, 3000 cGy

Study Dates of enrollment Evidence
Colombat et al. 2006 1999-2001 Phase 2

Preceding treatment

Radiotherapy

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

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

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

Radiotherapy

One course

References

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed
  3. 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 contains dosing details in manuscript PubMed NCT00153530
    1. 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 PubMed

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 1992-1995 Pilot, >20 pts
Soussain et al. 2008 2000-2005 Phase 2

Preceding treatment

Chemotherapy

  • Busulfan (Myleran) by the following age-based criteria:
    • 60 years old or younger: 10 mg/kg PO or 8 mg/kg IV once per day on days -6, -5, and -4
    • 60 years old or older: 6 mg/kg PO or 4.8 mg/kg IV once per day on days -6, -5, and -4
  • Thiotepa (Thioplex) 250 mg/m2 IV once per day on days -9, -8, and -7
  • Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

Supportive therapy

Stem cell re-infusion occurs on day 0

References

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed

Relapsed or refractory, subsequent lines of therapy

Rituximab monotherapy

Regimen

Study Dates of enrollment Evidence
Batchelor et al. 2011 (NABTT-2201) 2004-NR Pilot, fewer than 20 pts

Targeted therapy

7-day cycle for up to 8 cycles

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00072449

Temozolomide monotherapy

Regimen

Study Dates of enrollment Evidence
Reni et al. 2007 2000-2005 Phase 2

Chemotherapy

28-day cycles

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed

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

28-day cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT00942747

Topotecan monotherapy

Regimen

Study Dates of enrollment Evidence
Voloschin et al. 2008 1998-2002 Phase 2, fewer than 20 pts
Fischer et al. 2006 2000-2004 Phase 2

Chemotherapy

Supportive therapy

21-day cycle for 6 to 10 cycles

References

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed

Prognosis

IELSG Prognostic Scoring System (2003)

  1. 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 PubMed
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