CNS lymphoma

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38 regimens on this page
53 variants on this page

Contents


Guidelines

NCCN

Spanish Lymphoma Group (GELTAMO)

Intrathecal, treatment

Cytarabine monotherapy

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Regimen

Study Evidence Comparator Efficacy
Glantz et al. 1999 Phase III Liposomal cytarabine Inferior ORR

Chemotherapy

One-month course (8 doses)

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 verified protocol PubMed

Cytarabine liposomal monotherapy

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Regimen

Study Evidence Comparator Efficacy
Glantz et al. 1999 Phase III Cytarabine Superior ORR

Chemotherapy

One-month course (2 doses)

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 verified protocol PubMed

Upfront therapy, randomized data

Cytarabine & Methotrexate

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Regimen

Study Evidence Comparator Efficacy
Ferreri et al. 2009 Randomized Phase II, >20 per arm High-dose MTX Seems to have superior CRR

Chemotherapy

21-day cycle for 4 cycles

Followed within 4 weeks by whole brain irradiation.

References

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

Methotrexate monotherapy

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Regimen

Study Evidence Comparator Efficacy
Ferreri et al. 2009 Randomized Phase II, >20 per arm High-dose MTX & Cytarabine Seems to have inferior CRR

Chemotherapy

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

21-day cycle for 4 cycles

Followed within 4 weeks by whole brain irradiation.

References

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

Upfront therapy, non-randomized or retrospective data

Ferreri regimen

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Regimen

Study Evidence
Ferreri et al. 2015 Phase II

To be completed

References

  1. 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

Lomustine, Methotrexate, Methylprednisolone, Procarbazine

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Regimen

Study Evidence
Hoang-Xuan et al. 2003 (EORTC 26952) Phase II

This was the first prospective phase II trial evaluating chemotherapy alone in older patients with PCNSL.

Chemotherapy

Intrathecal component:

Supportive medications

45-day course

Patients achieving PR or CR proceeded to lomustine, methotrexate, procarbazine maintenance.

References

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

MCP

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MCP: Methotrexate, CCNU (Lomustine), Procarbazine

Regimen

Study Evidence
Illerhaus et al. 2008 Phase II

Chemotherapy

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 (route not specified) q6h beginning 24 hours after start of MTX 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 verified protocol PubMed

Methotrexate monotherapy

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Regimen #1

Study Evidence
Thiel et al. 2010 (G-PCNSL-SG-1) Non-randomized portion of RCT

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

Patients with a complete response were randomized to whole-brain irradiation versus no further treatment. Patients with less than a complete response in the WB-XRT arm received salvage whole-brain irradiation and those in the no-WB-XRT arm received salvage HiDAC.

Regimen #2

Study Evidence
Montemurro et al. 2007 (OSHO-53) Phase II

Chemotherapy

  • Methotrexate (MTX) as follows:
    • Patients less than 60 years old: 8000 mg/m2 IV over 4 hours once per day on days 1 & 10
    • Patients greater than 60 years old: 6000 mg/m2 IV over 4 hours once per day on days 1 & 10

One course

Responders (CR or PR) proceeded to Bu/TT, then autologous hematopoietic stem cell transplant.

Regimen #3

Study Evidence
Herrlinger et al. 2005 (NOA-03) Phase II

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

Chemotherapy

14-day cycle for 6 cycles

Patients intolerant of MTX or not achieving CR after 6 cycles were randomized to salvage whole-brain irradiation versus PCV; see article for details.

Regimen #4

Study Evidence
Batchelor et al. 2003 (NABTT 96-07) Phase II

Chemotherapy

  • Methotrexate (MTX) 8000 mg/m2 IV over 4 hours once on day 1
    • The full dose of 8000 mg/m2 was only given if CrCl was at least 100 mL/min/1.73m2. For 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.

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

Patients achieving CR received two more cycles at the same dose and frequency and then proceeded to methotrexate maintenance.

References

  1. Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003 Mar 15;21(6):1044-9. link to original article contains verified protocol PubMed
  2. Herrlinger U, Küker W, Uhl M, Blaicher HP, Karnath HO, Kanz L, Bamberg M, Weller M; Neuro-Oncology Working Group of the German Society. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol. 2005 Jun;57(6):843-7. link to original article contains verified protocol PubMed content property of HemOnc.org
  3. 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 verified protocol PubMed
  4. 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 verified protocol PubMed
    1. 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) link to abstract
    2. 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

Methotrexate, then Cytarabine

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Regimen

Study Evidence
Abrey et al. 2003 Phase II

Part One

Supportive medications

14-day cycle for 5 cycles

Patients proceed to part two 72 hours after 5th dose of MTX or once the 5th dose MTX level has cleared:

Part Two

Supportive medications

  • Filgrastim (Neupogen) as follows:
    • Cycle 1: 10 mcg/kg SC once per day starting on day 4 and continued until stem cell collection complete
    • Cycle 2: 5 mcg/kg SC once per day continued for 2 weeks or until ANC greater than 3000/uL

1-month cycle for 2 cycles

Stem cell collection took place after the first cycle. Treatment was followed by BEAM, then autologous hematopoietic stem cell transplant.

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 verified protocol PubMed

Methotrexate, then Cytarabine & Thiotepa

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Regimen #1

Study Evidence
Illerhaus et al. 2006 Phase II

Chemotherapy

Supportive medications

One course

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

One course

This was for stem cell mobilization and was followed by BCNU/TT, then autologous hematopoietic stem cell transplant.

Regimen #2

Study Evidence
Illerhaus et al. 2008 Pilot, <20 patients

Chemotherapy

Supportive medications

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

21-day cycle for 2 cycles

Stem cells are mobilized and collected after the first cycle; this part was followed by BCNU/TT, then autologous hematopoietic stem cell transplant.

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 verified protocol 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 verified protocol 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

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Regimen

Study Evidence
Chamberlain et al. 2010 Phase II

Note: the bounds as described in the paper do not account for the situation where CrCl = 60 mL/min/1.73m2.

Chemotherapy

  • Methotrexate (MTX) as follows:
    • CrCl greater 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
  • Rituximab (Rituxan) 375 g/m2 IV once on day 8

14-day cycle for 4 to 6 cycles

Patients with a partial or complete response proceeded to High-dose methotrexate consolidation.

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. link to original article contains verified protocol link to PMC article PubMed

MPV

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MPV: Methotrexate, Procarbazine, Vincristine

Regimen

Study Evidence
Abrey et al. 2000 Non-randomized
DeAngelis et al. 2002 (RTOG 93-10) Phase II

Chemotherapy

Intrathecal chemotherapy

Supportive medications

  • Folinic acid (Leucovorin) as follows:
    • 20 mg PO every 6 hours x 12 doses, beginning 24 hours after IV Methotrexate (MTX) administration
    • 10 mg PO every 6 hours x 8 doses, beginning the evening of IT Methotrexate (MTX) 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)

14-day cycle for 5 cycles

Treatment in followed by whole-brain irradiation.

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

MT-R

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MT-R: Methotrexate, Temozolomide, Rituximab

Regimen #1

Study Evidence
Glass et al. 2016 (RTOG 0227) Phase I/II

This is the MTD of this phase I/II trial; it appears that only a single dose of rituximab was given.

Chemotherapy

Supportive medications

9-week course

Treatment followed by WB-XRT consolidation.

Regimen #2

Study Evidence
Rubenstein et al. 2013 (CALGB 50202) Phase II

Chemotherapy

Supportive medications

14-day cycle for 7 cycles

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

References

  1. Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013 Sep 1;31(25):3061-8. Epub 2013 Apr 8 link to original article contains verified protocol link to PMC article PubMed
  2. 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 verified protocol link to PMC article PubMed

MVBP

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

Regimen

Study Evidence
Colombat et al. 2006 Phase II

Chemotherapy

Intrathecal component: 6 doses total, timing is not specified

Supportive medications

2 courses, separated by 21 days

Responding patients (CR or PR) proceeded to cytarabine & ifosfamide for stem cell mobilization, followed by BEAM, then autologous hematopoietic stem cell transplant. Non-responders received cytarabine & etoposide salvage

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. 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 verified protocol PubMed

Nordic Regimen, older patients

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Regimen

Study Evidence
Pulczynski et al. 2015 Phase II

This regimen is meant for patients aged 66-75 years.

A cycles

B cycles

C cycles

21-day cycle for 6 cycles (A, then B, then C, then A, then B, then C)

Treatment followed by temozolomide maintenance.

References

  1. 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. link to original article contains verified protocol in supplement link to PMC article PubMed

Nordic Regimen, younger patients

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Regimen

Study Evidence
Pulczynski et al. 2015 Phase II

This regimen is meant for patients aged 18-65 years.

A cycles

B cycles

C cycles

21-day cycle for 6 cycles (A, then B, then C, then A, then B, then C)

References

  1. 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. link to original article contains verified protocol in supplement link to PMC article PubMed

R-MCP

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R-MCP: Rituximab, Methotrexate, CCNU (Lomustine), Procarbazine

Regimen

Study Evidence
Fritsch et al. 2011 Phase II

Chemotherapy

Supportive medications

  • Folinic acid (Leucovorin) (dose/route not specified) q6h 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 verified protocol PubMed

R-MP

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R-MP: Rituximab, Methotrexate, Procarbazine

Regimen

Study Evidence
Fritsch et al. 2016 (PRIMAIN) Phase II

Chemotherapy

  • 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
  • Methotrexate (MTX) 3000 mg/m2 IV over 4 hours once per day on on days 2, 16, 30
  • Procarbazine (Matulane) 60 mg/m2 PO once per day on days 2 to 11

42-day cycle for 3 cycles

Treatment followed by procarbazine maintenance.

References

  1. 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 verified protocol link to PMC article PubMed

R-MPV

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R-MPV: Rituximab, Methotrexate, Procarbazine, Vincristine

Regimen

Study Evidence
Shah et al. 2007 Phase II
Omuro et al. 2015 Phase II

Chemotherapy

Intrathecal component (only described in the Shah et al. 2007 trial):

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

Supportive medications

14-day cycle for 5 to 7 cycles

In Shah et al. 2007, followed in 3 to 5 weeks by whole-brain irradiation. In Omuro et al. 2015, patients proceeded to Bu/TT/Cy, then autologous hematopoietic stem cell transplant, after 5 cycles if CR achieved, or after 7 cycles for PR/CR at that time.

References

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

Consolidation and/or maintenance after upfront therapy

BCNU/TT, then auto HSCT

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BCNU/TT: BCNU (Carmustine), ThioTepa

Regimen #1

Study Evidence
Illerhaus et al. 2006 Phase II

Note that the day count starts from the very beginning of treatment.

Preceding treatment

Chemotherapy

Supportive medications

  • Granulocyte colony-stimulating factor starting on day 61, continued until WBC greater than 1 x 109/L for 3 days
  • "Standard supportive measures were taken according to institutional guidelines."

Stem cells re-infused on day 56

Treatment followed by whole-brain irradiation.

Regimen #2

Study Evidence
Illerhaus et al. 2008 Pilot, <20 patients

Preceding treatment

Chemotherapy

Stem cells re-infused on day 7

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 verified protocol 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 verified protocol 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

BEAM, then auto HSCT

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BEAM: BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen #1

Study Evidence
Colombat et al. 2006 Phase II

Preceding treatment

Chemotherapy

Day of transplant is not specified

Treatment followed by whole-brain irradiation.

Regimen #2

Study Evidence
Abrey et al. 2003 Phase II

Preceding treatment

Chemotherapy

Supportive medications

  • Filgrastim (Neupogen) 5 mcg/kg SC q12h starting on day +1, continuing until ANC greater than 1000/uL for 3 days or greater than 10,000/uL for 1 day

Stem cells reinfused on day 0

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 verified protocol 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. 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 verified protocol PubMed

Bu/TT, then auto HSCT

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Bu/TT: Busulfan, ThioTepa

Regimen

Study Evidence
Montemurro et al. 2007 (OSHO-53) Phase II

Preceding treatment

Chemotherapy

Stem cell re-infusion occurs on day 0

References

  1. 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 verified protocol PubMed

Bu/TT/Cy, then auto HSCT

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Bu/TT/Cy: Busulfan, ThioTepa, Cyclophosphamide

Regimen

Study Evidence
Omuro et al. 2015 Phase II

Preceding treatment

Chemotherapy

Stem cell re-infusion occurs on day 0

References

  1. 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 verified protocol link to PMC article PubMed

Cytarabine monotherapy

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Regimen

Study Evidence
Abrey et al. 2000 Non-randomized

Time interval of cycles is not described.

Preceding treatment

Chemotherapy

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 verified protocol 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

CYVE

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CYVE: CYtarabine, VEpesid (Etoposide)

Regimen

Study Evidence
Rubenstein et al. 2013 (CALGB 50202) Phase II

Preceding treatment

Chemotherapy

One course

References

  1. Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013 Sep 1;31(25):3061-8. Epub 2013 Apr 8 link to original article contains verified protocol link to PMC article PubMed

Lomustine, Methotrexate, Procarbazine

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Regimen

Study Evidence
Hoang-Xuan et al. 2003 (EORTC 26952) Phase II

====Preceding treatment==== *Lomustine, Methotrexate, Methylprednisolone, Procarbazine induction

Chemotherapy

Intrathecal component

Supportive medications

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; European Organization for Research and Treatment of Cancer Brain Tumor Group. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003 Jul 15;21(14):2726-31. link to original article contains verified protocol PubMed

Methotrexate monotherapy

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Regimen #1

Study Evidence
Chamberlain et al. 2010 Phase II

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) as follows:
    • CrCl greater 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 #2

Study Evidence
Batchelor et al. 2003 (NABTT 96-07) Phase II

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 8000 mg/m2 IV over 4 hours once on day 1
    • The full dose of 8000 mg/m2 was only given if CrCl was at least 100 mL/min/1.73m2. For 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.

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 verified protocol 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. link to original article contains verified protocol link to PMC article PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Thiel et al. 2010 (G-PCNSL-SG-1) Phase III Whole-brain irradiation Inconclusive whether non-inferior

Preceding treatment

No further treatment

References

  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 verified protocol PubMed
    1. 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) link to abstract
    2. 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

Procarbazine monotherapy

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Regimen

Study Evidence
Fritsch et al. 2016 (PRIMAIN) Phase II

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

  1. 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 verified protocol link to PMC article PubMed

Temozolomide monotherapy

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Regimen #1

Study Evidence
Glass et al. 2016 (RTOG 0227) Phase I/II

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
    • Other weeks: omitted

Regimen #2

Study Evidence
Pulczynski et al. 2015 Phase II

Preceding treatment

Chemotherapy

28-day cycles for one year or until relapse/progression

References

  1. 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. link to original article contains verified protocol in supplement link to PMC article PubMed
  2. 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 verified protocol link to PMC article PubMed

Whole brain irradiation

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Regimen #1

Study Evidence Comparator Efficacy
Abrey et al. 2000 Non-randomized
Thiel et al. 2010 (G-PCNSL-SG-1) Phase III No further treatment Inconclusive whether non-inferior

Preceding treatment

Radiotherapy

  • Whole-brain irradiation to 45 Gy in 1.5-Gy fractions (G-PCNSL-SG-1) or 1.8-Gy fractions (Abrey et al. 2000)

Treatment in Abrey et al. 2000 followed by high-dose cytarabine consolidation.

Regimen #2

Study Evidence
Glass et al. 2016 (RTOG 0227) Phase I/II

Preceding treatment

Radiotherapy

Whole-brain irradiation to 36 Gy in 1.20-Gy twice-per-day fractions on weeks 11 to 13

Treatment followed by temozolomide consolidation.

Regimen #3

Study Evidence
Ferreri et al. 2009 Nonrandomized

Preceding treatment

Radiotherapy

  • Radiation as follows:
    • Any responders: Whole-brain irradiation to 36 Gy plus 9 Gy boost to the tumor bed
    • Stable or progressive disease: Whole-brain irradiation to 40 Gy plus 9 Gy boost to the tumor bed

Regimen #4

Study Evidence
Shah et al. 2007 Phase II

Preceding treatment

Radiotherapy

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

Regimen #5

Study Evidence
Colombat et al. 2006 Phase II

Preceding treatment

Radiotherapy

  • Radiation as follows:
    • Complete responders: Whole-brain irradiation to 30 Gy in 1.8-Gy fractions
    • Partial responders: Whole-brain irradiation to 30 Gy in 1.8-Gy fractions plus 10 Gy boost to the tumor bed

Regimen #6

Study Evidence
Illerhaus et al. 2006 Phase II

Note that the day count starts from the very beginning of treatment.

Preceding treatment

Radiotherapy

  • Radiation as follows:
    • Complete responders: Whole-brain irradiation to 45 Gy in 1-Gy fractions, starting on day 90
    • Partial responders: Whole-brain irradiation to 50 Gy in 1-Gy fractions, starting on day 90

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 verified protocol 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. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002 Dec 15;20(24):4643-8. link to original article contains verified protocol PubMed
  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 verified protocol 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. 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 verified protocol 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 verified protocol PubMed
    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 PubMed
  6. Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F; International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18. link to original article contains verified protocol PubMed
  7. 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 verified protocol PubMed
    1. 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) link to abstract
    2. 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. 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 verified protocol link to PMC article PubMed

Relapsed or refractory, salvage therapy

Cytarabine monotherapy

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Regimen

Study Evidence
Thiel et al. 2010 (G-PCNSL-SG-1) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  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 verified protocol PubMed
    1. 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) link to abstract
    2. 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

CYVE

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CYVE: CYtarabine, VEpesid (Etoposide)

Regimen #1

Study Evidence
Soussain et al. 2001 Pilot, >20 pts
Soussain et al. 2008 Phase II

Chemotherapy

  • Cytarabine (Cytosar) as follows:
    • 2000 mg/m2 IV over 3 hours once per day on days 2 to 5
    • 50 mg/m2 IV over 12 hours once per day on days 1 to 5
  • Etoposide (Vepesid) 200 mg/m2 IV over 2 hours once per day on days 2 to 5

2 cycles

Responders proceeded to Bu/TT/Cy, then autologous hematopoietic stem cell transplant.

Regimen #2

Study Evidence
Colombat et al. 2006 Phase II

Preceding treatment

  • Non-response to MVBP x 2

Chemotherapy

Two courses

Treatment followed by whole-brain irradiation.

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 verified protocol 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. 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 verified protocol 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 verified protocol PubMed

Ifosfamide & Methotrexate

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Regimen

Study Evidence
Fischer et al. 2008 Retrospective

Chemotherapy

Supportive medications

  • Mesna (Mesnex) for prophylaxis of hemorrhagic cystitis
  • Folinic acid (Leucovorin) rescue starting 24 hours after start of Methotrexate (MTX) infusion
  • Sodium bicarbonate via IV fluid or PO routes used for urine alkalinization to maintain urine pH of at least 8
    • Check methotrexate levels 24, 48, and 72 hours after completion of methotrexate infusion.

Methotrexate (MTX) dose adjusted for 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.

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

References

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

Whole brain irradiation

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Regimen #1

Study Evidence
Thiel et al. 2010 (G-PCNSL-SG-1) Non-randomized portion of RCT

Preceding treatment

Radiotherapy

  • Whole-brain irradiation to 45 Gy in 1.5-Gy fractions

Regimen #2

Study Evidence
Colombat et al. 2006 Phase II

Preceding treatment

Radiotherapy

  • Whole-brain irradiation to 30 Gy in 1.8-Gy fractions plus 10 Gy boost to the tumor bed

Regimen #3

Study Evidence
Nguyen et al. 2005 Phase II

The authors do not clearly describe a pre-determined dosing protocol but report that the most common fraction size was 1.5 Gy.

Radiotherapy

  • 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

  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 verified protocol 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. 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 verified protocol PubMed
  3. 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 verified protocol PubMed
    1. 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) link to abstract
    2. 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

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Bu/TT/Cy: Busulfan, ThioTepa, Cyclophosphamide

Regimen

Study Evidence
Soussain et al. 2001 Pilot, >20 pts
Soussain et al. 2008 Phase II

Preceding treatment

Preparative regimen

  • Busulfan (Myleran) as follows:
    • Up to 60 years old: 10 mg/kg PO or 8 mg/kg IV once per day on days −6, −5, and −4
    • ≥60 years old: 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 medications

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 verified protocol 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 verified protocol PubMed

Relapsed or refractory, subsequent lines of therapy

Rituximab monotherapy

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Regimen

Study Evidence
Batchelor et al. 2011 Pilot, <20 pts

Chemotherapy

Up to 8 weeks of treatment

References

  1. 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 verified protocol link to PMC article PubMed

Temozolomide monotherapy

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Regimen

Study Evidence
Reni et al. 2007 Phase II

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 verified protocol link to PMC article PubMed

Temsirolimus monotherapy

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Regimen

Study Evidence
Korfel et al. 2016 Phase II

This is the dose used in stage 2 of this two-stage protocol.

Chemotherapy

Continued until progression or intolerance

References

  1. 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 verified protocol PubMed

Topotecan monotherapy

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Regimen

Study Evidence
Fischer et al. 2006 Phase II
Voloschin et al. 2008 Phase II, <20 pts

Chemotherapy

Supportive medications

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 verified protocol 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 verified protocol 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. to original article PubMed