Current Treatment Options in Oncology

, Volume 14, Issue 2, pp 185–197 | Cite as

Primary Central Nervous System Lymphoma

  • Stephane Doucet
  • Priya Kumthekar
  • Jeffrey Raizer
Lymphoma (LI Gordon, Section Editor)

Opinion statement

Primary central nervous system lymphoma (PCNSL) comprises approximately 5 % of all primary brain tumors. During the past two decades the incidence of PCNSL has increased, and as a result clinical research to determine the optimal treatment for PCNSL patients also has increased. Diagnosis is based on histopathologic findings traditionally established by biopsy only. More recent data raise controversy and challenges this biopsy-only paradigm, showing a potential advantage for surgical resection with progression-free survival (PFS) and overall survival (OS). Using high-dose intravenous (IV) methotrexate-based chemotherapy alone or as part of a regimen can lead to disease cure. The role of whole brain radiotherapy (WBRT) remains controversial and more frequently is omitted to avoid potential delayed neurocognitive effects, especially in patients older than age 60 years. Newer data from Memorial Sloan Kettering Cancer Center (MSKCC) using five cycles of Rituximab, Methotrexate, Vincristine, and Procarbazine (R-MVP) followed by low-dose WBRT (2,340 cgy), and then two cycles of Ara-C had excellent disease control with low neuro-toxicity and is now the basis of an ongoing RTOG (Radiation Treatment Oncology Group) trial comparing early versus delayed WBRT. Other chemotherapeutics and novel treatments, such as autologous stem cell transplantation, are being studied for potential use in PCNSL. Unlike many other primary brain tumors seen in adults, PCNSL is potentially curable; therefore, balancing treatment decisions with long-term neurocognitive effects and toxicities is crucial.


Primary CNS lymphoma Immunocompetent Chemotherapy Methotrexate Cytarabine Rituximab Temozolomide Topotecan Pemetrexed Salvage therapy Elderly Autologous stem-cell transplantation Whole-brain radiotherapy 



Stephane Doucet has received a scholarship from the CHUM Hospital Foundation. Both authors contributed equally to the manuscript.

Conflicts of Interest

Stephane Doucet declares no conflicts of interest.

Priya Kumthekar declares no conflicts of interest.

Jeffrey Raizer has board membership and stock options with Aurasense, is a consultant to Geron, received honoraria from Genentech/Roche and Novartis, received payment for development of educational presentations from Genentech/Roche.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Abrey LE, Batchelor TT, Ferreri AJ, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23:5034–43.PubMedCrossRefGoogle Scholar
  2. 2.
    Kluin P, Deckert M, Ferry J. Primary diffuse large B-cell lymphoma of the CNS. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 240–1.Google Scholar
  3. 3.
    National Cancer Institute. Surveillance epidemiology and end results. SEER Stat Fact Sheets: Lymphoma. Available at Accessed January 2013.
  4. 4.•
    Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol. 2012;14 Suppl 5:v1–49. This study provides the latest epidemiological data on Central Nervous System Tumors in the United States.PubMedCrossRefGoogle Scholar
  5. 5.
    Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ. Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer. 2011;105:1414–8.PubMedCrossRefGoogle Scholar
  6. 6.
    DeAngelis LM, Wong E, Rosenblum M, Furneaux H. Epstein-Barr virus in acquired immune deficiency syndrome (AIDS) and non-AIDS primary central nervous system lymphoma. Cancer. 1992;70:1607–11.PubMedCrossRefGoogle Scholar
  7. 7.
    Nakamura S, Jaffe ES, Swerdlow SH. EBV positive diffuse large B-cell lymphoma of the elderly. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 243–4.Google Scholar
  8. 8.
    Herrlinger U, Schabet M, Bitzer M, Petersen D, Krauseneck P. Primary central nervous system lymphoma: from clinical presentation to diagnosis. J Neurooncol. 1999;43:219–26.PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang D, Hu LB, Henning TD, et al. MRI findings of primary CNS lymphoma in 26 immunocompetent patients. Korean J Radiol. 2010;11:269–77.PubMedCrossRefGoogle Scholar
  10. 10.
    Deckert M, Paulus W. Malignant lymphoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. The 2007 WHO classification of tumours of the central nervous system. Lyon: IARC; 2007.Google Scholar
  11. 11.
    Shenkier TN, Blay JY, O'Neill BP, et al. Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group. J Clin Oncol. 2005;23:2233–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Mohile NA, Deangelis LM, Abrey LE. The utility of body FDG PET in staging primary central nervous system lymphoma. Neuro Oncol. 2008;10:223–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003;21:266–72.PubMedCrossRefGoogle Scholar
  14. 14.
    Abrey LE, Ben-Porat L, Panageas KS, et al. Primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol. 2006;24:5711–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Liu BL, Cheng JX, Zhang X, Zhang W, Cheng H. Limited role of surgery in the management of primary central nervous system lymphoma (Review). Oncol Rep. 2009;22:439–49.PubMedGoogle Scholar
  16. 16.
    Bataille B, Delwail V, Menet E, et al. Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg. 2000;92:261–6.PubMedCrossRefGoogle Scholar
  17. 17.
    DeAngelis LM, Yahalom J, Heinemann MH, Cirrincione C, Thaler HT, Krol G. Primary CNS lymphoma: combined treatment with chemotherapy and radiotherapy. Neurology. 1990;40:80–6.PubMedCrossRefGoogle Scholar
  18. 18.•
    Weller M, Martus P, Roth P, Thiel E, Korfel A: Surgery for primary CNS lymphoma? Challenging a paradigm. Neuro Oncol 2012. This retrospective study from the G-PCNSL-SG-1 challenges the old paradigm of the futility of surgery in PCNSL, but has not yet changes the recommandation of stereotactic biopsy for diagnosis of PCNSL.Google Scholar
  19. 19.
    Roth P, Wick W, Weller M. Steroids in neurooncology: actions, indications, side-effects. Curr Opin Neurol. 2010;23:597–602.PubMedCrossRefGoogle Scholar
  20. 20.
    Ferreri AJ, Reni M, Pasini F, et al. A multicenter study of treatment of primary CNS lymphoma. Neurology. 2002;58:1513–20.PubMedCrossRefGoogle Scholar
  21. 21.
    Hiraga S, Arita N, Ohnishi T, et al. Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas. J Neurosurg. 1999;91:221–30.PubMedCrossRefGoogle Scholar
  22. 22.
    Batchelor T, Carson K, O'Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003;21:1044–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Gerstner ER, Carson KA, Grossman SA, Batchelor TT. Long-term outcome in PCNSL patients treated with high-dose methotrexate and deferred radiation. Neurology. 2008;70:401–2.PubMedCrossRefGoogle Scholar
  24. 24.••
    Ferreri AJ, Reni M, Foppoli M, et al. 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;374:1512–20. This study is one of the three randomized study for the treatment of PCNSL. High dose Cytarabine has now been adopted as part of standard of care for the front-line treatment of PCNSL.PubMedCrossRefGoogle Scholar
  25. 25.••
    Thiel E, Korfel A, Martus P, et al. 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;11:1036–47. It is the largest prospective randomized study on PCNSL. It suggested that omission of WBRT in first-line setting might not compromise survival, but their primary hypothesis of non inferiority was not proven.PubMedCrossRefGoogle Scholar
  26. 26.
    Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000;18:3144–50.PubMedGoogle Scholar
  27. 27.
    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;24:4570–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007;25:4730–5.PubMedCrossRefGoogle Scholar
  29. 29.
    DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002;20:4643–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Omuro AM, DeAngelis LM, Yahalom J, Abrey LE. Chemoradiotherapy for primary CNS lymphoma: an intent-to-treat analysis with complete follow-up. Neurology. 2005;64:69–74.PubMedCrossRefGoogle Scholar
  31. 31.
    Balis FM, Poplack DG. Central nervous system pharmacology of antileukemic drugs. Am J Pediatr Hematol Oncol. 1989;11:74–86.PubMedCrossRefGoogle Scholar
  32. 32.
    Reni M, Ferreri AJ, Guha-Thakurta N, et al. Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate. Int J Radiat Oncol Biol Phys. 2001;51:419–25.PubMedCrossRefGoogle Scholar
  33. 33.
    Larouche J-F, Bergeron M, Hampson G, Illidge T, Delage R. Rituximab Cerebrospinal fluid levels in patients with primary central nervous system lymphoma treated with intravenous high dose rituximab [abtract 1644]. Presented at the 53rd ASH Annual meeting and Exposition. San Diego, USA; December 10-13, 2011.Google Scholar
  34. 34.
    Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–42.PubMedCrossRefGoogle Scholar
  35. 35.
    Chamberlain MC, Johnston SK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro Oncol. 2010;12:736–44.PubMedCrossRefGoogle Scholar
  36. 36.•
    Birnbaum T, Stadler EA, von Baumgarten L, Straube A. Rituximab significantly improves complete response rate in patients with primary CNS lymphoma. J Neurooncol. 2012;109:285–91. This is a retrospective single-center trial suggesting a significant increase in complete remission when Rituximab is use with combination chemotherapy in first-line setting.PubMedCrossRefGoogle Scholar
  37. 37.
    Khan RB, Shi W, Thaler HT, DeAngelis LM, Abrey LE. Is intrathecal methotrexate necessary in the treatment of primary CNS lymphoma? J Neurooncol. 2002;58:175–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Sandberg DI, Bilsky MH, Souweidane MM, Bzdil J, Gutin PH. Ommaya reservoirs for the treatment of leptomeningeal metastases. Neurosurgery. 2000;47:49–54. discussion 54-45.PubMedGoogle Scholar
  39. 39.
    Shibamoto Y, Ogino H, Hasegawa M, et al. Results of radiation monotherapy for primary central nervous system lymphoma in the 1990s. Int J Radiat Oncol Biol Phys. 2005;62:809–13.PubMedCrossRefGoogle Scholar
  40. 40.
    Ferreri AJ, Verona C, Politi LS, et al. Consolidation radiotherapy in primary central nervous system lymphomas: impact on outcome of different fields and doses in patients in complete remission after upfront chemotherapy. Int J Radiat Oncol Biol Phys. 2011;80:169–75.PubMedCrossRefGoogle Scholar
  41. 41.
    Bessell EM, Lopez-Guillermo A, Villa S, et al. Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments. J Clin Oncol. 2002;20:231–6.PubMedCrossRefGoogle Scholar
  42. 42.
    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;23:1507–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Plotkin SR, Betensky RA, Hochberg FH, et al. Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res. 2004;10:5643–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Newlands ES, Blackledge GR, Slack JA, et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer. 1992;65:287–91.PubMedCrossRefGoogle Scholar
  45. 45.
    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.PubMedCrossRefGoogle Scholar
  46. 46.
    Enting RH, Demopoulos A, DeAngelis LM, Abrey LE. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology. 2004;63:901–3.PubMedCrossRefGoogle Scholar
  47. 47.
    Reni M, Zaja F, Mason W, et al. Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer. 2007;96:864–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Baker SD, Heideman RL, Crom WR, Kuttesch JF, Gajjar A, Stewart CF. Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol. 1996;37:195–202.PubMedCrossRefGoogle Scholar
  49. 49.
    Fischer L, Thiel E, Klasen HA, et al. Prospective trial on topotecan salvage therapy in primary CNS lymphoma. Ann Oncol. 2006;17:1141–5.PubMedCrossRefGoogle Scholar
  50. 50.
    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;86:211–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Raizer JJ, Rademaker A, Evens AM, et al. Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer. 2012;118:3743–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Raizer J, DeAngelis L, Zelenetz A, Abrey L. Activity of rituximab in primary central nervous system lymphoma PCNSL. [abstract 642]. Presented at the 2000 ASCO Annual Meeting. New Orleans, USA; May 20-23, 2000.Google Scholar
  53. 53.
    Batchelor T, Lesser G, Grossman S. Rituximab monotherapy for relapsed or refractory primary central nervous system lymphoma [abstract 2043]. Presented at the 2008 ASCO Annual Meeting. Chicago, USA; May 28 - June3, 2008.Google Scholar
  54. 54.••
    Welch MR, Omuro A, Deangelis LM. Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan-Kettering Cancer Center. Neuro Oncol. 2012;14:1304–11. This study suggest that even in patient over the age 80, HD-MTX based chemotherapy is relatively well tolerated and possible.PubMedCrossRefGoogle Scholar
  55. 55.
    Omuro AM, Ben-Porat LS, Panageas KS, et al. Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol. 2005;62:1595–600.PubMedCrossRefGoogle Scholar
  56. 56.
    Ney DE, Reiner AS, Panageas KS, Brown HS, DeAngelis LM, Abrey LE. Characteristics and outcomes of elderly patients with primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center experience. Cancer. 2010;116:4605–12.PubMedCrossRefGoogle Scholar
  57. 57.
    Dahlborg SA, Henner WD, Crossen JR, et al. Non-AIDS primary CNS lymphoma: first example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy. Cancer J Sci Am. 1996;2:166–74.PubMedGoogle Scholar
  58. 58.
    Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995;333:1540–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Soussain C, Suzan F, Hoang-Xuan K, et al. 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;19:742–9.PubMedGoogle Scholar
  60. 60.
    Soussain C, Hoang-Xuan K, Taillandier L, et al. Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Societe Francaise de Greffe de Moelle Osseuse-Therapie Cellulaire. J Clin Oncol. 2008;26:2512–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Illerhaus G, Marks R, Ihorst G, et al. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol. 2006;24:3865–70.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Stephane Doucet
    • 1
  • Priya Kumthekar
    • 2
  • Jeffrey Raizer
    • 2
  1. 1.Department of Medicine, Division of Hematology-OncologyNorthwestern University, Feinberg School of MedicineChicagoUSA
  2. 2.Department of NeurologyNorthwestern University, Feinberg School of MedicineChicagoUSA

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