Advertisement

Journal of Neuro-Oncology

, Volume 104, Issue 1, pp 323–330 | Cite as

Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred?

  • Antonio Omuro
  • Luc Taillandier
  • Olivier Chinot
  • Monica Sierra del Rio
  • Charlotte Carnin
  • Marylin Barrie
  • Carole Soussain
  • Marie-Laure Tanguy
  • Sylvain Choquet
  • Veronique Leblond
  • Khe Hoang-Xuan
  • On behalf of the ANOCEF Group (French Neuro-Oncology Association).
Clinical Study – Patient Study

Abstract

Whole brain radiotherapy (WBRT) has been increasingly omitted as the first treatment of primary central nervous system lymphoma (PCNSL) because of neurotoxicity risks. However, neurotoxicity risks are lower in young (<60 years) patients; deferring WBRT may not be necessary and may compromise disease control. To investigate this question, we report a consecutive series of young (<60 years) PCNSL patients uniformly treated with a response-adjusted approach, with WBRT omitted in patients with chemosensitive disease. Treatment started with induction chemotherapy consisting of methotrexate (3 g/m2), CCNU, procarbazine, methylprednisolone and intrathecal methotrexate, cytarabine, and methylprednisolone. Patients achieving complete response (CR) received five additional chemotherapy cycles and no further treatment. Patients with less than CR were treated on an individual basis, typically with WBRT or high-dose chemotherapy (HDC) with stem cell rescue. Sixty-four patients were included (median age: 47; median KPS: 70). Median progression-free survival (PFS) was 12 months; median overall survival (OS) was 63 months (median follow-up: 108 months). Objective response after induction was 87% (CR: 54%; PR: 33%). To date, salvage WBRT has been given to a total of 27 patients and HDC to 29. Neurotoxicity developed in five patients (none in patients treated with chemotherapy only). Deferring WBRT in chemosensitive patients seems to compromise PFS but not OS. Neurotoxicity was reduced but not eliminated, as salvage WBRT was frequently required. HDC and WBRT were effective salvage treatments. As the objective of treatment in this population is a cure, withholding WBRT may not be the best strategy and deserves further investigation. Ongoing studies are investigating whether upfront treatment with HDC can replace WBRT in this setting.

Keywords

Primary central nervous system lymphoma Chemotherapy Radiotherapy Neurotoxicity 

References

  1. 1.
    Omuro AM, Abrey LE (2006) Chemotherapy for primary central nervous system lymphoma. Neurosurg Focus 21: E12. Available at http://thejns.org/loi/foc
  2. 2.
    Bessell EM, Lopez-Guillermo A, Villa S, Verger E, Nomdedeu B, Petit J, Byrne P, Montserrat E, Graus F (2002) 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 20:231–236PubMedCrossRefGoogle Scholar
  3. 3.
    Reni M, Ferreri AJ, Guha-Thakurta N, Blay JY, Dell’Oro S, Biron P, Hochberg FH (2001) 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 51:419–425PubMedCrossRefGoogle Scholar
  4. 4.
    DeAngelis LM, Delattre JY, Posner JB (1989) Radiation-induced dementia in patients cured of brain metastases. Neurology 39:789–796PubMedGoogle Scholar
  5. 5.
    Abrey LE, Yahalom J, DeAngelis LM (2000) Treatment for primary CNS lymphoma: the next step. J Clin Oncol 18:3144–3150PubMedGoogle Scholar
  6. 6.
    Omuro AM, Ben-Porat LS, Panageas KS, Kim AK, Correa DD, Yahalom J, Deangelis LM, Abrey LE (2005) Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 62:1595–1600PubMedCrossRefGoogle Scholar
  7. 7.
    Omuro AM, DeAngelis LM, Yahalom J, Abrey LE (2005) Chemoradiotherapy for primary CNS lymphoma: an intent-to-treat analysis with complete follow-up. Neurology 64:69–74PubMedCrossRefGoogle Scholar
  8. 8.
    Batchelor T, Carson K, O’Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R (2003) Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96–07. J Clin Oncol 21:1044–1049PubMedCrossRefGoogle Scholar
  9. 9.
    Herrlinger U, Kuker W, Uhl M, Blaicher HP, Karnath HO, Kanz L, Bamberg M, Weller M (2005) NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol 57:843–847PubMedCrossRefGoogle Scholar
  10. 10.
    Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B (2003) 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 21:2726–2731PubMedCrossRefGoogle Scholar
  11. 11.
    Pels H, Schmidt-Wolf IGH, Glasmacher A, Schulz H, Engert A, Diehl V, Zellner A, Schackert G, Reichmann H, Kroschinsky F, Vogt-Schaden M, Egerer G, Bode U, Schaller C, Deckert M, Fimmers R, Helmstaedter C, Atasoy A, Klockgether T, Schlegel U (2003) Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21:4489–4495PubMedCrossRefGoogle Scholar
  12. 12.
    Sandor V, Stark-Vancs V, Pearson D, Nussenblat R, Whitcup SM, Brouwers P, Patronas N, Heiss J, Jaffe E, deSmet M, Kohler D, Simon R, Wittes R (1998) Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 16:3000–3006PubMedGoogle Scholar
  13. 13.
    Omuro AM, Taillandier L, Chinot O, Carnin C, Barrie M, Hoang-Xuan K (2007) Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly. J Neurooncol 85:207–211PubMedCrossRefGoogle Scholar
  14. 14.
    Zhu JJ, Gerstner ER, Engler DA, Mrugala MM, Nugent W, Nierenberg K, Hochberg FH, Betensky RA, Batchelor TT (2009) High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncology 11:211–215PubMedCrossRefGoogle Scholar
  15. 15.
    Abrey LE, Batchelor TT, Ferreri AJM, Gospodarowicz M, Pulczynski EJ, Zucca E, Smith JR, Korfel A, Soussain C, DeAngelis LM, Neuwelt EA, O’Neill BP, Thiel E, Shenkier T, Graus F, van den Bent M, Seymour JF, Poortmans P, Armitage JO, Cavalli F (2005) Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034–5043PubMedCrossRefGoogle Scholar
  16. 16.
    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 (2001) 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 19:742–749PubMedGoogle Scholar
  17. 17.
    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 (2008) 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 26:2512–2518PubMedCrossRefGoogle Scholar
  18. 18.
    Juergens A, Pels H, Rogowski S, Fliessbach K, Glasmacher A, Engert A, Reiser M, Diehl V, Vogt-Schaden M, Egerer G, Schackert G, Reichmann H, Kroschinsky F, Bode U, Herrlinger U, Linnebank M, Deckert M, Fimmers R, Schmidt-Wolf IG, Schlegel U (2010) Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma. Ann Neurol 67:182–189PubMedCrossRefGoogle Scholar
  19. 19.
    Pels H, Juergens A, Glasmacher A, Schulz H, Engert A, Linnebank M, Schackert G, Reichmann H, Kroschinsky F, Vogt-Schaden M, Egerer G, Bode U, Schaller C, Lamprecht M, Hau P, Deckert M, Fimmers R, Bangard C, Schmidt-Wolf IG, Schlegel U (2009) Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study. J Neurooncol 91:299–305PubMedCrossRefGoogle Scholar
  20. 20.
    Ekenel M, Iwamoto FM, Ben-Porat LS, Panageas KS, Yahalom J, DeAngelis LM, Abrey LE (2008) Primary central nervous system lymphoma: the role of consolidation treatment after a complete response to high-dose methotrexate-based chemotherapy. Cancer 113:1025–1031PubMedCrossRefGoogle Scholar
  21. 21.
    Nguyen PL, Chakravarti A, Finkelstein DM, Hochberg FH, Batchelor TT, Loeffler JS (2005) Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol 23:1507–1513PubMedCrossRefGoogle Scholar
  22. 22.
    Hottinger AF, DeAngelis LM, Yahalom J, Abrey LE (2007) Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 69:1178–1182PubMedCrossRefGoogle Scholar
  23. 23.
    Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Roth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithauser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nagele T, Pietsch T, Bamberg M, Weller M (2010) 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 11:1036–1047PubMedCrossRefGoogle Scholar
  24. 24.
    Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W, Schultz C, Leibel S, Nelson D, Mehta M, DeAngelis LM (2006) Primary central nervous system lymphoma: the memorial Sloan-Kettering cancer center prognostic model. J Clin Oncol 24:5711–5715PubMedCrossRefGoogle Scholar
  25. 25.
    Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD (2008) Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncology 10:162–170PubMedCrossRefGoogle Scholar
  26. 26.
    Silvani A, Salmaggi A, Eoli M, Lamperti E, Broggi G, Marras CE, Fariselli L, Milanesi I, Fiumani A, Gaviani P, Erbetta A, Giovagnoli AR, Pollo B, Botturi A, Boiardi A (2007) Methotrexate based chemotherapy and deferred radiotherapy for primary central nervous system lymphoma (PCNSL): single institution experience. J Neurooncol 82:273–279PubMedCrossRefGoogle Scholar
  27. 27.
    Illerhaus G, Marks R, Muller F, Ihorst G, Feuerhake F, Deckert M, Ostertag C, Finke J (2009) 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 20:319–325PubMedCrossRefGoogle Scholar
  28. 28.
    Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, LaRocca R, Grant B, DeAngelis LM, Abrey LE (2007) Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25:4730–4735PubMedCrossRefGoogle Scholar
  29. 29.
    Neuwelt EA, Goldman DL, Dahlborg SA, Crossen J, Ramsey F, Roman-Goldstein S, Braziel R, Dana B (1991) Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol 9:1580–1590PubMedGoogle Scholar
  30. 30.
    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 (2003) 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 21:4151–4156PubMedCrossRefGoogle Scholar
  31. 31.
    Illerhaus G, Muller F, Feuerhake F, Schafer AO, Ostertag C, Finke J (2008) High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system. Haematologica 93:147–148PubMedCrossRefGoogle Scholar
  32. 32.
    Blay JY, Bouhour D, Carrie C, Bouffet E, Brunat-Mentigny M, Philip T, Biron P (1995) The C5R protocol: a regimen of high-dose chemotherapy and radiotherapy in primary cerebral non-Hodgkin’s lymphoma of patients with no known cause of immunosuppression. Blood 86:2922–2929PubMedGoogle Scholar
  33. 33.
    Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE (2006) 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 24:4570–4574PubMedCrossRefGoogle Scholar
  34. 34.
    Bessell EM, Graus F, Lopez-Guillermo A, Villa S, Verger E, Petit J, Holland I, Byrne P (2001) CHOD/BVAM regimen plus radiotherapy in patients with primary CNS non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 50:457–464PubMedCrossRefGoogle Scholar
  35. 35.
    DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ (2002) Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: radiation therapy oncology group study 93–10. J Clin Oncol 20:4643–4648PubMedCrossRefGoogle Scholar
  36. 36.
    Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, Frickhofen N, Feuerhake F, Volk B, Finke J (2006) High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol 24:3865–3870PubMedCrossRefGoogle Scholar
  37. 37.
    Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broet S, Linassier C, Lamy T (2006) 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 Transpl 38:417–420CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Antonio Omuro
    • 1
    • 2
  • Luc Taillandier
    • 3
  • Olivier Chinot
    • 4
  • Monica Sierra del Rio
    • 1
  • Charlotte Carnin
    • 3
  • Marylin Barrie
    • 4
  • Carole Soussain
    • 5
  • Marie-Laure Tanguy
    • 1
  • Sylvain Choquet
    • 1
  • Veronique Leblond
    • 1
  • Khe Hoang-Xuan
    • 1
  • On behalf of the ANOCEF Group (French Neuro-Oncology Association).
  1. 1.AP-HP, Groupe Hospitalier Pitie-Salpetriere, Service de Neurologie Mazarin, et Universite Pierre & Marie Curie Paris VIParisFrance
  2. 2.Department of NeurologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Centre Hospitalier Universitaire de NancyNancyFrance
  4. 4.Centre Hospitalier Universitaire La TimoneMarseilleFrance
  5. 5.Institut Curie-Hopital Rene HugueninSaint CloudFrance

Personalised recommendations