Abstract
High-dose (1–3.5 g/m2) methotrexate (MTX) followed by whole-brain radiation therapy (WBRT) has consistently improved length of survival in primary central nervous system lymphoma (PCNSL), but the prognosis remains dismal. To optimize and enhance the dose intensity of MTX, we applied MTX at 8 g/m2 to 20 patients with PCNSL. In an effort to lower the risk of neurotoxic treatment sequelae, the WBRT dose was reduced to 30 Gy in cases of complete remission after MTX therapy. Further, omission of WBRT and administration of stereotactic radiotherapy (SRT) were undertaken in 3 older patients. The overall response rate to the MTX therapy was 83%. The median progression free survival (PFS) was 54 months with a median overall survival (OS) of 57 months. Achieving a complete response after MTX therapy was significantly associated with a longer PFS. Late neurotoxicity was encountered in 4 (50%) of 8 patients who were aged 60 years or older and received WBRT, but in none of 12 patients who were aged less than 60 years or avoided WBRT. All older patients who underwent SRT sustained complete remission without a dementing disease. Intensifying the MTX dosage to 8 g/m2 appears more promising in comparison to results reported with MTX doses of 1–3.5 g/m2. In younger patients, the establishment of complete remission by intensified MTX therapy and subsequent WBRT with a relatively lower dose could promise durable tumor remission with an acceptable neurotoxicity. In older patients, WBRT should be avoided to sustain a meaningful survival, and SRT may provide a valid strategy in terms of enhancing local disease control without undue risk.
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Bataille B, Delwail V, Menet E, Vandermarcq P, Ingrand P, Wager M, Guy G, Lapierre F: Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg 92: 261-266, 2000
Blay JY, Conroy T, Chevreau C, Thyss A, Quesnel N, Eghbali H, Bouabdallah R, Coiffier B, Wagner J-P, Le Mevel A, Dramais-Marcel D, Baumelou E, Chauvin F, Biron P: High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol 16: 864-871, 1998
Hayakawa T, Takakura K, Abe H, Yoshimoto T, Tanaka R, Sugita K, Kikuchi H, Uozumi T, Hori T, Fuki H, Ushio Y, Nomura K, Matsutani M, Mohri N, Kamanishi T, Aozasa K, Nagashima K: Primary central nervous system lymphoma in Japan: a retrospective co-operative study by CNSLymphoma Study Group in Japan. J Neuro-Oncol 9: 197-215, 1994
Jellinger KA, Paulus W: Primary central nervous system lymphomas: an update. J Cancer Res Clin Oncol 119: 7-27, 1992
DeAngelis LM: Current management of primary central nervous system lymphoma. Oncology 9: 63-78, 1995
Nelson DF, Martz KL, Bonner H, Nelson JS, Newall J, Kerman DU, Thomson JW, Murray KJ: Non-Hodgkin's lymphoma of the brain: can high dose, large volume radiation improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 23: 9-17, 1992
Nelson DF: Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL). J Neuro-Oncol 43: 241-247, 1999
Blay JY, Bouhour D, Carrie C, Bouffet E, Brunat-Mentigny M, Philip T, Biron P: The CR5 protocol: a regimen of high-dose chemotherapy and radiotherapy in primary central nervous system lymphoma of patients with no known cause of immunosuppression. Blood 86: 2922-2929, 1995
Fine HA: Treatment of primary cerebral central nervous system lymphoma: still more questions than answers. Blood 86: 1093-1104, 1995
Glass J, Gruber ML, Cher L, Hochberg FH: Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg 81: 188-195, 1994
Hiraga S, Arita N, Ohnishi T, Kohmura E, Yamamoto K, Oku Y, Taki T, Sato M, Aozasa K, Yoshimine T: 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 91: 221-230, 1999
O'Brien P, Roos D, Pratt G, Liew K, Barton M, Poulsen M, Olver I, Trotter G: Phase II multicenter study of brief singleagent methotrexate followed by irradiation in primary CNS lymphoma. J Clin Oncol 18: 519-526, 2000
Shapiro WR: High-dose methotrexate in malignant gliomas. Cancer Treat Rep 61: 753-756, 1977
Bacci G, Gherlinzoni F, Picci P, Van Horn JR, Jaffe N, Guerra A, Ruggieri P, Biagini R, Capanna R, Toni A: Adriamycin-methotrexate high dose versus adriamycin- methotrexate dose as adjuvant chemotherapy for osteosarcoma of the extremities: a randomized study. Eur J Cancer Clin Oncol 22: 1337-1347, 1986
Delepine N, Delepine G, Bacci G, Rosen G, Desbois JC: Influence of methotrexate dose intensity on outcome of patients with high grade osteogenic osteosarcoma: analysis of the literature. Cancer 78: 2127-2135, 1996
Winkler K, Berson G, Delling G, Heise U, Kabisch H, Purfurst C, Berger J, Ritter J, Jurgens H, Gerein V: Neoadjuvant chemotherapy for osteogenic sarcoma: results of a cooperative German/Austrian study. J Clin Oncol 2: 617-624, 1984
Bleyer WA, Drake JC, Chabner BA: Neurotoxicity and elevated cerebrospinal-fluid methotrexate concentration in meningeal leukemia. N Engl J Med 289: 770-773, 1973
Tetet ML, Margolin KA, Doroshow JH, Akman S, Leong LA, Morgan RJ Jr, Raschoko JW, Slatkin N, Somlo G, Longmate JA, Carroll Ml, Newman EM: Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis. Cancer Chemother Pharmacol 46: 19-26,2000
Schlegel U, Pels H, Glasmacher A, Kleinschmidt R, Schmidt-Wolf I, Helmstaedter C, Fliessbach K, Deckert M, Van Roost D, Fimmers R, Bode U, Klockgether T: Combined systemic and intraventricular chemotherapy in primary CNS lymphoma: a pilot study. J Neurol Neurosurg Psychiatry 71: 118-122, 2001
Abrey LE, DeAngelis LM, Yahalom J: Long-term survival in primary CNS lymphoma. J Clin Oncol 16: 859-863, 1998
Abrey LE, Yahalom J, DeAngelis LM: Treatment for primary CNS lymphoma: the next step. J Clin Oncol 18: 3144-3150, 2000
Bessell EM, Graus F, Lopez-Guillermo A, Villa S, Verger E, Petit J, Holland I, Byrne P: CHOD/BVAM regimen plus radiotherapy in patients with primary CNS non-Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys 50: 457-464, 2001
Blay J, Gomez F, Sebban C, Bachelot T, Biron P, Guglielmi C, Hagenbeek A, Somers R, Chauvin F, Philip T: The international prognostic index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Blood 92: 3562-3568, 1998
Boiardi A, Silvani A, Pozzi A, Fariselli L, Broggi G, Salmaggi A: Chemotherapy is effective as early treatment for primary central nervous system lymphoma. J Neurol 246: 31-37, 1999
Ferreri AJ, Reni M, Dell"Oro S, Ciceri F, Bernardi M, Camba L, Ponzoni M, Terreni MR, Tomirotti M, Spina M, Villa E: Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients. Oncology 60: 134-140, 2001
Glass J, Shustik C, Hochberg FH, Cher L, Gruber ML: Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD). J Neuro-Oncol 30: 257-265, 1996
Allen JC, Rosen G, Mehta BM, Horten B: Leukoencephalopathy following high-dose IV methotrexate chemotherapy with leucovorin rescue. Cancer Treat Rep 64: 1261-1273, 1980
Guha-Thakurta N, Damek D, Pollack C, Hochberg FH: Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients. J Neuro-Oncol 43: 259-268, 1999
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: Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 16: 3000-3006, 1998
The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas. Summary and description of a working formulation for clinical usage. Cancer 49: 2112-2135, 1982
Hryniuk WM, Bertino JR: Treatment of leukemia with large doses of methotrexate and folinic acid: clinical-biochemical correlates. J Clin Invest 48: 2140-2155, 1969
Reni M, Ferreri AJM, Garancini MP, Villa E: Therapeutic management of primary central nervous system lymphoma in immunocompetent patients: results of a critical review of the literature. Ann Oncol 8: 227-234, 1997
Herrlinger U, Schabet M, Brugger W, Kortmann RD, Kuker W, Deckert M, Engel C, Schmeck-Lindenau HJ, Mergenthaler HG, Krauseneck P, Benohr C, Meisner C, Wiestler OD, Dichgans J, Kanz L, Bamberg M, Weller M: German Cancer Society Neuro-Oncology Working Group NOA-03 multicenter trial of single-agent high-dose methotrexate for primary central nervous system lymphoma. Ann Neurol 52: 247-252, 2002
Bessell EM, Lopez-Guillermo A, Villa S, Verger E, Nomdedeu B, Petit J, Byrne P, Montserrat E, Graus F: 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: 231-236, 2002
McAllister LD, Doolittle ND, Guastadisegni PE, Kraemer DF, Lacy CA, Crossen JR, Neuwelt EA: Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 46: 51-60, 2000
Neuwelt EA, Goldman DL, Dahlborg SA, Crossen J, Ramsey F, Roman-Goldstein S, Braziel R, Dana B: Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol 9: 1580-1590, 1991
Ferrari AJ, Reni M, Villa E: Primary nervous system lymphoma in immunocompetent patients. Cancer Treat Rev 21: 415-446, 1995
Ng S, Rosenthal MA, Ashley D, Cher L: High-dose methotrexate for primary CNS lymphoma in the elderly. Neuro-Oncology 2: 40-44, 2000
Schlegel U, Pels H, Oehring R, Blümcke I: Neurologic sequelae of treatment of primary CNS lymphoma. J Neuro-Oncol 43: 277-286, 1999
Solberg TD, Selch MT, Smathers JB, DeSalles AAF: Fractionated stereotactic radiotherapy: rationale and methods. Med Dosimetry 23: 209-219, 1998
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Watanabe, T., Katayama, Y., Yoshino, A. et al. Long-term Remission of Primary Central Nervous System Lymphoma by Intensified Methotrexate Chemotherapy. J Neurooncol 63, 87–95 (2003). https://doi.org/10.1023/A:1023760824739
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DOI: https://doi.org/10.1023/A:1023760824739