Objectives: To assess the feasibility and the activity, as well as the efficacy to treat meninges, of chemotherapy (CHT) containing high-dose methotrexate (HD-MTX) followed by radiation therapy (RT), without intrathecal CHT, in patients with primary central nervous system lymphoma. Methods: Eligibility criteria were histologically proven diagnosis, disease limited to the CNS, age ≤70, ECOG performance status ≤3, HIV-negative and no prior treatment. Thirteen patients (1996–1999; median age 54 years) received two courses of vincristine 1.4 mg/m2 day 1, MTX 3 g/m2 days 3 and 10 and procarbazine 100 mg/m2 days 1–14 every 4 weeks. Patients who achieved a complete remission were referred to RT, those with progressive disease were excluded from further study; all the remaining patients received a third course of CHT followed by RT. Results: Twelve patients responded to CHT (overall response rate = 92%, complete response rate = 77%): 9 underwent consolidation RT, 3 did not. Two patients experienced severe acute toxicity; lethal pulmonary thromboembolism and transient renal failure. Five patients relapsed: 2 after CHT and 3 after RT. Relapse was local in all cases, with a case of concomitant hepatic involvement. No cases of ocular or meningeal relapse were observed. In contrast to high-dose cytarabine-containing CHT, salvage therapy with temozolomide produced good results. Two patients died of treatment-related neurotoxicity. Six patients are alive with a median follow-up of 17 months, and a 2-year overall survival (OS) of 61%. The median survival of the 9 patients who completed the planned treatment is 25+ months with a 2-year OS of 80%. Conclusions: HD-MTX, procarbazine and vincristine followed by RT, without intrathecal therapy, produce similar results with respect to other HD-MTX-containing regimens. These results seem to suggest that adequate meningeal treatment is possible without intrathecal drug delivery, even in CSF-positive patients. Corroborating data from a larger series are, however, necessary. Temozolomide should be tested in relapsed patients in a phase II prospective trial.

Keywords:
Primary central nervous system lymphoma, Brain lymphoma, Non-Hodgkin’s lymphomas, Brain neoplasm, Meningeal lymphomatosis, Chemotherapy, intrathecal, Methotrexate, high dose
1.
Ferreri AJ, Reni M, Villa E: Primary central nervous system lymphoma in immunocompetent patients. Cancer Treat Rev 1995;21:415–446.
2.
Reni M, Ferreri AJ, 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 1997;8:227–234.
3.
Berry MP, Simpson WJ: Radiation therapy in the management of primary malignant lymphoma of the brain. Int J Radiat Oncol Biol Phys 1981;7:55–59.
4.
Nelson DF, Martz KL, Bonner H, Nelson JS, Newall J, Kerman HD, Thomson JW, Murray KJ: Non-Hodgkin’s lymphoma of the brain: Can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 1992;23:9–17.
5.
Blay JY, Conroy T, Chevreau C, Thyss A, Quesnel N, Eghbali H, Bouabdallah R, Coiffier B, Wagner JP, 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 1998;16:864–871.
6.
Laperriere NJ, Cerezo L, Milosevic MF, Wong CS, Patterson B, Panzarella T: Primary lymphoma of brain: Results of management of a modern cohort with radiation therapy. Radiother Oncol 1997;43:247–252.
7.
Pollack IF, Lunsford LD, Flickinger JC, Dameshek HL: Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 1989;63:939–947.
8.
Deangelis LM, Yahalom J, Heinemann MH, Cirrincione C, Thaler HT, Krol G: Primary CNS lymphoma: Combined treatment with chemotherapy and radiotherapy. Neurology 1990;40:80–86.
9.
Shibamoto Y, Tsutsui K, Dodo Y, Yamabe H, Shima N, Abe M: Improved survival rate in primary intracranial lymphoma treated by high-dose radiation and systemic vincristine-doxorubicin-cyclophosphamide-prednisolone chemotherapy. Cancer 1990;65:1907–1912.
10.
Glass J, Gruber ML, Cher L, Hochberg FH: Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: Long-term outcome. J Neurosurg 1994;81:188–195.
11.
Gabbai AA, Hochberg FH, Lingood RM, Bashir R, Hotleman K: High-dose methotrexate for non-AIDS primary central nervous system lymphoma. Report of 13 cases. J Neurosurg 1989;70:190–194.
12.
Deangelis KM, Yahalom J, Thaler HT, Kher U: Combined modality therapy for primary CNS lymphoma. J Clin Oncol 1992;10:635–643.
13.
Jellinger KA, Paulus W: Primary central nervous system lymphomas – An update. J Cancer Res Clin Oncol 1992;119:7–27.
14.
Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 1993;119:1093–1104.
15.
Stewart DJ, Russell N, Atack EA, Quarrington A, Stolbach L: Cyclophosphamide, doxorubicin, vincristine, and dexamethasone in primary lymphoma of the brain: A case report. Cancer Treat Rep 1983;67:287–291.
16.
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 1991;9:1580–1590.
17.
Cher L, Glass J, Harsh GR, Hochberg FH: Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: Preliminary results. Neurology 1996;46:1757–1759.
18.
Abrey LE, Deangelis LM, Yahalom J: Long-term survival in primary CNS lymphoma. J Clin Oncol 1998;16:859–863.
19.
Blay JY, Bouhour D, Carrie C, Bouffet E, Brunat-Mentigny M, Philip T, Biron P: 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 1995;86:2922–2929.
20.
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 Neurooncol 1996;30:257–265.
21.
Brada M, Hjiyiannakis D, Hines F, Traish D, Ashley S: Short intensive primary chemotherapy and radiotherapy in sporadic primary CNS lymphoma (PCL). Int J Radiat Oncol Biol Phys 1998;40:1157–1162.
22.
Boiardi A, Silvani A, Valentini S, Salmaggi A, Allegranza A, Broggi G: Chemotherapy as first treatment for primary malignant non-Hodgkin’s lymphoma of the central nervous system preliminary data. J Neurol 1993;241:96–100.
23.
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 1998;16:3000–3006.
24.
Bessell EM, Graus F, Punt JA, Firth JL, Hope DT, Moloney AJ, Lopez-Guillermo A, Villa S: Primary non-Hodgkin’s lymphoma of the CNS treated with BVAM or CHOD/BVAM chemotherapy before radiotherapy. J Clin Oncol 1996;14:945–954.
25.
Schultz C, Scott C, Sherman W, Donahue B, Fields J, Murray K, Fisher B, Abrams R, Meis-Kindblom J: Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: Initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol 1996;14:556–564.
26.
Cheng AL, Yeh KH, Uen WC, Hung RL, Liu MY, Wang CH: Systemic chemotherapy alone for patients with non-acquired immunodeficiency syndrome-related central nervous system lymphoma: A pilot study of the BOMES protocol. Cancer 1998;82:1946–1951.
27.
Fine HA: Treatment of primary central nervous system lymphoma: Still more questions than answers. Blood 1995;86:2873–2875.
28.
Slevin ML, Piall EM, Aherne GW, Harvey VJ, Johnston A, Lister TA: Effect of dose and schedule on pharmacokinetics of high-dose cytosine arabinoside in plasma and cerebrospinal fluid. J Clin Oncol 1983;1:546–551.
29.
Bender RA, Bleyer WA, Frisby SA, Oliverio VT: Alteration of methotrexate uptake in human leukemia cells by other agents. Cancer Res 1975;35:1305–1308.
30.
Zager RF, Frisby SA, Oliverio VT: The effects of antibiotics and cancer chemotherapeutic agents on the cellular transport and antitumor activity of methotrexate in L1210 murine leukemia. Cancer Res 1973;33:1670–1676.
31.
Skarin AT, Canellos GP: Methotrexate-leucovorin factor rescue regimens in diffuse large cell lymphoma. NCI Monogr 1987;5:71–76.
32.
Blay JY, Conroy T, Chevreau C, Thyss A, Eghbali H, Bouabdallah R, Wagner JP, Dramais-Marcel D, Baumelou E, Sebban C, Biron P: Late neurological toxicity after the treatment of primary cerebral lymphoma: Multivariate analysis on 208 patients. Proc Annu Meet Am Soc Clin Oncol 1997;16:A86.
33.
Macdonald DR, Cascino TL, Schold SCJ, Cairncross JG: Response cirteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277–1280.
34.
Kawakami Y, Tabuchi K, Ohnishi R, Asari S, Nishimoto A: Primary central nervous system lymphoma. J Neurosurg 1985;62:522–527.
35.
Ott RJ, Brada M, Flower MA, Babich JW, Cherry SR, Deehan BJ: Measurements of blood-brain barrier permeability in patients undergoing radiotherapy and chemotherapy for primary cerebral lymphoma. Eur J Cancer 1991;27:1356–1361.
36.
Chamberlain MC, Levin VA: Adjuvant chemotherapy for primary lymphoma of the central nervous system. Arch Neurol 1990;47:1113–1116.
37.
Abelson HT, Kufe DW, Skarin AT, Major P, Ensminger W, Beardsley GP, Canellos GP: Treatment of central nervous system tumors with methotrexate. Cancer Treat Rep 1981;65(suppl 1):137–140.
38.
O’Brien PC, Roos DE, Liew KH, Trotter GE, Barton MB, Walker QJ, Poulsen MG, Olver IN: Preliminary results of combined chemotherapy and radiotherapy for non-AIDS primary central nervous system lymphoma. Trans-Tasman Radiation Oncology Group (TROG). Med J Austr 1996;165:424–427.
39.
Deangelis LM, Sheiferheld W, Schold SC, Fisher B, Schultz CJ: Combined modality treatment of primary central nervous system lymphoma (PCNSL): RTOG 93-10. Proc Annu Meet Am Soc Clin Oncol 1999;18:A537.
40.
Abrey LE, Yahalom J, Deangelis LM: Treatment for primary CNS lymphoma: The next step. J Clin Oncol 2000;18:3144–3150.
41.
Shapiro WR, Young DF, Mehta BM: Methotrexate: Distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975;293:161–166.
42.
Shapiro WR, Posner JB, Ushio Y, Chemik NL, Young DF: Treatment of meningeal neoplasms. Cancer Treat Rep 1977;61:733–743.
43.
Dent S, Eapen L, Girard A, Hugenholtz H, DaSilva V, Stewart DJ: PROMACE-MOPP and intrathecal chemotherapy for CNS lymphomas. J Neurooncol 1996;28:25–30.
44.
Camilleri-Broet S, Martin A, Moreau A, Angonin R, Henin D, Gontier MF, Rousselet MC, Caulet-Maugendre S, Cuilliere P, Lefrancq T, Mokhtari K, Morcos M, Broet P, Kujas M, Hauw JJ, Desablens B, Raphael M: Primary central nervous system lymphomas in 72 immunocompetent patients: Pathologic findings and clinical correlations. Groupe Ouest Est d’étude des Leucémies et Autres Maladies du Sang (GOELAMS). Am J Clin Pathol 1998;110:607–612.
45.
Dorreen MS, Ironside JW, Bradshaw JD, Jakubowski J, Timperley WR, Hancock BW: Primary intracerebral lymphoma: A clinicopathological analysis of 14 patients presenting over a 10-year period in Sheffield. Q J Med 1988;67:387–404.
46.
Reni M, Ferreri AJ, Villa E: Second-line treatment for primary central nervous system lymphoma. Br J Cancer 1999;79:530–534.
© 2001 S. Karger AG, Basel
2001
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.