Disease Description

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DISEASE DESCRIPTION

Nonambulatory performance status and age older than 60 years are considered important poor prognostic indicators. In addition, presence of multiple neurological dysfunctions, elevated cerebrospinal fluid protein level, and nonhemispheric location of the tumor have been associated with a worse prognosis.[3] When tumor progression occurs, it is usually confined to the CNS and/or the eye. Occult systemic disease can be excluded by staging with bone marrow biopsy and CT scans of the chest, abdomen, and pelvis.[4]

Because of the diffuse nature of CNS lymphomas, aggressive surgical decompression with partial or gross total removal of the tumor is of no benefit to the patient. Median survival with surgery alone is in the range of only 1-5 months. Until recently, radiation therapy has been the standard treatment, with doses of up to 45 Gy using standard fractionation. When the Radiation Therapy Oncology Group used 40 Gy whole-brain irradiation and a 20 Gy boost to the tumor, the results were no better than had been previously reported, with median survival of 1 year and 28% surviving 2 years.[3,5] Disease recurs in the brain in 92% of patients despite the high doses of radiation. The addition of spinal axis radiation does not affect survival because it does not prevent cerebral relapse.

Two multicenter prospective trials used pre-irradiation cyclophosphamide, doxorubicin, vincristine, and dexamethasone followed by whole-brain irradiation.[6,7] Median survival times were no better than for radiation therapy alone. The failure of these and other combined modality trials [8-11] has been attributed to poor penetration of standard drugs through the blood- brain barrier and to increased neurotoxicity.[6,9-14] A retrospective review of 226 patients suggested improved results using high-dose methotrexate or cytarabine with radiation therapy over other combination regimens[15]

Due to the unsatisfactory results of whole-brain irradiation alone and to the neurologic toxic effects of chemotherapy and radiation therapy, there is now a major focus on trials with chemotherapy alone. There are now several single- institution reports in which systemic chemotherapy has been employed alone or with osmotic blood-brain barrier disruption.[8,12,13,16-18] Currently, most regimens are employing high-dose methotrexate and require hospitalization.[8,13,17,18] For patients who do not respond to chemotherapy alone or with radiation therapy, but are still responsive to salvage chemotherapy with cytarabine and etoposide, intensive chemotherapy with autologous peripheral stem cell transplantation is under evaluation.[19]

Severe cognitive deficits are reported with all intensive therapies due to iatrogenic leukoencephalopathy. Retrospective data suggest a decreased risk of dementia when chemotherapy is employed prior to radiation therapy and even less when radiation therapy is avoided.[1,2,15] The use of systemic chemotherapy alone, with or without osmotic blood-brain barrier disruption, may avoid the cognitive loss observed with radiation therapy.[2,15-17] Comparative trials with validated measures of cognitive function will be necessary to determine the value of delaying radiation therapy until relapse after high-dose chemotherapy.[2,20,21] Glucocorticoids can also produce substantial but short-lived remissions. Steroid efficacy may complicate the diagnostic evaluation by obscuring the histologic findings. New drugs that cross the blood-brain barrier are under clinical evaulation.[22]

Patients with AIDS-associated primary CNS lymphoma usually have very advanced human immunodeficiency virus (HIV) infections, with CD4+ counts less than 50 cells per milliliter.[23] Consequently, most patients die of opportunistic infections irrespective of therapy for the lymphoma. Groups that benefit most from radiation therapy (with or without antecedent chemotherapy) include those HIV-seropositive patients with no prior opportunistic infections or tumors for whom the CNS lymphoma is the AIDS-defining illness and those patients with a good performance status, high CD4 lymphocyte count (>100/mm3), and symptoms referable only to the CNS lymphoma.[1,24] Treatment of these patients requires special consideration. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)

References:

1. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Annals of Internal Medicine 119(11): 1093-1104, 1993.
2. Nasir S, DeAngelis LM: Update on the management of primary CNS lymphoma. Oncology (Huntington NY) 14(2): 228-234, 2000.
3. Pollack IF, Lunsford LD, Flickinger JC, et al.: Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 63(5): 939-947, 1989.
4. O'Neill BP, Dinapoli RP, Kurtin PJ, et al.: Occult systemic non-Hodgkin's lymphoma (NHL) in patients initially diagnosed as primary central nervous system lymphoma (PCNSL): how much staging is enough? Journal of Neuro-Oncology 25(1): 67-71, 1995.
5. Nelson DF, Martz KL, Bonner H, et al.: 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. International Journal of Radiation Oncology, Biology, Physics 23(1): 9-17, 1992.
6. O'Neill BP, O'Fallon JR, Earle JD, et al.: Primary central nervous system non-Hodgkin's lymphoma: survival advantages with combined initial therapy? International Journal of Radiation Oncology, Biology, Physics 33(3): 663-673, 1995.
7. Schultz C, Scott C, Sherman W, et al.: Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of Radiation Therapy Oncology Group protocol 88-06. Journal of Clinical Oncology 14(2): 556-564, 1996.
8. Brada M, Dearnaley D, Horwich A, et al.: Management of primary cerebral lymphoma with initial chemotherapy: preliminary results and comparison with patients treated with radiotherapy alone. International Journal of Radiation Oncology, Biology, Physics 18(4): 787-792, 1990.
9. Chamberlain MC, Levin VA: Primary central nervous system lymphoma: a role for adjuvant chemotherapy. Journal of Neuro-Oncology 14(3): 271-275, 1992.
10. Fine HA: Treatment of primary central nervous system lymphoma: still more questions than answers. Blood 86(8): 2873-2875, 1995.
11. Bessell EM, Graus F, Lopez-Guillermo A, et al.: CHOD/BVAM plus radiotherapy in patients with primary CNS non-Hodgkin's lymphoma. International Journal of Radiation Oncology, Biology, Physics 50(2): 457-464, 2001.
12. Abrey LE, DeAngelis LM, Yahalom J: Long-term survival in primary CNS lymphoma. Journal of Clinical Oncology 16(3): 859-863, 1998.
13. Blay JY, Bouhour D, Carrie C, et al.: 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(8): 2922-2929, 1995.
14. O'Brien P, Roos D, Pratt G, et al.: Phase II multicenter study of brief single-agent methotrexate followed by irradiation in primary CNS lymphoma. Journal of Clinical Oncology 18(3): 519-526, 2000.
15. Blay JY, Conroy T, Chevreau C, et al.: High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. Journal of Clinical Oncology 16(3): 864-871, 1998.
16. 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 Journal from Scientific American 2(3): 166-174, 1996.
17. Gabbai AA, Hochberg FH, Linggood RM, et al.: High-dose methotrexate for non-AIDS primary central nervous system lymphoma: report of 13 cases. Journal of Neurosurgery 70(2): 190-194, 1989.
18. Sandor V, Stark-Vancs V, Pearson D, et al.: Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. Journal of Clinical Oncology 16(9): 3000-3006, 1998.
19. 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. Journal of Clinical Oncology 19(3): 742-749, 2001.
20. DeAngelis LM: Primary central nervous system lymphoma: curable without toxicity? Cancer Journal from Scientific American 2(3): 137-139, 1996.
21. 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. Journal of Clinical Oncology 20(1): 231-236, 2002.
22. Reni M, Ferreri AJ, Landoni C, et al.: Salvage therapy with temozolomide in an immunocompetent patient with primary brain lymphoma. Journal of the National Cancer Institute 92(7): 575-576, 2000.
23. Levine AM: Acquired immunodeficiency syndrome-related lymphoma. Blood 80(1): 8-20, 1992.
24. Corn BW, Donahue BR, Rosenstock JG, et al.: Performance status and age as independent predictors of survival among AIDS patients with primary CNS lymphoma: a multivariate analysis of a multi-institutional experience. Cancer Journal from Scientific American 3(1): 52-56, 1997.

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