Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ¹ for more information.)

Because of the diffuse nature of central nervous system (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 to 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 (RTOG-8315 ²) used 40 Gy whole-brain radiation therapy (WBRT) and a 20 Gy boost to the tumor, the results were no better than had been previously reported with a median survival of 1 year and 28% of the patients surviving 2 years.[1,2] Disease recurs in the brain in 92% of patients despite 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, one of which is RTOG-8806 ³, used preirradiation cyclophosphamide, doxorubicin, vincristine, and dexamethasone followed by WBRT.[3,4] Median survival times were no better than for radiation therapy alone. The failure of these and other combined modality trials [5] has been attributed to poor penetration of standard drugs through the blood-brain barrier and to increased neurologic toxic effects.[3,5-10] A retrospective review of 226 patients suggested improved results with the use of high-dose methotrexate or cytarabine with radiation therapy rather than with other combination regimens.[11] A multicenter trial (RTOG-9310 ⁴) of 102 patients used high-dose methotrexate (2.5 g/m²) for five cycles, intravenous vincristine, oral procarbazine, intraventricular methotrexate, and either 45 Gy of WBRT or 36 Gy in a hyperfractionated schedule.[12] Median progression-free survival (PFS) was 24 months, and median overall survival (OS) was 37 months.[13][Level of evidence: 3iiiA] Severe delayed neurologic toxic effects were seen in 15% of patients. Another multicenter trial (EORTC-20962 ⁵) of 52 patients younger than 66 years used high-dose methotrexate, teniposide, carmustine, methylprednisolone, intrathecal methotrexate, cytarabine, and hydrocortisone followed by 40 Gy of radiation therapy; the median survival was 46 months, but a 10% toxic death rate occurred even in this younger patient population.[14][Level of evidence: 3iiiA] Follow-up was too short (median 27 months) to fully assess severe delayed neurologic toxic effects.

Because of unsatisfactory results of WBRT alone and the neurologic toxic effects of chemotherapy and radiation therapy, a major focus is now on trials with chemotherapy alone.[15] Several single-institution reports have shown that systemic chemotherapy has been employed alone or with osmotic blood-brain barrier disruption.[8,10,16-18] Currently, most regimens are employing high-dose methotrexate and require hospitalization.[8,10,17-20] A multicenter trial (NABTT-9607 ⁶) evaluated high-dose methotrexate alone (8 g/m²) for newly diagnosed patients, with whole-brain radiation therapy administered only at disease recurrence. With a median follow-up of 2 years, median PFS was 13 months and median OS had not been reached at 23-plus months.[21][Level of evidence: 3iiiA] Another multicenter trial (EORTC-26952 ⁷) of 50 patients older than 60 years used high-dose methotrexate (3 g/m²/cycle), lomustine, procarbazine, methylprednisolone, and intrathecal methotrexate and cytarabine. The 1-year PFS was 40%, and the median OS was 14.3 months in this older patient group with a median age of 72 years.[22][Level of evidence: 3iiiA] Another multicenter trial of 65 patients used both high-dose methotrexate and high-dose cytarabine, including ifosfamide, cyclophosphamide, vinca alkaloids, dexamethasone, and intrathecal methotrexate, cytarabine, and prednisolone. The median time-to-treatment failure was 15 months with a median survival of 34 months.[23][Level of evidence: 3iiiA] Severe delayed neurologic toxic effects were rarely seen in these chemotherapy-only trials (in the absence of subsequent radiation therapy). Reduction of dosage for subsequent radiation to 23.4 Gy has been applied for patients who achieve clinical complete response after induction chemotherapy.[24][Level of evidence: 3iiiDiii] Intensive chemotherapy with autologous peripheral stem cell transplantation is also under evaluation; neurologic toxic effects were not reported in the absence of radiation therapy.[25-29] These phase II results have never been tested in a randomized setting because of an insufficient number of patients.

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.[11,30,31] The use of systemic chemotherapy alone, with or without osmotic blood-brain barrier disruption, may avoid the cognitive loss observed with radiation therapy.[11,16,17,31] 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.[21,31-34] Glucocorticoids can also produce substantial but short-lived remissions. Steroid efficacy may complicate the diagnostic evaluation by obscuring the histologic findings. Other drugs that cross the blood-brain barrier are under clinical evaluation.[35,36]

Patients with acquired immunodeficiency syndrome (AIDS) associated primary CNS lymphoma usually have very advanced human immunodeficiency virus (HIV) infections, with CD4 counts less than 50 cells/mm³.[37] Consequently, most patients die of opportunistic infections regardless 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 (>100mm³), and symptoms referable only to the CNS lymphoma.[30,38] Treatment of these patients requires special consideration. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment ⁸ for more information.)

An international consortium performed a retrospective review of 83 HIV-negative patients with primary intraocular lymphoma.[39] In selected patients with no evidence of disseminated CNS disease, localized therapy with intraocular methotrexate or ocular radiation therapy is associated with equivalent outcomes seen with systemic chemotherapy and/or WBRT. Localized therapy with intraocular methotrexate or ocular radiation therapy did not affect relapse rate, median PFS, or median OS as compared to systemic chemotherapy and/or WBRT.[39][Level of evidence: 3iiiDiv]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with primary central nervous system lymphoma ⁹. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹⁰.

References

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Glossary Terms

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with progression-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.