Primary CNS Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Treatment Option Overview
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 the mid 1990s, radiation therapy had been the standard treatment, with doses of up to 45 Gy using standard fractionation. A prospective trial by the Radiation Therapy Oncology Group (RTOG-8315) used 40 Gy whole-brain radiation therapy (WBRT) and a 20 Gy boost to the tumor and found that 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 (including RTOG-8806) 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  has been attributed to poor penetration of standard drugs through the blood-brain barrier and to increased neurologic toxic effects.[3,5,6,7,8,9,10] 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.
During the fall of 1995, I had just turned 40 and was at the top of my legal
profession. But I suddenly found myself getting totally exhausted each weekend.
I was of no use to my wife, Ellie, or my kids.
One morning while using the treadmill, I saw stars. I drove myself to the
emergency room; the doctors there thought I was having a heart attack. But tests showed
no heart problems, so I went back to work -- I had to because I own my
business. My internist sent me to a cardiologist and other...
A multicenter trial (RTOG-9310) 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. Median progression-free survival (PFS) was 24 months, and median overall survival (OS) was 37 months.[Level of evidence: 3iiiA] Severe delayed neurologic toxic effects were seen in 15% of patients.
Another multicenter trial (EORTC-20962), which is now closed, was comprised of 52 patients younger than 66 years who 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.[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. Multiple reports have described systemic chemotherapy, which has been employed alone or with osmotic blood-brain barrier disruption, usually including high-dose methotrexate with frequent hospitalizations.[8,10,16,17,18,19,20,21]
A multicenter trial (NABTT-9607) evaluated high-dose methotrexate alone (8 g/m2) for newly diagnosed patients, with WBRT 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.[Level of evidence: 3iiiA] Another multicenter trial (EORTC-26952) 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.[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; 57% of patients age 60 or younger were still alive at a median follow-up of 8 years.[24,25][Level of evidence: 3iiiA]