Primary CNS lymphoma (PCNSL) is an aggressive primary brain tumor. Cranial irradiation alone rarely results in long-term disease control or prolonged survival. We prospectively studied the use of combination chemotherapy plus cranial irradiation in newly diagnosed patients with PCNSL. We enrolled 102 newly diagnosed, immunocompetent patients with PCNSL; 98 were assessable. Patients first received five cycles of methotrexate 2.5 g/m2, vincristine, procarbazine, and intraventricular methotrexate (12 mg). Whole-brain radiotherapy (RT) was administered to a total dose of 45 Gy and all patients received high-dose cytarabine after RT. Fifty-eight percent of patients with measurable disease had a complete response to preirradiation chemotherapy and 36% had a partial (> 50%) response, for a 94% response rate. Median progression-free survival was 24.0 months and overall survival was 36.9 months. Age was an important prognostic factor; median survival was 50.4 months in patients younger than 60 and only 21.8 months in those aged 60 or older (P < .001). Fifty-three percent of patients had grade 3 or 4 toxicity during induction chemotherapy, half of which was hematologic. However, 12 patients (15%) experienced severe delayed neurologic toxicity, eight of whom died.

Treatment  Chemotherapy was administered for five cycles over a 10-week period. Each cycle consisted of methotrexate at 2.5 g/m2 infused over 2 to 3 hours and vincristine 1.4 mg/m2 with a cap at 2.8 mg (2 m2). Urine alkalinization was accomplished with intravenous bicarbonate, and leucovorin rescue was initiated 24 hours after methotrexate administration at a dose of 20 mg orally every 6 hours for 12 doses. In addition to methotrexate and vincristine, procarbazine 100 mg/m2/d for 7 days was administered on cycles 1, 3, and 5. All patients underwent placement of an Ommaya reservoir, and 12 mg of methotrexate was given for five cycles the week after each dose of intravenous methotrexate. Intra-Ommaya methotrexate was followed by oral leucovorin 10 mg every 6 hours for eight doses beginning the evening after drug administration. Dexamethasone was administered on a standard schedule of 16 mg/d for the first week, 12 mg/d for week 2, 8 mg/d for week 3, 6 mg/d for week 4, 4 mg/d for week 5, and 2 mg/d for week 6 and was then discontinued; however, the dose of dexamethasone could be adjusted according to the patient’s neurologic condition. Whole-brain RT was planned for a total dose of 45 Gy in 1.80-Gy fractions. If ocular lymphoma was present, both eyes were included in the RT field to a total dose of 36 Gy in 20 fractions. Approximately halfway through the study there was growing evidence from single-institution experience that long-term survivors of combined methotrexate-based chemotherapy and cranial irradiation were developing permanent, severe neurotoxicity.9 This was a particularly significant issue for older patients. The study was then modified so that those patients who achieved a complete response at the end of 10 weeks of chemotherapy would receive a hyperfractionated whole-brain radiation course for a total dose of 36 Gy given in 1.20-Gy fractions twice daily for 15 days; the twice-daily RT doses were separated by a minimum of 6 hours.

At completion of cranial irradiation, all patients received two courses of high-dose cytarabine. Each course consisted of two doses separated by 24 hours of cytarabine 3 g/m2/d infused over 3 hours.

Toxicity
Nine patients experienced acute grade 3/4 CNS symptoms during induction chemotherapy. The most common abnormalities were confusion, somnolence, and headache. Although some of these symptoms may have been related to the underlying disease, they may also have been related to the therapy, particularly the high-dose methotrexate, and were recorded as such. Eighty-two patients received radiotherapy, 60 (73%) of whom experienced grade 3, 4, or 5 toxicities. Sixty-three percent of these toxicities were related to myelosuppression, which could have also been a consequence of the final cycle of chemotherapy. However, 12 patients (12 of 82 [15%]) experienced severe delayed neurologic toxicities characterized primarily as leukoencephalopathy; onset began a median time of 504 days (range, 80 to 1540 days) after the start of cranial irradiation. Leukoencephalopathy was seen as frequently in patients younger than 60 (seven of 50 [14%]) as in those 60 or older (six of 32 [19%]). Eight of these toxicities were fatal (10%); five of them occurred in patients 60 years of age or older (five of 32 [16%]) compared with three in the younger age group (three of 50 [6%]). Of the 27 patients who achieved a CR after chemotherapy and received standard RT, one (3.7%) developed grade 3 neurotoxicity. Three patients (23%) from the hyperfractionated group (n = 13) developed grade 4 (one patient) or grade 5 (two patients) neurotoxicity. There was no significant difference in MMSE scores at 8 months or time to decrease of MMSE score below 24, used as a measure of dementia, between these two groups (data not shown).