Phase II Multicenter Study of Brief Single-Agent Methotrexate Followed by Irradiation in Primary CNS Lymphoma

Abstract

P h a s e I I M u l t i c e n t e r S t u d y o f B r i e f S i n g l e -A g e n t M e t h o t r e x a t e F o l l o w e d b y I r r a d i a t i o n i n P r i m a r y C N S L y m p h o m aBy P. O'Brien, D. Roos, G. Pratt, K. Liew, M. Barton, M. Poulsen, I. Olver, and G. TrotterPurpose: To assess, in a multi-institutional setting, the impact on relapse, survival, and toxicity of adding two cycles of intravenous methotrexate to cranial irradiation for immunocompetent patients with primary CNS lymphoma.Patients and Methods: Forty-six patients with a median age of 58 years and Eastern Cooperative Oncology Group performance status 0 to 3 were entered onto this phase II study. The protocol consisted of methotrexate 1 g/m 2 on days 1 and 8 followed by cranial irradiation on day 15. A whole-brain dose of 45 Gy was followed by a boost of 5.4 Gy. Intrathecal chemotherapy and spinal irradiation were given only to patients for whom cytologic examination of CSF was positive for CNS lymphoma. The median follow-up time was 36 months, with a minimum potential follow-up of 12 months.Results: Median survival was 33 months, with 2-year probability of survival 62% ؎ 15% (95% confidence interval). Twenty patients have relapsed. The predominant site of relapse was the brain. Neither performance status nor age was found to influence survival. Six patients developed a dementing illness at a median of 16 months after treatment, and three of these died as a consequence.Conclusion: A brief course of intravenous methotrexate before cranial irradiation is associated with 2-year and median survival rates superior to those reported for radiotherapy alone and similar to more intensive combined-modality regimens. Neurotoxicity remains an important competing risk for these patients.

Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study

“…Clinical trials in PCNSL have exploited therapy with high-dose MTX alone [15][16][17], MTXbased polychemotherapy [3,18] and combination of MTX-based chemotherapy with whole brain radiotherapy [19][20][21][22][23]. MTX as a sole treatment in two multicenter trials at a dosage of 8g/m 2 every 14 days for six cycles has resulted in complete response (CR) rates of 29%/52%…”

A Systematic Overview of Radiation Therapy Effects in Non-Hodgkin's Lymphoma

“…Prospective studies with chemotherapy including highdose methotrexate followed by radiotherapy have shown median survival of 33 Á/60 months and 5-year survival of 22 Á/40% (43,47,48) in comparison to median survival of 17 Á/21 months and 5-year survival of 26 Á/27% reported with radiotherapy alone in recent retrospective series (49,50). All studies comprise few patients.…”

Fotemustine, Teniposide and Dexamethasone in Treating Patients with CNS Lymphoma

“…Results from several studies of high-dose methotrexate have shown improved disease control and longer survival (Obrien et al, 2000;Hoang-Xuan et al, 2003). Effective combination chemotherapy regimens have been developed to incorporate methotrexate and wholebrain radiotherapy (DeAngelis et al, 2002;Batchelor et al, 2003;Wang et al, 2013).…”

“…There is a clear need to continue to try to optimize chemotherapy regimens and to explore combinations specifically formulated to take account of pharmacokinetic principles of drug delivery to the CNS. Agents such as methotrexate in high dosage have been used to overcome this, sometimes with attempts to disrupt the barrier by altering osmotic gradients (McAllister et al, 2000;Omuro et al, 2007). As high-dose methotrexate can penetrate the CNS, it is an attractive option for the treatment of PCNSL; therefore, other lipophilic drugs that can cross the blood-brain barrier have also been studied.…”

“…For patients with proven leptomeningeal disease, intrathecal chemotherapy (usually methotrexate or cytarabine) used to be the standard treatment (McAllister et al, 2000). There is evidence that the addition of chemotherapy can achieve modest improvement in disease-free and overall survival ( OBrien et al, 2000;Pels et al, 2003). However, modern combination chemotherapy regimens used for the treatment of systemic non-Hodgkin lymphoma have mostly proven ineffective in PCNSL because of the drugs' poor penetration of the CNS and their inability to cross the blood-brain barrier (Mead et al, 2000).…”