title: High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial.
abstract: BACKGROUND
  Chemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma.
  
  
  METHODS
  This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18-75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3.5 g/m(2) on day 1 (n=40) or methotrexate 3.5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice a day on days 2-3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00210314.
  
  
  RESULTS
  All randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6-30) and 46% (31-61), respectively, (p=0.006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25-55) and 69% (55-83), respectively, (p=0.009). Grade 3-4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 [92%] vs six [15%]). Four patients died of toxic effects (three vs one).
  
  
  CONCLUSIONS
  In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone.
  
  
  BACKGROUND
  Swiss Cancer League.
authors.affiliation: Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy. andres.ferreri@hsr.it
authors.forename: Andrés J M
authors.initials: AJ
authors.lastname: Ferreri
authors.forename: Michele
authors.initials: M
authors.lastname: Reni
authors.forename: Marco
authors.initials: M
authors.lastname: Foppoli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martelli
authors.forename: Gerasimus A
authors.initials: GA
authors.lastname: Pangalis
authors.forename: Maurizio
authors.initials: M
authors.lastname: Frezzato
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Cabras
authors.forename: Alberto
authors.initials: A
authors.lastname: Fabbri
authors.forename: Gaetano
authors.initials: G
authors.lastname: Corazzelli
authors.forename: Fiorella
authors.initials: F
authors.lastname: Ilariucci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rossi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Soffietti
authors.forename: Caterina
authors.initials: C
authors.lastname: Stelitano
authors.forename: Daniele
authors.initials: D
authors.lastname: Vallisa
authors.forename: Francesco
authors.initials: F
authors.lastname: Zaja
authors.forename: Lucía
authors.initials: L
authors.lastname: Zoppegno
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Aondio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Avvisati
authors.forename: Monica
authors.initials: M
authors.lastname: Balzarotti
authors.forename: Alba A
authors.initials: AA
authors.lastname: Brandes
authors.forename: José
authors.initials: J
authors.lastname: Fajardo
authors.forename: Henry
authors.initials: H
authors.lastname: Gomez
authors.forename: Attilio
authors.initials: A
authors.lastname: Guarini
authors.forename: Graziella
authors.initials: G
authors.lastname: Pinotti
authors.forename: Luigi
authors.initials: L
authors.lastname: Rigacci
authors.forename: Catrina
authors.initials: C
authors.lastname: Uhlmann
authors.forename: Piero
authors.initials: P
authors.lastname: Picozzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzulli
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Franco
authors.initials: F
authors.lastname: Cavalli
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D003131:Combined Modality Therapy; D016371:Cranial Irradiation / Q000379:methods; D003561:Cytarabine / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D016016:Proportional Hazards Models; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D008727:Methotrexate