This protocol has been superseded as it is the consensus of the haematology reference committee that this dose of methotrexate is not commonly used in clinical practice.
A search of the literature did not find strong evidence to support the use of high dose methotrexate (HD-MTX) alone in the treatment of PCNSL. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the phase II study by Batchelor et. al.r
The study conducted by Batchelor et. al assessed HD-MTX alone in patients with newly diagnosed PCNSL. Between June 1998 and December 1999, 25 patients were accrued to receive HD-MTX 8 g/m2 every 2 weeks for a maximum of 8 cycles initially. Patients who achieved CR were given an extra two cycles of consolidation which was followed by maintenance treatment of 8 g/m2 every 28 days for 11 cycles.r
The primary end point was radiographic response (complete response (CR) or partial response (PR)) and secondary end points were survival and progression-free survival. This study indicates that methotrexate monotherapy results in radiographic response proportions comparable to potentially more toxic combination regimens. However the median progression-free survival is inferior to that achieved with other more toxic combination chemotherapy plus radiation regimens.r
Ferreri et. al conducted a randomized phase II study, in which monotherapy with HD-MTX was compared with HD-MTX combined with high dose cytarabine (HDAC). Between March 2004 and December 2007, 79 patients were either treated with 4 courses of MTX 3.5 g/m2 every 21 days or with the same MTX dose combined with cytarabine 2 doses of 2 g/m2/day on days 2 to 3.r
Primary endpoint was complete remission rate after chemotherapy. Secondary endpoints were overall response rate, response duration for responder patients, overall and failure-free survival, meningeal relapse rate, and neurotoxicity. This study concluded that the addition of HDAC to HD-MTX provides improved outcome compared with HD-MTX alone.
More recently, Thiel et alr conducted a phase III randomised, non-inferiority trial involving 551 patients with newly diagnosed PCNSL. The trial investigated whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiation therapy for overall survival. Between May 2000 and May 2009, patients were randomised to receive 6 cycles of high-dose methotrexate (HD-MTX) 4 g/m2 every 14 days or HD-MTX plus ifosfamide 1.5 g/m2 on days 3 to 5 of a 14 day cycle.
The primary end point was overall survival. Several secondary endpoints were assessed: rate of complete response with first-line chemotherapy, whole brain radiation therapy, or high-dose cytarabine; progression-free survival; toxic effects according to WHO’s 1996 classification; and delayed neurotoxicity assessed by clinical examination, and by white matter changes or brain atrophy on MRI or CT. No significant difference in overall survival was recorded when whole brain radiation therapy was omitted from first-line chemotherapy in patients with newly diagnosed PCNSL.
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Batchelor et al 2003 |
Yes |
Yes |
- |
Ferreri et al 2009 |
Yes |
No |
MTX 3.5 g/m2 or MTX 3.5 g/m2 on day 1 + cytarabine 2 g/m2 bd on day 2 to 3 every 3 weeks for 4 cycles |
Case series |
N/A |
N/A |
N/A |
- |
Observational studies |
N/A |
N/A |
N/A |
- |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
Sep 2013 |
Yes |
N/A |
- |
BCCA |
Feb 2013 |
Yes |
No |
8 g/m2 (cycle 1 to 4) and 3.5 g/m2 (cycle 5 to 8) every 2 weeks |
CCO |
Aug 2012 |
Yes |
N/A |
- |
Efficacy
There was a total response of 74% (CR: 52%, 12 of 23 patients; PR: 22%, 5 of 23 patients) whereas 5 patients progressed during methotrexate treatment. The median number of cycles to CR was 6.r
Median progression-free survival for all patients was 12.8 months and median overall survival had not been reached at 22.8+ months of follow up.r
© Journal of Clinical Oncology 2003
An improved response (46% vs 18% CR rate) and survival (35% vs 24% 3 year EFS) was found in the combination arm.r
© The Lancet 2009
© The Lancet 2010
Toxicity
The toxicity was modest after 287 cycles of high-dose methotrexate. 12 patients experienced 18 episodes of grade 3 or 4 toxicity. However 4 of these 18 episodes were unlikely to be methotrexate related. 13 patients experienced no grade 3 or 4 toxicity.r
However in the study by Ferreri et al, toxicity was considerably increased in the combination arm with 90% vs 15% grade 3 or 4 neutropenia and 23% vs 3% infections. Moreover, in the combination arm in 18% of patients interruption of treatment due to toxicity was necessary, and dose reduction was necessary in 40% of patients. Treatment-related mortality was 8% in the HD-MTX + HDAC arm, compared with 3% in the monotherapy arm.r
© The Lancet 2009
© The Lancet 2010