Abstract
Primary central nervous system lymphoma (PCNSL) is a rare disorder with a poor prognosis. The mainstay of treatment is single agent or combination high dose (≥3.5g/m2) methotrexate (HDMTX) based regimens. There is no consensus as to which dose of HDMTX improves outcomes in patients with PCNSL but doses of MTX greater than 3 g/m2 intravenously achieve therapeutic cerebrospinal fluid (CSF) concentrations.
To determine if there is an optimal or total dose of HDMTX in PCNSL therapies that results in improved progression free (PFS) or overall survival (OS).
Patients at Moffitt Cancer Center with PCNSL were identified using our institutional database between January 1, 2000 and September 30, 2011. Patients with complete treatment data who were treated with HDMTX were included in this study. HDMTX was defined as MTX at a dose ≥ 3.5g/m2. Patient demographics, clinical, and treatment data were collected and analyzed. Treatment information collected included the starting dose of HDMTX, IV rituximab use, MTX toxicity and clearance, cycles of MTX, and total amount of MTX administered (g/m2).
Data were analyzed using descriptive statistics and the Kaplan-Meier (KM) method was used to estimate median PFS and OS using the log rank test. P value of <0.05 was considered significant. All data was analyzed using SPSS statistical software version 21.0.
A total of 51 patients were identified (Table 1).
Characteristics of Patients with Primary CNS Lymphoma Treated with High dose Methotrexate
| Variable (N=51) | Result | |
|---|---|---|
| Age (Median) | 60 (17-85) | |
| % Male | 43% (22) | |
| % Caucasian | 90% (46) | |
| % ECOG 0-1 | 71% (36) | |
| HIV positive | 1 (2%) | |
| % positive CSF cytology | 12% (6) | |
| Neurological Symptoms | Seizure | 8 (16%) |
| Motor deficit | 21 (41%) | |
| Sensory deficit | 3 (6%) | |
| Headache/confusion | 15 (29%) | |
| Visual | 4 (8%) | |
| Location of lymphoma | Cerebral | 40 (78%) |
| Cerebellar | 11 (22%) | |
| Other chemotherapy with high dose MTX | 9 (18%) | |
| Initial Rituximab therapy | 32 (63%) | |
| Initial high dose MTX dose | 3.5g/m2 | 12 (23%) |
| 3.6-7.9g/m2 | 5 (10%) | |
| 8g/m2 | 34 (67%) | |
| MTX dose reductions (N=48) | 13 (26%) | |
| Total grams/m2 of MTX (Mean) | 6.07±2.2 | |
| Delayed MTX clearance (N=45) | 22 (43%) | |
| Liver Toxicity MTX (N=43) | Grade 3 | 11 (22%) |
| Grade 4 | 2 (4%) | |
| Renal Toxicity MTX (N=44) | Grade 3 | 2 (4%) |
| Grade 4 | 0 | |
| Days to clear MTX (mean) N=43 | 3.9±1.9 | |
| MTX level 24 hours (mean) N=43 | 5.6±5.2 | |
| MTX level 48 hours (mean) N=43 | .35±.37 | |
| MTX level 72 hours (mean) N=31 | .16±.18 |
| Variable (N=51) | Result | |
|---|---|---|
| Age (Median) | 60 (17-85) | |
| % Male | 43% (22) | |
| % Caucasian | 90% (46) | |
| % ECOG 0-1 | 71% (36) | |
| HIV positive | 1 (2%) | |
| % positive CSF cytology | 12% (6) | |
| Neurological Symptoms | Seizure | 8 (16%) |
| Motor deficit | 21 (41%) | |
| Sensory deficit | 3 (6%) | |
| Headache/confusion | 15 (29%) | |
| Visual | 4 (8%) | |
| Location of lymphoma | Cerebral | 40 (78%) |
| Cerebellar | 11 (22%) | |
| Other chemotherapy with high dose MTX | 9 (18%) | |
| Initial Rituximab therapy | 32 (63%) | |
| Initial high dose MTX dose | 3.5g/m2 | 12 (23%) |
| 3.6-7.9g/m2 | 5 (10%) | |
| 8g/m2 | 34 (67%) | |
| MTX dose reductions (N=48) | 13 (26%) | |
| Total grams/m2 of MTX (Mean) | 6.07±2.2 | |
| Delayed MTX clearance (N=45) | 22 (43%) | |
| Liver Toxicity MTX (N=43) | Grade 3 | 11 (22%) |
| Grade 4 | 2 (4%) | |
| Renal Toxicity MTX (N=44) | Grade 3 | 2 (4%) |
| Grade 4 | 0 | |
| Days to clear MTX (mean) N=43 | 3.9±1.9 | |
| MTX level 24 hours (mean) N=43 | 5.6±5.2 | |
| MTX level 48 hours (mean) N=43 | .35±.37 | |
| MTX level 72 hours (mean) N=31 | .16±.18 |
ECOG: Eastern Cooperative Oncology Group, MTX: methotrexate
Median PFS was 13months (0-33) and median OS 43months (29-57). The addition of IV rituximab or other chemotherapy failed to improve PFS or OS. HDMTX dose reductions or the total dose of HDMTX administered did not significantly impact PFS or OS. Similarly, when comparing dosing of HDMTX there was no significant difference in 8g/m2 versus 3.5g/m2 (PFS p=0.56, OS p=0.68), or between patients receiving 8g/m2 versus <8g/m2 (PFS p=0.77, OS p=0.6) (Figure 1). Patients receiving 8g/m2 versus those receiving <8g/m2 of HDMTX had similar baseline characteristics except for more liver function abnormalities in the 8g/m2 group.
(A) Progression Free Survival and (B) Overall Survival comparing Methotrexate (HD MTX) at 8gm2 vs <8g/m2
(A) Progression Free Survival and (B) Overall Survival comparing Methotrexate (HD MTX) at 8gm2 vs <8g/m2
Differences in initial dosing of HDMTX or total dose of HDMTX therapy did not influence outcomes in our patients with PCNSL. Dose reductions in HDMTX, addition of other chemotherapeutic agents, or rituximab were not associated with improved PFS or OS. An intriguing plateau was observed in OS in the 8gm/m2 arm despite similar PFS, suggesting that the receipt of novel therapies in the relapsed setting may contribute to OS. Multicenter collaborative clinical trials are needed to further assess the optimal initial dose of HDMTX to administer in PCNSL.
No relevant conflicts of interest to declare.
