Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood–brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe outcomes among different HDMTX doses (low, <3 g/m²; intermediate, 3–4.9 g/m²; high, ≥5 g/m²) and regimens used in the treatment of PCNSL. A PubMed search resulted in 26 articles reporting clinical trials using HDMTX for PCNSL, from which 35 treatment cohorts were identified for analysis. The median dose of HDMTX used for induction was 3.5 g/m² (interquartile range IQR, 3–3.5); the intermediate dose was most frequently used in the studies examined (24 cohorts, 69%). Five cohorts used HDMTX monotherapy, 19 cohorts used HDMTX + polychemotherapy, and 11 cohorts used HDMTX + rituximab ± polychemotherapy. Pooled overall response rate (ORR) estimates for low, intermediate, and high dose HDMTX cohorts were 71%, 76%, and 76%, respectively. Pooled 2-year progression-free survival (PFS) estimates for low, intermediate, and high HDMTX dose cohorts were 50%, 51%, and 55%, respectively. Regimens that included rituximab showed a tendency to have higher ORR and 2-year PFS than those that did not include rituximab. These findings indicate that current protocols utilizing 3–4 g/m² of HDMTX in combination with rituximab provide therapeutic efficacy in PCNSL.

Objectives: To determine the incidence of delayed methotrexate elimination (DME) and acute kidney injury (AKI) and their associations with clinical outcomes in patients receiving high-dose methotrexate (HDMTX) for cancer treatment. Methods: The HDMTX European Registry collected medical records data from 12 institutions in 5 European countries to investigate the clinical practice patterns of healthcare providers utilizing HDMTX for cancer treatment. Cancer types included were acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL), non-Hodgkin lymphoma (NHL), osteosarcoma, and other CNS cancers. Primary endpoints were the incidence of DME and AKI; secondary endpoints were clinical outcomes, including hospital length of stay (LOS), delay in the subsequent course of treatment, methotrexate dose reduction, and omission of next course of treatment. Associations between the primary and secondary endpoints were analyzed with Chi-square and Wilcoxon rank-sum tests. Results: Among the 2501 total HDMTX courses analyzed, DME occurred in 302 courses (12.1%), and AKI in 384 courses (15.4%). DME incidence was highest in courses for PCNSL (18.2%) and NHL (17.2%); AKI incidence was highest in ALL courses (21.0%). Incidence of DME and AKI varied by age and methotrexate infusion duration among the different cancer types. Occurrence of DME was associated with longer delays prior to the next course of treatment, longer hospital LOS, and more frequent methotrexate dose reductions and dose omissions. Conclusions: While HDMTX is a very effective and safe treatment, administration of efficacious doses of methotrexate can lead to AKI and DME, and no single or combination of patient or treatment factors was found to reliably predict their occurrence. Thus, diligent monitoring of methotrexate levels is imperative for early detection and prompt management of nephrotoxicity in all settings where HDMTX treatment is administered.

Objectives: We aimed to determine whether the occurrence of early-onset toxicities due to 5-fluorouracil (5-FU) in treatment-naive patients undergoing their first cycle of FOLFOX/FOLFIRINOX was associated with decreased overall survival, increased risk of treatment cessation, and hospitalization. Methods: This was a retrospective cohort study using patient information from community oncology practices. Patients who received their first dose of 5-FU from 1 January 2015 through 1 August 2023 were included. The occurrence of an early-onset 5-FU-related toxicity (during 5-FU infusion or up to 96 h after infusion completion) in the first cycle of FOLFOX/FOLFIRINOX was the explanatory variable. The primary endpoint was overall survival (OS); secondary endpoints included early treatment cessation and early hospital admission. Results: In total, 3988 patients were included; the median age was 62.9 years and 57.5% were male. Early-onset toxicities were observed in 19.1%, with vomiting, thrombocytopenia, and diarrhea being most common. Patients with early-onset toxicities had a median OS of 2.5 years [95% CI 2.2 to 2.9] compared with 5.3 years [95% CI 4.7 to 5.8] in patients without early-onset toxicities (p < 0.001). The occurrence of early-onset toxicities was associated with an adjusted hazard ratio of 1.61 [95% CI 1.44 to 1.80] and was also significantly associated with early treatment cessation (odds ratio [OR] 1.53, 95% CI 1.30 to 1.80) and early hospital admission (OR 8.69, 95% CI 3.45 to 24.18). Conclusions: Early-onset toxicities related to 5-FU during the first cycle of FOLFOX/FOLFIRINOX treatment were associated with poor outcomes. Early recognition and prompt intervention are pertinent to improve outcomes in patients receiving fluoropyrimidine chemotherapy.