Strikingly Reduced Toxicities of Fotemustine-Based Chemotherapeutics Than High-Dose Methotrexate-Containing Regimens with Comparable Efficacy

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Background: High-dose methotrexate (HD-MTX)-based chemotherapy followed by whole-brain radiotherapy is the most commonly used approach for patients with newly diagnosed Primary central nervous system lymphoma (PCNSL). However, HD-MTX is a hospital-based drug requiring adequate fluid management and may not be well tolerated in elderly patients with an increased prevalence of comorbid illness. Fotemustine is a third-generation nitrosourea, which is easily penetrated through the blood-brain barrier (BBB) due to its high fat-soluble and low molecular weight, and is indicated for primary brain tumors and disseminated malignant melanoma. Our Center has innovatively conducted three prospective clinical trials using fotemustine-based regimens for the treatment of newly diagnosed PCNSL patients (Wu J et al, J Neurooncol 2018, Wu J et al, Cancer Biol Med 2021, Zhang X et al, ASH 2022), the results of the above studies suggest that the fotemustine-containing regimen has efficacy in the treatment of newly diagnosed PCNSL and has few toxic side effects. Therefore, this study increased the sample size, extended the follow-up time and set up a control group to analyze the efficacy and safety of fotemustine-containing regimens compared with HD-MTX-containing regimens in the treatment of newly diagnosed PCNSL patients. Methods: From April 2011 to December 2021, 114 patients with newly diagnosed PCNSL who received HD-MTX-containing regimens (HD-MTX plus cytarabine [HD-MA], rituximab, HD-MTX plus temozolomide [R-MT]) or fotemustine-containing regimens (fotemustine, teniposide plus dexamethasone [FTD], fotemustine, temozolomide plus dexamethasone [FVD], rituximab, fotemustine, pemetrexed plus dexamethasone [RFPD]) were retrospectively analyzed in this study. Among them, 27 and 15 patients received the HD-MA and R-MT protocol, respectively; 15, 12, and 45 patients received the FTD, FVD and R-FPD protocol, respectively. Results: Of the 114 patients, the objective response rate (ORR) did not differ significantly between the HD-MTX-containing group and the fotemustine-containing group (67% vs 68%, P=0.879). The median follow-up time for 114 patients was 28.5 months (range 2-122 months). Neither the progression free survival (PFS) (P=0.783) nor the overall survival (OS) (P=0.918) exhibited remarkably difference between HD-MTX-containing group and fotemustine-containing group. Notably, we noted that patients treated with HD-MTX-containing regimens experienced more serious adverse events, including leukopenia, anemia, thrombocytopenia, digestive tract toxicity, and mucosis (all P < 0.05) than those undergoing fotemustine-containing therapeutics. Conclusion: Fotemustine-based chemotherapeutics conferred a safer effect on newly-diagnosed PCNSL patients compared with HD-MTX-containing regimens together with comparable efficiency.

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