L-Methylfolate for Brain Cancer: Promising Results?

Key Findings

This phase I trial evaluated high-dose L-methylfolate (LMF) combined with temozolomide and bevacizumab in 14 patients with recurrent IDH wild-type high-grade glioma. No maximum tolerated dose (MTD) was identified, indicating safety. Median overall survival (mOS) was 9.5 months (95% CI: 9.1–35.4), numerically higher than the historical control of bevacizumab alone (8.6 months; 95% CI: 6.8–10.8). Six patients survived >650 days. DNA methylation analysis in six post-mortem brain samples revealed a 25% increase in methylated CpGs compared to baseline tumors. Adverse events were mild (grade 2), including diarrhea (7%), reflux (7%), and dysgeusia (7%).

Study Design

The study was an open-label, observational phase I trial conducted in 2022. It enrolled 14 patients (13 with glioblastoma multiforme [GBM], 1 with anaplastic astrocytoma) who had progressed after prior therapies. The primary objective was safety, with secondary endpoints including efficacy (mOS) and DNA methylation changes. Sample size was small, and historical controls were used for comparison. Duration of treatment or follow-up was not explicitly reported.

Dosage & Administration

The study tested high-dose LMF in combination with temozolomide (150–200 mg/m²/day for 5 days/cycle) and bevacizumab (10 mg/kg every 2 weeks). LMF doses ranged from 15 mg/day to 50 mg/day, though exact dosing schedules (e.g., frequency, duration) were not detailed in the summary. Administration routes were unspecified but likely oral (as LMF is typically administered).

Results & Efficacy

• Survival: mOS of 9.5 months (95% CI: 9.1–35.4) vs. historical control of 8.6 months (95% CI: 6.8–10.8). Overlap in confidence intervals suggests no statistically significant difference, but six patients survived >650 days, indicating potential subpopulation benefits.
• DNA Methylation: 25% increase in methylated CpGs in post-mortem brain samples compared to baseline tumors, suggesting LMF may enhance epigenetic effects.
• Safety: Low incidence of grade 2 adverse events (7% each for diarrhea, reflux, dysgeusia); no severe (grade ≥3) events reported.

Limitations

• Small Sample Size: Only 14 patients (13 GBM, 1 anaplastic astrocytoma) limit statistical power.
• Historical Controls: Comparison to prior bevacizumab monotherapy data introduces confounding variables (e.g., patient variability, treatment protocols).
• Observational Design: Cannot establish causality between LMF and survival/methylation changes.
• Lack of Dose-Response Data: No clear dose-dependent trends due to unspecified dosing tiers.
• Short-Term Follow-Up: Duration not reported, limiting assessment of long-term efficacy or safety.

Clinical Relevance

This study suggests that LMF (up to 50 mg/day) combined with temozolomide and bevacizumab is safe and well-tolerated in recurrent glioma patients, with preliminary signals of prolonged survival in a subset. The observed DNA methylation changes support LMF’s role as an epigenetic modulator, though clinical significance remains unclear. For supplement users, these results highlight potential adjuvant applications in oncology but underscore the need for larger randomized trials to confirm efficacy. The lack of severe adverse events aligns with LMF’s established safety profile in other contexts (e.g., depression, methylation support), though high-dose regimens require further monitoring.

Note: The study’s URL is listed as https://pubmed.ncbi.nlm.nih.gov/35392283/ (PubMed ID: 35392283). Full methodology details (e.g., dosing schedules, trial phase specifics) may reside in the complete manuscript.