Advancing Non-Small Cell Lung Cancer Treatment: A Case Series on Pemetrexed Intrathecal Chemotherapy Monitored Through Circulating Tumor DNA in Cerebrospinal Fluid

Abstract Intrathecal pemetrexed (IP) treatment represents a promising approach for managing leptomeningeal metastasis (LM) in cancer patients. However, a standardized and measurable method to evaluate the efficacy of IP for non-small cell lung cancer (NSCLC) patients with LM is currently lacking. This report describes three NSCLC-LM cases treated with IP following progression with tyrosine kinase inhibitors (TKIs) alone. We observed their responses through next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) extracted from cerebrospinal fluid (CSF). The outcomes were favorable for patient 1 and 2, whereas patient 3 experienced a relapse. Notably, changes in the allele frequency (AF) of ctDNA mutations corresponded with clinical outcomes across these patients, which were also corroborated by multiple traditional clinical markers. This observation is significant, particularly in patient 3, where ctDNA monitoring effectively described the patient's temporary improvement followed by deterioration. Furthermore, in patient 2, the transition from a positive to a negative cytological test, alongside persistent positive NGS results, underscores the higher sensitivity of NGS compared to conventional cytological analysis. This suggests that longitudinal ctDNA monitoring using CSF samples may serve as an effective and independent method for assessing and dynamically tracking the response to IP treatment in NSCLC-LM patients. This approach has the potential to refine therapeutic strategies and improve patient outcomes.