P01.04.b long-term cognitive toxicity in small cell lung cancer population: early clinical, neuroimaging, and serological biomarkers

Abstract BACKGROUND Small cell lung cancer patients (SCLC) are treated with platinum-based chemotherapy, thoracic radiation, and some of them will also receive prophylactic cranial irradiation (PCI). Following therapy, nearly 45% of SCLC will exhibit moderate to severe cognitive impairment (CI). The aim of our study was to identify early biomarkers including clinical, serological and changes in brain structure associated with an increased risk of CI in SCLC population. MATERIAL AND METHODS Fifty-two SCLC were prospectively recruited from January 2019-December 2022 at our institution and evaluated at diagnosis using a neuropsychological battery (NPS), a structural MRI (T1-weighted), and serological markers including: a) cytokines (interleukin 1, 2, 6, 8, 10 and TNF alpha) and b) single nucleotide polymorphisms (SNP) of apolipoprotein E (APOE), multidrug resistance protein (MDR1) and brain-derived neurotrophic factor (BDNF). They were also clinically and NPS evaluated at 1-month following chemotherapy-before PCI, at 3-6 months, at one-year and at 2-3 years post-PCI. Voxel-based morphometry (T1-VBM) was used to analyze gray matter (GM) integrity. RESULTS Of the 52 patients included, 70% were male, median age was 65 years (46-82). Most (94%) had an ECOG PS ≤1. Half had hypertension (52%) and dyslipidemia (46%); one third (36%) moderate alcoholism and 25% were diabetic. Nearly half (54%) had limited stage and received cisplatin-based chemotherapy (52%). One third (29%, n=15) exhibited brain metastasis (BM): 4 at baseline (8%) and the other during follow-up (21%). Regarding smoking, median packs per year was 45 (12-100). Twenty-nine (56%) received cranial radiation, most of them (n=22, 42%) PCI (25Gy). Median overall survival was 18 months (2.5, 71); twenty-one (40%) were alive at the end of the study.Nearly half of our cohort (48%, n=25) exhibited CI: 31% (n=16) at baseline and another 17% (n= 9) during follow-up. CI group performed significantly worse in all the domains explored, especially in verbal memory (p < 0.001) and executive functioning (p < 0.001). Only smoking habit resulted significantly different between groups: CI patients were heavier smokers (p=0.04). VBM analysis showed that CI group exhibited significant GM damage in anterior and mid cingulate, superior, and inferior temporal gyrus, precuneus and fusiform gyrus. GM volume positively correlated with measures of cognitive functioning at baseline (all correlations, p <0.04). We found no differences regarding cytokines levels or SNPs of APOE, MDR1 and BDNF between groups. CONCLUSION This study confirms that nearly half of the SCLC population exhibit CI. Of greater interest, however, is the fact that most of them already exhibit CI before therapy that seem to correlate with GM alterations previously described in this population. In addition, smoking seems to be the most important clinical risk factor.