An integrated multidisciplinary analysis of pre-treatment cachexia in locally advanced non–small cell lung cancer.

Abstract

8040 Background: Cancer-associated cachexia is underdiagnosed and not routinely captured in cancer registries, despite its negative impact on quality of life and survival. We aim to determine the prevalence of cachexia in patients with locally advanced NSCLC and to perform a multidisciplinary characterization of cachexia to inform the development of future therapeutic interventions. Methods: In this prospective study, 51 patients diagnosed with locally advanced unresectable NSCLC candidates to concurrent chemoradiotherapy followed by immunotherapy at the HUB-ICO Comprehensive Cancer Centre (2022-2024) were included. The primary objectives were to (1) determine the frequency of cachexia according to Fearon’s criteria and (2) characterize patients before and after completing chemoradiotherapy in terms of nutritional status, metabolic parameters, body composition and circulating cytokine levels. Baseline assessment results are reported here. Results: Most patients were male (80%) and ever smokers (98%), with a median age of 68 years. All patients completed the planned concurrent chemoradiotherapy regimen, whereas only 43% initiated durvalumab consolidation therapy. At baseline, 27 patients met the diagnostic criteria for cachexia (53%, 95% CI 39-66) and women were more likely to have cachexia than men (80% vs 46%, respectively), although this difference was not statistically significant. Cachexia was significantly associated with more advanced tumor stage (p < 0.001), worse performance status (p = 0.027), lower skeletal muscle index (p = 9e-4) and reduced total adipose tissue index (p = 0.004), elevated C-Reactive Protein blood levels (p = 0.004), moderate to severe malnutrition (p < 0.001), reduced caloric intake (p = 0.007) and decreased physical strength (p = 0.001). Cachectic patients had lower fat intake compared with non-cachectic individuals (p = 0.006), while protein intake was similar in both subgroups. Proteomic profiling using the O-link platform identified significant differences in circulating cytokine levels between cachectic and non-cachectic patients. Cachexia was associated with significantly increased levels of CCL23, IL-6, C1QA, CSF1, motilin and agouti-related protein (AGRP), among others, which showed varying degrees of correlation with caloric intake. By contrast, GDF-15 was significantly associated with weight loss (p = 0.00014) but showed no association with caloric intake or body composition parameters. Conclusions: This prospective study reveals that cancer-associated cachexia is highly prevalent in patients with unresectable locally advanced NSCLC before treatment initiation. Beyond previously described inflammatory mediators, we identified several understudied cytokines, which may contribute to the progression of the cachexia phenotype and represent potential targets for future therapeutic interventions.