Pathogenesis, Diagnostic Pathways, and New Therapeutic and Nutritional Strategies for Pancreatic Cancer-Associated...

Background/Objectives: Pancreatic cancer-associated cachexia (CAC) is a complex, multifactorial and multi-organ metabolic syndrome affecting approximately 80% of patients with pancreatic ductal adenocarcinoma (PDAC). Recent epidemiological data show that cachexia is a primary cause of mortality in PDAC, directly accounting for approximately 30% of cancer-related deaths and significantly limiting the tolerability of cancer therapy and is associated with adverse effects of treatment. It is defined by systemic weight loss, skeletal muscle atrophy (sarcopenia), and adipose tissue depletion, often driven by systemic inflammation and metabolic dysregulation. Methods: The literature was searched in PubMed and Scopus using combinations of keywords. The search covers the literature between 2016 and 2026, but papers before this period were also included because of their historical importance. Studies with higher evidential value, such as prospective studies, randomized controlled trials, and meta-analyses, were prioritized and emphasized in our analysis. Results: CAC in PC arises from a systemic inflammatory response driven by tumor-host interactions and the release of pro-inflammatory mediators, such as growth differentiation factor 15 (GDF-15) and parathyroid hormone-related protein (PTHrP), which promotes anorexia and weight loss. The most commonly used diagnostic criteria include unintentional weight loss of more than 5% of body mass within 6 months, a body mass index (BMI) below 20 kg/m², or weight loss greater than 2% in the presence of sarcopenia. Emerging evidence supports the use of AI-based body composition analysis and novel biomarkers, including GDF-15 levels, to improve the detection and monitoring of cachexia. This review highlights that, despite the absence of pharmacological agents specifically approved for CAC in the United States and Europe, current guidelines recommend multimodal supportive care, including low-dose olanzapine, nutritional support, and exercise-based interventions. Furthermore, we identify recent phase 2 trials targeting the GDF-15 pathway, such as the GDF-15 inhibitor ponsegromab, which have demonstrated significant improvements in body weight and physical activity, suggesting a potential breakthrough in targeted therapies for CAC. Conclusions: CAC in PDAC represents a critical unmet medical need in oncology. It manifests as a lethal systemic pathology that demands early identification and targeted personalized pharmacological and nutritional interventions. Early diagnosis and targeted intervention represent promising strategies for improving survival and quality of life in this high-risk patient population.