Extracellular Vesicles as Predictive Biomarkers for Chemotherapy-Induced Peripheral Neuropathy
Extracellular Vesicles as Predictive Biomarkers for Chemotherapy-Induced Peripheral Neuropathy
The goal of this clinical trial is to learn whether extracellular vesicles (EVs) in the blood can be used as biomarkers to predict chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer patients receiving chemotherapy with taxanes, platinum compounds, or antimitotic drugs. The main questions the study aims to answer are whether blood levels of EVs change in patients who develop CIPN during and after chemotherapy and whether specific features of EVs, including lipids and microRNAs, are associated with the development and severity of CIPN. Participants will be followed from before the start of chemotherapy until six months after treatment ends to evaluate how changes in EVs relate to nerve damage caused by chemotherapy. During the study, participants will provide blood samples before chemotherapy, at the end of treatment, and six months later for measurement and molecular analysis of EVs, will complete questionnaires about neuropathy symptoms, and will undergo simple, non-invasive nerve function tests using a tuning fork (diapason) and a Neuropen device. This study does not test cancer drugs; instead, it aims to identify biological markers in blood that may help predict which patients are at higher risk of developing CIPN, with the goal of improving monitoring and care during cancer treatment.
CIPN is a frequent and often long-lasting complication of treatment with several commonly used antineoplastic agents, including taxanes, platinum compounds, and antimitotic drugs. The condition primarily affects sensory neurons of the dorsal root ganglia and peripheral nerve fibers, leading to symptoms such as numbness, tingling, pain, and loss of vibration or tactile sensation. The severity and persistence of CIPN vary markedly between individuals, and currently there are no validated biological markers that allow early identification of patients at increased risk or objective monitoring of neurotoxicity during treatment. As a result, CIPN is usually detected only after clinical symptoms appear, at a stage when nerve damage may already be established and difficult to reverse.
EVs are membrane-bound particles released by virtually all cell types and present in large numbers in biological fluids, including blood. They contain proteins, lipids, and nucleic acids that reflect the physiological and pathological state of their cells of origin. Because EVs can originate from neural and glial cells and can cross biological barriers, they provide a potential window into otherwise inaccessible tissues such as the peripheral nervous system. Changes in EV concentration, membrane composition, and RNA cargo have been reported in several neurological and neurodegenerative conditions, supporting their potential role as circulating indicators of neuronal injury and dysfunction.
This study is designed to evaluate whether longitudinal changes in circulating EVs are associated with the development of CIPN in patients undergoing chemotherapy. Blood samples collected at predefined time points will be used to isolate and quantify EVs and to characterize selected molecular components of their cargo, including membrane lipids and microRNAs. These EV-based measurements will be evaluated in relation to standardized clinical and neurophysiological assessments of peripheral neuropathy performed over the course of treatment and follow-up. By integrating biological and clinical data, the study aims to explore whether EV-derived markers reflect early neurotoxic effects of chemotherapy and whether they may capture individual susceptibility to CIPN.
The study uses a single-group, longitudinal design in which each participant serves as their own reference over time. This approach allows the evaluation of intra-individual changes in EV-related parameters across the different phases of chemotherapy exposure and recovery. It is particularly suited for biomarker discovery in conditions such as CIPN, where baseline inter-individual variability is high and where the key biological signal of interest is the change from an individual's pre-treatment state. This design also avoids the need for a concurrent untreated control group, which would not be ethically or clinically appropriate in this setting.
EVs will be isolated from plasma using standardized protocols designed to preserve vesicle integrity and minimize contamination from non-vesicular particles. Quantitative analysis will be performed to determine the concentration of circulating EVs, expressed as vesicles per microliter, at each study time point. In addition, qualitative analyses will be carried out to investigate specific components of EV cargo that may be relevant to nerve injury and inflammation. These include selected classes of membrane lipids, such as phosphatidylcholine, sphingomyelin, and cholesterol, which are known to influence membrane stability and signaling, as well as microRNAs involved in neuronal function, stress responses, and neuroinflammatory pathways. The combination of quantitative and molecular profiling is intended to provide a multidimensional view of EV dynamics in relation to chemotherapy exposure.
Clinical evaluation of CIPN will be performed using validated symptom-based questionnaires and objective bedside tests of peripheral nerve function. These assessments capture both patient-reported experience and physician-based measures of sensory impairment, allowing a more comprehensive characterization of neurotoxicity than either approach alone. By relating EV-based measurements to these clinical data over time, the study will explore whether changes in EV concentration or composition precede, accompany, or follow the onset of neuropathic symptoms.
Individual susceptibility to CIPN is influenced by multiple factors, including demographic characteristics, pre-existing neuropathy, and genetic background. Although the primary focus of this study is on EV-derived biomarkers, relevant clinical and demographic information will be collected to allow exploratory analyses of how these factors may interact with EV patterns. This will help to distinguish EV changes that are primarily driven by chemotherapy-induced nerve damage from those that reflect underlying patient-specific characteristics.
Because the study does not modify or assign cancer treatments, all oncologic care will proceed according to standard clinical practice. The additional procedures introduced by the study are limited to blood sampling and non-invasive neurological assessments. These procedures are intended solely to support biomarker analysis and phenotypic characterization of CIPN and are not expected to interfere with therapeutic decisions or outcomes.
By focusing on EVs as circulating indicators of peripheral nerve injury, this study aims to generate data that may support the future development of minimally invasive tools for monitoring neurotoxicity in patients receiving chemotherapy. If specific EV-based patterns are found to be associated with CIPN, this could open the way to earlier identification of at-risk individuals and to more personalized management of neurotoxic side effects, with the ultimate goal of improving quality of life for cancer survivors.
Inclusion Criteria:
Exclusion Criteria:
massimiliano.ruscica@unimi.it0039 0250318220
ornella.garrone@policlinico.mi.it0039 0255032556