Age-related patterns in chemotherapy-induced peripheral neuropathy across outcome measures: A rapid review

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-dependent side effect of chemotherapy regimens including taxanes, platinum drugs, vinca alkaloids and proteasome inhibitors. It is caused, in part, by microtubule disruption, dysregulation of mitochondrial calcium, damage to mitochondrial DNA, inflammation, glutamate imbalance and other disruptions that affect neuronal axons. CIPN presents as a constellation of sensory, motor, and autonomic signs and symptoms in approximately 19 to 85% of people undergoing treatment with these agents. Common manifestations include numbness, tingling, hypoesthesia, allodynia, pain, balance problems, cramps, and dizziness. The pattern and severity of these signs and symptoms vary widely among people, with some experiencing a single symptom or very few, and others experiencing a combination of many. Older age may be an important risk factor for CIPN, due in part to aging-related factors such as comorbidities (e.g., diabetes), renal impairment leading to reduced drug elimination, and slower nerve conduction and neurotransmitter release resulting from demyelination. With the aging population and advances in treatments improving survival rates, many older survivors will be forced to cope with the negative impacts of cancer treatments in addition to normal age-related health challenges. A better understanding of CIPN in the context of aging could lead to the design of age-tailored treatments that address the unique needs of adults across different life stages. Unfortunately, our understanding of aging and CIPN remains extremely limited. Numerous types of health outcome measures exist, each providing distinct ways to assess health status and evaluate the benefits and adverse effects of interventions in clinical trials and other research contexts. Patient‐reported outcome measures (PROMs) capture patients’ own perspectives on their health condition through validated questionnaires. Performance-based outcome measures (PerfOMs) assess functional abilities using standardized tests that require specific equipment or procedures and the involvement of a trained professional. Observer-reported outcome measures (ObsROM) rely on observations of behaviours and health-related incidents by family members, caregivers, or anyone other than the patient or a health professional. Clinician-reported outcome measures (ClinROMs) are assessments of a patient’s condition, functional or cognitive behaviour and clinical signs that are evaluated and interpreted by a health professional. Lastly, Biomarker outcomes or Laboratory values involve the analysis of biological samples collected and processed using standard protocols. A major challenge to our understanding of CIPN across the adult lifespan is that there are many measures of CIPN, but no gold standard measure. Commonly used PROMs include questionnaires like the EORTC QLQ-CIPN20 and the FACT-GOG NTX which measure patient self-reported severity of sensory, motor and autonomic symptoms. A widely used ClinROM is the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE), which allows clinicians to grade the severity and impact on daily activities of adverse events, such as CIPN, on a grade from 1 (asymptomatic, mild symptoms) to 5 (death). PerfOMs like the Timed Up and Go measure balance and falls. Biomarkers, including liver enzymes such as ALT and AST, have also been associated with CIPN. As a result of the lack of a gold standard, studies typically rely on a mix of outcome measures and outcome measure types to describe patients’ CIPN experience. However, important differences may arise across outcome measurement types. Several factors may contribute to these inconsistencies: symptom severity may be assessed differently across raters; clinicians or even patients may underestimate, overlook, or underreport CIPN; and subtle CIPN-related changes over time may be more difficult to detect with some measurement types than others. There are currently no comprehensive reviews examining age-related patterns in the experience or manifestation of CIPN. Identifying these patterns across multiple outcome measure types is essential to understanding how CIPN presents across the adult lifespan. As cancer survival improves and the population ages, clarifying the relationship between age and CIPN is increasingly important to understand how to tailor treatment strategies to sustain quality of life as patients age. Aims 1) Describe the relationship between age and CIPN among adults treated with neurotoxic chemotherapies; 2) Document patterns in these relationships across outcome measure types.