Assessing Functional Impairments in Patients With Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Background Continuous advancements in diagnosis and treatment of cancer lead to rising numbers of cancer survivors and to increasing life expectancy (Jemal et al., 2023). However, the progress in systemic therapy also brings challenges in the management of side effects. Chemotherapy-induced peripheral neuropathy (CIPN) is one major complication of several anti-cancer therapies, especially of taxanes and platinum salts (Banach et al., 2017). In a meta-analysis of studies investigating taxanes and platinum salts, the average prevalence of CIPN was > 60% in the first 3 months after cessation of chemotherapy and about 30% after 6 months (Seretny et al., 2014). Symptoms usually begin during chemotherapy at a lower intensity and tend to increase if chemotherapy is continued. As a result, dose reductions and, ultimately, discontinuation of chemotherapy are frequently necessary in order to avoid high-grade CIPN, which hampers daily activities and diminishes quality of life (Bhatnagar et al., 2014). In most cases, initially only sensory function is affected (Kroigard et al., 2014), leading to symmetric tingling and hypoesthesia of fingertips and/or tiptoes. If the causing agent is continued, the CIPN symptoms could spread proximally to the fingers, hands, forearms and/or feet and legs, respectively. At a later stage, motor function is also affected, leading to a loss of strength and immobility (Kroigard et al., 2014). Within the first year after chemotherapy, symptoms may not resolve at all (Pachman et al., 2015) or may even intensify (Trivedi et al., 2023). The mechanisms leading to CIPN are complex, multifactorial and still not fully understood. The type of chemotherapeutic agent, its dose and treatment interval have all been shown to influence risk of CIPN (Was et al., 2022; Zajaczkowska et al., 2019). Microtubule disruption, oxidative stress and mitochondrial damage, altered ion channel activity, myelin sheath damage, DNA damage, immunological processes and neuroinflammation may play a key role (Was et al., 2022; Zajaczkowska et al., 2019). Unfortunately, there is still no effective pharmacological or non-pharmacological treatment of CIPN available. Several approaches with antidepressants, antiepileptics, magnesium, calcium, vitamins E and B6, glutamine, glutathione, N-acetyl-cysteine, omega-3 fatty acids, alpha lipoic acid, topical ketamine, acupuncture, or magnetic field therapy have not shown reproducible and significant relief of symptoms (Hershman et al., 2014; Hwang et al., 2020).

Recently, our group was funded by Paracelsus Medical University's Research Promotion Fund (PMU FFF) to investigate home-based electrotherapy using either transcutaneous electrical nerve stimulation (TENS) or high-tone external muscle stimulation (HTEMS) as a new strategy to improve CIPN symptoms (Schaffler-Schaden et al., 2020). This randomized clinical trial demonstrated a significant reduction in sensory and motor symptoms after eight weeks of home-based electrotherapy in both arms, measured with the EORTC QLQ-CIPN20 questionnaire and the grade of CIPN according to CTCAE v4.0 (Sassmann et al., 2024). Further, in secondary data analysis of this study (under review in Frontiers of Neurology),it was observed that TENS and HTEMS improve CIPN symptoms differently. While TENS was effective in diminishing burning pain sensations, HTEMS was able to reduce numbness and tingling of feet and/or hands.

However, our data which indicated treatment success relies on patients' subjective ratings via specific questionnaires (e.g. EORTC QLQ CIPN 20 or C-30). These assessments are all well validated and reliable, but cannot objectively capture the restrictions on everyday life due to CIPN (Park et al, 2019). In order to assess objectively whether an intervention improves patients' everyday lives, additional assessments are needed. In the present study, a novel test battery using functional tasks will be developed and validated against in a cohort of CIPN patients, chemotherapy patients without cipn and matched healthy controls. Once this test battery has been established, a prospective, interventional multicenter study is planned to examine the effects of electrotherapy.

Hereby, it is hypothesized that (1) In CIPN patients, results of the functional tasks correlate to outcomes of the EORTC-QLQ-CIPN20 and EORTC-QLQ-C30 questionnaires.

(2) The performance of CIPN patients in the functional tasks will be lower compared to healthy and chemotherapy patients withou CIPN controls.