Development and prevention of chemotherapy-induced peripheral neuropathy and associated impairments of postural control: The role of physical activity and structured exercise programs

"Avoid inactivity!" is a central statement in the physical activity guidelines, not only for healthy people but also for cancer patients. This clear appeal is based on a body of evidence that has grown exponentially over the last decade, showing that exercise is not – as originally thought – harmful to cancer patients, but can positively influence a number of acute, persistent and late treatment-related side effects. While tumor-related fatigue is probably the most frequently investigated side effect in exercise oncology research, chemotherapy-induced peripheral neuropathy (CIPN) has been addressed much less frequently. CIPN refers to a condition of peripheral nerve damage and degeneration processes caused by various neurotoxic chemotherapeutic agents. Affected patients mainly suffer from sensory symptoms, such as tingling, burning, pain, and numbness in hands and/or feet. A more severe CIPN may also be accompanied by motor symptoms, including e.g. paresis. The frequently resulting functional limitations, which are particularly evident in impaired fine motor skills and postural control deficits, play a key role in the loss of independent performance of various activities of daily living. CIPN thus has a major negative impact on quality of life, but possibly also on recurrence and mortality rates due to chemotherapy dose-modifications with increasing CIPN symptom burden. Effective prevention and treatment measures, however, do not yet exist, creating an urgent need for further research. The cumulative dissertation at hand is therefore intended to con-tribute to this research area by (a) comprehensively analyzing the association between CIPN and postural control of cancer patients before, during and up to six months after neurotoxic chemotherapy, and (b) addressing the preventive potential of exercise on the onset of CIPN during neurotoxic chemotherapy. The underlying three manuscripts are based on the data of a randomized controlled trial (PIC study, prevention of chemotherapy-induced peripheral neuropathy through sensorimotor training), designed to evaluate the preventive potential of regular sensorimotor exercise training (SMT) and resistance training (RT) during neurotoxic chemo-therapy compared to usual care (UC). Within this RCT, comprehensive state-of-the art assessment techniques were used to quantify postural control (center of pressure (COP) analysis via force plate) as well as CIPN signs and symptoms (Total Neuropathy Score, EORTC QLQ-CIPN20 questionnaire). The first manuscript investigated postural control in cancer patients (sub-sample of the UC group, n = 35) before and after neurotoxic chemotherapy and compared these data to healthy aged, gender, height, and weight one-to-one matched controls (HMC, n = 35). Despite a larger proportion of patients showing reduced sensory nerve quality at baseline, postural control did not differ from the HMC population. However, three weeks after completion of neurotoxic chemotherapy, cancer patients showed significantly increased temporal and spatial COP measures in bipedal balance tasks, compared to baseline and HMC. These balance deficits were most evident under visual deprivation. Together with the increased CIPN signs and symptoms shown, this may indicate that the neurotoxic agents have impaired the somatosensory feedback, which was further supported by negative correlations, especially between COP parameters and electrophysiologically assessed sensory and motor nerve function (nerve conduction studies, NCS). The second manuscript completes the postural control analysis i.a. with a description of postural control development within six months after chemotherapy. Interestingly, our UC patients (n = 54) recovered from postural instability despite persisting CIPN signs and symptoms and pathologic NCS findings. Due to this counterintuitive course and because the correlation analyses in Manuscript I revealed only moderate associations of postural control with clinically assessed CIPN signs and symptoms three weeks after neurotoxic chemotherapy, we analyzed whether postural control in cancer patients treated with neurotoxic agents is additionally affected by other factors than CIPN alone. Based on regression models, the influence of age, BMI, sensory and motor nerve function (NCS), physical activity and muscle strength on the course of postural control during and after neurotoxic chemotherapy was analyzed. The regression model showed that worse baseline sensory nerve function was a preventive factor for the impairment of postural control, while worse baseline motor nerve function predicted a greater impairment of postural control. However, no influencing factors for the regeneration of postural control in the follow-up period were found within our models. We assumed, that (pre-)therapeutically disturbed somatosensory inputs may induce adaptive processes, such as muscular co-contractions or sensory reweighting, that have compensatory effects and allow recovery of postural control, while CIPN signs and symptoms and pathologic peripheral nerve function persist. Finally, the third manuscript aimed to provide evidence on the preventive potential of exercise on CIPN. Therefore, the complete PIC study cohort of N = 159 cancer patients were analyzed. Our primary intention-to-treat analysis revealed that neither SMT nor RT was able to prevent the onset of CIPN signs and symptoms during neurotoxic chemotherapy. However, as mean attendance rates within the exercise groups were relatively low (overall 61 %), we excluded non-adherent patients for exploratory per-protocol analysis (attendance rate < 67 %). The results showed that subjectively perceived sensory symptoms in the feet increased less during chemotherapy in the adherent exercisers (pooled group: SMT + RT) compared to UC. Moreover, on the functional level, we identified a better course of muscular strength in favor of this group, but only a trend-level preventive effect for postural control. Additionally, we observed better results in terms of overall quality of life, physical and role functioning, and fatigue in the adherent exercisers, as well as enhanced chemotherapy compliance by means of relative dose intensity. In conclusion, this cumulative dissertation provides comprehensive information about postural control in cancer patients before, during and up to six months after neurotoxic chemo-therapy and its associations to CIPN signs and symptoms, but also CIPN-independent influencing factors. However, the methods used cannot provide a final explanation for the regeneration of postural control despite persisting nerve damage after the end of chemotherapy, which needs to be investigated in future analyses. On the other hand, the present work makes an important contribution to the evaluation of the preventive potential of exercise on CIPN during neurotoxic chemotherapy by demonstrating that SMT and/or RT alleviate subjectively perceived sensory CIPN symptoms in the feet, if an appropriate training stimulus is achieved. Additionally, better chemotherapy compliance was observed in these patients, which may further positively affect recurrence and mortality rates. Even if these results are based on secondary analyses and need to be verified by future studies, they are in line with the large body of evidence in exercise oncology recommending regular exercise throughout the entire cancer continuum