Background
Chemotherapy-induced peripheral neuropathy (CIPN) is caused by neurotoxic agents in cancer therapy. Oxaliplatin and vinca-alkaloids are two of the main agents responsible for CIPN. Oxaliplatin inhibits DNA synthesis and repair due to its ring structure, which causes the death of neural cells. Vinca-alkaloids cause axonal damage and disrupt axonal transport via microtubular damage. The main cancer patients affected by oxaliplatin are colorectal, NHL and breast cancer patients, while lymphoma patients but also ALL and pulmonary cancer patients mainly receive vinca-alkaloids. Peripheral sensory nerves are especially sensitive to toxins. Damage caused to these fibres leads to various sensory and motor dysfunctions. Patients suffer from symptoms such as loss of sensation, apparent as numbness, tingling or burning, dysaesthesia, reduced or absent Achilles tendon reflexes [
1,
2] pain, and loss of balance control leading to instable gait, as well as an increased incidence of accidents and falls [
3].
Even though CIPN is such a prevalent and clinically relevant side effect [
4], not only diminishing patients’ quality of life, but also leading to treatment delays, dose reductions or even discontinuation of therapy, affecting the outcome and compromise survival [
5], little research has been done to investigate the potentially beneficial effects of specific exercises to counteract the various motor and sensory dysfunctions.
To date, CIPN cannot be prevented and there is no consent regarding the treatment of CIPN. Research has focused on pharmacological therapies aimed at reducing CIPN or treating selected side effects while [
6‐
8] this has been helpful for neuropathic pain, it does not address the many other side effects of CIPN [
9‐
12]. On the contrary, many of these agents have been shown to have additional negative side effects [
13]. An exercise intervention has now revealed promising results. In a first clinical trial, we [
14] conducted an exercise intervention consisting of endurance, strength and sensorimotor training (SMT) twice a week for 36 weeks, accompanying lymphoma patients from diagnosis to completion of treatment. The study revealed a significant reduction of neuropathic symptoms. Patients exercising were able to reduce CIPN-related symptoms (e.g., peripheral deep sensitivity) by 87%, while in the control group no change (0%) was detected. After 36 weeks, 55% of the control group still had symptoms related to CIPN while only 4% remained with CIPN in the intervention group.
Furthermore, a positive tendency regarding the incidence of CIPN could be detected. Unfortunately, the sample size was too small in this study to show significant results. The majority of expertise on exercise and peripheral neuropathy (PNP) arises from research on patients with diabetic neuropathy. In a systematic review [
15], we evaluated all exercise intervention studies for neuropathic patients independent of the cause. We found that for toxically induced PNP such as CIPN, balance exercises were most beneficial for motor as well as sensory symptoms.
Taking previous findings into consideration, this strengthened our presumption that SMT played a decisive role in the study by Streckmann et al. [
14], as studies in healthy adults have revealed that SMT has the potential to counteract some of the mentioned side-effects of PNP. SMT is characterized by functional adaptations of the neuromuscular system [
16,
17], regeneration of neuromuscular structures [
18] and the diminished prevalence of injuries [
19,
20], leading to improved proprioception [
17], intermuscular coordination and balance control, causing fewer falls [
21] and increasing mobility. Furthermore, studies with strength training alone or in combination with endurance training showed little to no significant intergroup differences. In line with these findings, Steimann [
22] and Vogt [
4] evaluated the subjective effectiveness of physiotherapy (gait training and balance exercises) and ergotherapy (e.g., walking on granulate material), while Steimann also looked at electrotherapy. Both found that patients experienced ergotherapy and physiotherapy as very helpful. One case report on a breast cancer patient, suffering from painful CIPN, showed improved balance after balance training [
23].
Targeting similar mechanisms as SMT, though possibly addressing different sensory qualities, whole body vibration (WBV) has also been taken into consideration. Previous studies investigating WBV have shown a positive impact on parameters influenced by the side-effects of PNP. Kawanabe et al. [
24] and Bogaerts et al. [
25] showed that elderly individuals improve their gait after vibration exercises. Rittweger [
26] and Kirchner et al. [
27] found WBV to have a positive impact on pain reduction, while further studies showed an effect on deconditioned skeletal muscle [
28], improved isometric strength [
26,
29,
30], postural sway [
31] and reduced fall frequency [
25]. Schönsteiner et al. [
32], performed a multimodal exercise program containing WBV, massage and physical exercises with CIPN patients (
N = 131), achieving less symptoms and pain, improved physical fitness and better coordination. Both SMT and WBV require very little time and effort, but have a high impact. Especially for cancer patients, this aspect plays an important role, as therapy can be very strenuous for the patients. Training and devices are feasible, meet the requirements of hospital hygiene and are portable for all phases of therapy, even in isolation. Training is therefore even possible during cytopenias, often a limiting factor for exercise interventions concomitant to therapy.
We therefore conducted a randomized, controlled, pilot study assessing cancer patients with neurologically confirmed CIPN to either SMT (
n = 10), WBV (
n = 10) or a control group (n = 10) with no intervention additionally comparing them to an age- and gender matched healthy control group (n = 10). WBV and SMT were feasible for patients with CIPN and both exercise groups benefited (improved reflex activity of the Achilles- and patella tendon), peripheral deep sensitivity and pain) from 6 weeks of intervention twice a week [
33].
To summarize, there are no existing prevention trials assessing the potentially beneficial effects of exercise for the onset of CIPN and only very little is known about the effects of exercise on the symptoms of CIPN. Based on our previous findings as well as from practical experience with patients, we hypothesize that SMT and WBV prevent the onset of CIPN on the one hand and/or can influence the progress of CIPN and associated motor and sensory symptoms such as balance control, coordination and mobility, as well as sensitivity, proprioception and pain, enhancing patients’ quality of life and assuring the best clinical outcome by enabling patients to receive their planned therapy regimen.
Discussion
Expected key results
To date there is no prevention or effective treatment for neuropathies though it presents a diagnostic dilemma as physicians need to find the balance between patients’ quality of life and the effectiveness of medical therapy. Our main study aim is therefore to evaluate the potential of sensorimotor training and whole-body vibration to prevent CIPN. We expect that both interventions (SMT and WBV) will be able to prevent or at least postpone the incidence of CIPN and in case of occurrence at least reduce the severity of subjective and objective CIPN-related symptoms such as loss of peripheral deep sensitivity, pain, weakened or absent reflexes or loss of balance control, enabling patients to receive their planned medical therapy. A successful implementation would therefore be of high clinical relevance.
Benefits and risks
Patients have the potential benefit of being able to prevent the incidence of CIPN or at least reduce their debilitating symptoms of CIPN without any further side-effects. We do not expect any complications. The interventions have no negative influence on their medical therapy. All groups receive the best medical standard. However, we have to account for the possibility that patients with neuropathic pain in the lower extremities may possibly experience some pain during the vibration exercises at higher frequencies. Due to the low submaximal intensity, the position taken on the platform, and the well-established, non-invasive assessment methods, we believe the possible risk is very low for patients. The electroneurography is a neurological routine assessment that is not associated with any specific risk. Due to the fact that electricity is used, it is possible that some patients may experience this sensation as uncomfortable or painful.
Potential for bias
In an exercise intervention study, where patients have to be trained and supervised by qualified exercise therapists, patients are aware of their allocation to the treatment or control group. It is therefore essential that investigators performing the assessments are blinded as to which arm patients are in and are not allowed to train the patients and vice versa. All measurements are performed using highly standardized procedures. Assessments are standardized as well as aligned among the investigators. Patients will additionally be asked not to reveal the result of randomisation to any investigator except of course to the exercise therapist. The study can therefore be considered single-blinded. To further reduce bias, all three centres are equipped with identical technology enabling optimal conditions for comparable data collection. The study coordinator (FS) is the same for all study centres and training of study assistants is identical. All assessments within an individual are always performed by the same trained investigator. Assessments are performed according to standardized operating procedures, at the same time of day, in the same room and maintaining a consistent temperature. Regular meetings are held to optimize coordination of data collection and collaboration among the study centres. Follow-up measurements will be carried out by investigators who are unaware of the treatment allocation, resulting in an unbiased assessment of the outcome. A randomized study design will essentially rule out confounding.
Perspectives
Our results may contribute to improved supportive care in oncology, thereby enhancing quality of life, enabling the optimal medical therapy in neuropathic cancer patients and, eventually, possibly even improving survival for these patients.
We furthermore expect that the proposed interventions will lead to an improvement of motor and sensory functions (such as balance control, coordination, sensitivity, reflexes, pain) impacted by CIPN. It will help understand the underlying mechanisms of SMT and WBV on motor and sensory functions impaired by PNP. It could assure best clinical outcomes by improving the side-effects of CIPN without interfering with the planned therapy regime, impacting supportive care for cancer patients. Patients’ mobility, autonomy and activities of daily living could be maintained. Consequently, patients’ quality of life would be increased. Further possible side-effects (e.g., fatigue) could be decreased and secondary diseases reduced. Additionally, patients’ social reintegration could be enhanced. The results can help develop recommendations for patients suffering from CIPN, improving supportive care for cancer patients.
We furthermore aim at publishing the results in peer-reviewed scientific journals, raising the awareness of the scientific community for this topic. Furthermore, we will create guidelines, training recommendations, and manuals for clinical practice and health care professionals that can directly be translated into patients’ everyday lives. Finally, our results will form the foundation for future research on this topic.