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The preventive effect of sensorimotor- and vibration exercises on the onset of Oxaliplatin- or vinca-alkaloid induced peripheral neuropathies - STOP

The preventive effect of sensorimotor- and vibration exercises on the onset of Oxaliplatin- or... Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and clinically relevant side effect of chemotherapy. Approximately 50% of all leukemia, lymphoma, colorectal- and breast cancer patients are affected. CIPN is induced by neurotoxic chemotherapeutic agents and can manifest with sensory and/or motor deficits. It is associated with significant disability and poor recovery. Common symptoms include pain, altered sensation, reduced or absent reflexes, muscle weakness, reduced balance control and insecure gait. These symptoms not only affect activities of daily living, subsequently reducing patients’ quality of life, they have far more become a decisive limiting factor for medical therapy, causing treatment delays, dose reductions, or even discontinuation of therapy, which can affect the outcome and compromise survival. To date, CIPN cannot be prevented and its occurrence presents a diagnostic dilemma since approved and effective treatment options are lacking. Promising results have recently been achieved with exercise. We have revealed that sensorimotor training (SMT) or whole body vibration (WBV) can reduce the symptoms of CIPN and attenuate motor and sensory deficits. We furthermore detected a tendency that it may also have a preventive effect on the onset of CIPN. Methods: We are therefore conducting a prospective, multicentre, controlled clinical trial involving 236 oncological patients receiving either oxaliplatin (N = 118) or vinca-alkaloid (N = 118) who are randomized to one of two interventions (SMT or WBV) or a treatment as usual (TAU) group. Primary endpoint is the time to incidence of neurologically confirmed CIPN. Secondary endpoints are pain, maintenance of the functionality of sensory as well as motor nerve fibres as well as the level of physical activity. The baseline assessment is performed prior to the first cycle of chemotherapy. Subsequent follow-up assessments are conducted at 12 weeks, after completion of chemotherapy, and at a 3-month follow-up. Patients who develop CIPN receive an additional assessment at this time point, as it represents the primary endpoint. Discussion: We hypothesize that SMT and WBV prevent the onset or delay the progression of CIPN, decrease the likelihood of dose reductions or discontinuation of cancer treatment and improve patients’ quality of life. Trial registration: Deutsche Register Klinischer Studien (DRKS00006088, registered 07.05.2014). Keywords: Exercise, Neuromuscular, Sensory deficits, Motor performance, Quality of life, Cancer therapy, Neurotoxic agents, Physical activity * Correspondence: f.streckmann@dshs-koeln.de; fiona.streckmann@unibas.ch; fiona.streckmann@usb.ch Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933 Cologne, Germany Department of Sport, Exercise and Health, University of Basel, Birsstr. 320B, 4052 Basel, Switzerland Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Streckmann et al. BMC Cancer (2018) 18:62 Page 2 of 10 Background neuropathic patients independent of the cause. We Chemotherapy-induced peripheral neuropathy (CIPN) is found that for toxically induced PNP such as CIPN, caused by neurotoxic agents in cancer therapy. Oxaliplatin balance exercises were most beneficial for motor as well and vinca-alkaloids are two of the main agents responsible as sensory symptoms. for CIPN. Oxaliplatin inhibits DNA synthesis and repair Taking previous findings into consideration, this due to its ring structure, which causes the death of neural strengthened our presumption that SMT played a decisive cells. Vinca-alkaloids cause axonal damage and disrupt role in the study by Streckmann et al. [14], as studies in axonal transport via microtubular damage. The main healthy adults have revealed that SMT has the potential to cancer patients affected by oxaliplatin are colorectal, NHL counteract some of the mentioned side-effects of PNP. and breast cancer patients, while lymphoma patients but SMT is characterized by functional adaptations of the also ALL and pulmonary cancer patients mainly receive neuromuscular system [16, 17], regeneration of neuro- vinca-alkaloids. Peripheral sensory nerves are especially muscular structures [18] and the diminished prevalence of sensitive to toxins. Damage caused to these fibres leads to injuries [19, 20], leading to improved proprioception [17], various sensory and motor dysfunctions. Patients suffer intermuscular coordination and balance control, causing from symptoms such as loss of sensation, apparent as fewer falls [21] and increasing mobility. Furthermore, numbness, tingling or burning, dysaesthesia, reduced or studies with strength training alone or in combination absent Achilles tendon reflexes [1, 2] pain, and loss of with endurance training showed little to no significant balance control leading to instable gait, as well as an intergroup differences. In line with these findings, increased incidence of accidents and falls [3]. Steimann [22] and Vogt [4] evaluated the subjective effect- Even though CIPN is such a prevalent and clinically iveness of physiotherapy (gait training and balance exer- relevant side effect [4], not only diminishing patients’ cises) and ergotherapy (e.g., walking on granulate quality of life, but also leading to treatment delays, dose material), while Steimann also looked at electrotherapy. reductions or even discontinuation of therapy, affecting Both found that patients experienced ergotherapy and the outcome and compromise survival [5], little research physiotherapy as very helpful. One case report on a breast has been done to investigate the potentially beneficial cancer patient, suffering from painful CIPN, showed effects of specific exercises to counteract the various improved balance after balance training [23]. motor and sensory dysfunctions. Targeting similar mechanisms as SMT, though possibly To date, CIPN cannot be prevented and there is no addressing different sensory qualities, whole body vibra- consent regarding the treatment of CIPN. Research has tion (WBV) has also been taken into consideration. focused on pharmacological therapies aimed at reducing Previous studies investigating WBV have shown a posi- CIPN or treating selected side effects while [6–8] this has tive impact on parameters influenced by the side-effects been helpful for neuropathic pain, it does not address the of PNP. Kawanabe et al. [24] and Bogaerts et al. [25] many other side effects of CIPN [9–12]. On the contrary, showed that elderly individuals improve their gait after many of these agents have been shown to have additional vibration exercises. Rittweger [26] and Kirchner et al. negative side effects [13]. An exercise intervention has [27] found WBV to have a positive impact on pain re- now revealed promising results. In a first clinical trial, we duction, while further studies showed an effect on [14] conducted an exercise intervention consisting of deconditioned skeletal muscle [28], improved isometric endurance, strength and sensorimotor training (SMT) strength [26, 29, 30], postural sway [31] and reduced fall twice a week for 36 weeks, accompanying lymphoma frequency [25]. Schönsteiner et al. [32], performed a patients from diagnosis to completion of treatment. The multimodal exercise program containing WBV, massage study revealed a significant reduction of neuropathic and physical exercises with CIPN patients (N = 131), symptoms. Patients exercising were able to reduce CIPN- achieving less symptoms and pain, improved physical related symptoms (e.g., peripheral deep sensitivity) by fitness and better coordination. Both SMT and WBV 87%, while in the control group no change (0%) was require very little time and effort, but have a high detected. After 36 weeks, 55% of the control group still impact. Especially for cancer patients, this aspect plays had symptoms related to CIPN while only 4% remained an important role, as therapy can be very strenuous for with CIPN in the intervention group. the patients. Training and devices are feasible, meet the Furthermore, a positive tendency regarding the requirements of hospital hygiene and are portable for all incidence of CIPN could be detected. Unfortunately, the phases of therapy, even in isolation. Training is therefore sample size was too small in this study to show signifi- even possible during cytopenias, often a limiting factor cant results. The majority of expertise on exercise and for exercise interventions concomitant to therapy. peripheral neuropathy (PNP) arises from research on We therefore conducted a randomized, controlled, patients with diabetic neuropathy. In a systematic review pilot study assessing cancer patients with neurologically [15], we evaluated all exercise intervention studies for confirmed CIPN to either SMT (n = 10), WBV (n = 10) Streckmann et al. BMC Cancer (2018) 18:62 Page 3 of 10 or a control group (n = 10) with no intervention and are given the opportunity to participate in the preferred additionally comparing them to an age- and gender intervention after completion of the study. The interven- matched healthy control group (n = 10). WBV and SMT tions and assessments take place at the respective centers. were feasible for patients with CIPN and both exercise Data is assessed at 3 to 5 measuring time points, groups benefited (improved reflex activity of the depending on the length of medical therapy and a poten- Achilles- and patella tendon), peripheral deep sensitivity tial incidence of CIPN (Fig. 2 and Fig. 3). The baseline and pain) from 6 weeks of intervention twice a week [33]. assessment (T0) is performed prior to the first cycle of To summarize, there are no existing prevention trials chemotherapy. All patients are re-assessed after three assessing the potentially beneficial effects of exercise for the months (T1). For most patients, this is simultaneously onset of CIPN and only very little is known about the effects the post-therapy measurement (Tp) (Fig.2), while for of exercise on the symptoms of CIPN. Based on our previous patients who are treated for more than three months it findings as well as from practical experience with patients, represents an interim assessment (T1) (Fig.3), in order we hypothesize that SMT and WBV prevent the onset of to ensure comparability regardless of the entity. These CIPN on the one hand and/or can influence the progress of patients have an additional assessment upon completion CIPN and associated motor and sensory symptoms such as of their medical therapy (~6 months). The follow-up balance control, coordination and mobility, as well as sensi- measurement is performed three months after comple- tivity, proprioception and pain, enhancing patients’ quality of tion of chemotherapy (T2) in order to compensate for life and assuring the best clinical outcome by enabling any potential coasting effects. Each assessment has a patients to receive their planned therapy regimen. duration of 90 min at most. To ensure the detection of CIPN, patients are informed about possible symptoms of Methods/design CIPN and asked to report back to the study coordinators Study participants and recruitment immediately. Furthermore, patients are regularly asked We plan to enrol 236 newly diagnosed haematological/ for potential symptoms by their physicians. Additionally, oncological patients who are scheduled to receive a short neurological test battery is performed every chemotherapy containing either oxaliplatin or a vinca- 6 weeks. Sports therapists will be blinded and must not alkaloid, aged ≥18 years, with the mental and physical ask patients about CIPN symptoms during the interven- ability to provide signed informed consent and partici- tions in order to obtain comparability with the control pate in the study. Patients are recruited at three partici- group. In case a CIPN is neurologically confirmed, pating centres: The University Hospital of Cologne, the patients are also tested at this time point (Ti). St. Antonius Hospital in Eschweiler and the joint prac- tice for oncology and hematology at the Sachsenring in Assessment - primary endpoint Cologne. Exclusion criteria is a pre-existing neuropathy In order to assess the time to incidence of a neurologic- of other cause. Therefore, patients will be assessed clin- ally confirmed CIPN, a comprehensive Neurophysio- ically for signs of neuropathy and will undergo nerve logical assessment that includes the entire symptom conduction studies prior to randomization. Neuropathy pattern of CIPN, is necessary (Table 1): will be defined electrophysiologically as CMAP ampli- Nerve conduction studies are performed by trained, certi- tude below 5 mV, SNAP amplitude below 5 μV, and fied andblindedexaminers.For patients of the University nerve conduction velocity below 40 m/s of tibial or sural Hospital Cologne as well as the joint practice at Sachsenr- nerve). Further exclusion criteria are previous therapies ing, neurophysiological assessments are performed in the containing neurotoxic agents, any contraindication for Electrophysiology Laboratory of the Department of Neur- whole body vibration (instable bone metastases, acute ology, University Hospital Cologne. Patients in Eschweiler leg thrombosis, a fracture in the lower extremities in the areseenbyalocal neurologist. Assessment methodsare past 2 years, foot ulcers, artificial hips or other osteo- standardized and aligned among the investigators. Further- synthesis), and myocardial infarction, angina pectoris or more, patients are asked not to mention the arm they are heart disease (NYHA III-IV) within the past six months. participating in to the investigators. Examiners are trained by a gold-standard examiner using a standard operating Experimental design procedure and certified prior to the study. The study follows a prospective, randomized controlled design, allocating patients to three groups: an interven- tion group receiving SMT, an additional intervention Nerve conduction studies group receiving WBV, and a control group (Fig. 1). For nerve conduction studies, motor and sensory Patients in the two intervention groups receive a defined nerves are assessed. Compound muscle action poten- exercise program twice a week in addition to treatment as tials (CMAP), distal motor latency, conduction vel- usual (TAU). Patients in the control group receive TAU ocity, and F-waves are obtained from the tibial nerve. Streckmann et al. BMC Cancer (2018) 18:62 Page 4 of 10 The tibial nerve is stimulated at the ankle and poplit- show irregularities, a neuroelectrography is required in eal fosse. Antidromic sensory nerve conduction order to detect and document a possible CIPN. studies are performed in the sural nerve. Sensory The test battery contains the following assessments: nerve action potentials (SNAPs) are recorded from the lateral malleolus with surface electrodes. Skin 1. Peripheral deep sensitivity is evaluated by the temperature is monitored and maintained above 32 °C use of a Rydel-Seiffer tuning fork (128 Hz) with a using a heater if necessary. scale from 0 to 8. Due to age related neural We furthermore conduct a standardized neurological deconditioning, values ≤4 are pathological for clinical test battery that is a feasible assessment method patients ≥60 years old, while for patients under for oncological patients in order to check for first neuro- 60 years old, ≤5isregardedaspathological[34]. pathic symptoms. It is used as a pretest to screen for 2. The Reflex action of the Achilles- as well as the CIPN related symptoms. Should one of the components patellar tendon is assessed with a reflex hammer Fig. 1 Overview of the study design Streckmann et al. BMC Cancer (2018) 18:62 Page 5 of 10 Fig. 2 Measuring time points for patients with 3 months of therapy and graded on a 3-point scale (1 = agile, 2 = weak, 3 maintain an upright position with their knees slightly =missing). flexed (~30°), hands at their side and their gaze straight 3. Sense of position is assessed by asking patients if ahead for 30 s. The cumulative change in sway paths they can recognize a change of position in their first during this period is registered and serves as a measure toe, with their eyes closed. of postural control. To minimize bias through potential 4. Perception of touch is evaluated by learning effects, each position is repeated three times. symmetrically stroking the outsides of the Additionally, failed attempts are recorded should a patient patients’ legs and feet in order to detect reduced seek hold. The tasks become progressively more difficult or altered sensation due to demyelination or as previous studies (see reference [37] for review) have axonal degeneration [30, 35]. shown that postural tasks with different complexity serve 5. The strength of the lower leg muscles is best to test for changes in stance stability after balance assessed by requesting the patient to actively training. To assess the dynamic stance, a balance pad is move their legs against the resistance of the additionally placed on top of the force plate. examiner’s arm. The examiner then grades the strength on a six-point scale (0 = no activity, 1 = Questionnaires visual contraction without motor effect, 2 = FACT/GOG-Ntx - questionnaire The particular sector movement under elimination of gravity, 3 = of the FACT/GOG-Ntx [Functional Assessment of movement under gravity, 4 = movement against Cancer Therapy/Gynaecology Oncology Group – slight resistance 5 = normal force). Neurotoxity] is used to document and assess the severity of the subjective PNP symptoms [38]. This questionnaire Assessment – Secondary endpoints has been validated and contains eleven items which Postural control allow an assessment of the extent of PNP symptoms – A force plate (Leonardo Mechanograph®, Novotec med- from “not at all” to “very much” [25]. ical, Pforzheim, Germany) is used to assess changes in the center of pressure during upright static and dynamic EORTC-QLQ-CIPN20 The EORTC-QLQ-CIPN20 is a stance. The assessment follows a standardized protocol phase IV questionnaire that we are evaluating for N. (see Table 1). Primarily, the supporting foot is deter- Aaronson in the course of this study. It is a 20-item mined with a short test [36]. Patients are asked to questionnaire that was developed to elicit patients’ Fig. 3 Measuring time points for patients with more than 3 months of therapy Streckmann et al. BMC Cancer (2018) 18:62 Page 6 of 10 Table 1 Flow-chart of assessments Baseline T0 T1 Tp T2 Ti Status measurement Time points Prior to first After 3 months After medical 3 month Incidence every 6 weeks cycle of therapy follow-up CIPN therapy Intervention Training 2 x per week throughout entire medical therapy Patients offered to continue Anamnesis I Entity, stadium, pre-treatment, X pre-diseases, allergies, planed therapy, neurological anamnesis, CIPN relevant medication, social anamnesis Anamnesis II Begin of CIPN Symptoms, XX X reception of planed therapy. Amount of cycles, potential change of medication or therapy, CIPN relevant medication Anamnesis III Reception of CIPN relevant Only CG Only CG Only CG medication, therapy of CIPN Neurological Neuroelectrography XX XX X assessment (NCV, Amp) Neurological clinical tests XX XX X X battery Performance Static and dynamic postural XX XX X status control Questionnaires Subjective reduction of XX XX X symptoms (FACT/GOG-Ntx / EORTC CIPN 20) Quality of life (EORTC QLQ-C 30) Neuropathic pain (PainDETECT and VAS) Level of physical activity (FFKA) CIPN Chemotherapy-induced peripheral neuropathy, CG control group, NCV nerve conduction velocity, Amp amplitude, VAS visual analogue scale experience of symptoms and functional limitations re- questions are answered on a Likert scale ranging from lated to CIPN.The CIPN20 has 3 subscales: a sensory, a “not at all” to “very much”, which are summed up to motor, and an autonomic subscale. yield a total score that reflects neuropathic pain status. Pain DETECT is a validated and reliable screening tool EORCT-QLQ-C30 The EORTC-QLQ-C30-question- with high sensitivity, specificity and positive predictive naire is used to assess health-related quality of life. In accuracy [41, 42]. addition to a scale for “global quality of life”, the ques- tionnaire contains five functional scales (physical, emo- FFKA Physical activity levels are evaluated using the tional, social and cognitive functions, and role Freiburger Physical Activity Questionnaire (FFKA), a functions), three symptoms scales (fatigue, pain, nausea/ standardized and validated questionnaire that assesses vomiting), and single item scales of respiratory distress, the physical activities performed by a patient during the insomnia, loss of appetite, constipation, diarrhoea, and past 4 weeks. Based on the patients’ answers, MET- financial problems. The questionnaire has been validated scores are calculated [43, 44]. and translated into 81 languages and has been used in See Table 1 for Flow-chart of all assessments. more than 3000 studies worldwide. It is internationally regarded as reliable [39, 40]. Training program The interventions start immediately after randomization PainDETECT This questionnaire focuses on pain spe- and are continued throughout the entire medical therapy cifically related to PNP. It helps assess patients’ subject- (~3 to 6 months). Training sessions are supervised and ive experience of neuropathy-related pain. The take place twice a week in specific training rooms questionnaire includes 12 items that take the intensity, designed to meet the needs of oncological patients in an progression, and distribution of pain into account. The outpatient setting or during the hospital stay, in one of the Streckmann et al. BMC Cancer (2018) 18:62 Page 7 of 10 centers. Each session lasts for about 15 to 30 min. Recruitment of patients Depending on the type of intervention, the training will Patients are recruited in three centers: The University involve: Hospital Cologne/ CIO Cologne Bonn, the St.-Antonius- Hospital in Eschweiler, and the Oncological Practice at Sensorimotor training consists of progressively more the Sachsenring in Cologne. The numbers of patients difficult balance exercises on progressively instable are based on the average number of patients in the surfaces. Each patient performs 4 exercises per session respective centers per year over the past 2 years, following a standardized protocol (see Table 1). Each considering denial or drop-out and applied to the exercise is performed three times for 20 s, allowing a recruitment period. 40 s rest between each set and a 3-min rest between each exercise, to avoid neuronal fatigue. Patients are Data management and analyses asked to stand barefoot or in socks, their foot in a Data entry is continuously monitored by a data manager previously acquired “short-foot-position”, knees slightly (TN) and will be analyzed by a statistician (ML). For the flexed (30°), and to maintain balance. primary endpoint incident CIPN, censoring will be taken Vibration training takes place on a vibration platform into account by using log-rank tests, and multivariable (Galileo™, Pforzheim, Germany)®. Each training session Cox proportional hazard regression models will be used to consists of four sets of 30 s to 1 min vibration. The test for differences between groups and to estimate treat- frequency of the vibrating platform ranges between 18 ment effects. For categorical secondary endpoints, Fisher’s and 35 Hz with a 2 mm amplitude. Between sets, the exact test and Wilcoxon signed-rank tests and multivari- patients rest for at least 1 min to avoid fatigue. Patients able logistic regression models will be performed. For con- are asked to stand on the platform barefoot and on their tinuous outcomes (including scores derived from self- forefeet or if they are too instable, an 80/20% distribution report questionnaires), t-tests and multivariable linear or of weight on the forefeet rather than the heels. median regression models will be used. Multivariable models will adjust for study center, type of chemotherapy, Each training session allows for individual progression type of cancer, gender, and age. Intention-to-treat analyses within a standardised selection of exercises (see Table 1) will be conducted based on complete cases and on multi- and is documented by the sports therapist. ply imputed data using a conditional imputation [48]. Statistical procedures and sample size estimation Discussion Central computerized randomisation (RITA) using a Expected key results modified minimization procedure with stochastic com- To date there is no prevention or effective treatment for ponent according to Pocock and Simon is performed neuropathies though it presents a diagnostic dilemma as [45]: intervention 1: intervention 2:control = 1:1:1, strati- physicians need to find the balance between patients’ fied by study center and type of therapy (Oxaliplatin, quality of life and the effectiveness of medical therapy. Vinca-alkaloids). In trials under similar conditions, a Our main study aim is therefore to evaluate the potential balanced randomization has been achieved using this of sensorimotor training and whole-body vibration to algorithm [14]. prevent CIPN. We expect that both interventions (SMT Sample size calculation is based on the primary end- and WBV) will be able to prevent or at least postpone point incident CIPN. Power calculation is based on the the incidence of CIPN and in case of occurrence at least following scenario: The assumed incidence rate with reduce the severity of subjective and objective CIPN- TAU is 90%, which was informed by a review of the related symptoms such as loss of peripheral deep sensi- literature. In both intervention groups, we assumed tivity, pain, weakened or absent reflexes or loss of an incidence rate of 75%. The effect size corresponds balance control, enabling patients to receive their to a relative risk of about 0.60, which is a clinically planned medical therapy. A successful implementation meaningful effect size. Using the log-rank test (1-β = would therefore be of high clinical relevance. 0.8, two-sided α = 0.05), we need a total of 196 evalu- able patients, 65 per group [46, 47]. We anticipate a Benefits and risks drop-out rate of 10%, yielding a total of 236 patients Patients have the potential benefit of being able to pre- to be recruited for this study, 79 per group. This cal- vent the incidence of CIPN or at least reduce their culation is conservative as we may achieve additional debilitating symptoms of CIPN without any further power performing the final analysis using a multivari- side-effects. We do not expect any complications. The able Cox proportional hazards regression model interventions have no negative influence on their adjusting for study center, type of chemotherapy, type medical therapy. All groups receive the best medical of cancer, gender, and age. standard. However, we have to account for the possibility Streckmann et al. BMC Cancer (2018) 18:62 Page 8 of 10 that patients with neuropathic pain in the lower extrem- It could assure best clinical outcomes by improving the ities may possibly experience some pain during the side-effects of CIPN without interfering with the vibration exercises at higher frequencies. Due to the low planned therapy regime, impacting supportive care for submaximal intensity, the position taken on the plat- cancer patients. Patients’ mobility, autonomy and activ- form, and the well-established, non-invasive assessment ities of daily living could be maintained. Consequently, methods, we believe the possible risk is very low for patients’ quality of life would be increased. Further pos- patients. The electroneurography is a neurological rou- sible side-effects (e.g., fatigue) could be decreased and tine assessment that is not associated with any specific secondary diseases reduced. Additionally, patients’ social risk. Due to the fact that electricity is used, it is possible reintegration could be enhanced. The results can help that some patients may experience this sensation as develop recommendations for patients suffering from uncomfortable or painful. CIPN, improving supportive care for cancer patients. We furthermore aim at publishing the results in peer- Potential for bias reviewed scientific journals, raising the awareness of the In an exercise intervention study, where patients have to scientific community for this topic. Furthermore, we will be trained and supervised by qualified exercise thera- create guidelines, training recommendations, and man- pists, patients are aware of their allocation to the treat- uals for clinical practice and health care professionals ment or control group. It is therefore essential that that can directly be translated into patients’ everyday investigators performing the assessments are blinded as lives. Finally, our results will form the foundation for to which arm patients are in and are not allowed to train future research on this topic. the patients and vice versa. All measurements are per- Abbreviations formed using highly standardized procedures. Assess- CIPN: Chemotherapy-induced peripheral neuropathy; EORTC-QLQ- ments are standardized as well as aligned among the C30: European Organisation for Research and Treatment of Cancer – Quality of Life Questionnaire – 30 item core questionnaire; EORTC-QLQ- investigators. Patients will additionally be asked not to CIPN20: European Organisation for Research and Treatment of Cancer – reveal the result of randomisation to any investigator Quality of Life Questionnaire – 20 item CIPN-specific questionnaire; FACT- except of course to the exercise therapist. The study can GOG-Ntx: Functional Assessment of Cancer Therapy/Gynaecology Oncology Group – Neurotoxity; FFKA: Freiburger Fragebogen für Körperliche Aktivität – therefore be considered single-blinded. To further level of physical activity questionnaire; PNP: peripheral neuropahy; reduce bias, all three centres are equipped with identical SMT: Sensorimotor training; WBV: whole-body vibration technology enabling optimal conditions for comparable data collection. The study coordinator (FS) is the same Acknowledgements We acknowledge the support of Harald Schubert and Novotec, who are for all study centres and training of study assistants is supplying the vibration- and force plates for the duration of the study as identical. All assessments within an individual are always well as offering advisory and technical support. performed by the same trained investigator. Assessments are performed according to standardized operating pro- Funding This study is funded by the German Cancer Aid (Deutsche Krebshilfe – DKH cedures, at the same time of day, in the same room and 70112048), Buschstraße 32, 53,113 Bonn. The study funders have no maintaining a consistent temperature. Regular meetings influence on study design, collection, management, analysis, and are held to optimize coordination of data collection and interpretation of data, writing of the report, and the decision to submit the report for publication. collaboration among the study centres. Follow-up mea- surements will be carried out by investigators who are Availability of data and materials unaware of the treatment allocation, resulting in an The anonymized datasets used and/or analysed during the current study will unbiased assessment of the outcome. A randomized be available from the corresponding author on reasonable request. study design will essentially rule out confounding. Authors’ contributions FS designed the study protocol. WB, FTB, HCL, MH, VR and ML contributed to Perspectives the design of the study. FS organises the study in all recruiting centres (i.e., Our results may contribute to improved supportive care recruitment, data collection). FS, TE, TS and PH are responsible for patient recruitment and contributed to the protocol. HCL and MB are responsible for in oncology, thereby enhancing quality of life, enabling neurological assessments. CK is responsible for the coordination and conduction the optimal medical therapy in neuropathic cancer of the training in Cologne. VR assist FS and WB in all organisational matters. ML patients and, eventually, possibly even improving is responsible for overall data management and statistical analysis. FS, WB, HCL, MB and ML will furthermore be responsible for data interpretation. FS wrote the survival for these patients. present manuscript. All authors revised the study protocol, read and approved We furthermore expect that the proposed interven- the final manuscript. FS is the guarantor. tions will lead to an improvement of motor and sensory functions (such as balance control, coordination, sensi- Ethics approval and consent to participate The study has received consent by the Ethics Committee of the German tivity, reflexes, pain) impacted by CIPN. It will help Sport University as well as the University Hospital Cologne (see Table 1 for understand the underlying mechanisms of SMT and approvals). Patients are required to give written informed consent prior to WBV on motor and sensory functions impaired by PNP. any study engagement. Streckmann et al. BMC Cancer (2018) 18:62 Page 9 of 10 Consent for publication 15. Streckmann F, Zopf EM, Lehmann HC, May K, Rizza J, Zimmer P, Gollhofer A, Not applicable Bloch W, Baumann FT. Exercise intervention studies in patients with peripheral neuropathy: a systematic review. 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White IR, Carpenter J, Horton NJ. Including all individuals is not enough: lessons for intention-to-treat analysis. Clin Trials. 2012;9(4):396–407. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Pubmed Central

The preventive effect of sensorimotor- and vibration exercises on the onset of Oxaliplatin- or vinca-alkaloid induced peripheral neuropathies - STOP

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Pubmed Central
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© The Author(s). 2018
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1471-2407
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1471-2407
DOI
10.1186/s12885-017-3866-4
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Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and clinically relevant side effect of chemotherapy. Approximately 50% of all leukemia, lymphoma, colorectal- and breast cancer patients are affected. CIPN is induced by neurotoxic chemotherapeutic agents and can manifest with sensory and/or motor deficits. It is associated with significant disability and poor recovery. Common symptoms include pain, altered sensation, reduced or absent reflexes, muscle weakness, reduced balance control and insecure gait. These symptoms not only affect activities of daily living, subsequently reducing patients’ quality of life, they have far more become a decisive limiting factor for medical therapy, causing treatment delays, dose reductions, or even discontinuation of therapy, which can affect the outcome and compromise survival. To date, CIPN cannot be prevented and its occurrence presents a diagnostic dilemma since approved and effective treatment options are lacking. Promising results have recently been achieved with exercise. We have revealed that sensorimotor training (SMT) or whole body vibration (WBV) can reduce the symptoms of CIPN and attenuate motor and sensory deficits. We furthermore detected a tendency that it may also have a preventive effect on the onset of CIPN. Methods: We are therefore conducting a prospective, multicentre, controlled clinical trial involving 236 oncological patients receiving either oxaliplatin (N = 118) or vinca-alkaloid (N = 118) who are randomized to one of two interventions (SMT or WBV) or a treatment as usual (TAU) group. Primary endpoint is the time to incidence of neurologically confirmed CIPN. Secondary endpoints are pain, maintenance of the functionality of sensory as well as motor nerve fibres as well as the level of physical activity. The baseline assessment is performed prior to the first cycle of chemotherapy. Subsequent follow-up assessments are conducted at 12 weeks, after completion of chemotherapy, and at a 3-month follow-up. Patients who develop CIPN receive an additional assessment at this time point, as it represents the primary endpoint. Discussion: We hypothesize that SMT and WBV prevent the onset or delay the progression of CIPN, decrease the likelihood of dose reductions or discontinuation of cancer treatment and improve patients’ quality of life. Trial registration: Deutsche Register Klinischer Studien (DRKS00006088, registered 07.05.2014). Keywords: Exercise, Neuromuscular, Sensory deficits, Motor performance, Quality of life, Cancer therapy, Neurotoxic agents, Physical activity * Correspondence: f.streckmann@dshs-koeln.de; fiona.streckmann@unibas.ch; fiona.streckmann@usb.ch Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933 Cologne, Germany Department of Sport, Exercise and Health, University of Basel, Birsstr. 320B, 4052 Basel, Switzerland Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Streckmann et al. BMC Cancer (2018) 18:62 Page 2 of 10 Background neuropathic patients independent of the cause. We Chemotherapy-induced peripheral neuropathy (CIPN) is found that for toxically induced PNP such as CIPN, caused by neurotoxic agents in cancer therapy. Oxaliplatin balance exercises were most beneficial for motor as well and vinca-alkaloids are two of the main agents responsible as sensory symptoms. for CIPN. Oxaliplatin inhibits DNA synthesis and repair Taking previous findings into consideration, this due to its ring structure, which causes the death of neural strengthened our presumption that SMT played a decisive cells. Vinca-alkaloids cause axonal damage and disrupt role in the study by Streckmann et al. [14], as studies in axonal transport via microtubular damage. The main healthy adults have revealed that SMT has the potential to cancer patients affected by oxaliplatin are colorectal, NHL counteract some of the mentioned side-effects of PNP. and breast cancer patients, while lymphoma patients but SMT is characterized by functional adaptations of the also ALL and pulmonary cancer patients mainly receive neuromuscular system [16, 17], regeneration of neuro- vinca-alkaloids. Peripheral sensory nerves are especially muscular structures [18] and the diminished prevalence of sensitive to toxins. Damage caused to these fibres leads to injuries [19, 20], leading to improved proprioception [17], various sensory and motor dysfunctions. Patients suffer intermuscular coordination and balance control, causing from symptoms such as loss of sensation, apparent as fewer falls [21] and increasing mobility. Furthermore, numbness, tingling or burning, dysaesthesia, reduced or studies with strength training alone or in combination absent Achilles tendon reflexes [1, 2] pain, and loss of with endurance training showed little to no significant balance control leading to instable gait, as well as an intergroup differences. In line with these findings, increased incidence of accidents and falls [3]. Steimann [22] and Vogt [4] evaluated the subjective effect- Even though CIPN is such a prevalent and clinically iveness of physiotherapy (gait training and balance exer- relevant side effect [4], not only diminishing patients’ cises) and ergotherapy (e.g., walking on granulate quality of life, but also leading to treatment delays, dose material), while Steimann also looked at electrotherapy. reductions or even discontinuation of therapy, affecting Both found that patients experienced ergotherapy and the outcome and compromise survival [5], little research physiotherapy as very helpful. One case report on a breast has been done to investigate the potentially beneficial cancer patient, suffering from painful CIPN, showed effects of specific exercises to counteract the various improved balance after balance training [23]. motor and sensory dysfunctions. Targeting similar mechanisms as SMT, though possibly To date, CIPN cannot be prevented and there is no addressing different sensory qualities, whole body vibra- consent regarding the treatment of CIPN. Research has tion (WBV) has also been taken into consideration. focused on pharmacological therapies aimed at reducing Previous studies investigating WBV have shown a posi- CIPN or treating selected side effects while [6–8] this has tive impact on parameters influenced by the side-effects been helpful for neuropathic pain, it does not address the of PNP. Kawanabe et al. [24] and Bogaerts et al. [25] many other side effects of CIPN [9–12]. On the contrary, showed that elderly individuals improve their gait after many of these agents have been shown to have additional vibration exercises. Rittweger [26] and Kirchner et al. negative side effects [13]. An exercise intervention has [27] found WBV to have a positive impact on pain re- now revealed promising results. In a first clinical trial, we duction, while further studies showed an effect on [14] conducted an exercise intervention consisting of deconditioned skeletal muscle [28], improved isometric endurance, strength and sensorimotor training (SMT) strength [26, 29, 30], postural sway [31] and reduced fall twice a week for 36 weeks, accompanying lymphoma frequency [25]. Schönsteiner et al. [32], performed a patients from diagnosis to completion of treatment. The multimodal exercise program containing WBV, massage study revealed a significant reduction of neuropathic and physical exercises with CIPN patients (N = 131), symptoms. Patients exercising were able to reduce CIPN- achieving less symptoms and pain, improved physical related symptoms (e.g., peripheral deep sensitivity) by fitness and better coordination. Both SMT and WBV 87%, while in the control group no change (0%) was require very little time and effort, but have a high detected. After 36 weeks, 55% of the control group still impact. Especially for cancer patients, this aspect plays had symptoms related to CIPN while only 4% remained an important role, as therapy can be very strenuous for with CIPN in the intervention group. the patients. Training and devices are feasible, meet the Furthermore, a positive tendency regarding the requirements of hospital hygiene and are portable for all incidence of CIPN could be detected. Unfortunately, the phases of therapy, even in isolation. Training is therefore sample size was too small in this study to show signifi- even possible during cytopenias, often a limiting factor cant results. The majority of expertise on exercise and for exercise interventions concomitant to therapy. peripheral neuropathy (PNP) arises from research on We therefore conducted a randomized, controlled, patients with diabetic neuropathy. In a systematic review pilot study assessing cancer patients with neurologically [15], we evaluated all exercise intervention studies for confirmed CIPN to either SMT (n = 10), WBV (n = 10) Streckmann et al. BMC Cancer (2018) 18:62 Page 3 of 10 or a control group (n = 10) with no intervention and are given the opportunity to participate in the preferred additionally comparing them to an age- and gender intervention after completion of the study. The interven- matched healthy control group (n = 10). WBV and SMT tions and assessments take place at the respective centers. were feasible for patients with CIPN and both exercise Data is assessed at 3 to 5 measuring time points, groups benefited (improved reflex activity of the depending on the length of medical therapy and a poten- Achilles- and patella tendon), peripheral deep sensitivity tial incidence of CIPN (Fig. 2 and Fig. 3). The baseline and pain) from 6 weeks of intervention twice a week [33]. assessment (T0) is performed prior to the first cycle of To summarize, there are no existing prevention trials chemotherapy. All patients are re-assessed after three assessing the potentially beneficial effects of exercise for the months (T1). For most patients, this is simultaneously onset of CIPN and only very little is known about the effects the post-therapy measurement (Tp) (Fig.2), while for of exercise on the symptoms of CIPN. Based on our previous patients who are treated for more than three months it findings as well as from practical experience with patients, represents an interim assessment (T1) (Fig.3), in order we hypothesize that SMT and WBV prevent the onset of to ensure comparability regardless of the entity. These CIPN on the one hand and/or can influence the progress of patients have an additional assessment upon completion CIPN and associated motor and sensory symptoms such as of their medical therapy (~6 months). The follow-up balance control, coordination and mobility, as well as sensi- measurement is performed three months after comple- tivity, proprioception and pain, enhancing patients’ quality of tion of chemotherapy (T2) in order to compensate for life and assuring the best clinical outcome by enabling any potential coasting effects. Each assessment has a patients to receive their planned therapy regimen. duration of 90 min at most. To ensure the detection of CIPN, patients are informed about possible symptoms of Methods/design CIPN and asked to report back to the study coordinators Study participants and recruitment immediately. Furthermore, patients are regularly asked We plan to enrol 236 newly diagnosed haematological/ for potential symptoms by their physicians. Additionally, oncological patients who are scheduled to receive a short neurological test battery is performed every chemotherapy containing either oxaliplatin or a vinca- 6 weeks. Sports therapists will be blinded and must not alkaloid, aged ≥18 years, with the mental and physical ask patients about CIPN symptoms during the interven- ability to provide signed informed consent and partici- tions in order to obtain comparability with the control pate in the study. Patients are recruited at three partici- group. In case a CIPN is neurologically confirmed, pating centres: The University Hospital of Cologne, the patients are also tested at this time point (Ti). St. Antonius Hospital in Eschweiler and the joint prac- tice for oncology and hematology at the Sachsenring in Assessment - primary endpoint Cologne. Exclusion criteria is a pre-existing neuropathy In order to assess the time to incidence of a neurologic- of other cause. Therefore, patients will be assessed clin- ally confirmed CIPN, a comprehensive Neurophysio- ically for signs of neuropathy and will undergo nerve logical assessment that includes the entire symptom conduction studies prior to randomization. Neuropathy pattern of CIPN, is necessary (Table 1): will be defined electrophysiologically as CMAP ampli- Nerve conduction studies are performed by trained, certi- tude below 5 mV, SNAP amplitude below 5 μV, and fied andblindedexaminers.For patients of the University nerve conduction velocity below 40 m/s of tibial or sural Hospital Cologne as well as the joint practice at Sachsenr- nerve). Further exclusion criteria are previous therapies ing, neurophysiological assessments are performed in the containing neurotoxic agents, any contraindication for Electrophysiology Laboratory of the Department of Neur- whole body vibration (instable bone metastases, acute ology, University Hospital Cologne. Patients in Eschweiler leg thrombosis, a fracture in the lower extremities in the areseenbyalocal neurologist. Assessment methodsare past 2 years, foot ulcers, artificial hips or other osteo- standardized and aligned among the investigators. Further- synthesis), and myocardial infarction, angina pectoris or more, patients are asked not to mention the arm they are heart disease (NYHA III-IV) within the past six months. participating in to the investigators. Examiners are trained by a gold-standard examiner using a standard operating Experimental design procedure and certified prior to the study. The study follows a prospective, randomized controlled design, allocating patients to three groups: an interven- tion group receiving SMT, an additional intervention Nerve conduction studies group receiving WBV, and a control group (Fig. 1). For nerve conduction studies, motor and sensory Patients in the two intervention groups receive a defined nerves are assessed. Compound muscle action poten- exercise program twice a week in addition to treatment as tials (CMAP), distal motor latency, conduction vel- usual (TAU). Patients in the control group receive TAU ocity, and F-waves are obtained from the tibial nerve. Streckmann et al. BMC Cancer (2018) 18:62 Page 4 of 10 The tibial nerve is stimulated at the ankle and poplit- show irregularities, a neuroelectrography is required in eal fosse. Antidromic sensory nerve conduction order to detect and document a possible CIPN. studies are performed in the sural nerve. Sensory The test battery contains the following assessments: nerve action potentials (SNAPs) are recorded from the lateral malleolus with surface electrodes. Skin 1. Peripheral deep sensitivity is evaluated by the temperature is monitored and maintained above 32 °C use of a Rydel-Seiffer tuning fork (128 Hz) with a using a heater if necessary. scale from 0 to 8. Due to age related neural We furthermore conduct a standardized neurological deconditioning, values ≤4 are pathological for clinical test battery that is a feasible assessment method patients ≥60 years old, while for patients under for oncological patients in order to check for first neuro- 60 years old, ≤5isregardedaspathological[34]. pathic symptoms. It is used as a pretest to screen for 2. The Reflex action of the Achilles- as well as the CIPN related symptoms. Should one of the components patellar tendon is assessed with a reflex hammer Fig. 1 Overview of the study design Streckmann et al. BMC Cancer (2018) 18:62 Page 5 of 10 Fig. 2 Measuring time points for patients with 3 months of therapy and graded on a 3-point scale (1 = agile, 2 = weak, 3 maintain an upright position with their knees slightly =missing). flexed (~30°), hands at their side and their gaze straight 3. Sense of position is assessed by asking patients if ahead for 30 s. The cumulative change in sway paths they can recognize a change of position in their first during this period is registered and serves as a measure toe, with their eyes closed. of postural control. To minimize bias through potential 4. Perception of touch is evaluated by learning effects, each position is repeated three times. symmetrically stroking the outsides of the Additionally, failed attempts are recorded should a patient patients’ legs and feet in order to detect reduced seek hold. The tasks become progressively more difficult or altered sensation due to demyelination or as previous studies (see reference [37] for review) have axonal degeneration [30, 35]. shown that postural tasks with different complexity serve 5. The strength of the lower leg muscles is best to test for changes in stance stability after balance assessed by requesting the patient to actively training. To assess the dynamic stance, a balance pad is move their legs against the resistance of the additionally placed on top of the force plate. examiner’s arm. The examiner then grades the strength on a six-point scale (0 = no activity, 1 = Questionnaires visual contraction without motor effect, 2 = FACT/GOG-Ntx - questionnaire The particular sector movement under elimination of gravity, 3 = of the FACT/GOG-Ntx [Functional Assessment of movement under gravity, 4 = movement against Cancer Therapy/Gynaecology Oncology Group – slight resistance 5 = normal force). Neurotoxity] is used to document and assess the severity of the subjective PNP symptoms [38]. This questionnaire Assessment – Secondary endpoints has been validated and contains eleven items which Postural control allow an assessment of the extent of PNP symptoms – A force plate (Leonardo Mechanograph®, Novotec med- from “not at all” to “very much” [25]. ical, Pforzheim, Germany) is used to assess changes in the center of pressure during upright static and dynamic EORTC-QLQ-CIPN20 The EORTC-QLQ-CIPN20 is a stance. The assessment follows a standardized protocol phase IV questionnaire that we are evaluating for N. (see Table 1). Primarily, the supporting foot is deter- Aaronson in the course of this study. It is a 20-item mined with a short test [36]. Patients are asked to questionnaire that was developed to elicit patients’ Fig. 3 Measuring time points for patients with more than 3 months of therapy Streckmann et al. BMC Cancer (2018) 18:62 Page 6 of 10 Table 1 Flow-chart of assessments Baseline T0 T1 Tp T2 Ti Status measurement Time points Prior to first After 3 months After medical 3 month Incidence every 6 weeks cycle of therapy follow-up CIPN therapy Intervention Training 2 x per week throughout entire medical therapy Patients offered to continue Anamnesis I Entity, stadium, pre-treatment, X pre-diseases, allergies, planed therapy, neurological anamnesis, CIPN relevant medication, social anamnesis Anamnesis II Begin of CIPN Symptoms, XX X reception of planed therapy. Amount of cycles, potential change of medication or therapy, CIPN relevant medication Anamnesis III Reception of CIPN relevant Only CG Only CG Only CG medication, therapy of CIPN Neurological Neuroelectrography XX XX X assessment (NCV, Amp) Neurological clinical tests XX XX X X battery Performance Static and dynamic postural XX XX X status control Questionnaires Subjective reduction of XX XX X symptoms (FACT/GOG-Ntx / EORTC CIPN 20) Quality of life (EORTC QLQ-C 30) Neuropathic pain (PainDETECT and VAS) Level of physical activity (FFKA) CIPN Chemotherapy-induced peripheral neuropathy, CG control group, NCV nerve conduction velocity, Amp amplitude, VAS visual analogue scale experience of symptoms and functional limitations re- questions are answered on a Likert scale ranging from lated to CIPN.The CIPN20 has 3 subscales: a sensory, a “not at all” to “very much”, which are summed up to motor, and an autonomic subscale. yield a total score that reflects neuropathic pain status. Pain DETECT is a validated and reliable screening tool EORCT-QLQ-C30 The EORTC-QLQ-C30-question- with high sensitivity, specificity and positive predictive naire is used to assess health-related quality of life. In accuracy [41, 42]. addition to a scale for “global quality of life”, the ques- tionnaire contains five functional scales (physical, emo- FFKA Physical activity levels are evaluated using the tional, social and cognitive functions, and role Freiburger Physical Activity Questionnaire (FFKA), a functions), three symptoms scales (fatigue, pain, nausea/ standardized and validated questionnaire that assesses vomiting), and single item scales of respiratory distress, the physical activities performed by a patient during the insomnia, loss of appetite, constipation, diarrhoea, and past 4 weeks. Based on the patients’ answers, MET- financial problems. The questionnaire has been validated scores are calculated [43, 44]. and translated into 81 languages and has been used in See Table 1 for Flow-chart of all assessments. more than 3000 studies worldwide. It is internationally regarded as reliable [39, 40]. Training program The interventions start immediately after randomization PainDETECT This questionnaire focuses on pain spe- and are continued throughout the entire medical therapy cifically related to PNP. It helps assess patients’ subject- (~3 to 6 months). Training sessions are supervised and ive experience of neuropathy-related pain. The take place twice a week in specific training rooms questionnaire includes 12 items that take the intensity, designed to meet the needs of oncological patients in an progression, and distribution of pain into account. The outpatient setting or during the hospital stay, in one of the Streckmann et al. BMC Cancer (2018) 18:62 Page 7 of 10 centers. Each session lasts for about 15 to 30 min. Recruitment of patients Depending on the type of intervention, the training will Patients are recruited in three centers: The University involve: Hospital Cologne/ CIO Cologne Bonn, the St.-Antonius- Hospital in Eschweiler, and the Oncological Practice at Sensorimotor training consists of progressively more the Sachsenring in Cologne. The numbers of patients difficult balance exercises on progressively instable are based on the average number of patients in the surfaces. Each patient performs 4 exercises per session respective centers per year over the past 2 years, following a standardized protocol (see Table 1). Each considering denial or drop-out and applied to the exercise is performed three times for 20 s, allowing a recruitment period. 40 s rest between each set and a 3-min rest between each exercise, to avoid neuronal fatigue. Patients are Data management and analyses asked to stand barefoot or in socks, their foot in a Data entry is continuously monitored by a data manager previously acquired “short-foot-position”, knees slightly (TN) and will be analyzed by a statistician (ML). For the flexed (30°), and to maintain balance. primary endpoint incident CIPN, censoring will be taken Vibration training takes place on a vibration platform into account by using log-rank tests, and multivariable (Galileo™, Pforzheim, Germany)®. Each training session Cox proportional hazard regression models will be used to consists of four sets of 30 s to 1 min vibration. The test for differences between groups and to estimate treat- frequency of the vibrating platform ranges between 18 ment effects. For categorical secondary endpoints, Fisher’s and 35 Hz with a 2 mm amplitude. Between sets, the exact test and Wilcoxon signed-rank tests and multivari- patients rest for at least 1 min to avoid fatigue. Patients able logistic regression models will be performed. For con- are asked to stand on the platform barefoot and on their tinuous outcomes (including scores derived from self- forefeet or if they are too instable, an 80/20% distribution report questionnaires), t-tests and multivariable linear or of weight on the forefeet rather than the heels. median regression models will be used. Multivariable models will adjust for study center, type of chemotherapy, Each training session allows for individual progression type of cancer, gender, and age. Intention-to-treat analyses within a standardised selection of exercises (see Table 1) will be conducted based on complete cases and on multi- and is documented by the sports therapist. ply imputed data using a conditional imputation [48]. Statistical procedures and sample size estimation Discussion Central computerized randomisation (RITA) using a Expected key results modified minimization procedure with stochastic com- To date there is no prevention or effective treatment for ponent according to Pocock and Simon is performed neuropathies though it presents a diagnostic dilemma as [45]: intervention 1: intervention 2:control = 1:1:1, strati- physicians need to find the balance between patients’ fied by study center and type of therapy (Oxaliplatin, quality of life and the effectiveness of medical therapy. Vinca-alkaloids). In trials under similar conditions, a Our main study aim is therefore to evaluate the potential balanced randomization has been achieved using this of sensorimotor training and whole-body vibration to algorithm [14]. prevent CIPN. We expect that both interventions (SMT Sample size calculation is based on the primary end- and WBV) will be able to prevent or at least postpone point incident CIPN. Power calculation is based on the the incidence of CIPN and in case of occurrence at least following scenario: The assumed incidence rate with reduce the severity of subjective and objective CIPN- TAU is 90%, which was informed by a review of the related symptoms such as loss of peripheral deep sensi- literature. In both intervention groups, we assumed tivity, pain, weakened or absent reflexes or loss of an incidence rate of 75%. The effect size corresponds balance control, enabling patients to receive their to a relative risk of about 0.60, which is a clinically planned medical therapy. A successful implementation meaningful effect size. Using the log-rank test (1-β = would therefore be of high clinical relevance. 0.8, two-sided α = 0.05), we need a total of 196 evalu- able patients, 65 per group [46, 47]. We anticipate a Benefits and risks drop-out rate of 10%, yielding a total of 236 patients Patients have the potential benefit of being able to pre- to be recruited for this study, 79 per group. This cal- vent the incidence of CIPN or at least reduce their culation is conservative as we may achieve additional debilitating symptoms of CIPN without any further power performing the final analysis using a multivari- side-effects. We do not expect any complications. The able Cox proportional hazards regression model interventions have no negative influence on their adjusting for study center, type of chemotherapy, type medical therapy. All groups receive the best medical of cancer, gender, and age. standard. However, we have to account for the possibility Streckmann et al. BMC Cancer (2018) 18:62 Page 8 of 10 that patients with neuropathic pain in the lower extrem- It could assure best clinical outcomes by improving the ities may possibly experience some pain during the side-effects of CIPN without interfering with the vibration exercises at higher frequencies. Due to the low planned therapy regime, impacting supportive care for submaximal intensity, the position taken on the plat- cancer patients. Patients’ mobility, autonomy and activ- form, and the well-established, non-invasive assessment ities of daily living could be maintained. Consequently, methods, we believe the possible risk is very low for patients’ quality of life would be increased. Further pos- patients. The electroneurography is a neurological rou- sible side-effects (e.g., fatigue) could be decreased and tine assessment that is not associated with any specific secondary diseases reduced. Additionally, patients’ social risk. Due to the fact that electricity is used, it is possible reintegration could be enhanced. The results can help that some patients may experience this sensation as develop recommendations for patients suffering from uncomfortable or painful. CIPN, improving supportive care for cancer patients. We furthermore aim at publishing the results in peer- Potential for bias reviewed scientific journals, raising the awareness of the In an exercise intervention study, where patients have to scientific community for this topic. Furthermore, we will be trained and supervised by qualified exercise thera- create guidelines, training recommendations, and man- pists, patients are aware of their allocation to the treat- uals for clinical practice and health care professionals ment or control group. It is therefore essential that that can directly be translated into patients’ everyday investigators performing the assessments are blinded as lives. Finally, our results will form the foundation for to which arm patients are in and are not allowed to train future research on this topic. the patients and vice versa. All measurements are per- Abbreviations formed using highly standardized procedures. Assess- CIPN: Chemotherapy-induced peripheral neuropathy; EORTC-QLQ- ments are standardized as well as aligned among the C30: European Organisation for Research and Treatment of Cancer – Quality of Life Questionnaire – 30 item core questionnaire; EORTC-QLQ- investigators. Patients will additionally be asked not to CIPN20: European Organisation for Research and Treatment of Cancer – reveal the result of randomisation to any investigator Quality of Life Questionnaire – 20 item CIPN-specific questionnaire; FACT- except of course to the exercise therapist. The study can GOG-Ntx: Functional Assessment of Cancer Therapy/Gynaecology Oncology Group – Neurotoxity; FFKA: Freiburger Fragebogen für Körperliche Aktivität – therefore be considered single-blinded. To further level of physical activity questionnaire; PNP: peripheral neuropahy; reduce bias, all three centres are equipped with identical SMT: Sensorimotor training; WBV: whole-body vibration technology enabling optimal conditions for comparable data collection. The study coordinator (FS) is the same Acknowledgements We acknowledge the support of Harald Schubert and Novotec, who are for all study centres and training of study assistants is supplying the vibration- and force plates for the duration of the study as identical. All assessments within an individual are always well as offering advisory and technical support. performed by the same trained investigator. Assessments are performed according to standardized operating pro- Funding This study is funded by the German Cancer Aid (Deutsche Krebshilfe – DKH cedures, at the same time of day, in the same room and 70112048), Buschstraße 32, 53,113 Bonn. The study funders have no maintaining a consistent temperature. Regular meetings influence on study design, collection, management, analysis, and are held to optimize coordination of data collection and interpretation of data, writing of the report, and the decision to submit the report for publication. collaboration among the study centres. Follow-up mea- surements will be carried out by investigators who are Availability of data and materials unaware of the treatment allocation, resulting in an The anonymized datasets used and/or analysed during the current study will unbiased assessment of the outcome. A randomized be available from the corresponding author on reasonable request. study design will essentially rule out confounding. Authors’ contributions FS designed the study protocol. WB, FTB, HCL, MH, VR and ML contributed to Perspectives the design of the study. FS organises the study in all recruiting centres (i.e., Our results may contribute to improved supportive care recruitment, data collection). FS, TE, TS and PH are responsible for patient recruitment and contributed to the protocol. HCL and MB are responsible for in oncology, thereby enhancing quality of life, enabling neurological assessments. CK is responsible for the coordination and conduction the optimal medical therapy in neuropathic cancer of the training in Cologne. VR assist FS and WB in all organisational matters. ML patients and, eventually, possibly even improving is responsible for overall data management and statistical analysis. FS, WB, HCL, MB and ML will furthermore be responsible for data interpretation. FS wrote the survival for these patients. present manuscript. All authors revised the study protocol, read and approved We furthermore expect that the proposed interven- the final manuscript. FS is the guarantor. tions will lead to an improvement of motor and sensory functions (such as balance control, coordination, sensi- Ethics approval and consent to participate The study has received consent by the Ethics Committee of the German tivity, reflexes, pain) impacted by CIPN. It will help Sport University as well as the University Hospital Cologne (see Table 1 for understand the underlying mechanisms of SMT and approvals). Patients are required to give written informed consent prior to WBV on motor and sensory functions impaired by PNP. any study engagement. Streckmann et al. BMC Cancer (2018) 18:62 Page 9 of 10 Consent for publication 15. Streckmann F, Zopf EM, Lehmann HC, May K, Rizza J, Zimmer P, Gollhofer A, Not applicable Bloch W, Baumann FT. Exercise intervention studies in patients with peripheral neuropathy: a systematic review. 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White IR, Carpenter J, Horton NJ. Including all individuals is not enough: lessons for intention-to-treat analysis. Clin Trials. 2012;9(4):396–407. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit

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BMC CancerPubmed Central

Published: Jan 10, 2018

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