A randomized exploratory phase 2 study in patients with chemotherapy-related peripheral neuropathy evaluating whole-body vibration training as adjunct to an integrated program including massage, passive mobilization and physical exercises

Chemotherapy induced polyneuropathy (CIPN) is a frequent toxicity observed after chemotherapy [1], immunomodulatory drugs or proteasome inhibitors [2], but may also occur with a lower incidence after other novel anti-cancer drugs such as arsenic trioxide [3] or brentuximab [4]. The incidence of CIPN is estimated with 38%, in particular if combination chemotherapy was administered [5]. However the incidence varies depending on chemotherapy-schedule, duration of exposure, and assessment methods [6, 7]. Clinically, CIPN is characterized by sensory loss typically in a symmetrical, distal, “glove and stocking” distribution [8] that can lead to substantial interference with activities of daily life by severely disturbing fine motor skills, pain and insomnia. Furthermore, CIPN may be accompanied by motor and autonomic changes [9]. In a recently published meta-analysis including 4.179 patients a prevalence of CIPN was reported in the first month after chemotherapy of 68%, after 3 months of 60% and of 30% after 6 months [1]. Prevention of CIPN has been studied in several trials but without leading to consistent results in subsequent meta-analyses [10, 11]. Neuroprotective therapeutic approaches using amifostine, glutathione, acetyl-l-carnitine, glutamine, calcium/magnesium infusion, and gabapentin or pregabaline showed no or only little efficacy [12] as did adjuvant therapies with herbal medicine [13]. Treatment with electroacupuncture may be a therapeutic strategy for CIPN in patients with multiple myeloma. However, a randomized study is currently not available to confirm the results of the reported small phase-II study [14].

If CIPN is diagnosed during cancer therapy treatment options are limited; trials using antiepileptic or antidepressant drugs have been negative [15‐18]. Recently, one double-blinded randomized trial was positive showing a reduction of chemotherapy-induced peripheral neuropathic pain after 5 weeks of treatment with duloxetine [19].

CIPN heavily affects physical fitness by the severe consequences of loss of peripheral somatosensory information on human balance and locomotion [20, 21]. This observation prompted us to develop a stepwise training program with the aim to improve and specifically train skills necessary for daily life activities [22]. The program was composed of 15 sessions on a biweekly basis of two parts, (i) massage and passive mobilization in posture and transport layers to induce proprioceptive and tactile stimuli and (ii) gymnastics to improve physical fitness. A growing body of evidence indicates improvements of various neuromuscular parameters following whole-body vibration (WBV), such as power, strength, movement velocity, range of motion and in particular balance [23‐26]. However, WBV alone did not yet show a clear benefit for patients with peripheral neuropathy [27]. We hypothesized that applying WBV after massage and passive mobilization in posture and transport layers may harness the potential benefits of WBV to patients with CIPN. Therefore, we conducted an up-front randomized explorative phase 2 trial to investigate whether the addition of WBV to our program has the potential to improve outcome in patients with CIPN.

The aim of our study was to evaluate the relative impact of WBV within a structured training program to treat CIPN. Overall, the addition of WBV resulted in a significant reduction in time needed to complete the CRT (Fig. 2) indicating better fitness and balance as well as a significant reduced WDT (Fig. 3) as read out for improved sensory function after completion of the program.

All 131 patients were treated with massage, mobilization as well as physical exercises and were randomized for the addition of WBV (n = 66) during biweekly treatment sessions. N = 94 reached follow up after 15 treatment sessions. As primary endpoint we used the CRT as a surrogate marker for physical fitness and posture balance; secondary endpoints were Qol, the FACT/GOG-NTX, blinded quantitative sensory testing and physical examination. Based on a recently published meta-analysis a prevalence of CIPN as high as 68% in the first month after chemotherapy was reported with a resolution of symptoms in only 12% of the affected patients after 3 months [1] and persistence of symptoms up to 11 years after chemotherapy [35]. In contrast, in our study all patients experienced marked improvement in physical fitness and posture balance with more than 50% of the patients with a normal CRT, a marked improvement in quality of life based on symptoms and function scores assessed by EORTC QLQ-C30 as well as an improved tendon reflex status. However, still most of our patients suffered from tingling and discomfort in the feet as measured with the FACT/GOG-NTX. Although our study was not randomized versus observation, the overall results suggest an important beneficial impact of massage, mobilization as well as physical exercises in the management of CIPN. Furthermore, WBV applied in addition to this program seems to further improve outcome with in trend less patients suffering from discomfort in the feet, significantly better performance in the CRT and an improved WDT after completion of all training sessions. Compared to attempts with medical therapy using anti-epileptics or antidepressants [15‐18], anti-oxidative and other neuroprotective drugs [11, 12], as well as herbal medicine [13], our approach showed effects measured by objective endpoints including the CRT and the WDT as well as in subjective endpoints measured by the FACT/GOG-NTX. Interestingly, electroacupuncture also showed an improvement of CIPN measured with the FACT/GOG-NTX scale [14]. Due to the heterogeneity of applied chemotherapeutic agents and their combinations as well as limited sample size, we were not able to perform meaningful subset-analyses for selected agents or combinations. However, in our initial sample size calculation we underestimated the effect of massage, mobilization as well as physical exercises alone with a normalized CRT in 56% of our patients after completion of the program in the standard arm and thus we were not able to show the initially projected improvement. Nevertheless, the reported results showed an improvement in objective and subjective endpoints. CIPN affects mostly large Aβ myelinated fibers and unmyelinated C fibers [36]. The function of the unmyelinated C-fibers can be estimated by use of the WDT [33]. By the addition of WBV, we observed a reduction of the WDT by in median 1.1 °C in the experimental arm compared to 0.1 °C (p = 0.03) in the standard arm (Table 2). To our knowledge this is the first time such a finding has been described. A higher WDT was associated with a longer time needed for the CRT and significantly impacted the time needed for the CRT in our multivariable model with repeated measurements. Thus the WDT may be an early read-out of an improvement in CIPN.

In conclusion, the treatment of CIPN with a program including massage, mobilization as well as physical exercises and WBV had a significantly and clinically relevant beneficial impact on symptoms relieve, physical fitness and sensory function. The integration of this program into daily clinical practice is desirable but will require a structured prospective assessment of CIPN and importantly a specialized education of nursing staff.