Introduction

In recent years, there have been many progress in neoplastic disease treatment, both in terms of diagnosis, through the development of increasingly sensitive analysis tests, and their treatment, through the use of new drugs. Suffice it to say that the number of cancer survivors is rising constantly: for example, in the United States more than 16.9 million Americans (8.1 million males and 8.8 million females) with a history of cancer were alive on January 1st, 2019; this number is projected to reach more than 22.1 million by January 1st, 2030 [1].

With the rise in survivors of different kinds of tumors, there is more and more evidence of drug side effects. Indeed, survivors often develop physical limitations or pathological conditions caused by the chemotherapy treatment, and very often, these side effects are long-lasting, well beyond the end of the chemotherapy treatment [2, 3]. Although very effective for cancer treatment, antineoplastic drugs often determine side effects that can be very serious and could affect the quality of life (QoL). Chemotherapy-induced peripheral neuropathy (CIPN) is among the most relevant complication affecting the peripheral nervous system. Chemotherapy agents can cause a variety of neuropathies involving large and small fibers, with demyelinating and axonal features, determining sensory, motor, or autonomic dysfunction [4]. Prevalence of neuropathies is high (19–85%) especially if predisposing factors are present, including age, preexistent neuropathy, renal or hepatic function impairment, exposures to other neurotoxic agents, paraneoplastic antibodies, and independent cancer-associated neuropathy [5].

In the last few years, there has been an increase in the literature about the prevention and treatment of CIPN and the role of physical activity (PA) in managing the side effects of chemotherapy treatments.

PA for cancer survivors is recommended according to the international guidelines proposed by the sports medicine associations, such as the American College of Sports Medicine (ACSM), American Heart Association (AHA), American Cancer Society (ACS), and US Department of Health and Human Services (US DHHS) [6–8]. All these guidelines are similar, with minor variations.

In a concept paper published in 2017, a different approach has been proposed which takes into account the different characteristics of the European population compared to the American one, to provide a more suitable tool. These guidelines are not validated but adhere closely to the ACSM model [9].

Although it seems clear how the studies recognize the PA as an important role in terms of re-education to movement, countering negative effects, and QoL in cancer survivors, there are few references to the specific problem of CIPN.

This review aims to provide an overview of the role of PA as an adjunct preventative treatment for CIPN.

Methods

Pubmed and Scopus databases have been searched using various combinations of keywords related to CIPN and exercise and results were limited to manuscripts published in the last 20 years.

Studies had to include a PA intervention on cancer patient survivors who developed CIPN. Regardless of the design chosen by the authors, studies had to include a pre and post evaluation in order to assess the effect of the PA on patients at least as regards improvement of CIPN, balance, or QoL.

Further inclusion criteria were: English language, one or both genders from all races, all ages, and any diagnosis of cancer. Cross-sectional studies, case reports, published abstracts, dissertation materials, and conference presentations were not included.

The studies considered most influential, have been inserted in a summary table (Table 1) where the types of PA administered, quantity, and the respective effects of the intervention have been underlined.

CIPN

From a clinical point of view, CIPN may appear with different symptoms, which are caused by the action of chemotherapeutic agents on nerves.

These symptoms often involve sensory aspects, such as numbness, widespread pain, hypersensitivity to mechanical and cold stimuli, paresthesia, and loss of proprioception. CIPN could affect the QoL and increase the risk of falling as well [10].

Sensory disturbances usually reflect the underlying length-dependent sensory neuropathy that progresses with a subacute course affecting distal limbs first and eventually progressing in a distal-proximal direction.

Symptoms could appear both while taking medication (e.g., typically using platinum-based drugs) [21], and even a long time after treatment, in a condition called “coasting” [22].

It is very common for patients to develop tingling and numbness in the hands and feet during the first year of chemotherapy treatment follow-up. Symptoms in the lower limbs typically last longer than those in the upper limbs [23].

The mechanisms of action and molecular target of these chemotherapeutic agents are diverse and include both DNA and microtubular targets to arrest cell division and induce cell death. The pathobiology of CIPN, irrespective of the causative agent, shares some important similarities. For example, sensory neurons are those most affected and longer axons are damaged first. Histopathological changes associated with CIPN commonly involve large, myelinated fibers and result in sensorimotor symptoms such as hypersensitivity to mechanical stimuli or distal weakness due to mechanisms that are not entirely understood [24, 25].

There are six main substance groups that may damage peripheral sensory and motor fibers: platinum-based antineoplastics (particularly oxaliplatin and cisplatin), vinca alkaloids (particularly vincristine and vinblastine), epothilones (ixabepilone), taxanes (paclitaxel, docetaxel), proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide) [24].

Antineoplastic drugs may induce CIPN with different timing and modalities. Platinum-based drugs have the highest incidence of neurotoxicity with a rate ranging from 70% to 100% of all treated patients [26]. Furthermore, oxaliplatin may induce neuropathy in the very early phase of the treatment [27]. The mechanism of action of platinum-based drugs develops damage to the nucleus inhibiting the DNA replication and mRNA transcription [24].

Vinca alkaloids, used mainly to treat lung, brain, and bladder testicular cancer, may determine CIPN in up to 20% of treated patients [26]. The cytotoxic action of vinca alkaloids is provoked by its ability to bond the β-subunit of tubulin and inhibits microtubule formation [24].

The ixabepilone is an analog of epothilone B used in breast cancer patients and belongs to a relatively new class of anti-cancer drugs that act as tubulin destabilizers effectively preventing divisions of cancer cells. Evidence from clinical trials showed that 65% of patients treated with ixabepilone demonstrated symptoms of neuropathy, therefore reflecting a high incidence of CIPN [26]. Taxanes are drugs used for different types of cancer: breast, ovarian, lung, pancreatic, and prostate cancer. In relation to the type of taxanes used, there is a variety in the incidence of CIPN ranging from 11% to 87% [26]. Proteasome inhibitors are drugs used against multiple myeloma and achieve their anticancer effects by inhibiting the activity of the proteasome of cancer cells. This leads to an accumulation of aberrant proteins, hence the arrest of the cell cycle and finally to apoptosis. These drugs determine a moderate (20–30%) incidence of CIPN [26].

Immunomodulatory drugs such as thalidomide cause lower limb neuropathies estimated to affect 20% to 60% of all cancer patients treated with this drug [26].

Long-term effects of CIPN consist of depression, insomnia, and worse QoL. Although some risk factors have been identified such as age, pre-existing neuropathy, nutrient deficiency, and concomitant drugs facilitating neurotoxicity, these are difficult to overcome and CIPN incidence is still very high [28].

Literature on long-term effects is still very sparse, especially regarding the effects of thalidomide and bortezomib. In addition, there is ample literature regarding the effects of chemotherapy drugs but, only recently some studies have been considered the QoL of cancer patients with CIPN.

Prevention and therapy

Effect of PA in subjects with CIPN

The positive effects of PA in patients with CIPN have now been demonstrated by several studies. Indeed, it now seems well known how a resistance or endurance exercise program can significantly reduce the side effects of adjuvant therapies involving peripheral neuropathies [41].

A study conducted on mice has shown that PA carried out beforehand at the beginning of adjuvant therapy with paclitaxel, could have a preventive effect on the onset of thermal hypoalgesia and prevent the reduction of the number of unmyelinated axons [42]. Furthermore, although the data were not significant, a reduction in the diameter of the axons was noted in the group that did not perform exercise.

Apart from sensory deficits, antineoplastic drug cumulative dose, and cycle number, the risk of falls in persons with CIPN includes the severity of muscle weakness and performance status [43]. A recent review highlighted that PA always produces a positive effect on subjects, regardless of the type of exercise, dosage, and setting [44]. It was also pointed out that studies show a moderate/high risk of bias in addition to considering only an adult population. The same review also argues that, although endurance exercise appears to be very effective in counteracting the limiting effects of CIPN, no studies tested aerobic exercise alone to ameliorate CIPN.

In fact, a randomized controlled trial study by Kneis et al. [11] developed a protocol in which the control group performed only aerobic activity, and it was then compared to the intervention group where balance exercises were added. In this study, both groups benefited from their respective PA program in terms of neuropathy-related symptoms, suggesting that even endurance exercises alone can be effective in counteracting CIPN [11].

Due to the physiological diversity of the subject’s conditions, antineoplastic drug type and dose, and the difficulty of quantifying the degree of CIPN, the studies that have dealt with this topic show many differences both in type and quantity of exercises carried out. Although the benefit of a PA intervention is well established, it is not easy to find a standardization of the exercises to propose.

In a randomized study, Courneya et al. [45] showed how a higher intensity activity can be more effective than moderate activity for younger, normal weight, and more fit subjects [45]. This implies that individuals require different doses of PA depending on their baseline conditions.

Vollmers et al. [14] structured an intervention where subjects exercised twice a week during the course of chemotherapy and for six weeks thereafter. Although there are no details on the sensorimotor exercises performed, an increase in postural stability was detected in the intervention group [14].

Some authors have chosen an activity throughout the week, even every day [13, 14] while others have administered PA two or three times per week [14, 15]. However, all authors obtained encouraging results from their respective training protocols.

The methodology for carrying out the protocol is also at the discretion of the authors. Some prescribe exercises in a gym or in a specialized clinic, instead, other authors have the subjects carry out the training program independently at home [13, 17, 18]. Subjects are instructed about how to perform the exercises and, in some cases, also about effort perception in order to remain within predefined parameters avoiding excessive or insufficient training.

A mixed methodology was also used one group carried out the activity in the gym at a higher intensity (OnTrack: a moderate- to high-intensity, combined supervised resistance and aerobic exercise program), while another group carried out a more moderate home training program called “Onco-Move”: a low-intensity, home-based PA program. Although both programs produced positive outcomes, the group that performed higher intensity training reached better results [19].

Another mixed methodology was developed by McCrary et al. [20] in which a single group alternated exercises in a gym, assisted by an operator, and exercises carried out independently at their own home. Also, in this case, there was an improvement in the symptoms of CIPN as well as static and dynamic balance [20]. The Table 1 shows a summary of the studies assessing the effects of PA in relation to the type of exercise carried out.

It seems clear that there is no standardized methodology to evaluate the effects of PA in terms of methods of administering the exercises: type of activity, duration, and intensity.

However, it seems clear that, regardless of the method and exercises are chosen, the effects are always ameliorative compared to the control groups that do not carry out any type of activity. Notably, it would be useful to further investigate the effects of aerobic exercise alone as already proposed by Kanzawa-Lee et al. [44].

Conclusions

We could not find standardized protocols indicating which type of PA is better for subjects with CIPN, and no uniformity in the modality, quantity, or intensity of the exercises.

Perhaps this is because samples are always different and not homogeneous as regards age, medical therapy, and entry physical condition.

More randomized controlled trials are needed to assess the efficacy of specific exercise interventions in order to confirm the efficacy of a single type of PA and provide information to the clinicians about which kind of exercise is preferred to manage CIPN symptoms.

It seems that aerobic PA plays a decisive role against CIPN symptoms since aerobic exercise-containing interventions led to significant CIPN benefits [44].

Since endurance PA determined encouraging results in all studies, it is reasonable to think that this type of PA is to be preferred in the management of neuropathies. Walking may also be useful to improve dynamic balance.

As already suggested by Kanzawa-Lee et al. [44], it would be advisable to develop more protocols that use this training modality to better understand its value.

However, it seems clear that PA plays a decisive role in significantly reducing the side effects of chemotherapy compared to physical inactivity or usual care. The improvement effect of PA and a better QoL is a consequence of the improvement of specific training aspects (strength, balance, endurance). Exercise seems the best, non-invasive, and side-effect-free practice as an adjuvant treatment of CIPN.

Furthermore, in most of the studies, PA at home or supported by an operator in specialized structures (labs or gym) is the preferred modality. Future studies could consider PA performed in groups rather than individually in order to evaluate the positive effects on mood and motivation.