Oncol Rev (2010) 4:117–125 DOI 10.1007/s12156-010-0044-1
REVIEW
Treatment strategies for chemotherapy-induced peripheral neuropathy: potential role of exercise Karen Y. Wonders • Beverly S. Reigle Daniel G. Drury
•
Received: 12 January 2010 / Accepted: 11 March 2010 / Published online: 8 April 2010 Ó Springer-Verlag 2010
Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting effect of cancer therapy that often has negative implications on a patient’s quality of life. The pain associated with CIPN has long been recognized as one of the most difficult types of pain to treat. Historically, much effort has been made to explore pharmacological therapies aimed at reducing symptoms of CIPN. While many of these agents provide a modest relief in the symptoms of peripheral neuropathy, many have been shown to have additional negative side effects for cancer patients. Therefore, the authors suggest exercise rehabilitation as one lifestyle modification that may positively impact the lives of patients with CIPN. To our knowledge, there are currently no published clinical trials examining the role of exercise in preserving neurological function following chemotherapy. However, investigations using low-to-moderate intensity exercise as an intervention in patients with diabetic peripheral neuropathy and hereditary motor and sensory neuropathies have produced promising results. Given that cancer patients appear to tolerate exercise, it seems plausible that exercise rehabilitation could be used as an effective strategy to minimize CIPN-induced detriments to quality of life. K. Y. Wonders (&) Department of Health, Physical Education and Recreation, Wright State University, 316 Nutter Center, 3640 Colonel Glenn Hwy, Dayton, OH 45435, USA e-mail:
[email protected] B. S. Reigle College of Nursing, University of Cincinnati, 3110 Vine Street, Cincinnati, OH 45221, USA D. G. Drury Department of Health Sciences, Gettysburg College, Gettysburg, PA 17325, USA
Keywords Chemotherapy-induced peripheral neuropathy Exercise
Introduction Cancer, the second most common cause of death in the US, is a significant national health problem [1]. The American Cancer Society (ACS) [1] estimates that approximately 1.5 million people will develop cancer in 2009 and about 570,000 will die of the disease. Additionally, the financial costs of cancer are substantial, exceeding $220 billion in 2008 [2]. Positively, more than 11.4 million men and women are living today as cancer survivors [3] primarily due to early detection and advances in treatment options [1]. However, such treatments often result in long-term physical and psychological sequelae that impact the cancer survivor’s quality of life [4]. The challenge for health care providers today is to develop systems of long-term follow-up care, address the short- and long-term effects of current cancer therapy, and develop new curative therapies with minimal toxicities [4]. The current armaments for treating cancer include surgery, chemotherapy, irradiation, and biological, hormonal, and targeted therapies [1]. Treating cancer, for the most part, is based on an understanding of cellular kinetics and the growth of tumor cells [5]. By definition, cancer ‘‘is a group of diseases characterized by uncontrolled growth and spread of abnormal cells’’ [1]. Cancer cells involve DNA mutations that often occur during DNA replication. In the normal cell cycle, checkpoints facilitate DNA repair; however, tumor cells lose their checkpoint integrity and escape DNA repair [6]. The resulting mutations impact the regulatory mechanisms that restrict normal cell proliferation [6]. Chemotherapeutic agents, for example, interrupt the cell cycle to prevent cell proliferation [7] and typically are most effective
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when cells are actively dividing [6]. Using a combination of agents rather than just one provides a synergistic cell kill with the potential that less drug-resistant cells remain. The negative side of systemic chemotherapeutic agents is that normal cells, as well as malignant cells, are disrupted leading to many side and untoward effects and often long-term morbidities [7]. Treatment-related morbidities impact functional ability and quality of life. Many co-morbidities are encountered by cancer survivors, including nausea, vomiting, alopecia, fatigue, constipation/ diarrhea, bone marrow suppression, pain, mucositis, sleep disturbances, and peripheral neuropathy [5, 7]. Peripheral neuropathy is the most common neurological side effect of chemotherapy [8]. Damage to the peripheral nervous system caused by chemotherapy is referred to as chemotherapy-induced peripheral neuropathy (CIPN). CIPN is particularly problematic, as it often represents a dose-limiting side effect. The type and etiology of neuropathy is dependent on the chemotherapy agent administered (Table 1). While all drugs do not have the same potential toxicity, vincristine, paclitaxel, and cisplatin are the most neurotoxic [9]. Currently, the neurobiology underpinning CIPN is not fully understood, resulting in ineffective prophylactic and symptomatic treatments [10]. In light of the problems surrounding this treatment-related complication, the National Comprehensive Cancer Network (NCCN), published a multidisciplinary task force report addressing the management of neuropathy in cancer [11]. Thus, the purpose of this paper is to describe the etiology of CIPN as well as its impact on quality of life, delineate the variety of treatment options available to patients with CIPN, and to discuss the potential role of exercise in the management of symptoms related to this disorder.
Etiology of CIPN In healthy individuals, the transduction, conduction, and transmission of nociceptor activity involves peripheral and central nervous system pain pathways, which function in a protective and adaptive manner [12]. Damage to these pathways, whether induced by cancer or its treatments, can result in neuropathic pain [13]. Specifically, damage to small fibers (Ad- and C) produce pain symptoms that are often described as burning, paroxysmal, stabbing, or electric shock-like sensations [14] and are often accompanied by pins-and-needles sensations and itching. Autonomic effects may also result and include hearing loss and tinnitus, blurred vision, dysfunctional color perception, orthostatic hypotension, dizziness, and jaw pain [15, 16]. Pain tends to intensify at night or during cold, damp weather, and is exacerbated by movement of the affected limb [12].
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Clinical diagnosis of CIPN is often complex, as there are often more than one contributing mechanism [17]. The peripheral toxicity involved with CIPN is specific to each chemotherapy drug class, and in most cases, appears to be dose and duration dependent. In general, damage to peripheral nerves by chemotherapeutic agents may result in anomalous somatosensory processing of the peripheral nervous system [18]. Specifically, taxane and vinca alkaloid regimens appear to cause axonal damage [11]. Platinum drugs cause damage to the dorsal root ganglion and result in neuronopathy [11]. Cisplatin has been shown to disrupt axonal microtubule growth, which is necessary for axonal transport [19]. Finally, oxaliplatin toxicity is associated with calcium chelation, resulting in damage to ion channels and synaptic transmission [20]. Diagnostic testing is often multi-faceted and includes neurological examination, quantitative sensory testing, nerve conduction studies, and toxicity grading. Negative symptoms of CIPN include numbness and loss of sensation in the affected extremity. Positive symptoms include hypersensitivity to innocuous and noxious stimuli, such as gentle and/or blunt pressure and pinprick [21, 22]. Often, patients demonstrate hyperalgesia outside the original site of pain application that may extend to homologous sites in the opposite limb. This hyperalgesia is attributed to central sensitization through mechanisms in the dorsal horn of the spinal cord [23]. It is estimated that the incidence of CIPN ranges anywhere from 10 to 100%, depending on the antineoplastic agent, dose, and patient factors [24]. Patients at an increased risk for CIPN include those individuals previously affected by diabetes, alcoholism, or inherited neuropathies [8, 24]. Acute and chronic neurotoxic effects may develop immediately or within weeks or months after the discontinuation of treatment. Vincristine and oxaliplatin-based regimens often produce symptoms immediately following the first course of treatment. Vincristine symptoms include cranialnerve involvement, leading to such symptoms as seizures, quadriparesis, and numbness. Oxaliplatin often produces acute sensory symptoms in the mouth or throat that are exacerbated by exposure to cold [25]. However, other forms of chemotherapeutic agents induce a length-dependent neuropathy on small fibers that often does not present for up to several weeks after the final treatment [8].
Impact on quality of life A number of investigations have examined the relationship between neuropathic pain and health-related quality of life, utilizing such survey instruments as the Brief Pain Inventory and EuroQol to measure the interference of pain on daily activities [26–31]. In general, patients reported that walking was the most affected domain. This was followed
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Table 1 Peripheral neuropathy causing chemotherapy agents Chemotherapy drug class
Chemotherapy agent
Dose causing neurotoxicity
Clinical symptoms
Reversible
Taxane
Docetaxel
[175 mg/m2 cumulative dose
Mild to moderate numbness, tingling, autonomic neuropathy, and decreased joint position sense
Partially
Paclitaxel
[200 mg/m2 every 3 weeks
Burning/stabbing pain of hands and feet, reduced or absent Achilles tendon reflex, and weakness of distal muscles
Yes, rarely permanent
[15 mg cumulative dose
Wrist or foot drop, progressive quadriparesis, seizures, numbness, tingling, and burning pain in hands and feet
Variable recovery
Vinorelbine
[27 mg/m2 cumulative dose
Mild to moderate numbness and tingling of hands and feet, and reduced or absent Achilles tendon reflex
Partially
Oxaliplatin
[300 mg/m2 cumulative dose
Mild to moderate dysesthesias of extremities aggravated by cold, and reduced or absent Achilles tendon reflex
Yes, typically after 4–6 months
Vinca alkaloid
Platinum analogs
Vincristine
Pharmacological agents
Vitamin E Glutamine Venlafaxine Alpha-lipoic acid Venlafaxine
Alpha-lipoic acid Glutamine Carbamazepine Phenytoin Valproic acid Venlafaxin
Other
Cisplatin
[300 mg/m2 cumulative dose
Mild to moderate numbness and tingling of hands and feet, and decreased vibratory sensation, seizures
Yes, typically after one year
Carboplatin
400 mg/m2
Sensory neuronopathy
Improvement after completion of treatment
Thalidomide
[50 mg/day
Sensory painful length-dependent neuropathy
Improvement possible
Bortezomib
Unknown
Sensory or sensorimotor lengthdependent neuropathy, and demyelinating neuropathy
Improvement possible
Epothilones
Unknown
Sensory neuropathy
Improvement possible
Suramin
[350 lg/mL max plasma level
Gullian–Barre syndrome-like neuropathy
Improvement after completion of treatment
by general activities, sleep, work, mood, enjoyment of life, and relation with others [26, 27]. The presence and severity of pain was often shown to be associated with impairments in physical functioning [26–28]. Specifically, pain was found to have a significant and positive impact on physical functioning (r = 0.49, P \ 0.001 and r = 0.59, P \ 0.001) [27, 28]. Neuropathic pain was reported to significantly impact emotional functioning (P \ 0.001) [26] and cause depression and anxiety in patients [26, 27, 29]. In a study conducted by Bergbom-Engberg et al. [29], 32% of people surveyed indicated a decrease in well being due
Alpha-lipoic acid Glutamine Vitamin E
to pain (P \ 0.02). Likewise, both Zelman et al. [27] and Jensen et al. [28] reported significant, positive associations between emotional functioning and pain (r = 0.58, P \ 0.001 and r = 0.57, P \ 0.001, respectively). Social functioning also appears to be impacted by pain, as Zelman et al. [27] and Jensen et al. [28] reported significant, positive associations between this domain and pain (r = 0.60, P \ 0.001; and r = 0.54, P \ 0.001, respectively). Similarly, Galer et al. [28] reported that 50.5% of subjects surveyed reported that pain impacted social functioning. Sleep interference was consistently shown to be significantly associated with neuropathic pain [26–28, 30] as it is
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frequently among the most common pain-related problems reported by individuals with neuropathic pain [26]. In one study, a total of 57.1% of patients surveyed reported that pain disrupted their sleep patterns [30]. Likewise, Zelman et al. [27] and Jensen et al. [28] reported significant positive associations between sleep and pain (r = 0.71, P \ 0.001; and r = 0.51, P \ 0.001, respectively). Tasmuth et al. [31] reported that 50% of patients surveyed indicated that pain affected their global quality of life. Thus, to summarize, research indicates that the more severe the pain, the lower the levels of a patient’s overall quality of life.
Treatment strategies Due to the wide variety of symptoms and their negative impact on quality of life, treatment of neuropathic pain due to CIPN often requires a multidisciplinary approach. Effective treatment strategies may include a combination of pharmacological agents and exercise rehabilitation. Pharmacological agents Much effort has been made to explore pharmacological therapies to reduce CIPN. Some of these therapies provide modest improvements in neurological function. However, in some instances, these agents have been shown to have additional negative side effects for cancer patients. A discussion of some of these agents, their mechanism of action, and side effects follows. Alpha-lipoic acid is a cyclic disulfide broad spectrum antioxidant [32] that has been shown to be effective in animal models of CIPN treated with oxaliplatin, cisplatin, and vincristine. Alpha-lipoic acid has the ability to function in water and fat, enabling it to enter all parts of a nerve. Its mechanism involves regulation of acetyl-CoA, acetylation of tubulin, and increasing NGF-induced histone acetylation [33]. It is involved in the recycling of the antioxidants glutathione, vitamin C, and vitamin E [34] and increases the formation of glutathione. Side effects include headache, tingling, pins-and-needles sensation, rash, and muscle cramps. Carbamazepine is a sodium-channel inhibitor prescribed in the treatment of epilepsy. It has been reported to be effective against certain forms of pain associated with treatment from oxaliplatin, as sodium channel dysfunction is implicated in oxaliplatin-induced peripheral neuropathy [35]. Specifically, carbamazepine has been reported effective against the lancing and shooting pain components and less effective in the burning pain sensations [36]. The use of carbamazepine is associated with dizziness, drowsiness, and headache, as well as cardiac conduction defects,
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abnormalities in antidiuretic hormone secretion, loss of balance, and diplopia [37]. Gabapentin has also been used in the treatment of epilepsy for several years and has only recently been recognized for its role in treating neuropathic pain. Gabapentin was developed as a c-aminobutyric acid (GABA) analog and works by binding with subunits of the calcium channel [38]. While gabapentin has been found to be effective in painful diabetic neuropathy [39], preliminary trials have failed to demonstrate any benefit of the use of gabapentin to treat symptoms of CIPN [40]. In addition, its usage is associated with fatigue, blurred or double vision, muscle pain, swelling in extremities, tremor, and drowsiness [41]. Glutamine is an amino acid that serves as the main energy source for rapidly proliferating cells and plays a key role in the upregulation of nerve growth factor mRNA [42]. Studies involving human subjects indicate decreasing levels of nerve growth factor during therapy [43]. In addition, it has been reported that individuals with cancer typically have reduced levels of glutamine. Collectively, these findings provide support for the use of glutamine as a neuroprotective agent in individuals with cancer. Glutathione is an antiviral tripeptide produced naturally in the body and found within almost all cells. With respect to cancer, glutathione plays both protective and pathogenic roles. There appears to be a relationship between glutathione and glutathione-associated enzyme levels that leads to chemotherapy resistance [44, 45]. Glutathione levels appear to be elevated in bone [46], breast [47], colon [48], larynx [49], and lung [50] cancers. Increased levels of glutathione have been linked to increased chemotherapy resistance due to conjugation and detoxification involving glutathione, glutathione-transferases, and the glutathione S-conjugate export pump [51]. Specifically, resistance has been demonstrated in cisplatin/ifosfamide/vindesine combination therapies [52]. However, it has been reported that the cytotoxic effects of cisplatin may be regulated through the modulation of glutathione levels, via concurrent administration of glutathione and cisplatin. This has resulted in a reduction of CIPN, thought to be brought about by a reduction in platinum deposits [53, 54]. Lamotrigine is a neuroprotective agent that stabilizes sodium channels. In vitro studies suggest that lamotrigine modulates the release of glutamate. Studies examining its efficacy have reported positive effects on diabetic neuropathy [55] and neuropathic pain in the elderly [56]. However, one clinical trial failed to demonstrate any benefit of the use of Lamotrigine to treat symptoms of CIPN [57]. Adverse effects include loss of balance, dizziness, fatigue, memory and cognitive problems, and drowsiness [55]. Phenytoin is an anticonvulsant drug that has recently been reported to be effective at reducing visual analog
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scale pain scores [58]. Phenytoin works as a sodium channel stabilizer that reduces neuronal excitability. Excessive use of phenytoin is associated with neurological problems, including horizontal gaze, as well as loss of balance, drowsiness, dizziness, and inhibited insulin release. Although there is little evidence to support its clinical use, valproic acid has been used extensively in the management of neuropathic pain [59]. Its mechanism of action is unknown, although it is believed to increase levels of GABA in the brain. Side effects of valproic acid include a decrease in blood clotting mechanisms, which may lead to excessive bleeding. In addition, valproic acid is associated with drowsiness, dizziness, nausea, vomiting, and tremors [59]. Traditionally used as an antidepressant, venlafaxine has recently been found to attenuate peripheral nerve hyperexcitability [60]. Venlafaxine works in the selective reuptake of serotonin and norepinephrine. Its side effects include headaches, anxiety, drowsiness, and increased blood pressure. Vitamin E is a fat-soluble antioxidant that inhibits the peroxidation of polyunsaturated fatty acids. Fat-malabsorption disorders are typically associated with peripheral neuropathy, and reports indicate that people with peripheral neuropathy tend to be deficient in vitamin E [61]. Clinical trials have demonstrated evidence of neuroprotection with vitamin E supplementation during treatment with paclitaxel or cisplatin [62, 63], and studies indicate that its usage may reduce mortality rates associated with certain forms of cancer [64]. The prophylactic agents, amifostine, corticosteroids, diethyldithiocarbamate, electrolyte infusions, recombinant human leukemia inhibitory factor, nimodipine, and ORG2766, have also been identified as potential neuroprotective agents in CIPN. However, human studies have shown little or no evidence of neuroprotection [65–71]. Exercise rehabilitation Due to the side effects associated with the use of many pharmacological agents, other interventions that address CIPN should be considered. An intervention that has the potential of preventing or alleviating CIPN is exercise rehabilitation. Several studies have illustrated the beneficial effects of exercise in attenuating numerous cancer treatment-related toxicities and enhancing the quality of life of patients [72–79]. However, to our knowledge, there have been no published clinical trials examining the role of exercise in preserving neurological function following chemotherapy. Numerous studies on the effect of exercise in populations with diabetic peripheral neuropathy and hereditary
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motor and sensory neuropathy have produced promising results that could translate to the cancer population. Specifically, chronic aerobic exercise training has been shown to prevent the onset, or modify the natural history of diabetic peripheral neuropathy [80–82]. In addition, several studies report improvements in muscular strength following moderate resistance exercise programs in patients with hereditary motor and sensory neuropathies [83–86]. Diabetic peripheral neuropathy most often presents as distal symmetric damage to the small and large nerve fibers [80] and is associated with poor glycemic control, obesity, dyslipidemia, retinopathy, microalbuminuria, and smoking [87]. Its exact mechanism is unknown; however, hypotheses center around transitions in sarcoplasmic/endoplasmic reticulum Ca2?-ATPase (SERCA) and the activity of the human epidermal growth factor receptor-2 (ErbB2). SERCA is a 110-kDa integral protein located on the membrane of the sarcoplasmic reticulum and causes muscle relaxation by translocating Ca2? from the cytoplasm to the lumen of the sarcoplasmic reticulum [88]. Molecular cloning analyses have identified three distinct SERCA genes, SERCA1, SERCA2, and SERCA3. These genes encode five Ca2? pump isoforms, each of which are produced by alternate mRNA splicing and are expressed in a developmental and tissue-specific manner [88]. The SERCA1 gene encodes two isoforms, SERCA1a and SERCA1b. Both are entirely expressed in the fast-twitch fibers of skeletal muscle, with SERCA1a predominantly observed in adults and SERCA1b primarily found in the fetal/neonatal stages of life. The SERCA2 gene also encodes two alternatively spliced species. SERCA2a is the primary isoform expressed in the heart and slow-twitch fibers of skeletal muscle, while SERCA2b is ubiquitously expressed in all tissues and found in high levels in smooth muscle tissues. The SERCA3 isoform is restricted to specialized cell types, including epithelial and endothelial cells [89]. The decreased levels of insulin observed in diabetes restricts glucose uptake, thereby affecting the metabolism and function of skeletal muscle [90]. As a result, shifts in skeletal muscle fiber types and SERCA expression tend to be hallmark signs of diabetic peripheral neuropathy. Specifically, research has demonstrated a transition of slow-tofast fiber types in skeletal muscle, with a concurrent decrease in SERCA2a [91]. Another possible mechanism underlying diabetic peripheral neuropathy involves the activity of ErbB2. ErbB2 belongs to a family of genes involved in the regulation of normal tissue growth and development [92]. Genetic evidence demonstrates that increased activity of ErbB2 promotes the development of sensory neuropathies indicative of diabetic peripheral neuropathy. Activation of ErbB receptors may occur by ligand binding [93] or
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overexpression of the receptor [94]. Research has found that the endogenous proteins that regulate ErbB2 activity may influence the development of sensory neuropathies, and inhibition of ErbB2 may decrease the deficits of tactile sensitivity in diabetic peripheral neuropathy [95]. It is possible that changes in SERCA2a expression and activation of ErbB2 may also be involved in the pathogenesis of CIPN. Research indicates that several forms of chemotherapy, including docetaxel- and paclitaxel-based regimens, result in a decreased mRNA expression for SERCA2a transport proteins, leading to impaired skeletal muscle relaxation [96]. In addition, the overexpression of ErbB2 occurs in approximately 20–30% of breast and ovarian cancers [97] and is associated with neoplastic transformation and tumor development [98], as well as shorter time to relapse and lower overall survival [99]. Exercise has been shown to have a local effect on peripheral nerves, inducing changes in both the vasculature and metabolic systems [80]. Short-term exercise stimulates endothelium-dependent vasodilatation and endoneurial blood flow [100]. Long-term exercise has a positive effect on oxygen delivery, as increased blood flow exposes blood vessels to shear stress, which augments vasodilation [101]. Research also demonstrates improvements in Ca2? handling and increased expression of SERCA2a following long-term, moderate endurance training [102–104]. While there have been no investigations to demonstrate the efficacy of exercise training on ErbB2-inhibitors in populations with peripheral neuropathy, one investigation showed that 10 weeks of exercise training attenuated cardiac dysfunction in rats by reducing oxidative stress [105]. Oxidative stress is believed to be an underlying cause of the neuronal damage observed in many forms of peripheral neuropathies [106, 107]. Thus, it is feasible to assume that an individual who has experienced a reduction in muscular strength and functional ability due to CIPN may experience improvements following an exercise program. A second potential benefit of exercise rehabilitation in the CIPN population may be a reduction in pain associated with peripheral neuropathy. This pain has long been recognized as one of the more difficult types of pain to treat, and often is so severe that it interferes with an individual’s quality of life [13]. In healthy subjects, acute exercise has been shown to transiently decrease pain perception; a condition referred to as exercise-induced hypoalgesia (EIH). Specifically, pain thresholds and pain tolerance levels have been reported to increase both during and following exercise. In addition, intensity ratings of pain appear to decrease following exercise. At present, the optimal intensity of aerobic exercise needed to produce a hypoalgesic effect is unknown, but several investigations have been conducted in this area of research [108–113]. In general, aerobic exercise intensities between 60 and 75%
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have been found to produce EIH [108, 109]. In women, hypoalgesia has been reported following aerobic exercise at 85% HRmax [110]. In addition, EIH has been reported following self-selected aerobic exercise intensities, in which the exercise intensity was determined by the subject [111, 112]. Although reports are limited, EIH has also been observed following resistance training exercise. An investigation conducted by Koltyn et al. [113] reported an increase in pain thresholds following 45-min of resistance exercise performed at 75% of an individual’s 1-RM. In light of the above findings, it is plausible to hypothesize that exercise rehabilitation would be beneficial for an individual with CIPN [80–86, 108–113]. Given that cancer patients appear to tolerate a regular physical activity program, exercise rehabilitation is one lifestyle modification that should be recommended to this population to mitigate peripheral nerve damage caused by chemotherapy. The exercise rehabilitation program should help patients adapt to changes in physical functioning. The goals of the exercise rehabilitation program should be to maximize functional capacities, prolong or maintain independent function, and improve quality of life. Studies on populations with hereditary motor and sensory neuropathy indicate that a minimum of 12 weeks of low to moderate resistance training (approximately 30% overload) result in strength gains [83–85] that improve functional ability [86]. It is important to watch for signs that indicate that the muscles are being over-exercised. Symptoms of this include, but are not limited to, muscle weakness within 30 min of the completion of exercise and excessive muscle soreness between 24 and 48 h after the bout of exercise [114, 115]. Aerobic exercise training should also be part of an exercise program, with the intent to increase cardiovascular performance and pain tolerance, and decrease fatigue and depression scores. Available data suggest that the endurance exercise program should be low impact; approximately 50% of the patient’s heart rate reserve [80, 116] and must include a proper warm up and cool down component.
Summary In closing, CIPN is a common, dose-limiting effect of cancer therapy that often negatively impacts a patient’s quality of life. While much effort has been made to explore pharmacological therapies aimed at reducing CIPN, many of these agents have been shown to have additional negative side effects for cancer patients. Exercise rehabilitation is one lifestyle modification that could positively impact the lives of patients with CIPN, provided that the program is of low-moderate intensity and involves a proper warm up and cool down.
Oncol Rev (2010) 4:117–125 Conflict of interest
None.
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