**4.1.** *Pharmacological agents*

There has been much effort put into exploring pharmacological therapies to effectively reduce CIPN. To date, research has shown that some of these therapies provide modest improve‐ ments in neurological function. Unfortunately, in some cases, these agents have been shown to have additional negative side effects for cancer patients. The following text provides a discussion of some of these agents, their mechanism of action, and possible side effects.

Alpha-lipoic acid is a cyclic disulfide broad-spectrum antioxidant [27] that has been recently used in research for treatment of CIPN. It has been shown to be effective in animal subjects of CIPN treated with oxaliplatin, cisplatin, and vincristine. Alpha-lipoic acid has the ability to enter all parts of a nerve because it displays the unique capability of functioning in both water and fat. They utilize this ability and other mechanisms by involving the regulation of acetyl-CoA, acetylation of tubulin, and increasing NGF-induced histone acetylation [28]. Alpha-lipoic acid also increases the formation of glutathione and is involved in the recycling of antioxi‐ dants such as glutathione, vitamin C, and vitamin E [29]. A few possible side effects of the treatment includes headache, tingling, pins-and-needles sensation, rash, and muscle cramps.

Another possible treatment for CIPN is carbamazepine; a sodium-channel inhibitor prescri‐ bed in the treatment of epilepsy. Sodium channel dysfunction is linked to oxaliplatin-in‐ duced peripheral neuropathy [30] and carbamazepine has been reported to be an effective treatment against certain forms of pain associated with oxaliplatin. The reported areas of

effectiveness with carbamazepine have been against the lancing and shooting pain compo‐ nents with less effectiveness seen in burning pain sensations [31]. Side effects of using carbamazepine include dizziness, drowsiness, and headache, as well as cardiac conduction defects, abnormalities in antidiuretic hormone secretion, loss of balance, and diplopia [9].

Another solution used in the treatment of epilepsy that has been recently acknowledged for its role in treating neuropathic pain is gabapentin. Gabapentin has been found to be effective in painful diabetic neuropathy [32] by binding with subunits of the calcium channel [33]. It was originally developed as a γ-aminobutyric acid (GABA) analogue and has been associat‐ ed with symptoms such as fatigue, blurred or double vision, muscle pain, swelling in extremities, tremor, and drowsiness [34].

Previously, it has been reported that individuals with cancer more often than not have shown reduced levels of glutamine. Glutamine is an amino acid that functions as the primary energy source for rapidly proliferating cells. It also plays a significant role in the upregulation of nerve growth factor, mRNA [35]. Additionally, studies involving human subjects report reduced levels of nerve growth factor during therapy [36]. Together, these findings provide support the use of glutamine as a neuroprotective agent in individuals with cancer.

Glutathione is an antioxidant and antiviral tripeptide. It has been reported that concurrent administration of glutathione and cisplatin results in a reduction of CIPN. This is thought to be due to a reduction in platinum deposits, as glutathione has a high affinity for heavy metals [37, 38]. However, increased levels of glutathione have been linked to chemotherapy resistance in bone marrow, breast, colon, larynx, and lung cancers [39].

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 [40] and neuropathic pain in the elderly [41]. Adverse effects include loss of balance, dizziness, fatigue, memory and cognitive problems, and drowsiness [40].

Phenytoin is an anticonvulsant drug that works as a sodium channel stabilizer, which works to reduce neuronal excitability. Phenytoin has recently been seen to be effective at decreas‐ ing visual analogue scale pain scores [42]; however, excessive use of the drug has been associated with neurological problems such as horizontal gaze. Other associated problems include loss of balance, drowsiness, dizziness, and inhibited insulin release.

Valproic acid has been used quite extensively in the management of neuropathic pain [43]; however, there is little evidence to support its clinical use currently. It is believed to increase levels of GABA in the brain, yet its mechanism of action is unknown. Side effects reported with use of the drug include a decrease in blood clotting mechanisms, which may lead to exces‐ sive bleeding. Valproic acid has also been associated with side effects such as drowsiness, dizziness, nausea, vomiting, and tremors [43].

Venlafaxine is a drug that has traditionally been used as an antidepressant, but is currently being looked at for its beneficial effects in cancer patients. Venlafaxine works in the selective reuptake of serotonin and norepinephrine and has been recently found to lessen the hyperex‐ citability of peripheral nerves [44]. However, reported side effects with venlafaxine can include headaches, anxiety, drowsiness, and increased blood pressure.

Vitamins have also been studies as a possible means of controlling symptoms of neuropathy. Vitamin E is a fat-soluble antioxidant that prevents the peroxidation of polyunsaturated fatty acids. Typically in patients with peripheral neuropathy, there is usually an accompanied deficiency of vitamin E [45] and a greater chance of developing fat-malabsorption disorders. Vitamin E supplementation during treatment with paclitaxel or cisplatin [46, 47] has demon‐ strated evidence of neuroprotection in clinical trials. These same trials have indicated that Vitamin E supplementation may reduce mortality rates associated with certain forms of cancer [48].

Other prophylactic agents that have been identified as potential neuroprotective agents in CIPN include amifostine, corticosteroids, diethyldihiocarbamate, electrolyte infusions, recombinant human leukemia inhibitory factor, nimodipine, and ORG-2766. These agents have only been tested in animal populations; however, human studies have shown little or no evidence of neuroprotection [49–55].

### **4.2.** *Exercise rehabilitation*

effectiveness with carbamazepine have been against the lancing and shooting pain compo‐ nents with less effectiveness seen in burning pain sensations [31]. Side effects of using carbamazepine include dizziness, drowsiness, and headache, as well as cardiac conduction defects, abnormalities in antidiuretic hormone secretion, loss of balance, and diplopia [9].

Another solution used in the treatment of epilepsy that has been recently acknowledged for its role in treating neuropathic pain is gabapentin. Gabapentin has been found to be effective in painful diabetic neuropathy [32] by binding with subunits of the calcium channel [33]. It was originally developed as a γ-aminobutyric acid (GABA) analogue and has been associat‐ ed with symptoms such as fatigue, blurred or double vision, muscle pain, swelling in

Previously, it has been reported that individuals with cancer more often than not have shown reduced levels of glutamine. Glutamine is an amino acid that functions as the primary energy source for rapidly proliferating cells. It also plays a significant role in the upregulation of nerve growth factor, mRNA [35]. Additionally, studies involving human subjects report reduced levels of nerve growth factor during therapy [36]. Together, these findings provide support

Glutathione is an antioxidant and antiviral tripeptide. It has been reported that concurrent administration of glutathione and cisplatin results in a reduction of CIPN. This is thought to be due to a reduction in platinum deposits, as glutathione has a high affinity for heavy metals [37, 38]. However, increased levels of glutathione have been linked to chemotherapy

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 [40] and neuropathic pain in the elderly [41]. Adverse effects include loss of balance, dizziness, fatigue, memory and cognitive problems,

Phenytoin is an anticonvulsant drug that works as a sodium channel stabilizer, which works to reduce neuronal excitability. Phenytoin has recently been seen to be effective at decreas‐ ing visual analogue scale pain scores [42]; however, excessive use of the drug has been associated with neurological problems such as horizontal gaze. Other associated problems

Valproic acid has been used quite extensively in the management of neuropathic pain [43]; however, there is little evidence to support its clinical use currently. It is believed to increase levels of GABA in the brain, yet its mechanism of action is unknown. Side effects reported with use of the drug include a decrease in blood clotting mechanisms, which may lead to exces‐ sive bleeding. Valproic acid has also been associated with side effects such as drowsiness,

Venlafaxine is a drug that has traditionally been used as an antidepressant, but is currently being looked at for its beneficial effects in cancer patients. Venlafaxine works in the selective reuptake of serotonin and norepinephrine and has been recently found to lessen the hyperex‐

the use of glutamine as a neuroprotective agent in individuals with cancer.

resistance in bone marrow, breast, colon, larynx, and lung cancers [39].

include loss of balance, drowsiness, dizziness, and inhibited insulin release.

dizziness, nausea, vomiting, and tremors [43].

extremities, tremor, and drowsiness [34].

438 Neurooncology - Newer Developments

and drowsiness [40].

Most preventative and treatments option thus far have come accompanied with a variety of side effects. Due to this, options other than the use of pharmacological interventions that target CIPN should be considered. Exercise rehabilitation is a potential avenue for preventative measures as well as alleviating CIPN symptoms in cancer patients. Many previous research trials have shown beneficial effects of exercise in offsetting countless cancer treatment-related toxicities as well as enhancing the quality of life of the patients. However, clinical trials examining the role of exercise in preserving neurological function following chemotherapy are limited. One recent investigation on the current exercise behaviors of breast cancer patients diagnosed with CIPN patients reported that those individuals who met the amount of recommended physical activity levels reported a significantly higher quality of life and experienced significantly less pain than their sedentary counterparts [56]. A follow-up investigation examined the effect of 12 weeks of supervised exercise training on symptoms of CIPN and found that exercise training positively impacted neurological function. Specifically, unpleasant skin sensations and sensitivity related to neuropathic pain were attenuated following chronic exercise training [57].

While the mechanisms underlying the role of exercise in neuroprotection are unclear, several theories have been circulated. With neuropathy, muscle mass atrophies cause significant decreases in muscular strength [24]. This decline in strength appears to be slow and progres‐ sive. It also appears to affect distal muscle groups more so than proximal muscles. Research‐ ers have indicated that this muscle weakness translates into impaired motor performance skills and a reduced exercise capacity [29]. However, several studies have reported improvements in muscular strength following moderate resistance exercise programs in patients with hereditary motor and sensory neuropathies [20, 21], as well as diabetic neuropathies, and those associated with fibromyalgia and chronic fatigue [3, 26–28, 39, 40]. In light of these findings, many researchers recommend that exercise training serve as an important component in the comprehensive treatment plan for patients with peripheral neuropathy [3, 23, 27]. Moderate to intense strength training and aerobic exercise appears to be well tolerated by these pa‐ tients [23] and is associated with improvements in motor function and nerve conduction velocity [26, 28], as well as improved muscle reinnervation and increased axon regeneration [22]. In addition, one investigation reported that low intensity treadmill exercise promoted Schwann cell proliferation in the injured peripheral nerve [25]. In light of these findings, it is feasible to assume that an individual who has experienced a reduction in muscular strength and functional ability due to CIPN may experience similar improvements following an exercise program.

Those affected by CIPN typically experience large amounts of pain associated with peripher‐ al neuropathy and can be severe enough that it interferes with an individual's quality of life [13]. This type of pain has long been recognized as one of the more difficult types of pain to treat; however, exercise rehabilitation may be able to reduce the amount of pain accompany‐ ing peripheral neuropathy. In healthy individuals, studies have shown that acute exercise can temporarily decrease pain perception; a condition known as exercise-induced hypoalgesia (EIH). Specifically, there have been reported increases in pain thresholds and pain tolerance levels both during and after exercise. Even further, there appears to be a decrease in intensi‐ ty ratings of pain following exercise. To date, research in these areas has yet to determine the optimal intensity of aerobic exercise needed to produce a hypoalgesic effect [58–63]. Typically, exercising at intensities between 60 and 75% of maximum heart rate has been found to produce EIH [58, 59]. Thus far, it has been reported that women tended to experience hypoalgesia following aerobic exercise at 85% HRmax [60]. In most research that has been performed, subject has self-selected their aerobic exercise intensities in which they reported EIH following the exercise bout [61, 62]. EIH has also been observed following resistance exercise training, though reports are limited in this area. In a study conducted by Koltyn and Arbogast [63], it was shown that following 45 min of resistance exercise at 75% of the subject's 1-RM, increases in pain thresholds were observed.

Exercise rehabilitation programs should be designed in order to help patients familiarize themselves to changes in physical functioning. Further, goals of the program should target three main areas: maximize functional capacities, prolong or maintain independent function, and improve quality of life. For example, studies performed using populations with heredi‐ tary motor and sensory neuropathy have shown that a minimum of 12 weeks of low to moderate resistance training (approximately 30% overload) resulted in strength gains [64–66] that improved function ability [67]. An important area of concern for resistance training is watching for signs that indicate the muscles are being over-worked or exhausted. Symptoms of muscle exhaustion include, but are not limited to, muscle weakness within a half hour of completion of the exercise and excessive muscle soreness between 24 and 48 h after exercise [76, 77]. Training programs should also target aerobic exercise due to its associated benefits with cardiovascular performance and pain tolerance as well as decreased fatigue and depression scores. Currently, research suggests that endurance-based programs should be low impact or utilize approximately 50% of the patient's heart rate reserve [68, 69]. Studies in this area also suggest including a proper warm up and cool down component.
