**1. Introduction**

Currently the chemotherapeutic drugs are part of cancer treatment. Among their side effects, neurotoxicity at peripheral nervous system is a well recognize dose-limiting side effect. It is relevant because it causes persistent pain and sensory loss in cancer survivors. The prevalence of chemotherapy-induced peripheral neuropathy (CIPN) has been reported around 30% of patients at 6 months after treatment. It reaches up to 40% when patients are also examined with nerve conduction studies [1]. It is important to note that neurotoxicity could be subclinical, it means that it may start before patient starts to be symptomatic.

The clinical picture at presentation of CIPN is a length-dependent sensory polyneuropathy despite other combination of sensory, motor and autonomic nerve dysfunction are possible. It is important to recognize different types of sensory nerve fibers which are specific to different sensory modalities (touch, vibration, temperature and pain). All of these neurons have their cell bodies in the dorsal root ganglion (DRG). The thin-myelinated Aδ fibers and unmyelinated C fibers are known as small nerve fibers carrying thermal and painful stimulus to the brain. We need selective neurophysiological and histological techniques to evaluate them as well as to examine the function of the autonomic nervous system [2].

#### **Figure 1.**

*Different targets to produce neurotoxicity by chemotherapy.*


#### **Table 1.**

*Classification of commonly used chemotherapy drugs related to elevated risk of CIPN.*

*Chemotherapy-Induced Peripheral Neuropathy: Mechanisms and Clinical Assessment DOI: http://dx.doi.org/10.5772/intechopen.100495*

The most neurotoxic families of chemotherapeutic drugs are the platinum derivates (e.g. oxaliplatin, carboplatin or cisplatin), taxanes (e.g. paclitaxel and docetaxel), vinca alkaloids (e.g. vincristine), proteasome inhibitors (e.g. bortezomib) and immunomodulators (e.g. thalidomide and checkpoint inhibitors). Others, as methotrexate or arsenic salts are less frequently used. See **Figure 1** a general schema with different targets on the peripheral nervous system and in **Table 1** a list of them with their mechanism of neurotoxicity.

### **2. Acute neurotoxicity**

There are drugs that can produce acute neurotoxicity, a side effect commonly seen with oxaliplatin. It is characterized by transient paresthesia, dysesthesia and muscle cramps induced by cold exposure, a phenomenon often called cold allodynia that typically appears during or immediately after infusion of the treatment. It usually resolves within a few hours or days before the next oxaliplatin cycle [3]. Symptoms reported by patients include tingling paresthesia in the hands (100%), feet (42%) and orofacial area (50%) and also, pharyngeal or laryngeal regions, all of them triggered by cold (especially when drinking). More infrequently, patients report fasciculations (29%), jaw spasms (26%), cramps (20%), difficulty of swallowing (18%) and neuromyotonia-like syndrome. All these phenomena reveal an increase in sensory and motor nerve excitability related to the impairment of voltage-gated sodium channels induced by oxaliplatin [4]. A functional study demonstrated that oxaliplatin induces reversible slowing of sodium channel inactivation [5]. We know that it does not require discontinuation of treatment or dose reduction, but prolonging the time of infusion from 2 h to 4 or 6 h is recommended [6]. Some authors have found a relationship to later develop of chronic neuropathy [7, 8]. In particular when cold allodynia persists for days or weeks after infusion. Even some patients, continued to report residual symptoms in subsequent doses of oxaliplatin [9]. Another symptom that patients frequently ask is the Lhermitte's sign, a sudden lightening sensation radiate out into both arms or feet when neck flexion is forced. The mechanism to produce it at cervical spinal cord is unknown but usually self-limited despite in some exceptional cases it could appear lately and be persistent during months [10, 11].

It has been described in addition acute sensitization of nociceptors with paclitaxel, the paclitaxel-associate acute pain syndrome. It consists of aching or other pain sensations mainly at lower legs peaked on day 4 after paclitaxel initiation. This is related to fast infusion of treatment (3 hours) but also, indicates more risk to sensory neuropathy after 12 weeks of therapy [12].

#### **3. Targets of neurotoxicity at peripheral nerves**

Even when all body is exposed to chemotherapy, there are tissues more vulnerable to chemotherapy than others. This is the case of sensory neurons located at dorsal root ganglion (DRG) which are outside the protection of the blood–brain barrier. They are the principal targets of platinum derivates such us oxaliplatin, cisplatin or other platinum agents. Thus, neurons are damaged directly at DRG producing a progressive sensory neuronopathy. However, neurotoxicity also causes multiple lesions within the axons both for platinum agents and for other drugs as taxanes generating distal axonopathy. This will have different consequences for patients.

On one hand, the myelinated sensory nerve fibers lose their function. This is noted by many patients in a "glove and stocking" pattern of sensory loss involving

#### *Neurotoxicity - New Advances*

hands and feet. They frequently refer reduced precision to make fine movements with tip of the fingers which is noted by having less ability to cross buttons when dressing or when typing the computer. Also, gait disturbances affect their daily activities because of instability when walking in irregular ground or for descending stairs. On the other hand, thin myelinated (Aδ fibers) and unmyelinated (C fibers) carrying the information of temperature and pain are also damaged. A combination of negative and positive symptoms (see **Figure 2**) contributes to sensory disturbances. The unpleasant dysesthesias and neuropathic pain are consequence of the gain of function in damaged sensory nerve fibers that increases their excitability by producing spontaneous burning sensation or electric shocklike pain.

This clinical picture is common for all chemotherapy agents despite the mechanisms may differ among them. Also, it may determine the severity of axonal loss and its recovery since regeneration is expected to occur if the axon is affected distally whereas poor should be assumed in a neuronopathy. In general, we use the term sensory polyneuropathy for CINP when symptoms have a characteristic distance-dependent pattern even when we know that it is combined with sensory neuronopathy which has been demonstrated for oxaliplatin and cisplatin [13, 14].

There are other drugs such as vincristine, bortezomib or arsenic salts with ability to produce a more generalized axonal damage in all nerves. In this case, sensory deficits are accompanied by frequent muscular cramps, predominantly at night in both legs as well as distal weakness in upper and lower extremities because of motor neuropathy. Moreover, the failure in autonomic nerves leads to chronic constipation, reduced distal sweating and dizziness when standing (orthostatic hypotension) due to autonomic neuropathy or dysautonomia.

More recently, the introduction of the checkpoint inhibitors as a treatment for advance melanoma have opened the possibility of different immune-mediated neuromuscular manifestations reported as complication of the treatment in 75% of

#### **Figure 2.**

*Comparison of positive and negative symptoms in CIPN.*

*Chemotherapy-Induced Peripheral Neuropathy: Mechanisms and Clinical Assessment DOI: http://dx.doi.org/10.5772/intechopen.100495*

patients [15]. In this case acute demyelinating polyneuropathy (Guillain-Barré syndrome), demyelinating sensorimotor neuropathy, myositis or myasthenic syndrome have to be considered.

The combination of peripheral and central neurotoxicity at spinal cord should be considered in intrathecal infusion of chemotherapy. This is necessary for patients with acute leukemia treated with methotrexate. It has been described also after vincristine treatment. In this case, proximal motor roots can be unexpectedly block with a variable extension of myelitis at the level of lumbar infusion producing a complete paresis in lower limbs (paraparesis) with a lower abdomen level of sensory loss together with urinary dysfunction. This is a devastating situation that has been reported in few cases with poor prognosis for recovery [16, 17].
