**6. Neuropathic pain**

Tumors are not densely innervated by sensory neurons. [46, 47] Rapid tumor growth, however, frequently entraps surrounding nerves, causing mechanical injury, compression, ischemia or direct proteolysis.

Proteolytic enzymes that are produced by the tumor cells may cause injury to the sensory and sympathetic fibers, causing neuropathic pain.

Although the mechanisms that generate and keep up neuropathic pain are still not well understood, several therapies have proved to be useful for the control of neuropathic pain in the general population. Recently, the first animal model of cancer pain was developed through the injection of mouse osteolytic sarcoma cells into the intramedullary space of the mouse femur. A crucial component of this model is that the tumor cells are confined to the marrow space of the injected femur, without invading adjacent soft tissues. Once injected, the cancer cells proliferate, and both basal and movement-evoked pain responses increase as the tumor develops. These seem to be produce the same responses of patients with primary or metastatic bone cancer. [48, 50]

Additionally, the therapies aimed at tumor-cell eradication (such as chemotherapeutic agents) may also cause significant nerve fibers damage and lead to ensuing pain.

Potential mechanisms by which chemotherapeutic agents (such as paclitaxel and vincristine) may cause peripheral neuropathy include their ability to disrupt tubulin function. Tubulin polymerization is necessary for axonal transport of trophic factors, and drugs that interfere with this process may cause degeneration of sensory neurons and release of pro-inflammatory cytokines that sensitize directly the primary afferent nociceptors. [51] Chemotherapy-induced polyneuropathy may early develop during the first cycle of treatment but, in most cases, it appears 3-4 months after the first treatment.

Neuropathic pain is associated with dysesthesia, hyperalgesia, hyperpathia, and allodynia; such sensory disturbances occur predominantly at peripheral level, distally and symmetrical‐ ly, over the upper and lower limbs with a "gloves and socks" distribution; painful disturbances may spontaneously occur or be evoked by tactile or thermal stimuli, with a continuous or intermittent course. [52]

Initially, the symptoms can be insidious and attributable to other conditions, becoming painful in about 25% of patients. Patients with neuropathic pain may also show osteotendinous hyporeflexia, impairment of proprioception, muscle cramps and hypotrophy, reduced muscle tone with reduced muscular endurance, tremor, dystonia, and dyskinesia, resulting in impairment of sensory-motor coordination and sensory ataxia. [53]

The incidence and severity of neuropathic pain are highly dependent on the type of chemo‐ therapy protocol (mono- or poly-therapy with cumulative doses over time), the association with radiotherapy (RT), the age of patient, and co-morbidities such as diabetes, alcoholism, paraneoplastic neuropathies and other diseases affecting the nervous system.

In hormone-producing cancers deriving from endocrine tissues, the use of agents inhibiting the production or the activity of relevant hormones is a common feature, with particular regard to estrogens, progestins, androgens, corticosteroids, and thyroid hormones.

**6. Neuropathic pain**

68 Updates on Cancer Treatment

sympathetic fibers, causing neuropathic pain.

appears 3-4 months after the first treatment.

direct proteolysis.

bone cancer. [48, 50]

intermittent course. [52]

Tumors are not densely innervated by sensory neurons. [46, 47] Rapid tumor growth, however, frequently entraps surrounding nerves, causing mechanical injury, compression, ischemia or

Proteolytic enzymes that are produced by the tumor cells may cause injury to the sensory and

Although the mechanisms that generate and keep up neuropathic pain are still not well understood, several therapies have proved to be useful for the control of neuropathic pain in the general population. Recently, the first animal model of cancer pain was developed through the injection of mouse osteolytic sarcoma cells into the intramedullary space of the mouse femur. A crucial component of this model is that the tumor cells are confined to the marrow space of the injected femur, without invading adjacent soft tissues. Once injected, the cancer cells proliferate, and both basal and movement-evoked pain responses increase as the tumor develops. These seem to be produce the same responses of patients with primary or metastatic

Additionally, the therapies aimed at tumor-cell eradication (such as chemotherapeutic agents)

Potential mechanisms by which chemotherapeutic agents (such as paclitaxel and vincristine) may cause peripheral neuropathy include their ability to disrupt tubulin function. Tubulin polymerization is necessary for axonal transport of trophic factors, and drugs that interfere with this process may cause degeneration of sensory neurons and release of pro-inflammatory cytokines that sensitize directly the primary afferent nociceptors. [51] Chemotherapy-induced polyneuropathy may early develop during the first cycle of treatment but, in most cases, it

Neuropathic pain is associated with dysesthesia, hyperalgesia, hyperpathia, and allodynia; such sensory disturbances occur predominantly at peripheral level, distally and symmetrical‐ ly, over the upper and lower limbs with a "gloves and socks" distribution; painful disturbances may spontaneously occur or be evoked by tactile or thermal stimuli, with a continuous or

Initially, the symptoms can be insidious and attributable to other conditions, becoming painful in about 25% of patients. Patients with neuropathic pain may also show osteotendinous hyporeflexia, impairment of proprioception, muscle cramps and hypotrophy, reduced muscle tone with reduced muscular endurance, tremor, dystonia, and dyskinesia, resulting in

The incidence and severity of neuropathic pain are highly dependent on the type of chemo‐ therapy protocol (mono- or poly-therapy with cumulative doses over time), the association with radiotherapy (RT), the age of patient, and co-morbidities such as diabetes, alcoholism,

may also cause significant nerve fibers damage and lead to ensuing pain.

impairment of sensory-motor coordination and sensory ataxia. [53]

paraneoplastic neuropathies and other diseases affecting the nervous system.

About 40% of women treated with aromatase inhibitors (AI) present joint and muscular pain in a widespread, symmetrical distribution, often associated with morning stiffness that tends to fade with movement, as well as sleep disorders. The onset of pain, usually mild-to-moderate in intensity, typically occurs within the first few months after starting the therapy. Relevant risk factors include: age over 60 years, obesity, recent menopause, rheumatic diseases, previous chemotherapy and hormone replacement therapy, as well as use of anxiolytics and antide‐ pressants. Such symptoms are, most likely, related to the modification of the pain threshold as a direct consequence of the reduction of circulating estrogens, which have a peripheral antinociceptive effect and play an important role in the modulation of central pain. [54]

RT regimens play a synergistic role with CT, surgery, immunotherapy and hormone therapy for the control of primary and secondary tumor lesions, being also potentially useful to reduce the size or vascularization and bleeding of the tumor as well as to relieve the pain. With regard to the use of RT in palliative care, edema and inflammation in the tissues treated with radio‐ therapy frequently cause recurring pain. Radiodermatitis, whose severity ranges from simple rash to tissue necrosis, may result in skin discoloration with frequent association with hyperpathia.

Lymphedema causes pain because of locoregional tension within soft tissues and joint traction. These painful symptoms may even appear after a considerable time interval, being intensified by the load and the mobilization but, in advanced cases, pain is present even at rest, resulting in hypomobility and reduction of muscle tone.

Post-radiation fibrosis is a serious dose-dependent complication of RT and may involve the lungs and the soft tissues; fibrosis of skin and subcutaneous tissues (mainly in the neck, face and breast) results in hypomobility, compensatory postural defects, muscle and joint contrac‐ tures and pain.

Radiotherapy can also determine cervical and lumbar pain developing from a few months up to several years after the beginning of the therapy.

A brachial plexus neuropathy (plexopathy) can occur due to radiation treatment for breast cancer, head and neck or pulmonary apex, may represent a difficult differential diagnosis with the possibility of neoplastic infiltration of the plexus.

Post-radiation plexopathies preferentially affect the upper roots (C5-C6), while direct infiltra‐ tion by neoplastic cells normally involves the lower trunks (C7-C8-T1). The clinical picture may be initially characterized by dull and deep pain referred to the shoulder, armpit and arm, usually of mild-to-moderate intensity, associated with tingling paresthesia in the distribution root C5-C6-C7, followed by motor impairment, heaviness, predominantly proximal weakness, and functional limitations, especially with regard to flexion and abduction. [56]

Coexistence of plexopathy following radiotherapy and postsurgical lymph edema may occur as well, triggering a vicious circle in which limb pain is increased by the weight of the lymphedematous limb determining motor and functional impairment.

The progression of the neurological deficit occurs through multiple steps, with the final result being the flaccid paralysis of the upper limb.

The lumbosacral plexopathy is a rare, adverse effect following irradiation for pelvic, abdomi‐ nal, uro-gynecological, or bowel tumors. In 50-75% of lumbosacral plexopathy cases, the neuropathy starts at lower limbs level presenting as bilateral deficit affecting the distal surface sensitivity and, to a lesser degree, proprioceptive sensitivity; the motor deficit, mainly involving the districts innervated by the distal roots L5-S1 (55% of patients), presents as a bilateral, asymmetrical lower limbs deficit, resulting in impairment of dorsiflexion of the foot as well as gait and balance disorders. The coexisting pain radiating along the face of the posterolateral thigh and leg increases the risk of falls in association with sensorimotor deficits.

Among patients undergoing RT for prostate cancer, 20% of cases may develop a challenging neuropathy as earlier as after the first 12 months of RT, resulting in chronic pelvic pain often associated with dysuria, dyspareunia, rectal tenesmus, and abdominal pain.

Spine irradiation may cause vascular damage, demyelination, and focal necrosis of the white matter of the spinal cord, resulting in a post-RT myelopathy, which may be classified in acute, sub-acute, and chronic subtypes, depending on the time of onset after RT.

Cancer pain syndromes may be further classified as acute and chronic syndromes.

Acute pain syndromes have a sudden, well-defined onset, present with an identifiable cause (e.g. surgery). They are affected by sympathetic responses (fight or flight response), and are expected to improve with adequate care. The acute form most commonly occurs in head and neck cancers after treatment of the cervical-cephalic district, being characterized by a positive Lehermitte sign, stabbing pains in the neck exacerbated by flexion of the head, and radiation to the column and the limbs, with sensory, motor, and autonomic symptoms.

Chronic pain has a less distinct onset, shows a prolonged and fluctuating course, and is largely driven by central sensitization. [57]

In chronic pain, the algic symptom, referred to the dermatomes at or below the levels treated by RT, precedes the neurological signs and leads to increased difficulties in motor coordination and execution of daily activities. The chronic form may present as transverse myelitis, with tetraparesis or Brown-Sequard syndrome. [58]

A crucial question is whether the spinal cord and forebrain undergo significant neurochemical changes while chronic pain develops. Studies involving the mouse model of bone metastases pain, described above, revealed extensive neuro-chemical reorganization in the spinal cord segments that receive input from primary afferent neurons innervating the tumor-bearing bone.

Such changes include astrocytes hypertrophy, accompanied by decreased expression of glutamate re-uptake transporters. [59, 60]

This results in increased extracellular levels of the excitatory neurotransmitter glutamate and excitotoxicity within the central nervous system. The up-regulation of the proalgesic peptide dynorphin was also observed in the spinal cords of tumor-bearing animals.

Spinal-cord expression of dynorphin — a pro-nociceptive member of the opioid family [61, 62] - has been observed in animal models of neuropathic [63], inflammatory [64, 65], and sarcoma-induced bone cancer pain states. Cancer pain induces, therefore, a state of central sensitization, in which neurochemical changes in the spinal cord and forebrain promote an increased transmission of nociceptive information.

The progression of the neurological deficit occurs through multiple steps, with the final result

The lumbosacral plexopathy is a rare, adverse effect following irradiation for pelvic, abdomi‐ nal, uro-gynecological, or bowel tumors. In 50-75% of lumbosacral plexopathy cases, the neuropathy starts at lower limbs level presenting as bilateral deficit affecting the distal surface sensitivity and, to a lesser degree, proprioceptive sensitivity; the motor deficit, mainly involving the districts innervated by the distal roots L5-S1 (55% of patients), presents as a bilateral, asymmetrical lower limbs deficit, resulting in impairment of dorsiflexion of the foot as well as gait and balance disorders. The coexisting pain radiating along the face of the posterolateral thigh and leg increases the risk of falls in association with sensorimotor deficits. Among patients undergoing RT for prostate cancer, 20% of cases may develop a challenging neuropathy as earlier as after the first 12 months of RT, resulting in chronic pelvic pain often

Spine irradiation may cause vascular damage, demyelination, and focal necrosis of the white matter of the spinal cord, resulting in a post-RT myelopathy, which may be classified in acute,

Acute pain syndromes have a sudden, well-defined onset, present with an identifiable cause (e.g. surgery). They are affected by sympathetic responses (fight or flight response), and are expected to improve with adequate care. The acute form most commonly occurs in head and neck cancers after treatment of the cervical-cephalic district, being characterized by a positive Lehermitte sign, stabbing pains in the neck exacerbated by flexion of the head, and radiation

Chronic pain has a less distinct onset, shows a prolonged and fluctuating course, and is largely

In chronic pain, the algic symptom, referred to the dermatomes at or below the levels treated by RT, precedes the neurological signs and leads to increased difficulties in motor coordination and execution of daily activities. The chronic form may present as transverse myelitis, with

A crucial question is whether the spinal cord and forebrain undergo significant neurochemical changes while chronic pain develops. Studies involving the mouse model of bone metastases pain, described above, revealed extensive neuro-chemical reorganization in the spinal cord segments that receive input from primary afferent neurons innervating the tumor-bearing

Such changes include astrocytes hypertrophy, accompanied by decreased expression of

This results in increased extracellular levels of the excitatory neurotransmitter glutamate and excitotoxicity within the central nervous system. The up-regulation of the proalgesic peptide

dynorphin was also observed in the spinal cords of tumor-bearing animals.

associated with dysuria, dyspareunia, rectal tenesmus, and abdominal pain.

sub-acute, and chronic subtypes, depending on the time of onset after RT.

Cancer pain syndromes may be further classified as acute and chronic syndromes.

to the column and the limbs, with sensory, motor, and autonomic symptoms.

being the flaccid paralysis of the upper limb.

70 Updates on Cancer Treatment

driven by central sensitization. [57]

bone.

tetraparesis or Brown-Sequard syndrome. [58]

glutamate re-uptake transporters. [59, 60]

Classically, the main emphasis when examining the ascending conduction of pain has been placed on spino-thalamic tract neurons. This means that the general mood and attitude of the patient might also be a significant factor in determining the intensity and degree of pain.

Clinical studies, however, have resulted in the revision of such thesis, showing that attenuation of some forms of visceral cancer pain can be achieved by disruption of non-spinothalamic-tract axons. [66]

Chronic pain entails adverse effects on various organ systems, as seen with non oncological pain.

An inadequate treatment of pain has negative effects at the psychological, respiratory, cardiovascular, endocrine and metabolic, and gastrointestinal levels. The persistently active proalgesic stimulation affects both somatomotor neurons, generating reflex phenomena such as muscle spasm, and sympathetic neurons, with norepinephrine-mediated activation resulting in peripheral vasoconstriction, cardiac work increase, visceral hypotonia, and gastrointestinal and genito-urinary incontinence.

Indeed, the persistence of pain determines augmented sympathetic nerve activity, with increased release of catecholamines, antidiuretic hormone, (ADH), angiotensin II, aldosterone system, and related cytokines. The activation of the sympathetic-adrenal axis with release of corticotropin releasing hormone (CRH) and ADH activates a subset of processes that the body normally implements when facing emergency situations: in particular, activation of catabolic reactions (ie, those reducing the lean body mass) is accompanied by chronic fatigue and insomnia, as seen when dealing with stressing situations.

Mood disorders (anxiety, apathy, depression) associated with catabolic metabolism are accompanied by an imbalance in the levels of electrolytes, especially potassium. These changes affect the excitable tissues (muscles and nerves) as potassium is a regulator key of the electricity transmission; likewise, it may have effects on the nervous system and transmission of painful signals.

Gastrointestinal disorders (bloating, feelings of fullness, food intolerance, slow digestion) may also occur, as a consequence of the imbalance of electrolytes; indeed, peristalsis is implemented by muscles which, despite not being voluntarily controlled, have similar characteristics to the skeletal.

In addition, the state of catabolism induced by the action of stress factors affects blood regulation and storage of sugars, which are mostly accumulated in muscle tissue. Loss of muscular tissue leads, therefore, to a deregulation of glucose metabolism resulting in loss of appetite or excessive and unjustified sense of hunger (typically during the night). These two symptoms often alternate between each other.

Dysregulation of cortisol release results in peripheral vasoconstriction and limbs muscles catabolism. The inadequate cortisol regulation and the consequent loss of muscle mass can as well affect the amount of adipose tissue, leading to a relative increase of the latter. Chronic pain often predisposes to a complex series of physiological and psychosocial changes, which are an integral part of the chronic pain issue, being added to the existing burdens occurring to those who suffer. [67]
