Central and Peripheral Neurotoxicity Induced by Systemic Antitumor Therapy

Central and especially peripheral neurotoxicity due to systemic antineoplastic therapy are common and often dose-limiting side effects. In patients with chemotherapy-induced peripheral neurotoxicity (CIPN), recovery is generally partial with residual deficits in the majority of patients.

This Clinical Practice Guideline provides recommendations on the diagnosis, prevention and treatment of peripheral neurotoxicity and specific aspects of central neurotoxicity due to antineoplastic therapy.

> Incidence and risk factors

• Incidence

Depending on the individual antineoplastic drug, the incidence, severity, and clinical pattern of CIPN during treatment vary considerably. Regarding long-term toxicity, a study in 512 female cancer survivors showed that 47% of women had CIPN (median 6 years) after treatment.

• Risk factors associated with therapy

CIPN occurs in a dose-dependent manner, usually after several cycles of neurotoxic antineoplastic therapy, and is generally dependent on the single and cumulative doses administered, although duration of exposure, timing, and combination therapies are also potential risk factors.

• Individual risk factors

Individual risk factors for developing CIPN are not yet clearly established. For example, diabetes mellitus and increasing age (often defined as ≥75 years) have been proposed as strong independent risk factors.

However, simultaneous exposure to other nerve agents and preexisting neuropathy, as well as diseases/deficiencies per se that predispose to neuropathy, should be considered as potential risk factors [alcohol abuse, renal failure, hypothyroidism, vitamin deficiency, infections such as human immunodeficiency virus (HIV) and autoimmune rheumatological conditions. Smoking appears to increase the risk of paresthesia in the long term.

In cases with severe neurotoxicity, for example, motor compromise due to vincristine-induced CIPN, predisposing neurological diseases such as axonal Charcot-Marie-Tooth type 1A should be ruled out. These patients usually present predominant motor involvement and various deformities (hollow foot, stork legs).

> Evaluation/diagnosis

• Clinical pattern

The most common clinical presentation of CIPN is a predominantly sensory axonal neuropathy with occasional motor and autonomic involvement. Predominantly sensory fibers are affected, but some cytostatic agents cause a sensorimotor pattern. Symptoms of CIPN usually occur during the first 2 months of treatment, progress during active antineoplastic treatment, and then usually stabilize soon after treatment is completed. However, acute neurotoxicity induced by paclitaxel or oxaliplatin or even the "inertia phenomenon" such as worsening of neuropathic syndromes after treatment discontinuation must be taken into account.

With some agents (e.g., platinum compounds, vinca alkaloids, taxanes, and thalidomide), cell bodies in the dorsal root ganglion are more vulnerable to neurotoxic damage (often irreversible), due to a blood-brain barrier. less protective leading to sensory neuronopathy (ganglionopathy). The clinical picture may be asymmetrical and predominantly involves the sense of proprioception, but does not exclude the motor system.

Large sensory nerves are most commonly affected in CIPN in a length-dependent symmetric manner (retrograde axonopathy). Therefore, the typical clinical symptoms are predominantly sensory and normally include the so-called ’plus’ neuropathic features: acral pain, paresthesia, accompanied pain, allodynia and hyperalgesia. Sensory loss appears in a "sock-and-glove" distribution and leads to "negative" symptoms such as numbness in the hands and feet, including poor perception of light touch or vibration sensation.

Small fiber neuropathy represents the affection of the nerve endings of the fibers involved in the perception of temperature and pain, which is present, for example, in patients treated with vinca alkaloids, taxanes, thalidomide and bortezomib. It leads to a painful burning sensation in the feet (and/or hands) and even stabbing pain. On clinical examination, decreased pain perception and temperature sensation is typical in painful areas.

Motor fiber involvement (associated with reduced or absent deep tendon reflexes or even distal weakness, atrophy of small muscles of the feet, tremors, cramps) or autonomic or cranial nerve symptoms appear much more rarely than sensory damage.

The autonomic involvement that is typical of small fiber damage with vincristine and bortezomib use can lead to abdominal pain, constipation, postural hypotension, bladder disorders, delayed gastric emptying, and reduced heart rate variability.

• Practical aspects of evaluation

Early detection of CIPN is a key factor for adequate management. An initial and ongoing clinical evaluation (before each cycle) is a critical but often overlooked aspect. Ongoing evaluation could allow healthcare professionals to discover potential or pre-existing symptoms before neuropathy becomes irreversible. Therefore, pre-treatment evaluation may also require consultation with a neurologist if any concerns arise. So far, no biomarker has proven useful in diagnosing and monitoring CIPN.

• Neurophysiological examination

Conventional neurophysiological methods [electromyography (EMG) with nerve conduction studies] can provide complementary information to clinical evaluation and can identify pre-existing neuropathy, sometimes still subclinical, as separate risk factors for CIPN. However, conventional nerve conduction parameters often do not reflect patients’ symptoms and are not suitable for monitoring the severity of CIPN during therapy. Furthermore, it is often observed that, despite improvement in patients’ symptomatic clinical and functional recovery, neurophysiological evaluation shows only modest improvement.

Additional assessment tools, such as somatosensory potentials, can clarify whether proximal nerves have been affected or the presence of comorbidities in rare cases. An EMG may demonstrate acute hyperexcitability and chronic neurogenic changes due to motor axonopathy , but is not necessary for clinical routine. In small fiber neuropathies, all findings based on standard neurophysiological techniques may be normal and only a skin biopsy can demonstrate degeneration of small C (hot) and Aδ (cold) fibers.

In general, healthcare professionals tend to underestimate the symptoms that patients experience and that patients’ perception of CIPN is different from that of their healthcare professionals.

> CIPN prevention

• Pharmacological prevention

Many pharmacological agents have been studied for their potential to prevent neuropathy. To date, there is no effective agent to prevent CIPN and, therefore, no positive recommendation can be given for any of the agents studied.

• Non-pharmacological prevention

The available evidence advises against the use of acupuncture to prevent CIPN. Cryotherapy with frozen socks or gloves showed some promising results in small studies. Although the results are somewhat heterogeneous, prevention of CIPN with cryotherapy can be considered [II, C].

There is less evidence for the effectiveness of compression therapy with surgical gloves. In a small study of 42 patients, less neuropathy [subjectively measured by the Common Terminology Criteria for Adverse Events (CTCAE) and the Peripheral Neuropathy Questionnaire (PNQ)] was observed in the gloved hand compared to the other (ungloved) hand. . As there appears to be little harm from this intervention, it can be considered a preventive measure [III, C].

Many initial reports suggest a possible protective effect of exercise and functional training in CIPN. Therefore, it can be offered to patients at risk of developing CIPN [II, C]. Contraindications must be ruled out before starting any exercise.

> > Treatment of CIPN

> Pharmacological treatment

Effective pharmacological therapeutic options for patients with established CIPN are limited. When patients experience chronic CIPN, treatment approaches focus on reduction or relief of neuropathic pain [IV, A]. The treating physician should always keep in mind that neuropathic pain can be aggravated by sleep disorders, anxiety, depression, and central pain sensitization. To decrease the likelihood of central pain sensitization, early pain management is of utmost importance.

A. Oral drugs

- Selective serotonin reuptake inhibitors

Duloxetine is so far the only drug studied in CIPN in a large randomized trial showing moderate clinical benefit in patients with painful CIPN. In 231 patients with CIPN, a greater rate of pain reduction was found with duloxetine versus placebo (59% versus 38%). Therefore, duloxetine is recommended for the treatment of neuropathic pain [I, B]. Venlafaxine has also been shown to be effective in a small randomized trial and may be considered for the treatment of neuropathic pain [II, C].

- Anticonvulsants and tricyclic antidepressants

Anticonvulsants and tricyclic antidepressants have shown less proven efficacy. Based on knowledge in the treatment of "plus" neuropathic symptoms in general, membrane-stabilizing agents, such as anticonvulsants (pregabalin, gabapentin) or tricyclic antidepressants, may have the potential for symptom control in patients with CIPN. This could be a reasonable option if duloxetine has failed or there are contraindications. It is important to apply these suggested agents against neuropathic pain for at least 2 weeks at the appropriate dose to evaluate their effectiveness before switching to another option [V, B].

- Opioids

As a rescue option, opioids can be used to relieve neuropathic pain, but evidence is available for neuropathic pain from causes other than antineoplastic therapies. There is no convincing data to suggest that one opioid is better than another for neuropathic pain.

- Miscellaneous

There are no data to support the benefit of NSAIDs and glucocorticoids in the context of CIPN. However, an anti-inflammatory effect on the involvement of nociceptors in thermal fiber pain has been experienced and evidence for the effect of immunomodulation has been provided in an animal model of bortezomib-induced CIPN.

B- Topical local intervention

Based on the pathogenic mechanism of neurotoxicity, it should be mainly used in clinical suspicion of small fiber neuropathy.

- Menthol

In a phase II trial, 1% menthol cream was applied to the affected area and 31 of 38 evaluable patients showed substantial pain relief with minimal toxicity (p < 0.001). Although data from randomized studies are not available, topical low-concentration menthol cream should be considered as the cost is low and no adverse events have been reported [III, B].

- Topical baclofen/amitriptyline/ketamine

Topical treatment with a gel containing baclofen/amitriptyline and ketamine showed a non-significant improvement in sensory neuropathy in a randomized trial (n=208). Its use could be considered [II, C]. In contrast, a topical preparation of amitriptyline/ketamine was studied in 462 patients in a trial that did not show relief in pain, numbness, or tingling, so its use is not recommended [I, D].

- 8% capsaicin patches

Most of the evidence available for patches containing 8% capsaicin is derived from studies that are primarily in patients with diabetes mellitus. Some attempts were also made in patients with painful CIPN. They can be considered in patients with CIPN [III, C].

> Non-pharmacological treatment

Additionally, or if pharmacological therapy fails, the patient with CIPN may be offered the use of certain non-pharmacological strategies.

- Physical exercise

Many physical exercise approaches lack solid scientific evidence due to the fact that physical exercise has typically been applied in a multimodal setting. However, there is growing evidence that physical exercise and functional training reduce CIPN symptoms. Training to improve coordination, sensorimotor function, and fine motor skills should begin (at the latest) with the onset of overt CIPN, but may be initiated earlier, at the time treatment for potentially neurotoxic cancer is initiated [II, B]. Furthermore, this strategy is particularly important to improve physical function to prevent disability and falls, especially in older adults.

- Acupuncture

A 2017 Cochrane review indicated that, due to the limited data available, there is insufficient evidence to support or refute the use of acupuncture for neuropathic pain. However, several recent randomized phase II studies are encouraging. Specifically, in a study by Bao et al. (n=75), acupuncture resulted in significant improvement in CIPN symptoms. Acupuncture could be considered in selected patients to treat CIPN symptoms [II, C].

- Coding therapy

Scrambler therapy involves the use of a device to treat pain using non-invasive skin electrostimulation. However, the latest randomized pilot trial did not show any beneficial effect of scrambler therapy. Scrambler therapy is not recommended to treat CIPN [II, D].

• PROSPECT

The Proactive Self-Management Program for the Effects of Cancer Treatment (PROSPECT) represents a self-guided online cognitive and behavioral pain management intervention over an 8-week period to reduce pain resulting from CIPN. A randomized pilot trial (n=60) showed promising results. The intervention implies very little harm, so a weak recommendation in favor appears to be rational [II, C].

• Spinal cord stimulation

Spinal cord stimulation represents a neuromodulation technique used to treat truly refractory neuropathic and sympathetically mediated chronic pain. It is an invasive and expensive procedure and has been reported to be successful in several cases; however, there are no RCTs available in patients with CIPN. It can be discussed for selected patients [V, C].

• Neurofeedback

A randomized pilot study in 71 cancer survivors suggests potential benefit for electroencephalogram (EEG)-based neurofeedback. As the intervention involves very little harm, a weak recommendation in favor is justified [II, C].

> Support measures for security and self-management

• Assistance with daily living, sensory impairment

For sensory nerve damage with corresponding impairment in activities of daily living (ADL), assistive measures (e.g., electric toothbrushes, slip-on shoes, referral to occupational therapist, non-slip handles) may be useful for the patient [V, B].

• Assistance with activities of daily living, motor deficit

Problems arise with walking (specifically in the elderly), maintaining balance, driving, cycling, and standing still for long periods of time. Some useful strategies regarding fall risk assessment, safety measures, and ADL support measures include installing handrails in the bathroom/shower area, checking for slippery or uneven mats, using a cane or walker if walking. is unstable, use of non-slip footwear, among others.

Patients and their caregivers can develop their own strategies for accepting limitations. Support and information from healthcare professionals can improve them, correct them if they are considered harmful, and recommend other interventions that fit patients’ ADL patterns.

Caregivers should be included in educational discussions and topics. Safety concerns for sensory and motor deficits should be addressed early in treatment. A time frame of how long the CIPN may last should be part of the information.

• Safety and prevention information

Depending on the antineoplastic drug administered, safety and prevention information should be communicated to the patient before therapy begins. Particular attention should be paid to patients receiving oxaliplatin, since the corresponding acute neurotoxicity may include very unpleasant hyperexcitability (sensitivity to cold). Information before the first application is of utmost importance as the possible experience of laryngeal spasms and perceived dyspnea can lead to panic attacks.

> Ototoxicity

Ototoxicity is caused by peripheral damage to special sensory neurons in the cochlea. Cisplatin is one of the most ototoxic agents. This damage can lead to bilateral sensorineural hearing loss, which affects 20-75% of patients. Most patients experience some degree of tinnitus during cisplatin-based chemotherapy. Carboplatin (approximately 5% of patients) and vinca alkaloids may cause ototoxicity to a much lesser extent. Oxaliplatin very rarely causes ototoxicity.

• Risk factor’s

Risk factors for developing ototoxicity include increasing the cumulative dose of cisplatin, application schedule (cisplatin 100 mg/m 2 for 5 days is better than for 3 days [I, A]), young age, applications concomitant use of other ototoxic drugs (e.g., aminoglycosides and loop diuretics), prior/concomitant radiation therapy to the cochlea or cranial nerve VIII, preexposure hearing impairment, renal failure, and specific genetic variants [III, B].

• Evaluation/diagnosis

Before cisplatin therapy begins, the history should include questions related to your profession. If your livelihood depends on your hearing acuity, careful treatment planning is warranted. During treatment, patients should be encouraged to report early signs of hearing impairment.

For early detection of ototoxicity in adults receiving platinum agents, pure tone audiometry (including the broad frequency spectrum of 500 to 8000 Hz) is recommended [IV, A]. An initial evaluation should be performed before and at the end of therapy, at a minimum [IV, B]; This recommendation refers specifically to patients with testicular cancer since almost all studies were conducted in this patient population.

• Prevention

Although otoprotective treatment with sodium thiosulfate could offer significant patient benefit, it cannot currently be recommended as a standard treatment, due to uncertainty about possible tumor protection and lack of evidence among adult cancer patients [I, C]. None of the numerous other potential otoprotective agents can be recommended for the prevention of cisplatin ototoxicity [II, D]. They were shown to be of no benefit or the qualities of the studies were not suitable enough to draw final conclusions. At this point, no recommendation in favor of pharmacogenomics testing in routine practice is possible [III, A].

• Treatment

To date, there is no causal treatment strategy available. Hearing aids can help. Patients with profound hearing loss may benefit from cochlear implants. Other assistive devices (e.g., hearing trainers, telephone amplifiers) may also be beneficial. For patients suffering from tinnitus, cognitive behavioral strategies (CBT) can be offered [V, B].

For many antineoplastic drugs, toxicity is related to the route of administration and cumulative dose, and can range from brief, transient episodes to more severe chronic sequelae.

> Encephalopathy

This term is widely used to describe global brain dysfunction in the absence of primary structural brain disease. Only acute encephalopathy will be discussed here. Most clinical features of acute encephalopathy are nonspecific and do not reliably identify a particular etiology. In cancer patients, its appearance has been associated with classical chemotherapy.

In addition to these toxic causes, acute encephalopathy may be facilitated by concomitant septic disease, preexisting leukoencephalopathy, and metabolic changes (e.g., sodium disturbances). The clinical features of acute encephalopathy include changes in consciousness (from altered attention to confusion and delirium with psychotic symptoms), decreased consciousness (from drowsiness to coma), and changes in affect (apathy, anxiety, agitation).

The presentation of acute encephalopathy may also include focal signs such as paresis, speech disorders, seizures, and cranial nerve dysfunctions. It is necessary to intensify the diagnostic procedure if other clinical conditions and differential diagnoses such as cerebral bleeding or ischemia must be ruled out radiologically in patients at risk. In case of concomitant fever and meningeal irritation, an infectious cause should also be ruled out by examination of the cerebrospinal fluid (CSF) [V, B].

> Acute ifosfamide-induced encephalopathy

Risk factors for the development of acute encephalopathy may include: ifosfamide dosage, drug interactions (CYP2B6 inhibitors), renal impairment, low serum albumin, bulky abdominal disease, and prior treatment with cisplatin [V, B].

• Prevention and treatment

As prophylactic or therapeutic measures, methylene blue and/or thiamine and/or 5% glucose have been applied in small series. There are no controlled trials available for these agents and the possibility of spontaneous resolution of encephalopathy must be taken into account, therefore they are not recommended for the prevention and treatment of acute ifosfamide-induced encephalopathy [V, D]. Prophylactic use of exogenous albumin administration is also not effective and is not recommended [V, D].

Treatment is purely symptomatic and includes discontinuation of ifosfamide, electrolyte correction (if appropriate) and symptomatic treatment with, for example, benzodiazepines [V, B]. In almost all cases, spontaneous complete remission without sequelae can be observed.

> Posterior reversible encephalopathy syndrome

Patients present with acute neurological deficits including altered consciousness, visual disturbances, blindness, headaches, and seizures. Posterior reversible encephalopathy syndrome (PRES) is rare but increasingly diagnosed. A breakdown of the blood-brain barrier due to endothelial injury due to sudden changes in blood pressure leads to typical vasogenic edema. Posterior regions of the brain are more susceptible to injury due to reduced sympathetic innervation and blood pressure autoregulation.

Therefore, edema, which can be demonstrated on magnetic resonance imaging (MRI), affects the bilateral parietal-occipital lobes and predominates in the white rather than the gray matter. Risk factors include preexisting high blood pressure, renal failure, autoimmune diseases, high-dose antineoplastic therapy, and immunosuppression (e.g., cyclosporine) [V, B].

• Prevention and treatment

Tight control of blood pressure is crucial, especially when PRES is present [V, B]. Treatment requires cessation of anticancer therapy and antiepileptic treatment in case of seizures [V, B]. PRES is usually reversible with appropriate supportive treatment within 2 weeks. Reintroduction of previous antineoplastic therapy should be decided on an individual basis.

> Acute cerebellar syndrome

Cerebellar syndrome may develop in patients receiving, for example, high doses of cytarabine. It is characterized by dizziness, ataxia, dysarthria, vertigo with nausea and vomiting, and eye movement disorders that usually manifest 2 to 5 days after the start of treatment. In addition to a careful history and neurological examination, a T2 MRI demonstrating cerebellar hyperintensities and CSF excluding central nervous system (CNS) infection will help in finding the diagnosis. Risk factors may include liver and kidney failure, very high doses of antineoplastic drugs, and age >40 years [V, B].

• Prevention and treatment

There are no specific preventive measures or causal treatments available. The offending antineoplastic drug should be discontinued. Recovery is uncertain, including remission and persistence of ataxia incapacitating sitting and walking.

> Myelopathy

Transverse myelopathy can develop due to high levels of antineoplastic drugs in the CSF for at least 24 hours. It is a rare complication, but it can appear in patients after intrathecal treatment with methotrexate, cytarabine, cisplatin, among others. Patients suffer from back or leg pain followed by paraparesis or, more often, paraplegia, sensory loss, and sphincter dysfunction. MRI can show lesions in the dorsal column of the spinal cord. Symptoms of aseptic meningitis may occur. Risk factors include concurrent craniospinal radiation therapy and frequent lumbar injections.

• Prevention and treatment

No preventive measures based on evidence are established. Steroids injected slowly through the lumbar route, or treatment with high doses of folate metabolites, could be considered in patients with methotrexate-induced myelopathy. In general, recovery is variable; most patients show clinical improvement.

> Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a very rare and devastating CNS demyelinating disease, occurring almost exclusively in patients with compromised immune systems (primarily CD4 or CD8 immunosuppression). PML has been reported rarely in patients with an underlying hematologic malignancy treated with immunomodulatory drugs or antibodies.

Subacute neurological symptoms in a patient at increased risk for PML, together with typical MRI findings and detection of JC virus DNA in CSF, are sufficient for diagnosis. In the absence of effective prevention or specific treatment of PML, no recommendations can be made. The primary focus is to restore the host’s adaptive immune response, which appears to prolong survival and may minimize CNS injury and prevent severe disability.

> Aseptic meningitis

The occurrence of aseptic meningitis is generally associated with intrathecal administration of chemotherapeutics and can be seen in 10% to 50% of patients receiving treatment with methotrexate and, specifically, liposomal cytarabine. Signs of meningeal irritation (headache, neck stiffness, vomiting, fever, lethargy) usually develop within 2 to 4 hours after drug injection and usually last about 12 to 72 hours. This is the criterion that distinguishes iatrogenic bacterial infection, which is also usually accompanied by fever.

Symptoms resolve spontaneously with symptomatic treatment. A CSF culture should be performed for differential diagnosis. Although little evidence is available, there is sufficient clinical consensus for the concomitant use of corticosteroids (the most commonly used dose is 4 mg of intrathecal dexamethasone) to gradually prevent aseptic meningitis [V, C].

> Stroke and vasculopathy

There is an increased risk of thromboembolic stroke in, for example, platinum-based therapy and, less commonly, in treatment with 5-fluorouracil, gemcitabine and bleomycin. Risk factors include radiotherapy-induced vasculopathy as well as prothrombotic activity of the cancer itself.