Chemotherapy-Induced Peripheral Neuropathy: Assessment and Treatment Strategies for Advanced Practice Providers

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of numerous anticancer agents. CIPN can persist as chronic pain or sensory symptoms for months to years after discontinuation of the anticancer agent, affecting a patient’s quality of life, function, and morbidity. Although treatment recommendations are limited because of insufficient evidence, many pharmacologic and nonpharmacologic therapies are being explored to prevent and treat CIPN.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy that can persist for months to years after the discontinuation of therapy, contributing to reduced function and quality of life for patients with cancer (Li et al., 2021; Yoon & Oh, 2018). Seretny et al. (2014) conducted a large systematic review with 4,179 patients and found that the prevalence of CIPN after chemotherapy was 68% at one month, 60% at three months, and 30% at six months. The most common types of anticancer therapies associated with CIPN include platinum-based drugs (e.g., cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine), taxanes (e.g., paclitaxel, docetaxel), proteasome inhibitors (e.g., bortezomib), and immunomodulators (e.g., thalidomide). Colon and breast are the most common cancers associated with CIPN (Dan et al., 2024; Klafke et al., 2023; Li et al., 2021; Loprinzi, 2021; Yoon & Oh, 2018). Patients’ symptoms may vary based on the type of anticancer agent administered (see Table 1).

TABLE 1.

COMMON ANTICANCER AGENTS CAUSING CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

DRUG	POSSIBLE CLINICAL MANIFESTATIONS		THRESHOLD DOSE
	SENSORY	MOTOR OR DTRs
Platinum-based drugs
Cisplatin or carboplatin	LEs equal to UEs Stocking-glove distribution Painful paresthesia Numbness Decreased vibration sensitivity Loss of taste	Decreased DTRs Tremor Weakness	Cisplatin: greater than 350 mg/m2
Oxaliplatin	Cold-induced dysesthesias or allodynia: mouth, throat, UEs UEs greater than LEs Stocking-glove distribution Painful paresthesia or allodynia Numbness or tingling of extremities and mouth Diminished proprioception	Cold-induced cramps Muscle spasms Fasciculations Prolonged muscular contractions Deficits in fine motor tasks	Greater than 540–550 mg/m2
Vinca alkaloids
Vincristine	LEs greater than UEs Numbness or tingling Painful paresthesia: burning or sharp pain Loss of sensory discrimination (e.g., light touch, pinprick, vibration, temperature)	Weakness in LEs Wrist or foot drop (impaired dorsiflexion) Muscle cramps Decreased or absent DTRs Deficits in fine motor tasks or walking	Greater than 2–6 mg/m2
Taxanes
Paclitaxel or docetaxel	LEs greater than UEs Painful paresthesia Numbness or tingling Mechanical or cold allodynia Loss of pinprick sensitivity	Mild weakness in foot muscles Muscle cramps or aches Myalgia or arthralgia Decreased DTRs Deficits in fine motor tasks or walking	Paclitaxel: greater than 300 mg/m2 Docetaxel: greater than 100 mg/m2
Proteasome inhibitors
Bortezomib	LEs equal to UEs Painful paresthesia: burning or sharp pain Numbness or tingling	Mild weakness in LEs Muscle cramps or fasciculations Decreased DTRs	Greater than 16 mg/m2
Immunomodulators
Thalidomide	LEs equal to UEs Painful paresthesia Numbness	Weakness or tremor Muscle cramps or fasciculations Decreased DTRs	Greater than 20 g

DTRs—deep tendon reflexes; LEs—lower extremities; UEs—upper extremities

Note. Based on information from Li et al., 2021; Loprinzi, 2021; Starobova & Vetter, 2017; Yoon & Oh, 2018.

The presentation of CIPN can range from sensory symptoms, such as numbness, tingling, neuropathic (radiating or shooting) pain, and/or cold sensitivity; to motor symptoms, such as muscle weakness, cramping, difficulties with fine motor movement, and/or foot drop; to autonomic symptoms, such as dizziness, orthostatic hypotension, erectile dysfunction, urinary retention, dysphagia, constipation, or difficulties with hearing (Dan et al., 2024; Kanzawa-Lee, 2020; Knoerl, 2021; Li et al., 2021; Loprinzi, 2021). These symptoms can result in impaired mobility, balance, gait, and function, which further increase a patient’s risk of falls (Loprinzi, 2021). Patients with CIPN often report interference in social functioning, sleep, and work, which can negatively affect quality of life and psychological well-being (Dan et al., 2024; Dongxue et al., 2024). Patients with CIPN were also found to spend about $17,344 more in healthcare costs than a control group (Pike et al., 2012).

As patients with cancer are living longer, greater attention is needed to diagnose and treat the long-term side effects of oncologic treatment, specifically CIPN. Advanced practice providers (APPs) must identify patients at increased risk, monitor current evidence related to prevention and treatment, and educate patients appropriately.

Risk Factors

The primary risk factors for CIPN include the type, cumulative dose, length of treatment, and route of administration of the anticancer agent (Li et al., 2021; Maihöfner et al., 2021; Starobova & Vetter, 2017). Individual risk factors are not clearly established (Jordan et al., 2020); however, many potential risk factors have been identified in the literature (see Table 2).

TABLE 2.

POTENTIAL RISK FACTORS FOR CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

CHARACTERISTIC	RISK FACTOR
Patient-related characteristics	Older age
Comorbidities	Obesity, diabetes mellitus, thyroid dysfunction (e.g., hypothyroidism), infectious disease (e.g., hepatitis B or C, poliomyelitis, HIV), autoimmune rheumatologic conditions, renal insufficiency (e.g., decreased creatinine clearance), preexisting neuropathy (e.g., alcohol consumption, inherited), vitamin deficiencies (e.g., B12, B1, B6)
Medications	Metronidazole, misonidazole, sulfasalazine, or phenytoin
Lifestyle influences	Alcohol consumption, smoking, reduced physical activity, malnutrition (e.g., low albumin levels)

Note. Based on information from Jordan et al., 2020; Li et al., 2021; Maihöfner et al., 2021; Molassiotis et al., 2019; Seretny et al., 2014; Starobova & Vetter, 2017.

Pathophysiology

The pathophysiology of CIPN is not fully understood. CIPN’s underlying mechanism of action is multifactorial, with various sites of involvement, including the myelin sheath, dorsal root ganglion, and axonal components (Maihöfner et al., 2021; Starobova & Vetter, 2017; Yoon & Oh, 2018). The damage to the peripheral nerve fibers by anticancer agents leads to decreased nerve conduction velocity and excitability (Dan et al., 2024). The sensory nerve fibers are typically the most vulnerable; therefore, sensory symptoms are more common and usually occur earlier than motor or autonomic symptoms (Dan et al., 2024; Jordan et al., 2020; Maihöfner et al., 2021). The longest peripheral axons are most affected by anticancer agents, resulting in symptoms presenting more commonly in the lower extremities compared to the upper extremities and worse distally in a stocking-glove distribution pattern (Dan et al., 2024; Jordan et al., 2020; Maihöfner et al., 2021; Starobova & Vetter, 2017). In addition to peripheral nerve damage, anticancer agents may also lead to long-term central nervous system changes, contributing to chronic pain for patients (Maihöfner et al., 2021).

CIPN symptoms typically begin during the first two months of treatment and progress as treatment continues (Jordan et al., 2020). Although CIPN is anticipated to improve over time, many patients, particularly those receiving platinum-based drugs, may experience a coasting phenomenon, wherein symptoms continue to worsen for a few months after discontinuation of chemotherapy (Jordan et al., 2020; Loprinzi, 2021).

Diagnostic Workup

History of Present Illness

When gathering the history of present illness, it is important to understand which anticancer agent was used, when administration started, and whether the regimen is still being administered or when the last dose was received. The APP can inquire about the timing of CIPN onset and whether symptoms have progressively worsened, improved, or remained stable. In addition, the APP can assess risk factors or comorbidities that may be contributing to the patients’ symptoms (see Figure 1).

FIGURE 1. CASE PRESENTATION.

ADLs—activities of daily living; CTCAE—Common Terminology Criteria for Adverse Events

The most common clinical presentation of CIPN is sensory neuropathy. Neuropathic plus or positive symptoms include hyperalgesia (i.e., increased pain from a stimulus that normally provokes pain), allodynia (i.e., pain from a stimulus that does not normally provoke pain), dysesthesia (i.e., unpleasant and abnormal sensation, such as prickling, burning, lancinating, electric shock–like sensation), and paresthesia (i.e., abnormal but not unpleasant sensation, such as pins and needles sensation) (Jordan et al., 2020; Maihöfner et al., 2021; Yoon & Oh, 2018). Neuropathic minus or negative symptoms include hypoalgesia (i.e., diminished pain in response to a normally painful stimulus), hypoesthesia (i.e., decreased sensitivity to stimulation, such as numbness sensation), and impaired proprioception or vibratory sensation (Jordan et al., 2020; Maihöfner et al., 2021).

In addition to the reported symptoms, the history of present illness also addresses the impact of CIPN symptoms on the patient’s activities of daily living, sleep, work, social life, sexual function, and mood. CIPN of the upper extremities may limit fine motor tasks and independence with activities of daily living, whereas CIPN of the lower extremities may affect ambulation, balance, and fall risk.

Physical Examination

A focused CIPN physical examination includes psychiatric, neurologic, musculoskeletal, and skin examinations. Although there is no gold standard assessment tool, there are many patient-reported and clinician-reported tools available. The Common Terminology Criteria for Adverse Events, version 5.0, is most commonly used in clinical trials and grades symptoms on a scale ranging from 1 (mild) to 5 (death), depending on CIPN severity (Kanzawa-Lee, 2020). McCrary et al. (2017) conducted a systematic review exploring 117 CIPN assessment strategies and found that the Total Neuropathy Score clinical version and the Patient Neurotoxicity Questionnaire received the highest ratings for provider-reported and patient-reported tools, respectively (McCrary et al., 2017). The Total Neuropathy Score clinical version is useful in guiding the provider in assessing motor symptoms, autonomic symptoms, sensation to pinprick and vibration, strength, and deep tendon reflexes. Additional physical examination maneuvers include assessing proprioception, thermal sensation, gait, balance, and fine motor dexterity (Kanzawa-Lee, 2020). Physical examination findings for patients with CIPN typically include attenuated reflexes, reduced strength, and altered sensation (Kanzawa-Lee, 2020).

Testing and Diagnosis

Although there are no gold standard tests for diagnosing CIPN, the APP’s assessment and diagnosis of CIPN includes the history of present illness and physical examination findings. In addition, the APP may review additional laboratory and radiologic testing results to rule out other potential diagnoses, including thyroid function, vitamin tests (B₁₂, B₆, B₁, D, folate), hemoglobin A1C, serum protein electrophoresis, and methylmalonic acid. Electromyography and nerve conduction studies may also help to identify preexisting neuropathy (Jordan et al., 2020).

Patient Education

When administering an anticancer agent that is known to cause CIPN, the healthcare team can advise patients to report CIPN symptoms at onset to ensure early detection and prompt management (Dan et al., 2024). To promote patient safety and well-being, patient education includes the following (Dan et al., 2024; Jordan et al., 2020; Knoerl, 2021):

• Wearing gloves to avoid injuries when handling sharp, hot, or cold objects

• Wearing socks and properly fitted footwear

• Practicing foot care and inspecting the hands and feet for lacerations, sores, or burns

• Using night-lights and handrails and removing clutter

• Using skid-free shower and bathroom mats

• Ambulating with an assistive device, if needed

• Engaging in moderate activity and maintaining a balanced diet

• Practicing caution when driving or operating machinery

• Avoiding contact with cold objects and checking the temperature of kitchen and bath water

Prevention

Neither the American Society of Clinical Oncology (ASCO) nor the European Society for Medical Oncology–European Oncology Nursing Society–European Association of Neuro-Oncology (ESMO–EONS–EANO) clinical practice guidelines provide recommendations for preventing CIPN (Jordan et al., 2020; Loprinzi et al., 2020). Although the benefits of exercise and functional training on the prevention of CIPN are limited, Jordan et al. (2020) suggested that exercise is a reasonable therapy for patients at risk for developing CIPN. Although the mechanisms of action for cryotherapy and compression therapy are not fully understood, one review suggested that both therapies are safe treatments that could potentially be effective in preventing CIPN, possibly because of the reduction of blood flow perfusion and inflammation after cold or compression stimulation (Dan et al., 2024).

Treatment

Treatment for CIPN remains limited (Jordan et al., 2020; Loprinzi et al., 2020). To treat CIPN and prevent worsening symptoms, the ASCO clinical practice guidelines recommend adjusting the anticancer therapy by decreasing the dose, extending the medication interval, or discontinuing the regimen (Loprinzi et al., 2020). Depending on the grading of patients’ CIPN and its effect on their quality of life, patients and the oncologic team may have to weigh the risks and benefits to determine whether to reduce or discontinue the anticancer agent (Dan et al., 2024). Hertz et al. (2021) proposed a patient-centered decision framework that considers the risks and benefits of altering anticancer treatment, as well as disease- and patient-related factors, such as CIPN severity and persistence, treatment efficacy, and likelihood of survival.

A one-size-fits-all approach cannot be applied to the treatment of CIPN, and the choice of therapy must consider patients’ preferences and values, the best available evidence, and the expertise of the provider (Hole et al., 2023; Klafke et al., 2023). Treatment considerations for CIPN can vary depending on whether the goal is to relieve patients’ pain or improve function (see Figure 2). Of note, medications have not been found to be effective in treating the nonpainful symptoms of CIPN (Desai et al., 2022).

FIGURE 2. POSSIBLE TREATMENT CONSIDERATIONS FOR CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY: PAIN RELIEF VERSUS FUNCTIONAL IMPROVEMENT.

HEP—home exercises program; LIFU—low intensity focused ultrasound; PO—by mouth; TENS—transcutaneous electrical nerve stimulation

Pharmacologic Treatment

The ASCO and ESMO–EONS–EANO clinical practice guidelines recommend duloxetine as a first-line medication to treat painful CIPN, although the anticipated benefit is modest (Jordan et al., 2020; Loprinzi et al., 2020). The ESMO–EONS–EANO clinical practice guidelines further recommend the consideration of topical menthol cream, tricyclic antidepressants, anticonvulsants, tramadol, or strong opioids if duloxetine fails or is contraindicated (Jordan et al., 2020).

Additional pharmacologic therapies being explored for the treatment of CIPN include ketamine IV infusions, topical lidocaine or ketamine compounded creams, capsaicin patches, supplements, and cannabinoids (Cabezón-Gutiérrez et al., 2020; Dan et al., 2024; Kanzawa-Lee, 2020; Maher et al., 2017; Oh et al., 2021; Weiss et al., 2023).

Nonpharmacologic Treatment

Although the ASCO clinical practice guidelines do not provide recommendations for nonpharmacologic therapies to treat CIPN, the ESMO–EONS–EANO clinical practice guidelines recommend exercise and functional training, as well as the consideration of acupuncture, cryotherapy, and compression therapy (Jordan et al., 2020; Loprinzi et al., 2020). Exercise has been found to be effective in improving CIPN symptoms, quality of life, and balance and decreasing pain (Huang et al., 2024). Exercise can also promote nerve regeneration and relieve pain by improving blood oxygen saturation, tissue metabolism, nerve activity, and conduction velocity (Dan et al., 2024). Compression therapy can effectively improve CIPN symptoms, as well as symptoms of anxiety, depression, and sleep disorders (Dongxue et al., 2024).

Additional nonpharmacologic therapies being explored for the treatment of CIPN include low intensity focused ultrasound, massage, therapeutic touch, foot reflexology, neuromodulation, auricular acupressure, sensorimotor training, transcutaneous electrical nerve stimulation, photobiomodulation therapy, yoga, herbal remedies, mind–body therapies, meditation, and aromatherapy because of their safety, low side effect profiles, and potential benefit (Al Onazi et al., 2021; Dan et al., 2024; Kanzawa-Lee, 2020; Klafke et al., 2023; Patel et al., 2021; Ronconi et al., 2024).

Conclusion

CIPN can be a high-impact side effect of systemic therapy for as many as 68% of patients with cancer receiving chemotherapy, affecting patients’ function, quality of life, and mood. The current ASCO clinical practice guideline recommendations for the treatment of CIPN include adjusting the dose of the anticancer agent or prescribing duloxetine. Although the literature is limited regarding effective treatment for CIPN, many nonpharmacologic and pharmacologic therapies are being explored to assess their impact on pain relief and functional improvement for patients with CIPN. To ensure high-quality care, APPs must identify high-risk patients; assess the impact of CIPN on pain, function, and quality of life; and develop individual plans of care to promote safety, pain relief, and independence.

AT A GLANCE.

• CIPN can affect patients’ morbidity, function, and quality of life.

• Treatment for CIPN varies based on patients’ presentation of sensory, motor, and autonomic symptoms and goals of care to relieve pain or improve function.

• Advanced practice providers can appropriately diagnose and manage the long-term side effects of chemotherapies, such as CIPN, to improve patients’ physical and psychosocial well-being.