Introduction
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common side effects of cytotoxic chemotherapy and presents as a distal, symmetric polyneuropathy ( Table 28.1 ). Rates of CIPN depend on the agent being used but tend to occur in 60–70% of patients who receive neurotoxic agents. , According to one metaanalysis, the aggregate prevalence of CIPN is estimated to be 48%. Incidence is highest among patients receiving platinum-based drugs and taxanes, and slightly lower for bortezomib and vinca alkaloids. ,
| Cisplatin | Oxaliplatin | Oxaliplatin | Vincristine | Taxanes | Bortezomib | |
|---|---|---|---|---|---|---|
| Neuropathy type | Chronic peripheral neuropathy | Acute neuropathy | Chronic peripheral neuropathy, cramps and fasciculations at high doses, rare autonomic neuropathy | Chronic peripheral neuropathy, muscle cramps, autonomic neuropathy | Chronic peripheral neuropathy, myalgia, and myopathy at high doses, rare autonomic neuropathy | Chronic peripheral neuropathy, painful small fiber damage, rare myopathy, causes autonomic neuropathy |
| Incidence | ≥90% | 70% | 60–70% | 70–90% | 20–30% | |
| Cumulative dose | >350 mg/m 2 | Infusional | >550 mg/m 2 | >2–6 mg/m 2 | >300 mg/m 2 (PTX) >100 mg/m 2 (TXT) | >16 mg/m 2 |
| Unique clinical features | Dose-dependent | Resolved between cycles | Coasting | Progressive worsening | Worse with higher cumulative and single doses | |
| Other common side effects | Ototoxicity | Myelotoxicity | Myelotoxicity | Myalgias, myelotoxicity |
Clinical presentation
CIPN is generally a small fiber, sensory predominant polyneuropathy that is dose-dependent. Patients develop neuropathic symptoms in a distal, symmetric distribution, which typically include numbness, tingling, cramping, and at times weakness or burning pain in the feet and hands. When large fiber proprioceptive afferents are involved, patients may also develop impaired balance and falls, which can further impair quality of life. If CIPN is not recognized and chemotherapy doses not adjusted, delayed, or discontinued, permanent disability will occur. Most patients develop numbness first in the feet and hands. Neuropathic pain, motor weakness, or autonomic dysfunction are uncommon but may be seen with continued treatment as symptoms progress.
Clinical manifestations vary with the type of neurotoxic agent. For example, taxane chemotherapies, commonly used in treating breast, gynecologic, head/neck, and thoracic malignancies, tend to cause a sensory neuropathy with prominent numbness and tingling. Burning neuropathic pain occurs in only about 30–40% of taxane-induced CIPN. Neuropathy starts in the mid-to-late portion of the treatment and persists after patients complete their chemotherapy, often for weeks to months after the final dose. In contrast, oxaliplatin, which is commonly employed in regimens for gastrointestinal cancers, causes immediate cold hypersensitivity that occurs after each infusion as well as neuropathic pain, numbness, and tingling that worsens over time.
CIPN frequently persists after completion of cytotoxic therapy in about half of patients where it becomes a significant source of survivorship morbidity. In one study, CIPN was present in 68.1% of individuals when measured in the first month after chemotherapy, 60% at 3 months, and 30% at 6 months or more. Some patients even report neuropathic symptoms that persist for years after their last dose of chemotherapy. In rare cases, patients with no symptoms or only mild neuropathy during treatment go on to develop CIPN or experience paradoxical intensification of symptoms following the cessation of chemotherapy, often referred to as “coasting.” Thus, predicting who is at risk for CIPN is a priority.
Risk factors
A number of clinical factors can increase the risk of developing CIPN. Age, , preexisting peripheral neuropathy, , higher cumulative chemotherapeutic doses, , , , , smoking, diabetes mellitus, decreased creatinine clearance, and cold allodynia/hyperalgesia have all been shown to be associated with increased risk of CIPN. In addition, certain genetic polymorphisms may increase risk. Probably the most well-described genetic risk factor is PMP22 , the gene that, when duplicated, causes Charcot–Marie–Tooth disease type 1A and, when deleted, causes hereditary neuropathy with liability to pressure palsies (HNLPP). These individuals suffer debilitating weakness after even a single dose of vincristine, prompting the Food and Drug Administration (FDA) to issue a black box warning of vincristine use in cancer patients with Charcot–Marie–Tooth disease. In some studies, race and gender has been associated with higher risk of developing CIPN. African American women exhibited two to three times higher risk for developing CIPN relative to white women. , This increased risk has been associated with a unique, race-specific genetic haplotype in a DNA damage repair gene in women with taxane-induced CIPN. African American race has also been associated with increased risk of developing CIPN in patients with colorectal cancer. One study that investigated patients receiving platinum- and taxane-based chemotherapy for a variety of solid tumors in Hong Kong, Singapore, and the UK found that non‐Chinese Asians had higher-risk of developing neuropathy than Chinese or Caucasians. These associations need to be studied in larger samples while controlling for confounding variables before they will influence personalization of therapy. ,
Numerous other genetic polymorphisms have been associated with the development of CIPN, many having a role in the pharmacokinetics, absorption, distribution, metabolism, or excretion of chemotherapeutics and other drugs. Genetic alterations in glutathione transferases, cytochrome P450 enzymes, and ATP binding cassette proteins could alter the cellular uptake of cytotoxic drugs and promote accumulation of these agents in sensory neurons, potentially leading to neurotoxicity and the development of CIPN. , Unfortunately, none of the above risk factors have been validated in large cohorts, limiting the clinical use of pharmacogenomics in pretreatment screening. Despite this, these candidate genes are consistent with postulated pathophysiologic mechanisms of CIPN and provide fertile ground in which clinical trials investigating diagnostic tools and therapies are cultivated.
Pathophysiologic mechanisms
The pathophysiologic mechanisms of CIPN are multifactorial: oxidative stress and apoptosis, aberrations in calcium homeostasis, axon degeneration, changes in neuronal excitability, and neuroinflammation all promote the development of CIPN with greater or lesser contributions depending on the chemotherapy being used. Interestingly, despite similar mechanisms of action in their antiproliferative effect, the mechanisms of CIPN may differ among chemotherapeutic drugs within a class. For example, carboplatin toxicity predominantly affects the hematopoietic system, whereas cisplatin and oxaliplatin are much more neurotoxic. Similarly, among the vinca alkaloids, vincristine most commonly causes CIPN, whereas this is less common with vinblastine, vinflunine, and vinorelbine. ,
Making the diagnosis
CIPN shares significant clinical overlap with other diseases of the peripheral nervous system. When there is motor involvement in CIPN, the differential diagnosis is broad ( Table 28.2 ). However, correlating the timing of neuropathic symptoms with the onset of chemotherapy typically narrows etiologic considerations. CIPN is diagnosed clinically, often without the need for specialized testing (e.g., nerve conduction velocities). Unfortunately, there is no standardized approach to diagnosing CIPN. Clinician-reported grading is common with most providers using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Neuropathy Sensory subscale. Grading is performed prior to each treatment, typically by the primary treating oncologist or nurse, and a neuropathy score is assigned using elements from the history and physical examination ( Table 28.3 ). In general, grade 2 neuropathy indicates an impact on instrumental activities of daily living (IADLs), whereas grade 3 indicates impairment of routine ADLs. This scale is limited by inter-observer variability, and it has been shown to be less sensitive to changes in the severity of CIPN. Patient-reported outcome measures are frequently employed in clinical trials including the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 questionnaire. This instrument has good sensitivity to neuropathic symptoms and responsiveness to subtle changes in symptoms but correlates poorly with the degree of structural change or damage to the nerve itself. ,
| Cause | Comments | Workup |
|---|---|---|
| HIV-associated neuropathy | Symmetric distal, demyelinating, polyradiculopathy, or mononeuropathy | HIV antibody, viral load |
| Paraneoplastic | Sensory. Often associated with encephalitis, cerebellar ataxia, opsoclonus-myoclonus syndrome, and Lambert-Eaton myasthenic syndrome, among others | Paraneoplastic panel (i.e., anti-Hu and -CV2 antibodies are relevant to neuropathy) |
| Diabetes mellitus | Can present as distal symmetric sensory/sensorimotor polyneuropathy, autonomic neuropathy, mononeuropathy, or multiple mononeuropathies | Hemoglobin A1c, fasting plasma glucose |
| Hypothyroidism | Most typically carpal tunnel syndrome, rarely generalized, painful sensory polyneuropathy | TSH |
| Monoclonal gammopathy (e.g., Amyloidosis, MM, MGUS, WM, POEMS) | Typically painful dysesthesia of the hands and feet. Prominent autonomic involvement. | SPEP, UPEP, IF |
| Vitamin deficiency | Consider in patients with alcohol abuse, malabsorption, total parenteral nutrition, and bariatric surgery | B 1 , B 6 , B 12 , homocysteine, vitamin E, copper level, methylmalonic acid levels |
| Toxic | Numerous agents, many of which confer reduced sensory nerve action potentials on NCS | Alcohol, lead, mercury, arsenic levels |
| Sjogren’s syndrome | Length-dependent, pure small fiber and/or ganglionopathy | ANA, SS-A/Ro, SS-B/La |
| Vasculitis | Seen in a variety of conditions; RA, SLE, MCTD. Can be a mononeuropathy multiplex pattern or symmetric. Can be the result of drugs (e.g., leflunomide, tumor necrosis factor blockers) | |
| Hereditary neuropathy | HSAN, ALD/AMN, FAP, Tangier disease, all relatively rare, predominantly sensory | Genetic testing |
| Grade | |||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |
| Sensory neuropathy | Asymptomatic | Moderate symptoms; limiting instrumental ADL | Sensory alteration or severe symptoms; limiting self-care ADL | Life-threatening consequences; urgent intervention needed | Death |
| Motor neuropathy | Asymptomatic; clinical or diagnostic observation only | Moderate symptoms; limiting instrumental ADL | Sensory alteration or severe symptoms; limiting self-care ADL | Life-threatening consequences; urgent intervention needed | Death |
Neurology expertise is often sought in patients with an atypical presentation, when symptoms continue to worsen after discontinuation or completion of chemotherapy, or when other diagnoses (e.g., paraneoplastic or inflammatory neuropathy) are considered. Nerve conduction studies (NCS) can provide an objective assessment of clinical neuropathy but are often normal unless motor or large fiber sensory nerves are involved. NCS can be particularly helpful in differentiating CIPN from other peripheral neuropathies or paraneoplastic neuropathy when the diagnosis is in question. Quantitative skin testing (QST) allows for the assessment of small fiber, sensory nerve function but is more commonly employed in the research setting and is rarely incorporated into clinical care algorithms. Skin biopsy for assessment of intraepidermal nerve fiber density (IENF) can be helpful in demonstrating underlying sensory nerve fiber loss but is rarely needed in the appropriate clinical setting.
Treatment
Clinical trials evaluating prevention or treatment of CIPN have generally failed to bring effective therapies into the clinic. Numerous substances with diverse mechanisms have been trialed: alpha-lipoic acid, acetyl- l -carnitine, and glutathione are all antioxidants that, despite promising results in pilot studies, failed to demonstrate efficacy in preventing CIPN in phase III trials. Calcium and magnesium infusions were once routine in clinical practice but fell out of favor when large, randomized studies failed to show benefit. Many clinicians consider the use of neuropathic pain agents for symptomatic relief including gabapentin, pregabalin, tricyclic antidepressants, and others despite studies showing minimal benefit. Only venlafaxine and duloxetine have demonstrated efficacy for relief of painful paresthesias. Duloxetine is currently the only FDA-approved medication for the treatment of established CIPN. As a result, CIPN is managed by treatment delay, dose reduction, or discontinuation of chemotherapy altogether, which limits the delivery of life-saving drugs and can result in poorer patient outcomes.
Clinical cases
Although many antineoplastic agents have been associated with neurotoxicity, here we review four main groups of chemotherapeutic drugs that frequently cause CIPN: platinum-based antineoplastics (oxaliplatin), vinca alkaloids (vinblastine), taxanes (paclitaxel), and proteasome inhibitors (bortezomib). Each case provides a practical example for understanding the clinical presentation and management of CIPN and highlights clinical pearls that are common to all agents.
Case. A 65-year-old woman was diagnosed with invasive breast cancer after a screening mammogram revealed a focal asymmetry within the medial inferior right breast. Diagnostic mammogram revealed a BI-RADS IV, 8-mm solid mass in the upper inner right breast, suspicious for malignancy. Core biopsy showed invasive ductal carcinoma, grade 3, estrogen receptor 99%, progesterone receptor 60%, HER2/Neu+. She underwent a right lumpectomy with sentinel lymph node biopsy with negative margins and negative lymph node, pT1bN0M0. She received adjuvant chemotherapy with weekly paclitaxel and trastuzumab, which she initially tolerated well. After three cycles, she developed intermittent tingling in her fingers that spontaneously resolved after a few minutes. Throughout treatment, these symptoms progressed to involve the entire dorsal surface of the hands resolving prior to the next dose of treatment. After eight cycles of weekly paclitaxel, symptoms worsened from intermittent to constant, and she developed similar numbness and tingling in her toes and the soles of her feet. The patient also developed bilateral lower extremity edema, intermittent sensations of dyspnea, and a macular rash of the bilateral upper extremities. Because of these symptoms, her ninth cycle of chemotherapy was delayed and her subsequent cycle of paclitaxel was dose-reduced by 20%. Despite this, her sensory symptoms persisted, and after eleven cycles she began to experience intermittent, painful burning in her feet. She had no limitations in her ADLs or IADLs. Her physical examination was significant for normal gait, ambulation, and full strength of the upper and lower extremities. Sensory examination was normal except for subjective reduction in light touch and temperature in the distal legs bilaterally below the ankles and fingertips. The remainder of the examination was normal. Laboratory workup was normal, including normal blood glucose, hemoglobin A1c, folate, vitamin B 12 , thyroid function studies, and rapid-plasma reagin. NCS revealed right lower leg sural nerve latency of 3.6 milliseconds, amplitude of 10 microvolts, and conduction velocity of 49 meters per second. She also underwent nerve ultrasound, which showed an enlarged right median nerve (cross-sectional area: 21.8 mm 2 ). Two months after her final dose of chemotherapy, the patient reported that her neuropathy had resolved.
Teaching Points. This case highlights two important principles of managing CIPN including: (1) additional contributors to peripheral nerve injury should be identified and managed in CIPN patients, and (2) CIPN is a clinical diagnosis with objective measures of nerve function often used to rule out alternative etiologies.
Screen for treatable causes . The first principle is to evaluate and screen for treatable causes, contributors, and exacerbating conditions including diabetic neuropathy, vitamin B 12 or folate deficiency, hypothyroidism, undiagnosed syphilis, or other readily treatable causes including alcohol consumption. Peripheral neuropathy as part of a paraneoplastic syndrome should be considered in selected patients with an atypical presentation, worsening of neuropathy after cessation of chemotherapy, and with selected cancers such as squamous and small-cell lung cancers, gynecologic cancers, and lymphoma which are the most common to be associated with this complication. The patient in this case had none of these risk factors, had onset of symptoms after initiation of a neurotoxic agent, and worsening with increasing number of doses. Consideration of the route of administration and cumulative dose is important as well; for example, methotrexate rarely causes peripheral neuropathy except when administered via the intrathecal route, and CIPN usually develops within the first 2 months of treatment, as in this patient.
Objectives measures of CIPN . The second important principle is the role of objective assessment measures. Objective measures of peripheral neuropathy provide valuable information about the extent of axonal loss in patients with CIPN. Although NCS is the gold standard for diagnosis of most toxic peripheral neuropathies, it is frequently normal in CIPN. Compound sensory action potentials (CSAP) and compound motor action potentials (CMAP), which are measured during NCS, provide information about large fiber nerve function. Reduction in action potential amplitude indicates axonal loss, whereas slowed conduction velocities and conduction block suggest demyelination and could indicate an immune-mediated cause (e.g., paraneoplastic). NCS is most sensitive to changes in larger fiber A-beta (6–12 μm, myelinated, altered touch detection to monofilaments) but not to changes in small A-delta fibers (1–5 μm, myelinated, altered sharpness detection) and nociceptors such as C-fibers (0.2–1.5 μm, unmyelinated, hot, cold, burning pain).
Quantitative sensory testing . QST is a psychophysical assessment method that quantifies function of the somatosensory system. QST interrogates sensory nerve fibers of varying sizes by applying specific, calibrated stimuli and recording the subject’s response. QST differs from the usual NCS and somatosensory-evoked potentials in that it requires a response from the subject to judge whether or not a stimulus is felt and/or whether or not the stimulus is perceived as painful. QST has been used in over 1000 patients treated with neurotoxic chemotherapies and represents a complimentary assessment tool for evaluating the clinical impact of small fiber neuropathy but has principally been used in research studies. Patient-reported outcomes include the EORTC QLQ-CIPN20, which has been shown to be more sensitive than NCI grading with good internal validity. , The total neuropathy score (TNS) combines symptom reporting with objective nerve assessment using NCS and has been used in clinical trials. , The TNS offers a wider range of values (0–40) compared with the CTCAE and may be more capable of discriminating between moderate and severe neuropathy in patients who experience no limitation in their ADLs. Skin biopsy is another technique that allows for objective quantification of IENF density. This minimally invasive technique has been validated across multiple different disorders of the peripheral nervous system and correlates well with clinical assessment. , Reduction in IENF density has been demonstrated in skin biopsies from patients with CIPN who received neurotoxic chemotherapies. Taxane use has been associated with distal reduction in IENF density, , as in this patient ( Fig. 28.1 ).
Studies are ongoing evaluating novel methods of predicting, screening, diagnosing, and tracking CIPN. We have previously explored the role of neuromuscular ultrasound to noninvasively assess gross nerve structure in CIPN ( Fig. 28.2 ). The patient in this case was enrolled in a cross-sectional study comparing methods of objective assessment of CIPN and underwent NCS. Right median, right tibial, and right sural sensory conduction studies were normal. Her nerve ultrasound revealed an enlarged median nerve, which may have contributed to the early onset of symptoms in the hands. Anecdotally, this presentation is not uncommon in patients with taxane-induced CIPN. Whether treatment of carpal tunnel syndrome in these patients is beneficial is controversial.
Taxane-Induced Peripheral Neuropathy Summary. Taxanes, including paclitaxel, docetaxel, and cabazitaxel, have been used for nearly 30 years to treat a variety of cancers including breast, ovarian, non–small-cell lung cancer, and prostate cancer. Frequency and intensity of CIPN is higher for paclitaxel than docetaxel and cabazitaxel. , Albumin-bound paclitaxel (Nab-paclitaxel) was developed to reduce toxicity, though the rate of CIPN is similar to the parent compound. In patients treated with taxanes, neuropathy is typically sensory predominant. It classically is reported as a stocking-and-glove distribution, though many patients first describe numbness and tingling in the hands followed by symptoms in the feet bilaterally. Taxanes contribute to CIPN through several mechanisms. Microtubule disruption confers antineoplastic activity to taxanes but also impairs axonal transport of synaptic vesicles containing neurotransmitters. Taxanes alter peripheral nerve excitability and calcium homeostasis, leading to hyperexcitability and hyperalgesia in rodent models of CIPN. , Paclitaxel is directly mitotoxic, promoting the formation of free radicals and reactive oxygen species that damage neuronal mitochondria. This promotes inflammatory cytokine production, disruption of the electron transport chain, demyelination, and apoptosis. Finally, the role of the immune system in the pathogenesis of CIPN caused by taxanes is garnering interest, as paclitaxel has been shown to directly stimulate Toll-like receptors and promote the influx of inflammatory leukocytes, leading to demyelination and loss of nerves in the dorsal root ganglion.
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