Chemotherapy-induced peripheral neuropathy (CIPN) is a nerve-damaging side effect of antineoplastic agents in the common cancer treatment, chemotherapy. CIPN afflicts between 30% and 40% of patients undergoing chemotherapy. Antineoplastic agents in chemotherapy are designed to eliminate rapidly dividing cancer cells, but they can also damage healthy structures, including the peripheral nervous system. CIPN involves various symptoms such as tingling, pain, and numbness in the hands and feet. These symptoms can impair activities of daily living, such as typing or dressing, reduce balance, and increase risk of falls and hospitalizations. They can also give cause to reduce or discontinue chemotherapy. Researchers have conducted clinical trials and studies to uncover the various symptoms, causes, pathogenesis, diagnoses, risk factors, and treatments of CIPN.
Symptoms and signs CIPN symptoms manifest themselves as deficits in sensory, motor, and/or autonomic functions of varying intensity, and they can significantly reduce a patient's functional quality of life. Sensory symptoms affecting the hands and feet generally develop first. Sensory side effects are caused when nerves in the most distal parts of the limbs are damaged. Patients may experience numbness, tingling, altered touch sensation, gait and balance disturbances, burning pain, thermal allodynia or hyperalgesia, impaired vibration sense, extreme temperature sensitivity, paresthesia, and/or dysesthesia as part of sensory damage. On the other hand, motor symptoms are less frequently seen as sensory symptoms. Motor symptoms of CIPN can include cramping, distal weakness, difficulty handling small objects, and impaired movements. In severe cases, motor symptoms can lead to complete immobilization and severe disability. Finally, autonomic symptoms usually involve orthostatic hypotension, constipation, and altered urinary function. A patient experiencing CIPN symptoms may have difficulty performing daily functionalities like walking, dressing themselves, writing, typing, and other activities related to the hands and feet.
The prevalence of these symptoms is highest in the first month after the completion of chemotherapy at 68.1%, but as many as 30% of patients still report CIPN symptoms six months after the completion of chemotherapy. Paclitaxel and oxaliplatin, representatives from two of the six major antineoplastic agents causing CIPN, cause acute neuropathy, which manifests during or immediately after treatment infusion. The other four groups of agents generally cause late symptoms that emerge weeks after the completion of chemotherapy. In both cases, the severity of the symptoms are generally proportional to the dose of the treatment drug received, and the severity of the symptoms may warrant a reduction in the chemotherapy dosage. Pain and sensory abnormalities can persist for months or years after treatment completion. Some patients may experience "coasting," where symptoms intensify after completion of treatment. As such, patients can be cancer-free and still suffer from disabling neuropathy induced by cancer treatment.
Causes There are six main agent groups found in chemotherapy treatment that damage the sensory, motor, and autonomic neurons and therefore cause CIPN: platinum-based compounds, taxanes, vinca alkaloids, epothilones, proteasome inhibitors and immunomodulatory drugs.
Platinum-based compounds Platinum-based compounds, namely oxaliplatin, cisplatin, and carboplatin (which is noticeably less neurotoxic than cisplatin), are used to treat several types of solid tumors, such as stomach, liver, lung, ovarian, brain, and uterine cancers. These agents can damage dorsal root ganglia neurons by forming adducts with nuclear and mitochondrial DNA. This damage can cause neuronal apoptosis, programmed cell death, which leads to neuropathy. Additionally, functional neuronal deficits have been identified, independent of structural damage, e.g. ion channelopathy, impaired spike encoding in the central and peripheral nervous system. Specific side effects of platinum compounds include hearing loss, tinnitus, and dysesthesia. These symptoms generally begin with the or third cycle of treatment and can last long after treatment completion. Indeed, the "coasting" phenomenon mentioned in the Symptoms section is a direct effect of platinum agents. Of the platinum compounds, research has shown cisplatin to be the most frequently involved in peripheral neuropathy.
Taxanes Taxanes, including paclitaxel (and protein-bound pactiltaxel e.g. abraxane), docetaxel, and cabazitaxel, are used to treat ovarian, breast, non-small cell lung, and prostate cancers. These drugs interfere with the normal cycling of microtubule depolymerization and repolymerization in small diameter sensory fibers to create sensory dominant neuropathy. Sensory side effects include paresthesias, dysesthesias, numbness, altered proprioception, and loss of dexterity in fingers and toes. Motor and autonomic symptoms are less frequent but possible. Symptoms may start days after the patient receives their first dose of chemotherapy, are dose dependent, and tend to improve after completion of treatment. However, in some cases, symptoms can persist six months or later following the completion of chemotherapy. Of the taxanes, paclitaxel has the most intense symptoms that may last for the longest time.
Vinca alkaloids Vinca alkaloids, including vincristine, vinblastine, vinorelbine, and vindesine, are used to treat tumors such as Hodgkin lymphoma, testicular cancer, and non-small cell lung cancer. These drugs inhibit the assembly of microtubules and thus disrupt axonal transport in the cell body of peripheral nerves. Vinca alkaloids induce sensorimotor neuropathy, decreased sensation, in the hands and feet. Symptoms of vinca alkaloids include muscle weakness, initial pain after receiving an infusion, and cramping. These symptoms usually appear within the first three months of treatment. Of the vinca alkaloids, the most neurotoxic drug is vincristine. Vincristine disrupts the microtubular axonal transport system, which induces axonal neuropathy, distal numbness and tingling, and pain.
Epothilones Epothilones, mainly ixabepilone, are relatively new drugs that can be used to treat non-small lung, ovarian, and prostate cancers. Epothilones cause microtubule disruption (like taxane-based drugs), which impairs axonal transport and leads to hyperexcitability of peripheral neurons. They can cause neuropathy characterized by paresthesias, numbness, and pain in the hands and feet. Sensory and motor symptoms are commonly seen in patients treated with epothilone, which generally results in muscle weakness, while autonomic symptoms are rarely seen. The symptoms of this drug occur during treatment and tend to stop after completion. As of 2019, epothilones are not approved by the Food and Drug Administration for patient usage and are generally used only for patients not responding to other available chemotherapies.
Proteasome inhibitors Proteasome inhibitors, namely bortezomib, are used in the treatment of multiple myeloma and certain types of lymphoma. Bortezomib increases the production of sphingosine-1 phosphate, tumor necrosis factor α, and interleukin-1β, which ultimately leads to the development of neuropathic pain. The side effects of receiving bortezomib include chronic, distal, and symmetrical sensory peripheral neuropathy and neuropathic pain syndrome which may last for weeks, months, or years after treatment completion.
Immunomodulatory drugs Immunomodulatory drugs, mainly thalidomide, are used to treat multiple myeloma. The anticancer mechanism of these drugs are not completely understood, but they are believed to accelerate neuronal cell death and block angiogenesis. Side effects of thalidomide-induced peripheral neuropathy include sensory symptoms, possible motor impairment, and gastrointestinal and cardiovascular autonomic manifestations. The symptoms of immunomodulatory drugs may dictate whether treatment is continued or discontinued, and they can last long-term after chemotherapy completion.
Risk factors There are various factors that appear to predict the development of CIPN symptoms. Genetically, there are currently multiple single nucleotide polymorphisms potentially associated with CIPN, as identified through the Genome Wide Association Studies. The reported polymorphisms are associated with a range of protein including voltage-gated sodium channels, Schwann cell function-related proteins, receptors for cell surface collagen, receptors involved in neuronal apoptosis, neuronal crest cell development, and an enzyme involved in pyruvate metabolism.
Additionally, there are various diagnoses that may increase a patient's risk of developing CIPN: 1) A history with acquired or hereditary neuropathy from diabetes, renal disease, hypothyroidism, connective tissue disease, or vitamin deficiencies is a risk factor. 2) A diagnosis of current or previous infectious disease such as Human Immunodeficiency Virus, Poliomyelitis, and Hepatitis B or C may increase a patient's risk. 3) Exposure to medications linked to neurotoxicity, such as cyclosporine, vancomycin, and cimetidine, in the treatment of a previous diagnosis.
There are also personal and treatment characteristics that may be potential risk factors: 1) Older age 2) Chemotherapy type 3) Cumulative dosage of chemotherapy treatment 4) Smoking history 5) History of alcohol intake 6) Dietary history 7) Race 8) Gender 9) Inactive lifestyle. In particular, the cumulative dosage of chemotherapeutic agents is a well-recognized risk factor of CIPN.
Diagnosis
Evaluation of a patient's medical history for the risk factors listed above is essential in the assessment of CIPN because CIPN symptoms may overlap with other comorbid conditions. Furthermore, the heterogeneity of CIPN means that patients describe their neuropathic symptoms in different ways. Some may report the impact of neuropathy in their daily life (e.g. difficulty with buttons, dropping objects, difficulty walking, etc.), and others might report traditional distal extremity numbness, burning, or pain. To assess the impact of symptoms on a patient's quality of life, clinicians currently use the Quality of Life Questionnaire-CIPN twenty item scale (CIPN-20) developed by the European Organisation for Research and Treatment of Cancer. The CIPN-20 asks patients to rate their experience with different symptoms during a given period of time using scores from 1 ("not at all") to 4 ("very much"). The results provide clinicians with critical information on a patient's functional limitations in relation to their exposure to potentially neurotoxic chemotherapeutic agents. In addition to the CIPN-20, the clinical Total Neuropathy Score for CIPN (TNS-c) can also be used to assess neuropathy signs and symptoms. The TNS-c has shown to be highly accurate in scoring the severity of CIPN, especially how it changes.