Chemotherapy-induced peripheral neuropathy

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.[3] 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.[3] 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.[3] Finally, autonomic symptoms usually involve orthostatic hypotension, constipation, and altered urinary function.[3] 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.[2]

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.[4] 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.[1] 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.[2] 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.[3] As such, patients can be cancer-free and still suffer from disabling neuropathy induced by cancer treatment.[3]

There are six main agent groups found in chemotherapy treatment that damage the sensory, motor, and autonomic neurons and therefore cause CIPN: 1) platinum-based compounds 2) taxanes 3) vinca alkaloids 4) epothilones 5) proteasome inhibitors 6) immunomodulatory drugs.[3] The mechanisms, side effects, and symptom duration for each of these groups are summarized below.

1) 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.[3] These agents can damage dorsal root ganglia neurons by forming adducts with nuclear and mitochondrial DNA.[1] 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[5] and peripheral nervous system.[6][7] 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.[3]

2) 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.[3] 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.[8] Of the taxanes, paclitaxel has the most intense symptoms that may last for the longest time.[3]

3) 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.[3] 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.[3] 

4) Epothilones, mainly ixabepilone, are relatively new drugs that can be used to treat non-small lung, ovarian, and prostate cancers.[3] 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.[3]

5) 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.

6) Immunomodulatory drugs, mainly thalidomide, are used to treat multiple myeloma.[3] 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.[3] 

There are various factors that appear to predict the development of CIPN symptoms.[4] Genetically, there are currently multiple single nucleotide polymorphisms potentially associated with CIPN, as identified through the Genome Wide Association Studies.[9] 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.[3]

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.[9] 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.[10] 3) Exposure to medications linked to neurotoxicity, such as cyclosporine, vancomycin, and cimetidine, in the treatment of a previous diagnosis.[10]  

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.[10] In particular, the cumulative dosage of chemotherapeutic agents is a well-recognized risk factor of CIPN.

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.[11] 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.[11] 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 Organization 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.[12] 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.[13][14]

Physical examination to assess motor function, reflexes, gait and balance, and sensation also plays a key role in the diagnosis of CIPN.[11] First, motor testing involves assessment of muscle tone and bulk, which may be decreased in patients with CIPN due to atrophy and hypotonia. Commonly affected muscle groups to look out for include the distal muscles of the hands, feet, and ankles.[11] Second, a patient's reflexive response should be tested. The reflexes of patients with CIPN are frequently diminished, if not gone entirely. Dysfunction of the Achilles reflex is especially common.[11] Third, gait testing includes testing a patient's ability to walk on their heels and toes. Patients with distal foot weakness, a symptom of CIPN, may be unable to walk on their heels and commonly drag their toes while walking. The Romberg sign should also be tested to indicate a patient's sense of balance. If patients are unable to stand with their feet together and their eyes closed, proprioceptive loss, commonly seen with CIPN, can be assumed.[11]

Finally, sensory testing should include the assessment of pain, vibration, and position sense. With their eyes closed, patients will be subjected to various stimuli to test their sensation. Pain can be tested with sharp stimulus such as a pin or a toothpick. Patients with CIPN may report objective numbness, dysesthesia, or increased pain with this pinprick test.[11] Vibratory sensation can be tested using a tuning fork applied to distal interphalangeal joints in the fingers and toes. Patients with CIPN commonly report vibratory sensation lasting less than eight seconds of absent vibration.[11] Position sense can be tested by having a patient close his or her eyes with an examiner moving a distal joint up or down. Patients with CIPN will often be unable to correctly determine the direction of movement.[11]

In addition to examination of neurological symptoms, analysis of the administered drugs, the cumulative dosage, and the clinical characteristics and duration of the neuropathic symptoms are also important in the diagnosis of CIPN.[1] First, clinicians must consider if the patient received a neurotoxic chemotherapeutic known to induce CIPN, such as the drugs from the six main groups mentioned above (i.e. platinum-based compounds, taxanes, vinca alkaloids, epothilones, proteasome inhibitors, and immunomodulatory drugs). It is also important to consider the route of drug administration because there are some drugs that may not be associated with neurotoxicity, unless administered through a certain route. For example, methotrexate is rarely correlated with neurotoxicity except when administered intrathecally, and bortezomib neurotoxicity can decrease with subcutaneous administration.[9] Second, the drug dose the patient received, and if its amount is commensurate with developing CIPN, must be considered.[1] The immunomodulatory drug bortezomib, for example, is more likely to cause neurotoxicity in a cumulative dose of 20 grams. Finally, the characteristics and the duration of a patient's symptoms should be analyzed. The onset of symptoms during or close after chemotherapy is generally described as affecting sensation in the feet first, then in the hands and fingers.[1] If a patient experiences such abnormalities in sensation, then CIPN should be suspected. Furthermore, most CIPN symptoms appear during the first two months of treatment, progress during treatment, and stabilize after completion. It would be unexpected for CIPN to first appear weeks or months after the last dose of chemotherapy treatment.[1]

In CIPN, sudomotor function, through electrochemical skin conductance allows for an objective quantification of small fiber impairment and is easy to implement in the clinic.[15][16]

Various institutions, universities, and organizations have dedicated years to performing clinical trials and conducting research on CIPN. The scientific community has had multiple breakthroughs in the mechanisms, prevention, and treatment of CIPN. In 2017, the National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee convened a meeting of CIPN and oncology management experts in the Clinical Trials Planning Meeting to evaluate the state of current research and plan ahead for future investigation.[8] The goals of the meeting included identification of optimal outcome measures to define the CIPN phenotype, establishment of parameters that guide the evaluation of clinically meaningful effects, the adoption of approaches for inclusion of translational and biomarker and/or genetic measures, and discussion of the next steps to implement ideas into future clinical trials. Some of the lessons and limitations they learned from conducting past CIPN research are that 1) there was insufficient collaboration between pre-clinical and clinical researchers 2) patient reported CIPN symptoms are more sensitive than clinician-based assessments 3) there is substantial heterogeneity in the forms of neuropathy manifested across different patients 4) there are promising and understudied behavioral interventions for CIPN that may appeal more to patients who do not want pharmacological treatments. Based on these lessons, the experts concluded that a multifaceted approach is needed to alleviate the burden of CIPN including more well-planned phase II intervention clinical trials, more longitudinal studies on the risk factors of CIPN, and the development of research networks to connect work from different research facilities. Overall, more research is needed to advance understanding of CIPN etiology, risk assessment, development, and treatment (e.g. duloxetine, genetic targets, and exercise).[8] There are some drugs which are being evaluated in clinical trials. For example, tetrodotoxin (TTX) is very promising and showed efficacy for treating chemotherapy-induced peripheral neuropathy in clinical trials.[26]