Chemotherapy-induced peripheral neuropathy (CIPN) is a
nerve
A nerve is an enclosed, cable-like bundle of nerve fibers (called axons). Nerves have historically been considered the basic units of the peripheral nervous system. A nerve provides a common pathway for the Electrochemistry, electrochemical nerv ...
-damaging side effect of
antineoplastic agents in the common
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
treatment,
chemotherapy
Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
.
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
The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...
.
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 trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s and studies to uncover the various symptoms, causes,
pathogenesis
In pathology, pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes .
Descript ...
, diagnoses, risk factors, and treatments of CIPN.
Symptoms and signs
CIPN symptoms manifest themselves as deficits in
sensory,
motor
An engine or motor is a machine designed to convert one or more forms of energy into mechanical energy.
Available energy sources include potential energy (e.g. energy of the Earth's gravitational field as exploited in hydroelectric power gene ...
, 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
Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...
, impaired vibration sense, extreme temperature sensitivity,
paresthesia
Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or Chronic condition, chronic and has many possible underlying causes. Paresthesia is usually p ...
, and/or
dysesthesia
Dysesthesia is an unpleasant, abnormal sense of touch. Its etymology comes from the Greek word "dys," meaning "bad," and "aesthesis," which means "sensation" (abnormal sensation). It often presents as pain but may also present as an inappropriate, ...
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
Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...
,
constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...
, 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
Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered b ...
and
oxaliplatin
Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication (platinum-based antineoplastic class) used to treat colorectal cancer. It is given by intravenous, infusion into a vein.
Common side effects include paresth ...
, 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,
taxane
Taxanes are a class of diterpenes. They were originally identified from plants of the genus ''Taxus'' (yews), and feature a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapy agents. Cabazitaxel was FDA app ...
s,
vinca alkaloid
''Vinca'' alkaloids are a set of Antimitotic agent, anti-mitotic and Anti-microtubule activity, anti-microtubule alkaloid agents originally derived from the periwinkle plant ''Catharanthus roseus'' (basionym ''Vinca rosea'') and other ''vinca'' p ...
s,
epothilone
Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.
Epothilones were ...
s,
proteasome inhibitors and
immunomodulatory drugs.
Platinum-based compounds
Platinum-based compounds, namely
oxaliplatin
Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication (platinum-based antineoplastic class) used to treat colorectal cancer. It is given by intravenous, infusion into a vein.
Common side effects include paresth ...
,
cisplatin
Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...
, and
carboplatin
Carboplatin, sold under the brand name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is a ...
(which is noticeably less neurotoxic than cisplatin), are used to treat several types of solid
tumors
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
, such as
stomach
The stomach is a muscular, hollow organ in the upper gastrointestinal tract of Human, humans and many other animals, including several invertebrates. The Ancient Greek name for the stomach is ''gaster'' which is used as ''gastric'' in medical t ...
,
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
lung
The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
,
ovarian,
brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
, and
uterine cancers.
These agents can damage
dorsal root ganglia
A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dors ...
neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s by forming
adduct
In chemistry, an adduct (; alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all components. The resultant is ...
s with
nuclear
Nuclear may refer to:
Physics
Relating to the nucleus of the atom:
*Nuclear engineering
*Nuclear physics
*Nuclear power
*Nuclear reactor
*Nuclear weapon
*Nuclear medicine
*Radiation therapy
*Nuclear warfare
Mathematics
* Nuclear space
*Nuclear ...
and
mitochondrial
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
.
This damage can cause neuronal
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, 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
The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...
.
Specific side effects of platinum compounds include hearing loss,
tinnitus
Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
, 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
Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-cel ...
, and
cabazitaxel, are used to treat ovarian,
breast
The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
,
non-small cell lung, and
prostate
The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
cancers.
These drugs interfere with the normal cycling of
microtubule
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...
depolymerization Depolymerization (or depolymerisation) is the process of converting a polymer into a monomer or a mixture of monomers. This process is driven by an increase in entropy.
Ceiling temperature
The tendency of polymers to depolymerize is indicated by ...
and repolymerization in small diameter sensory fibers to create sensory dominant neuropathy. Sensory side effects include paresthesias, dysesthesias, numbness, altered
proprioception
Proprioception ( ) is the sense of self-movement, force, and body position.
Proprioception is mediated by proprioceptors, a type of sensory receptor, located within muscles, tendons, and joints. Most animals possess multiple subtypes of propri ...
, and loss of
dexterity
Fine motor skill (or dexterity) is the coordination of small muscles in movement with the eyes, hands and fingers. The complex levels of manual dexterity that humans exhibit can be related to the nervous system. Fine motor skills aid in the growt ...
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
Vincristine, also known as leurocristine and sold under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin lym ...
,
vinblastine
Vinblastine, sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer. This includes Hodgkin's lymphoma, non-small-cell lung cancer, bladder canc ...
,
vinorelbine
Vinorelbine, sold under the brand name Navelbine among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer and non-small cell lung cancer. It is given by injection into a vein or by mout ...
, and
vindesine
Vindesine, also termed Eldisine, is a semisynthetic vinca alkaloid derived from the flowering plant '' Catharanthus roseus.'' Like the natural (e.g. vinblastine and vincristine) and semisynthetic vinca alkaloids (e.g. vinorelbine and vinflunine ...
, are used to treat tumors such as
Hodgkin lymphoma
Hodgkin lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the lymph nodes. The condition was named a ...
,
testicular cancer
Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle or swelling or pain in the scrotum. Treatment may result in infertility.
Risk factors include an c ...
, 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
Ixabepilone ( INN; also known as azaepothilone B, codenamed BMS-247550) is a pharmaceutical drug developed by Bristol-Myers Squibb as a chemotherapeutic medication for cancer.
History
Ixabepilone is a semi-synthetic analog of epothilone B, a ...
, 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
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
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
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...
and certain types of
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
. 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
Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral administered medication used to treat a number of cancers (e.g., multiple myeloma), graft-versus-host disease, and many skin disorders (e.g., complication ...
, 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
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
. Side effects of thalidomide-induced peripheral neuropathy include sensory symptoms, possible motor impairment, and
gastrointestinal
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...
and
cardiovascular
In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
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
In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
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 channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels.
Classific ...
s,
Schwann cell
Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include Satellite glial cell, satellite ...
function-related proteins, receptors for cell surface
collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
, receptors involved in neuronal apoptosis, neuronal crest cell development, and an enzyme involved in
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic ...
metabolism
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
.
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
Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
,
renal disease,
hypothyroidism
Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...
,
connective tissue
Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...
disease, or
vitamin
Vitamins are Organic compound, organic molecules (or a set of closely related molecules called vitamer, vitamers) that are essential to an organism in small quantities for proper metabolism, metabolic function. Nutrient#Essential nutrients, ...
deficiencies is a risk factor.
2) A diagnosis of current or previous infectious disease such as
Human Immunodeficiency Virus
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of th ...
,
Polio
Poliomyelitis ( ), commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 75% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe ...
myelitis, and
Hepatitis B
Hepatitis B is an infectious disease caused by the '' hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. ...
or
C may increase a patient's risk.
3) Exposure to medications linked to
neurotoxicity
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...
, such as
cyclosporine
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, ecz ...
,
vancomycin
Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously ( injection into a vein) to treat complicated skin infections, bloodstream infections, endocarditis, bone an ...
, and
cimetidine
Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.
With the development of proton pump ...
, 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
In medicine, comorbidity refers to the simultaneous presence of two or more medical conditions in a patient; often co-occurring (that is, concomitant or concurrent) with a primary condition. It originates from the Latin term (meaning "sicknes ...
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.
Physical examination to assess
motor function, reflexes,
gait
Gait is the pattern of Motion (physics), movement of the limb (anatomy), limbs of animals, including Gait (human), humans, during Animal locomotion, locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on s ...
and balance, and sensation also plays a key role in the diagnosis of CIPN.
First, motor testing involves assessment of muscle tone and bulk, which may be decreased in patients with CIPN due to
atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...
and
hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but it is a potential manifestation of many different dis ...
. Commonly affected muscle groups to look out for include the distal muscles of the hands, feet, and ankles.
Second, a patient's reflexive response is tested. The reflexes of patients with CIPN are frequently diminished, if not gone entirely. Dysfunction of the
Achilles reflex is especially common.
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 is also frequently tested to indicate a patient's sense of balance. If patients are unable to stand with their feet together and their eyes closed,
proprioceptive
Proprioception ( ) is the sense of self-movement, force, and body position.
Proprioception is mediated by proprioceptors, a type of sensory receptor, located within muscles, tendons, and joints. Most animals possess multiple subtypes of propri ...
loss, commonly seen with CIPN, can be assumed.
Finally, sensory testing includes 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
Dysesthesia is an unpleasant, abnormal sense of touch. Its etymology comes from the Greek word "dys," meaning "bad," and "aesthesis," which means "sensation" (abnormal sensation). It often presents as pain but may also present as an inappropriate, ...
, or increased pain with this pinprick test.
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.
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.
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.
First, clinicians consider if the patient received a neurotoxic chemotherapeutic known to induce CIPN, such as the drugs from the six main groups (i.e.
platinum-based compounds,
taxane
Taxanes are a class of diterpenes. They were originally identified from plants of the genus ''Taxus'' (yews), and feature a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapy agents. Cabazitaxel was FDA app ...
s,
vinca alkaloid
''Vinca'' alkaloids are a set of Antimitotic agent, anti-mitotic and Anti-microtubule activity, anti-microtubule alkaloid agents originally derived from the periwinkle plant ''Catharanthus roseus'' (basionym ''Vinca rosea'') and other ''vinca'' p ...
s,
epothilone
Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.
Epothilones were ...
s,
proteasome inhibitors, and
immunomodulatory drugs). The route of drug administration is also considered 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.
Second, the drug dose the patient received, and if its amount is commensurate with developing CIPN, may be considered.
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 are 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.
If a patient experiences such abnormalities in sensation, then CIPN may 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.
In CIPN,
sudomotor
Sudomotor function refers to the autonomic nervous system control of sweat gland activity in response to various environmental and individual factors. Sweat production is a vital thermoregulatory mechanism used by the body to prevent heat-related ...
function, through
electrochemical skin conductance
Electrochemical skin conductance (ESC) is an objective, non-invasive and quantitative electrophysiological measure of skin conductance through the application of a pulsating direct current on the skin. It is based on reverse iontophoresis and ...
allows for an objective quantification of small fiber impairment and is easy to implement in the clinic.
Treatment and prevention
Pharmacological
Prevention
A 2020
American Society of Clinical Oncology
The American Society of Clinical Oncology (ASCO) is a professional organization representing physicians of all oncology sub-specialties who care for people with cancer. Founded in 1964 by Fred Ansfield, Harry Bisel, Herman Freckman, Arnoldus G ...
(ASCO) report provided an updated list of drugs tested and not recommended for prevention of CIPN. These recommendations are evidence-based, informed by
randomized trials (RCTs) and guided by expert clinical experience.
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Acetyl-L-carnitine
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All-trans retinoic acid
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Amifostine
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Amitriptyline
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, and a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headac ...
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Calcium magnesium
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Cannabinoid
Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
s
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Diethyldithiocarbamate
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Glutamate
Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
/
Glutamine
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
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Glutathione
Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...
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Metformin
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, ...
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Minocycline
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N-acetylcysteine
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Nimodipine
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Omega-3 fatty acid
Omega−3 fatty acids, also called omega−3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond three atoms away from the terminal methyl group in their ...
s
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Org 2766
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Oxcarbazepine
Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with ...
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Retinoic acid
Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...
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Venlafaxine
Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...
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Vitamin B
B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. They are a chemically diverse class of compounds.
Dietary supplements containing all eight are referred to as a vita ...
*
Vitamin E
Vitamin E is a group of eight compounds related in molecular structure that includes four tocopherols and four tocotrienols. The tocopherols function as fat-soluble antioxidants which may help protect cell membranes from reactive oxygen speci ...
Treatment
A 2020 ASCO report provided an updated list of drugs tested and not recommended for treatment of CIPN. These recommendations are evidence-based, informed by RCTs and guided by expert clinical experience.
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Gabapentin
Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat neuropathic pain and also for partial seizures of epilepsy. It is a commonly used medication for the treatment of neuropath ...
/
pregabalin
Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless legs syndrome, opioid withdrawal, generalized anx ...
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Tricyclic antidepressant
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...
s
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Baclofen
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Ketamine
Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...
*
Amitriptyline
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, and a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headac ...
* Oral
cannabinoid
Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
s
As of 2020,
duloxetine
Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive–compulsive disorder, fibromyalgia, neuropathic pain, central sensitization, and ...
is the only drug that is currently recommended to treat established CIPN. There are data from various clinical trials demonstrating that duloxetine decreases CIPN pain and other CIPN symptoms. However, it does not eliminate CIPN symptoms, and it can also have unwanted side effects such as dizziness, dry mouth, constipation, and diarrhea. It is not approved by the Food and Drug Association for treatment of CIPN.
Behavioral
There are promising and safe behavioral interventions for CIPN that have been suggested to be helpful based on randomized clinical trials: 1)
stretching
Stretching is a form of physical exercise in which a specific muscle or tendon (or muscle group) is deliberately expanded and flexed in order to improve the muscle's felt elasticity and achieve comfortable muscle tone. The result is a feelin ...
2)
walking
Walking (also known as ambulation) is one of the main gaits of terrestrial locomotion among legged animals. Walking is typically slower than running and other gaits. Walking is defined as an " inverted pendulum" gait in which the body vaults o ...
3)
resistance (strength) training 4)
balance exercises 5)
yoga
Yoga (UK: , US: ; 'yoga' ; ) is a group of physical, mental, and spiritual practices or disciplines that originated with its own philosophy in ancient India, aimed at controlling body and mind to attain various salvation goals, as pra ...
6)
meditation
Meditation is a practice in which an individual uses a technique to train attention and awareness and detach from reflexive, "discursive thinking", achieving a mentally clear and emotionally calm and stable state, while not judging the meditat ...
.
Stretching, including nerve-gliding, is frequently included in a CIPN treatment plan to improve nerve excursion across joints, promote
axoplasmic flow
Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondrion, mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, throug ...
, and decrease
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
.
Examples of stretching exercises for the neck and upper limbs include shoulder rolls, overhead arm reaches, and arm extensions. Examples of stretches for the lower body include lunges and hamstring pulls. Stretches like these have been clinically shown to help alleviate pain and restore at least some mobility in patients with CIPN.
Walking can be effective in alleviating CIPN symptoms by boosting muscle power, increasing blood circulation, and improving balance. Walking provides low to moderately intense
aerobic exercise
Aerobic exercise, also known as cardio, is physical exercise of low to high intensity that depends primarily on the aerobic energy-generating process. "Aerobic" is defined as "relating to, involving, or requiring oxygen", and refers to the use of ...
(60–85% of heart rate reserve), and a regular walking schedule can decrease intensity and frequency of neuropathic symptoms while promoting healthy nerve growth and function.
Resistance (strength) training has been tested in various clinical settings, and it has been shown to be helpful in treating CIPN symptoms such as temperature sensitivity, numbness, and tingling.
By building muscle, strength training can improve a patient's ability to perform daily activities, improve balance, and reduce the risk of falling. Examples of strength training exercises include squats, overhead press, and calf raises.
Balance exercises, such as tightrope exercises and hip flexion, are shown to be effective in reducing pain and improving quality of life for patients with CIPN. They are important in enhancing a patient's
proprioception
Proprioception ( ) is the sense of self-movement, force, and body position.
Proprioception is mediated by proprioceptors, a type of sensory receptor, located within muscles, tendons, and joints. Most animals possess multiple subtypes of propri ...
, coordination, and preventing falls.
Somatic yoga is often used by cancer survivors for symptom management, and it has been found to improve physical and mental health for patients with CIPN.
Yoga combines movement, breathing exercises, and meditation to foster connection between the mind and body. Practice may decrease pain-associated stress and help a patient relax through modulation of the
neuroendocrine system through the
hypothalamic-pituitary-adrenal axis. Yoga's emphasis on dynamic movement can lead to improvement in flexibility, strength, balance, and stability, all of which may be negatively impacted by CIPN.
Meditation helps to alleviate CIPN symptoms and CIPN-related stress by helping a patient relax and improve attention skills.
By improving self-control and attention span, mediation helps to create emotional stability and enhances psycho-emotional balance.
Despite the potential of these interventions, none of them have been shown to definitively help with CIPN as of the 2020 ASCO report.
and therefore more research is needed.
Other therapeutics
Cryotherapy
Cryotherapy, sometimes known as cold therapy, is the local or general use of low temperatures in medical therapy. Cryotherapy can be used in many ways, including whole body exposure for therapeutic health benefits or may be used locally to treat ...
for patients with CIPN involves wearing frozen gloves and socks or ice packs to prevent and relieve symptoms.
Various studies have been conducted to trial cryotherapy or cryocompression therapy, and their results are largely inconclusive. One study demonstrated that the development of CIPN symptoms were significantly delayed after the usage of cryotherapy.
Another concluded that there was no significant difference between control groups receiving chemotherapy and treatment groups receiving cryotherapy in addition to chemotherapy.
The second study's results did, however, support that frozen gloves improved some measures of patient-reported quality-of-life.
Similarly,
compression therapy for patients with CIPN involves placing limbs in tight gloves or shoes. Studies testing compression therapy reported that sensory neuropathy was reduced in patients using tight surgical gloves. These studies are not conclusive, and additional
randomized trials investigating the efficacy of cryotherapy and compression therapy for prevention and treatment of CIPN are ongoing.
No conclusive recommendations about either therapy can be made as of 2020, although the potential harms of both are believed to be low to moderate.
Scrambler therapy is an electro-analgesia therapy that is designed to block the conduction of nerve fibers to produce an
analgesic
An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
effect through
transcutaneous electrical nerve stimulation (TENS).
In other words, this therapy should interfere with (“scramble”) the pain signal transmission of neurons by replacing it with “non-pain” information.
One randomized trial evaluating the success of scrambler therapy in alleviating CIPN symptoms found no significant differences between treatment and control groups. Another trial testing scrambler therapy with patients with CIPN found patient-reported neuropathy symptoms and quality-of-life to be improved from baseline status. As of 2020, no conclusive recommendations can be made for scrambler therapy, but its potential harm is believed to be low.
Current research
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
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
'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.
The goals of the meeting included identification of optimal outcome measures to define the CIPN
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
, establishment of parameters that guide the evaluation of clinically meaningful effects, the adoption of approaches for inclusion of translational and
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
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
Etiology (; alternatively spelled aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek word ''()'', meaning "giving a reason for" (). More completely, etiology is the study of the causes, origins ...
, risk assessment, development, and treatment (e.g. duloxetine, genetic targets, and exercise).
There are some drugs which are being evaluated in clinical trials. For example,
tetrodotoxin
Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an Order (biology), order that includes Tetraodontidae, pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Alt ...
(TTX) is very promising and showed efficacy for treating chemotherapy-induced peripheral neuropathy in clinical trials.
References
{{Medicine
Chemotherapy
Cancer
Peripheral nervous system disorders