A Little-Known Side Effect of Chemotherapy: Chemotherapy-Induced Peripheral Neuropathy

Riley Lipman

Illustrations by Anna-Kate Pittman

Throughout our lifetimes, many of us will feel the life-altering effects of cancer in one way or another. Even if we have not experienced the disease firsthand, it is likely that someone close to us has. An estimated 19.3 million people worldwide were diagnosed with cancer in 2020, and this already disturbingly large number is expected to grow by 47% to 28.4 million people by 2040 [1]. Given how common cancer is, many people are at least somewhat familiar with chemotherapy, a medical regimen that uses powerful drugs to target fast-growing cells in your body [2]. Unfortunately, this life-saving cancer treatment is a double-edged sword — while effective in fighting several forms of cancer, many of the drugs used for chemotherapy treatment can simultaneously have damaging large-scale effects on a person’s nervous system. These unintended consequences of chemotherapy can have detrimental effects on a cancer patient’s quality of life [3]. While the severity of side effects varies from person to person, symptoms often take a physical toll [4]. Those who undergo chemotherapy often feel weak and frail due to treatment [5, 6]. When people think of chemotherapy, they often think of the more visible side effects caused by the treatment, such as vomiting and hair loss. One of the overlooked side effects is the development of an understudied side effect called Chemotherapy-Induced Peripheral Neuropathy (CIPN). 

What is Chemotherapy-Induced Peripheral Neuropathy?

When chemotherapy treatment tampers with biological mechanisms vital for nervous system functioning, it has debilitating effects that impact basic human function on a broad scale, from holding a pencil or tying shoelaces. People with CIPN experience symptoms caused by damage to the nerves that control sensation and movement in the arms, legs, hands, and feet. A person receiving chemotherapy described CIPN as “not one of those high profile things that you think about when you think about chemotherapy, like the nausea, the vomiting, the hair loss” [5, 7]. Yet, for nearly 70% of people undergoing chemotherapy, the symptoms of CIPN take the biggest toll on both their physical and mental health out of all the chemotherapy-induced symptoms they experience [8, 9, 10]. Broadly, these symptoms include pain, extreme sensitivity to temperature, and numbness in the hands and feet, all of which significantly impact even the most basic functions [11, 12]. Tasks such as writing your name, brushing your teeth, fastening buttons, or taking a bite of food can become difficult. People often have difficulty with manipulating small objects, like pencils, particularly if not looking directly at them [12]. One person described their loss of sensation in their hands when eating food: “sometimes, when I was holding a bowl, the bowl would suddenly drop…. My [hands] had no strength at all” [13]. Another person described a similar sensation when trying to write their name and said that their “handwriting became very ugly… [they] could not even sign properly.” CIPN can also affect a person’s ability to stand up and stay balanced, especially in poorly lit environments. Nearly a year after completing chemotherapy treatment, one person continued to experience pain in their legs and had “no strength to walk,” even to the bathroom [13]. Some state that CIPN is even “worse than having cancer because it changed [their] lifestyle” more than the disease itself [7]. People can begin to experience symptoms of CIPN during chemotherapy treatment, and some symptoms, such as numbness and tingling, can persist for years to come [14]. CIPN occurs in approximately 68% of individuals within the first month of completing chemotherapy, and continues to affect 30% of people 6 months after they finish treatment [12]. 

CIPN involves severe damage to the nerves outside of the brain and spinal cord, which comprise the peripheral nervous system [15]. The peripheral nervous system is a two-way highway: it carries signals and sensations to the brain, and also transports signals of movement to our extremities, such as our arms and legs. When anticancer drugs block this highway, communication between the brain and body is severed; sensory input can no longer reach the brain, and motor output from the brain can no longer reach the rest of the body. This disruption causes symptoms including mild tingling and numbness in fingers and toes, sensitivity to temperatures, burning sensations, and sharp, stabbing pain. Damage to the peripheral nervous system can even inhibit individuals from performing daily tasks like eating, writing, or walking. 

Many patients persist through the challenging side effects of CIPN, continuing their painful cancer treatment in the hopes of increasing their chances of survival. Doctors have reported that some patients resist suggestions to stop or reduce their dose of chemotherapy, even when their CIPN becomes hard to manage [7]. Nonetheless, CIPN is a very common reason that patients cite when asked what caused them to stop their chemotherapy treatment before its conclusion [7, 16, 17, 18]. Today, when an individual experiences these difficult side effects of CIPN, the predominant approach by doctors is to delay, reduce, or discontinue chemotherapy altogether, giving their symptoms the opportunity to improve with time. However, preemptively halting one’s cancer treatment to alleviate the debilitating symptoms of CIPN can also jeopardize their journey to being cancer-free [18]. 

How Does CIPN Attack the Nervous System?

Our body's nervous system is divided into the central nervous system (CNS) — the brain and spinal cord — and the peripheral nervous system (PNS). These two divisions of our nervous systems are protected from pathogens and toxins by specialized biological barriers. The blood vessels that line our brain, which make up the blood-brain barrier (BBB), selectively regulate what substances enter and exit [19]. Think of the BBB as a strong, tall, castle wall that is tightly guarded. This castle wall has a gate that only opens to let certain things pass. The BBB only lets certain particles and molecules through. Without this tight layer of protection around the brain, unwanted molecules and cells would easily be able to pass through and affect cognitive function. The tight regulation of the BBB’s gates keeps toxic chemotherapy drugs from directly damaging our brain and spinal cord. However, the blood vessels that line our peripheral nervous system, which make up the blood nerve barrier (BNB), are less protected than the BBB. The BNB has less tightly regulated gates with fewer guards fortifying its barrier, and its gates can easily be swung open, allowing more to pass through. Because the walls of the BNB are not as fortified as the strong walls of the BBB, it is easier for potential toxins to enter the peripheral nervous system as opposed to the brain [20]. As such, dangerous intruders, such as toxic chemicals, are able to accumulate in peripheral nerves. When chemicals interfere with the functioning of cells in that area it can potentially cause nerve death. The degeneration of peripheral nerves due to the loss of the cells that comprise these nerves is thought to be the underlying mechanism of CIPN [21].  

A Deeper Look Into the Destructive Mechanisms of CIPN

Neurologists continue to investigate the mechanisms underlying the development of CIPN in hopes of better combating its debilitating effects. Many different components of the cells within the peripheral nervous system are at risk of harm from various anticancer drugs, such as the mitochondria, which facilitate energy production and metabolic processes [22]. Think of the mitochondria as a power plant. A power plant produces energy for a city, but also releases greenhouse gasses that pollute the air. Similarly, when mitochondria pump out energy to be used by neurons, one of the nasty byproducts they release are reactive oxygen species (ROS), which are dangerous to the cell in large quantities [23]. Antioxidants, like the ones plentiful in the fruits and vegetables that we eat, can help clean up excess ROS and act as the air filters of the power plant [23]. They are the cells’ normal maintenance system for clearing out unwanted byproducts of energy production. When ROS levels are steady and controlled, mitochondria are able to produce energy efficiently and the antioxidants can easily play their role, allowing the power plant to run smoothly. But when the power plant of the city is not functioning properly, the city as a whole can no longer sustain itself. 

This cycle of energy production in the mitochondria of neurons is thrown out of balance when chemotherapeutic drugs interfere [18]. When chemotherapeutic drugs are administered, they disrupt the energy production system of the cell. ROS levels increase and antioxidants can no longer keep up with filtering and clearing away harmful byproducts; therefore, mitochondria are flooded with an excess of ROS and begin to break down [18]. This puts cells in a harmful state called oxidative stress [22]. Neurons are heavily dependent on mitochondria for energy production, which are utilized to power a variety of neuronal processes. When the major energy producing machines are disrupted, the neuron’s ability to function is similarly disrupted. Neurons impacted by oxidative stress are no longer able to produce the energy required to function and communicate with each other properly, so they die [24]. The death of neurons responsible for sending sensory information to the brain prevents the peripheral system from carrying these signals. This dysfunction plays a direct role in the development of CIPN [25]. 

Oxaliplatin: A Double-Edged Sword

There are a wide range of chemotherapeutic drugs frequently administered to treat cancer. The physiological side effects vary between different classes of drugs due to their chemical properties — ranging from acute and fleeting pain to permanent and potentially irreversible neuronal damage. While different chemotherapeutic agents may impact the mitochondria of neurons in different ways, many chemotherapeutic drugs disrupt neuronal energy production, causing neuronal death. Some of the most neurotoxic chemotherapy drugs are platinum-based drugs, such as Oxaliplatin, which causes CIPN in 70% to 100% of all people the drug is administered to [26, 27]. Oxaliplatin can damage peoples’ sensory systems within hours of treatment, with the effects sometimes persisting long after their therapy is complete [28]. At a cellular level, Oxaliplatin damages the mitochondria of neurons, leading to a buildup of harmful reactive oxygen species, and eventual neuronal death [29]. Because of the aggregation of damaged mitochondria in the sensory nerves of individuals taking Oxaliplatin, this drug may cause the aforementioned symptoms [30]. At the beginning of treatment, people taking Oxaliplatin describe feelings of numbness and tingling in their hands and feet, though they often find it difficult to describe the sensation: “the word numb does not do it … you have to be in my toes to know what it feels like. It's not a nice feeling at all. I am aware now that it's there… There's nothing I can do” [7]. As the Oxaliplatin dose increases over time, symptoms progress, and severe sensory damage often begins to interfere with everyday abilities.

Looking Forward: Diagnosing and Treating CIPN

There is currently no clinical consensus on how to diagnose, manage, or cure the devastating neurological complications of chemotherapy treatment [31]. Fortunately, research is being conducted to build an archive of potential treatments for CIPN. One therapeutic approach — based on the strong possibility that at least part of the damage caused by CIPN is due to oxidative stress — is to use antioxidants [32].  Groups of antioxidants patrol the cell and reduce excess ROS buildup, alleviating oxidative stress and the damage it can cause in mitochondria [33]. Antioxidant drugs have been associated with a significant decrease in oxidative stress and may be promising candidates for further study to treat CIPN, due to their restorative effects within the nervous system  [33, 34].

The lack of standardization in tools used for clinical assessment, evaluation, and diagnosis of CIPN has significantly hindered the ability to address symptoms at their onset [20]. While there are a number of tools available for assessing CIPN, there is currently no universally-accepted approach for diagnosis of the disorder [35]. Determining whether an individual is experiencing  CIPN requires more than a routine blood test; verbal reports from the individual on their experience are paramount to diagnosing CIPN symptoms. Doctors usually assess pain by asking a person to rate their pain on a scale of 1-10 [36]. This approach may be ineffective because pain is subjective and pain tolerance varies between people, so doctors may have a hard time understanding the severity of one’s discomfort. Further, the way in which people describe their pain to their physician may vary.  Many chemotherapy patients say that it is nearly impossible to be able to describe the sensations caused by CIPN to their doctors; it is something that someone would have to experience themselves in order to understand. In an attempt to express their symptoms verbally, people with CIPN often utilize analogies. They use phrases such as “moving insects” when describing numbness on their skin and compare sensations to jellyfish stings [7]. Abstract descriptions such as these show just how difficult it is to standardize and treat CIPN. 

Fortunately, recent studies are beginning to explore ways to standardize CIPN diagnosis, such as by using quantitative sensory testing (QST). QST counts neurons in images of the peripheral nervous system to evaluate neuron death in a quantifiable manner [37]. This approach is promising because it removes the subjectivity of verbal pain descriptions. Medical practitioners using QST can theoretically customize treatment plans based on a person’s unique level of nerve degeneration. However, the implementation of QST is still in its initial stages — today, there are still no assessment tools that have proven to be clinically effective. As a result, there is no standardized approved way to go about diagnosing or analyzing individual cases of CIPN [38]. The creation and utilization of instruments to quantify symptomatology of CIPN will allow clinicians to learn more about the causes of CIPN, in order to determine how to best diagnose and treat it.

Conclusion

Even though CIPN is one of the most debilitating side effects of chemotherapy, many patients tend to be more aware of the common side effects of chemotherapy such as hair loss and fatigue and don’t consider CIPN [7]. However, CIPN presents a significant issue for the treatment of cancer patients because it can compromise one's quality of life and ability to continue treatment. Because of CIPN’s complexity, it has been difficult to find preventive strategies or effective treatments for the disease. Defining the mechanisms underlying the pain symptoms of CIPN is crucial to developing preventive measures and treatment strategies, as well as quality of life for individuals battling cancer.

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