Steph’s Note: Olivia White is a PGY1 resident at Duke University Hospital. She was born and bred in Auburn, AL, and has moved all over the Southeast, including completing her PharmD at University of Kentucky. She’s planning on staying at Duke for the upcoming year as one of their PGY2 Oncology residents. Following residency, she hopes to become a board-certified oncology pharmacist who works closely with a college of pharmacy, and she would like to continue her practice at an NCI-designated comprehensive cancer center. In her free time, she loves to cook, garden, hunt down cool restaurants in the area, and traveling to the mountains of North Carolina.

A Quick Intro to Chemotherapy-Induced Peripheral Neuropathy (CIPN)

As of January 2019, there were an estimated 16.9 million cancer survivors in the United States. As our patient survivorship continues to increase, it’s estimated that the US will have approximately 22.2 million cancer survivors by the year 2030. Strong work, right?! Go team!

Now, what’s the price of this increased survivorship?

Many people know that chemotherapy can come with several complications, and many classically think of chemotherapy-induced nausea and vomiting. And while this is a debilitating adverse event, there are many other side effects that are just as clinically significant. Enter chemotherapy-induced peripheral neuropathy (CIPN). CIPN prevalence has been estimated to be as high as 68.1% in the first month after chemotherapy. Therefore, because we have more patients surviving cancer in the US, it should be just as important to take into account the overall quality of life of the patient following chemotherapy completion – bringing us to our topic today.

CIPN is agent-dependent and has been reported in varying rates from 19% to 85%, depending on the administered oncolytic. Risk factors that predispose patients to CIPN include the following:

age,
a history of neuropathy even prior to chemotherapy initiation,
history of smoking,
impaired renal function,
exposure to other neurotoxic chemotherapeutic agents,
paraneoplastic antibodies, and
direct cancer-associated neuropathy.

Additionally, there have been specific single-nucleotide polymorphisms (SNPs) that have demonstrated a higher risk of CIPN.

This adverse event extends beyond affecting solely the quality of life for our cancer patients. Having CIPN can actually impact the dose and frequency of chemotherapy a patient will receive. Take a moment to let that sink in…

That means that depending on the incidence and severity of the CIPN, some patients could potentially have a shortened overall survival or decreased length of time prior to disease progression because they are unable to receive full regimens of chemotherapy. Additionally, cancer patients who develop CIPN have demonstrated a three times increased risk of falling. For this reason, this demonstrates a need to both prevent and adequately treat this symptom profile in our patients.

Most Common Offending Agents and Presentations of CIPN

As mentioned earlier, CIPN is an agent-dependent adverse event, and so we need to review the agents that most commonly cause this. We would be remiss if we didn't also discuss the specific mechanisms that drive these toxicities and their individual presentations.

Before going into each individual agent, however, it’s important that we first review the types of neuropathy. Check out the flowsheet below for an overview.

Looking at this more in depth, we have peripheral neuropathy that can either be of an acute or chronic onset. For some patients who receive certain agents, their chronicity of neuropathy can be associated with a ‘coasting’ phenomenon. Despite this sounding like a cool surfing analogy, this actually occurs when the neuropathy continues to build after chemotherapy administration for months or more, and therefore it can be considered the most debilitating of the types of CIPN.

The acute neuropathies are generally associated more with an acute onset of pain (think days/weeks). Once we swing into the chronic neuropathy category, the majority of patients experience the ‘sensory’ type as opposed to the motor or autonomic varieties.

So, unlike diabetes-associated neuropathy, where patients can have both sensory and autonomic presentations over a longer time period, sensory neuropathy is the primary presentation observed in the CIPN patient population. Classically, this neuropathy is in a ‘stocking-glove’ distribution, meaning that it usually begins with the patient’s toes and fingers and then progresses proximally.

Below are the most common offending agents when it comes to CIPN as well as what the usual symptomatology looks like. Next we’ll discuss further the specific classes, mechanisms, and presentations associated with each of our offending agents.

Platinum-Based Antineoplastics (Cisplatin, Carboplatin, Oxaliplatin)

As one of the most well-defined presentations, it is the unfortunate truth that neuropathy is a major dose-limiting factor of platinum therapy. It has been demonstrated that cisplatin-induced peripheral neuropathy occurs in both a time- and dose-dependent fashion, with up to 92% of patients who receive cumulative doses between 500-600 mg/m^2 experiencing some degree of neuropathy.

Carboplatin is generally thought to be less toxic, with neuropathy observed in 13-42% of patients. Oxaliplatin somewhat deserves a highlight of its own, and so we’ll focus on that a little later. It’s estimated that oxaliplatin-induced peripheral neuropathy occurs in 5-98% (yeah, that range covers the gamut doesn’t it) of patients within hours of infusion and may last up to 5-7 days. Therefore, the neuropathy associated with the platinum agents can both be acute and chronic in nature.

The mechanism driving these toxicities isn’t fully understood; however, it is thought that the anti-tumor mechanism of the agents is responsible for both neuroinflammation and altered excitability of our peripheral neurons. Specifically, it’s believed that these therapies alter the structure or function of the neuronal and glial cells. When thinking of the presentation of platinum agents’ neurotoxicity, it is usually the classic, chronic sensory peripheral neuropathy.

Oxaliplatin patients trying to avoid the cold. (Image)

The exception to this is oxaliplatin-associated peripheral neuropathy. This is a cold-induced neuropathy in the acute phase. This is associated with cold-related paresthesias of the hands and feet, pharyngolaryngeal dysesthesias (aka a feeling of difficulty to breathe), jaw spasms, fasciculations, and muscle cramps. As you can imagine, this is an adverse event that is strongly counseled on and emphasized by practitioners with our patients prior to starting oxaliplatin-based therapeutic regimens. The key to avoiding this adverse event is to stay away from overly cold things – this can include anything from opening your freezer to ensuring you wear adequate outerwear in the cold, etc.

Immunomodulatory Drugs (Lenalidomide, Pomalidomide, Thalidomide)

Peripheral neuropathy associated with this drug class is most commonly associated with thalidomide, which due to both the adverse event profile and associated REMS program, is generally avoided compared to its counterparts, lenalidomide and pomalidomide. However, peripheral neuropathy is a class effect and thus is still important to mention in this setting. The risk of neurotoxicity is thought to be dose-dependent.

In addition to the classic sensory symptoms and signs of peripheral neuropathy, patients can also experience motor impairment and autonomic manifestations with this drug class (think more DM-associated neuropathy for these patients). This is especially something to consider in our multiple myeloma population, since these patients tend to be older at baseline, putting them generally at an increased risk of both this adverse event and falls.

The mechanism causing the CIPN associated with this class is generally not fully understood, but it has been suggested that the immunomodulatory effect of this medication is the primary driver. Specifically, it’s thought that the metabolite of this drug class may cause DNA cleavage, but there are more clinical trials needed to confirm this.

Taxanes (Paclitaxel)

The incidence of neuropathy associated with taxanes has been estimated to be as high as 87%. The most commonly CIPN-associated taxane is paclitaxel. The presentation associated with this class is generally sensory-dominant, specifically as a loss of dexterity predominantly in the toes and fingers. Motor and autonomic development has been described in the literature but is much less frequent. Acute neuropathy is seen in this group as well, and therefore patients may see symptoms start to appear within days after their initial dose. In some patients, these symptoms can last years, if not life-long.

RE: the taxanes and CIPN… when it rains, it pours. (Image)

The mechanism driving the neurotoxicity of taxanes is multifactorial. This is thought to be an off-target effect of the taxane’s mechanism. By inhibiting the microtubule function in peripheral neurons, this leads to altered neuronal activity and hyperexcitability. Furthermore, it’s thought that taxanes impact this through mitochondrial damage, thus inducing apoptosis and demyelination of peripheral nerves. Finally, as the cherry on top, taxanes lead to the activation of immune cells, leading to the release of pro-inflammatory cytokines and inducing neuro-inflammation.

Vinca Alkaloids (Vincristine)

Vinca alkaloids were actually originally developed from the periwinkle plant, and while that may mean that they sound pretty and nice – this actually can be a toxic drug class. Vinca alkaloids do not cross the blood-brain barrier but instead directly impact the cell bodies of peripheral nerves. Neuropathy associated with this class is dose-dependent and most commonly associated with vincristine use.

Symptoms usually appear within the first 3 months of treatment, usually beginning within 4-5 weeks after treatment, and are often characterized by pain in the hands and feet (think again that classic CIPN stocking-glove distribution). Other symptoms that patients may experience later on include muscle weakness, specifically weakness in their wrists and dorsiflexors.

It’s believed that neuropathy induced by vinca alkaloids disrupts the microtubular axonal transport system, thereby inducing distal axonal degradation. As you can imagine, this leads to pain associated with neuropathic symptoms.

Proteasome Inhibitors (Bortezomib)

Approximately 34% of patients receiving bortezomib experience neuropathy. The presentation of bortezomib-associated neuropathy is chronic, distal, and symmetrical, often associated with a neuropathic pain syndrome that can last for weeks, months or, even years. This toxicity is thought to be dose-dependent, similar to the previously discussed toxicities. The subcutaneous formulation of bortezomib has been demonstrated to have a lower incidence of neuropathy without reduced therapeutic efficacy, and therefore it is most commonly used in treatment today.

When looking at the mechanism driving proteosome inhibitor-associated neuropathy, it is believed that bortezomib has action in the astrocytes. It may induce genetic modulation in these cells causing the increase in presynaptic glutamate and creating neuropathic pain. Additionally, bortezomib promotes the release of pro-inflammatory cytokines contributing to neuroinflammation. Of note, increased severity of bortezomib neuropathy has been observed in myeloma patients with low levels of vitamin D, and therefore, it is often prudent to monitor vitamin D in these patients.

This is a good highlight of the locations on the axon that these agents can have an impact. (Image)

Now that we’ve had the opportunity to review the offending agents and their most common clinical presentations, we’ll now discuss what we can DO. What are the interventions that can support these patients? For the purposes of prevention and treatment, we’ll be referencing the ASCO 2020 Guidelines for management of peripheral neuropathy.

Prevention of CIPN: Dos and Don’ts

As you can see from these recommendations, there aren’t really any preventative options that we have solid evidence for. However, I do think it’s important to note the strong evidence AGAINST using acetyl-L-carnitine for prevention. This specifically has been driven by two trials.

One of these trials incorporated patients who received paclitaxel therapy and found that in the patients receiving acetyl-L-carnitine, peripheral neuropathy was actually worse than placebo. A recent long-term follow-up to this analysis confirmed that acetyl-L-carnitine therapy resulted in statistically significantly worse CIPN over two years. With that being said, it’s pretty safe to say we should definitely avoid use of this in our patients.

On the other hand, when looking at promising options, there has been data to support exercise, cryotherapy, compression therapy, and/or cryo-compression. Ganglioside-monosialic acid has also demonstrated some efficacy for prevention of taxane-induced peripheral neuropathy, but it has yet to be studied in the US.

Any of these therapies can be considered as long as they are considered safe for an individual patient, but it is important to emphasize to our patients that there is a lack of efficacy data for these preventative options.

Treatment of CIPN: Dos and Don’ts

As you can see, similar to preventative strategies, we don’t have many options for treatment of CIPN. Let’s discuss duloxetine though and focus on what makes this drug an option in our patients.

When looking at the studies that have supported its use, there have been two primary studies published to suggest there is a benefit with duloxetine therapy. One randomly assigned patients with CIPN to three pharmacotherapy groups: venlafaxine (previously thought of as beneficial, then demonstrated otherwise), duloxetine, and placebo. In this trial, the authors reported a statistically significant decreased incidence of neuropathy in the duloxetine group compared to the other two groups. The second study assessed patients taking duloxetine vs vitamin B12 and found a significant difference with the duloxetine group.

However, there was one specific study I’d like to mention that compared duloxetine 60 mg daily and pregabalin 150 mg daily. Despite having a smaller cohort (~40 patients in each arm), this study found that there was a benefit of pregabalin therapy over the duloxetine group. The majority of the patients in this study started treatment while receiving chemotherapy, and there was some improvement related to chemotherapy discontinuation as well. Therefore, despite having no other data supporting pregabalin at this time, it does seem that gabapentinoids could be creeping up as another option for our patients who are experiencing CIPN.

Other options that have demonstrated promise include exercise, acupuncture, and scrambler therapy. Despite these approaches needing more research before changing practice, it’s important to consider the safety and efficacy of these therapies, and potentially suggest these to patients when thought to be indicated.

The tl;dr of CIPN

As you can see from today’s discussion, CIPN is a key adverse event we should keep in mind when counseling and monitoring our oncology patients. Through different mechanisms, this side effect is observed with several different chemotherapy classes and can have a major impact on our patients’ quality of life. When it comes to the preventative and treatment options for our patients, there is little data supporting an overall strategy, but as of right now, duloxetine is our drug of choice. With more studies to come, hopefully we can minimize the impact this adverse event to ensure our patients receive optimal care.

The Pharmacist's Guide to Chemotherapy-Induced Peripheral Neuropathy