• Nadine Stunzi

Chemotherapy Induced Peripheral Neuropathies, Top 3 Things You Should Know!


Peripheral neuropathies within the cancer population are very common. They can be caused by treatment of all forms such as radiation, surgery, chemotherapy or even from the tumour itself. As chemotherapy is the most common cause of peripheral neuropathies, this blog will focus primarily on chemotherapy induced peripheral neuropathies (CIPN); how they occur and how to manage them with current evidence.


Akin to my previous blogs, within the spirit of good science, I will highlight best practice but also ‘young science’ and review interventions that are low risk. The approach is similar to my previous blog on cold immersion/palmar cooling and its use in breast cancer related hormone therapy. You can count on young science and current evidence-based tools to be prevalent within all my blogs! If you’re looking for an opinion piece, strong sweeping statements or recycling of the same old approaches, stop here.


Science is always teaching us; so we have to take what we can, share it as it evolves but remain humble and curious.


We are about to take a deep dive and then get a practical aerial point of view. Let’s start today by building some curiosity around our nervous system; the essence of what makes us human. Diving a little deeper into what defines a ‘peripheral neuropathy’, as compared to a neuropathy that is caused by chemotherapy. We will then discuss 3 tips to best manage chemotherapy induced peripheral neuropathies (CIPN).





What Does ‘Peripheral’ Mean?


Our central nervous system includes our brain and spinal cord. As the cord is encapsulated by the spinal column and the blood brain barrier surrounds the skull, the central system is therefore less exposed to toxins as compared to the peripheral system. The nerves immediately branching out of the spinal cord are known as nerve roots, along with their branches often form a bundle known as a ‘plexus’. All of these components outside the brain and spinal cord are termed peripheral and are increasingly vulnerable to the effects of chemotherapy.





Imagine a tree as a symbol of your nerves…

The trunk is a nerve root and its first branching area right after the trunk is a ‘plexus’; an area right before it branches out into many complex branching patterns. An example of a plexus would be the one found in the anterior chest wall close to the shoulder called your brachial plexus which is often impacted in the breast cancer population by lymph node dissections and mastectomy surgeries. Another example is the cervical plexus found in the anterior neck; radical neck dissection surgeries may cause plexopathies or neuropathies within the head and neck cancer population.


As cancer rehab physiotherapists, we often assess for plexopathies (impact to a plexus) such as brachial plexopathy when considering the location of radiation and surgery, differentiating them from chemotherapy induced peripheral neuropathies. As you can imagine if the main branching area of the tree has been impacted, many of the branches further down will be impacted experienced as symptoms in the hands and feet. As chemotherapy induced peripheral neuropathies are most often experienced in the hands and feet, plexopathies can often be misdiagnosed.





Included in your peripheral system is your autonomic nervous system; it's working all the time with little conscious thought. It controls many functions such as breathing, sexual function, blood pressure, bladder/bowel and digestion. Changes in your bladder and bowel and/or digestion that arise acutely during chemo treatment are actually classified as chemotherapy induced peripheral neuropathies. Think of the peripheral system as the entire relay, taking signals from your organs and the outside physical environment back to the central system (spinal cord and brain). Kind of like how less sunlight to leaves relays the info to the roots to store more sugar for the coming months. The peripheral system is always picking up signals and changing accordingly.


What is a Neuropathy vs a Chemotherapy Induced Peripheral Neuropathy (CIPN)?


Any dysfunction to the components of peripheral system (nerve roots, branching nerves and autonomic nerves) are considered peripheral neuropathies. Nerves can get jangly and involve many symptoms; such as pain, numbness or muscle weakness.


There are 3 forms of nerve injury: cut, press or stretch

A direct cut to a nerve’s core while in surgery is known as peri-operative ‘neurotmesis’. Neurotmesis nerve injury is irreversible and therefore not considered a neuropathy. Radical neck dissections often involve neurotmesis of the spinal accessory nerve; a rehab plan specific to spinal accessory nerve palsy is there for needed to assure healthy functioning of the shoulder and neck due to the muscle groups that are permanently lost. Within the breast cancer population post mastectomy, neurotmesis of the long thoracic nerve can occur, known as long thoracic nerve palsy. Both palsies mentioned above can result in shoulder dysfunction and impaired muscle motor control.





A second form of nerve injury known as ‘neuropraxia’ can occur through compression of nerves within adhesions of healing tissues or tight myofascial interfaces. Nerves need to slide and glide with ease, when they get sticky within a healing wound this often results in shooting pain or zinging.


Neuropraxia secondary to wound healing is typically only in one limp close to the side of the wound, worsened with limp movement and is unilateral in nature. This helps differentiate it from neuropathy related to chemotherapy. CIPN often occurs in both sides evenly effecting primarily sensory nerves only.


The 3rd type of nerve injury is ‘axonotmesis’; this occurs when only the sheath of the nerve is impacted as opposed to the core. Axonotmesis can occur when nerves are being stretched a side during surgery. Most commonly, breast cancer related neuropathies are caused by neuropraxia or axonotmesis in the chest wall and thorax. Most often the intercostal nerve, medial and lateral pectoral, thoracodorsal, intercostal nerves and long thoracic are impacted and can lead to a variety of symptoms (Chappell et al. 2020). If nerves were injured by traction or compression forces, the damage is often reversible but at times very slow to regenerate.





Within the breast cancer population, peripheral neuropathies are often generalized into post-mastectomy pain syndrome (PMPS). Radical mastectomies and axillary lymph node dissections (ALND) are the most common cause for pain in PMPS (Chappell et al. 2020). Often resulting in nerve injury of varying degrees as mentioned above, it’s important to differentiate it from chemotherapy induced peripheral neuropathy related pain. Other post treatment complications such as frozen shoulder, rotator cuff weakness and scapular dysfunction can also lead to PMPS but are often well managed with a personalized rehab plan from a cancer physiotherapist.


A cancer rehab initial assessment including a neuropathy assessment performed by a cancer physiotherapist provides an accurate neuropathy diagnosis, differentiating CIPN from other neuropathies. A clinical assessment may allow for the type of nerve impairment to be identified (motor, sensory, vibration sensory loss, joint position sense changes). A baseline can then be documented allowing for advocacy regarding treatment timing and dose, if symptoms worsen. Most importantly, patients can then get started immediately on a rehab plan specific to their neuropathy diagnosis.



How do Chemotherapy Induced Peripheral Neuropathies Occur?


Despite all the treatments within a cancer journey potentially impacting your peripheral nervous system, chemotherapy is the most common. Chemotherapy is classified as cytotoxic and at times cardio-toxic. Cytotoxic drugs of the following are known to have potential effects on your peripheral nervous system:


  • Taxanes (i.e. Taxol, Taxotere)

  • Plantinums (i.e. Cisplatin, Carboplatin)

  • Vinca Alkaloids (i.e. Vincristine, Vinblastine)

  • Targeted therapies such as Bortezomib, Eribulin





In 2020, a systematic review pulled 257 references, a bird’s eye view of the relevant clinical studies within CIPN research (Loprinzi et al. 2020). It was found that oxaliplatin and paclitaxel were the most prominent in causing insult to the peripheral system. Often the symptoms peak 2-3 days post chemotherapy infusion; an effect known as Nadir.


Symptoms associated with oxaliplatin typically present in the upper extremities and have a cumulative effect intensifying with each cycle. Paclitaxel however, typically impacts the lower extremities and often first presents as pain (Loprinzi et al. 2020). Paclitaxel associated symptoms don’t tend to accumulate but stabilize or even decrease between cycles.


Injury to the peripheral nerves is due to a change in intra-cellular transport. Different classes of cytotoxic medications effect various cellular components such as the myelin coating of the nerve, the mitochondria powerhouse, the transport microtubules or dorsal root ganglia. In other words, the transportation of goods down the nerve’s core known as an axon is altered leading to alterations at the very end of the chain.


Imagine a tree whose roots are rich with nutrients yet whose leaves are yellowing. Hence peripheral neuropathies are often experienced in the fingertips or ends of the feet; this is the last part of the branching system where only leftover nutrients remain. If a CIPN worsens, typically the symptoms move closer to the body, moving up the limbs.


Neurotoxic insult can occur within the peripheral and autonomic system. Typically, most impact is on the sensory nerves that tell us where we are in space, known as joint position sense. The type of nerve impairment can be assessed in a neuropathy assessment. The most common symptoms are numbness, tingling and pain (Loprinzi et al. 2020). Other nerve types may be impacted, and symptoms can present as:






Motor neuropathy symptoms:

  • Weakness

  • Muscle wasting

  • Shakiness

  • Muscle cramping

  • Difficulty walking


Sensory neuropathy symptoms:

  • Altered sensations of pain (numbness or hypersensitivity)

  • Pain with swallowing

  • Trunk or hip pain ~3 days post chemotherapy injection

  • Altered perceptions of temperature, vibration, or touch

  • Electrical, burning or shooting sensations

  • Numbness, tingling, or itchiness


Autonomic nerves:

  • Constipation or diarrhea

  • Bladder incontinence

  • Dizziness

  • Blood pressure changes





Tip #1) Speak To Your Oncologist and Track Your Symptoms


Pre-existing conditions may put you at higher risk. Patients are at a greater risk of CIPN onset if they have had any neuropathies prior to their diagnosis or have a family history of neuropathies. Additional risk factors are age, obesity, diabetes, and previous lymph node removal. Make sure to discuss your health history at great length with your oncologist to understand your risk stratification for CIPN. Knowing that oxaliplatin and paclitaxel chemotherapies are correlated with a higher probability of CIPN, take the time to discuss all the chemotherapy options.


Dose delay, dose reduction and chemotherapy change can be an option! Those with cancer are often in survival mode; symptoms are typically pushed to the wayside at whatever the cost to prioritize treatment. In the case of neuropathies, the changes can be permanent, so if your functioning is being greatly impacted and symptoms are worsening, speak to your oncologist right away. There are options. You can discuss medications that are less known to cause CIPN or consider changing the chemotherapy dose and schedule. Your quality-of-life matters.





Tip #2) Optimize Your Safety


If you have developed CIPN in either your hands or feet, there are several tips to reduce the chance of falls and keep you safe


  • Prevent accidental burns by using oven mitts when handling hot plates. Check the temperature of your hot water tank at home, keep it less than 40 degrees Celsius.

  • If you are a falls risk, consider a mobility assessment through a cancer physiotherapist and the prescription of a walker or cane

  • Use handrails on the stairs, grab bars in the shower, mats in the tub and assure there isn’t tripping hazards such as loose rugs or clutter around your home

  • If you can’t feel the gas pedal and brake pressure through your shoe, consider a cancer physiotherapy assessment to assess if you’re safe to drive

  • When doing dishes, wear rubber gloves as it provides a better grip and protects your hands from cuts

  • Keep your house well-lit inside and out.





Tip #3 Try Low Risk Young Science


Considering playing with the cold...

Looking at the American Society of Clinical Oncology 2020 guidelines for the management and prevention of chemotherapy induced peripheral neuropathies, there are a few interventions that are noted as young science with low-risk stratification and using cold is one of them. These interventions were classified as needing larger sample sizes and definitive studies to confirm efficacy. The intervention ‘cryotherapy’, plays to the theme of cold exposure from my last blog. Cold use and CIPN studies started with Danish investigators in 2013 noting that patients who received distal-extremity cryotherapy in the form of frozen mitts had reductions of docetaxel induced neuropathies by approximately 50% (Eckhoff L et al. 2013).





Curiosity was planted and other studies have since taken place, including one larger unblinded randomized control trial of 180 patients treated with oxaliplatin and/or docetaxel paclitaxel who were assigned frozen mitts to wear during chemotherapy infusions. This study showed improvements in quality of life and reductions in neuropathy related symptoms. Excitingly, the research group has moved onto phase 3 trials (Beijers AJM 2020).


In my opinion, is it a low-risk intervention to put natural ice in a bag and squeeze it in the palm of your hands during chemo infusions, and worth the chance that it may delay the onset or reduce the intensity of CIPN. Less data is available for feet, but unless you find placing ice packs on your feet an embarrassing feat, then perhaps it’s another intervention worth playing with!


Feel free to share your photos on IG tagging @the.cancer.physio to help people trying these tools to feel less alone in it all!


Consider exercise as medicine...

I hope you aren’t surprised as I’ve mentioned the value of exercise for symptom management and survivorship in many blogs. Exercise is another low-risk intervention of younger science that needs larger sample sizes to show its efficacy but is yielding some exciting results!





One study with over 350 patients showed irritable symptoms of hot/cold associated with neuropathies were significantly reduced in those that underwent a 6 week home based exercise program while undergoing chemotherapy treatment (Zimmer et al. 2018). These results helped the national cancer institute to start a randomized cooperative oncology group to trial exercise as an intervention to better manage CIPN. As chemotherapy is often riddled with fatigue, consider aligning yourself with a cancer physiotherapist throughout your chemotherapy to receive a personalized rehab plan and the support to stick it through. Habit formation is actually really hard even for a fully healthy individual that isn't battling fatigue and we know that support works!


On a nerdier note, exercise can actually increase neural energy, meaning it can effect memory, attention and learning as per the amazing work of Dr. Wendy Suzuki Dean of New York University. Although it is an extrapolation, if exercise can create neuroplasticity impacting learning and attention, maybe it can also strengthen the pathways we have that remain after CIPN.


Take balance as an example…

Imagine that many sensory nerves in your feet were impacted by chemotherapy, but not all of them. By working on balance, a rehab plan specific to your neuropathy and starting exercise as medicine, maybe the intact pathways can become stronger. If these pathways can strengthen their efficacy in relaying information to the brain, exercise may possibly reduce your falls risk and help better manage the neuropathy. Kind of like how someone who is visually impairs becomes heightened in their other available senses as they use them more and more; adaptations can occur!





So once again I hope this leaves you with some evidence rich tools, some young science and more importantly curiosity. With curiosity comes openness; the ability to try a few rehab tools, hopefully providing a sense of control and making the journey of cancer just a little bit better.


As always, thank you for your interest in exercise as medicine and cancer rehab!


Kindly,

The Cancer Physio













References


Beijers AJM, Bonhof CS, Mols F, et al: Multicenter randomized controlled trial to evaluate the

efficacy and tolerability of frozen gloves for the prevention of chemotherapy-induced peripheral neuropathy.

Ann Oncol 31:131-136, 2020


Chappell, A. G., Bai, J., Yuksel, S., & Ellis, M. F. (2020). Post-Mastectomy Pain Syndrome: Defining

Perioperative Etiologies to Guide New Methods of Prevention for Plastic Surgeons. World

journal of plastic surgery, 9(3), 247–253. https://doi.org/10.29252/wjps.9.3.247

Courneya KS, McKenzie DC, Mackey JR, et al: Subgroup effects in a randomised trial of different

types and doses of exercise during breast cancer chemotherapy. Br J Cancer 111:1718-1725, 2014


Eckhoff L, Knoop AS, Jensen MB, et al: Risk of docetaxel-induced peripheral neuropathy among

1,725 Danish patients with early stage breast cancer. Breast Cancer Res Treat 142:109-118, 2013


Loprinzi, C. L., Lacchetti, C., Bleeker, J., Cavaletti, G., Chauhan, C., Hertz, D. L., . . . Hershman, D. L.

(2020). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult

cancers: ASCO guideline update. Journal of Clinical Oncology, 38(28), 3325-3348.

doi:10.1200/jco.20.01399


Ruddy KJ, Le-Rademacher J, Lacouture ME, et al: Randomized controlled trial of cryotherapy to

prevent paclitaxel-induced peripheral neuropathy (RU221511I); an ACCRU trial. Breast 48:89-97, 2019

Zimmer P, Trebing S, Timmers-Trebing U, et al: Eight-week, multimodal exercise counteracts a

progress of chemotherapy-induced peripheral neuropathy and improves balance and strength in metastasized

colorectal cancer patients: A randomized controlled trial. Support Care Cancer 26:615-624, 2018